close

Вход

Забыли?

вход по аккаунту

?

CONDENSATION OF AMIDES WITH CARBONYL COMPOUNDS. BENZYL-CARBAMATE WITH ALDEHYDES AND ALPHA-KETO ACIDS.

код для вставкиСкачать
INFORMATION TO USERS
This material was produced from a microfilm copy of the original document. While
the most advanced technological means to photograph and reproduce this document
have been used, the quality is heavily dependent upon the quality of the original
submitted.
The following explanation of techniques is provided to help you understand
markings or patterns which may appear on this reproduction.
1. The sign or "target" for pages apparently lacking from the document
photographed is "Missing Page(s)". If it was possible to obtain the missing
page(s) or section, they are spliced into the film along with adjacent pages.
This may have necessitated cutting thru an image and duplicating adjacent
pages to insure you complete continuity.
2. When an image on the film is obliterated with a large round black mark, it
is an indication that the photographer suspected that the copy may have
moved during exposure and thus cause a blurred image. You will find a
good image of the page in the adjacent frame.
3. When a map, drawing or chart, etc., was part of the material being
photographed the photographer followed a definite method in
"sectioning" the material. It is customary to begin photoing at the upper
left hand corner of a large sheet and to continue photoing from left to
right in equal sections with a small overlap. If necessary, sectioning is
continued again - beginning below the first row and continuing on until
complete.
4. The majority of users indicate that the textual content is of greatest value,
however, a somewhat higher quality reproduction could be made from
"photographs" if essential to the understanding of the dissertation. Silver
prints of "photographs" may be ordered at additional charge by writing
the Order Department, giving the catalog number, title, author and
specific pages you wish reproduced.
5. PLEASE NOTE: Some pages may have indistinct print. Filmed as
received.
X erox U niversity M icrofilm s
300 North Zeeb Road
Ann Arbor. Michigan 43106
LD3907
M -lt.S S 'n
1941
Mnrtell, Arthur Earl, 1916TI3 4 ? con^ensa^on
amides
with carbonylcompounds:
benzyl carbamate with aldehydes and alpha keto acids, by
Arthur E. M artell... [Baltimore, 1941]
cover-tiUe, 878-887 p. 251Abstract of thesis <p h . d.)—New York university, 1ML
By Arthur E. Martell and Robert M. Herbst.
“Reprinted from the Journal of organic chemistry, voL 6, no. & Noveta-
be^ l f e !^ :p-88T*
1. Amides. 2. Carbonyl compounds. 8. Benzyl carbamate. 4. A lde­
hydes. 5. Condensation products (Chemistry)
r. Herbst, Robert
Max, 1904joint author.
A 42-2488
New York univ. Libraries
for Library of Congress f
■ QD28LCTM8
t2,t
X erox U niversity M icrofilm s,
Shelf Ust
Ann Arbor, Michigan 48106
Condensation of Auldss olth Carbogyl Owpwadi
Bonarl Carbanats olth Aldohydsa and- Alpha-Kstp AolAa
Submitted la Partial Fulflllmsnt of tbs
Requironsets for the Degros of
Doctor of Philosophy
at
loo York University
*7
Arthur K. Marts11
April, 1041*
ACKHOW
IgPOM
EM
T
The author oiOhoa to express his
indebtedness to Professor Robert V*Herbst
for his invaluable guidance and interest
throughout the eourse of th is research*
CONTENTS
Page
1
Introd uct ion
Chapter Z
In tr oduotcry Diaou salon
2
Chapter II
Dlsous■ion of Experimental work
9
Chapter III Experimental Work
21
Preparation of Materials
Benzyl Carbamate
21
oc-Ketoglutarlo Acid
23
Phenylpyruvi o Aold
25
Benzoylfonaio AeId
25
Condensat ion Product a of Benzyl Carbamate
e lth Carbonyl Compounds and their Hydrolyses
H,N' -Dicarbobenzoxy-3-raethylbutylidenedla mine
26
N,N' -Dioarbobensoaybensylldens diamine
28
H,N' -Dioarbobenzoxy-p-me thoxybenxyliden edlamlne
30
N,N*-Diearbobenzoxy-3, 4-methylenedloxyben zylidenedlamina
32
H, N*-Dioarbobenzoxyfurfurylids nediamine
34
o^o^DioarbobeneoxyaB&nopropionia
Acid
Page
37
oc-pic »rbobenzoxyamino-*$-ph«iy1propionic Acid
39
cvCarbobenxoxyaminoc innamio Acid
41
Action of Benzyl Carbamate on
o^-Carbobensozyaminooiimamio Acid
43
ot-Carbobenzoxyaminooiniuuaic Acid
from o^o6.DioarbobenzoKyaralno-^phenyIpr opionic Aold
44
cVCarbobenzoocyainino-ofr-hydroxyglutaryl Laotone
46
Condensation of Benzyl Carbamate elth
Benzoylfermlc Aold
46 a
Reduotion of condensation Products
Reduction of N,N*-Dicarbdbensoxybenzylidene diamine
47
Reduction of N#N»-Dicarbcbenzoocy-pmethoxybenzylidenediamine
48
Reduction of V#N*«Dloarbdbenzozy«S,4methylened loxybenzy1ldenediamine
49
Reduction of N, N*-Dioarboberusoaqr-5-
Pago
raethylbutylidenediaraine and M
rN*Dioarbobenzcayftn?furylidenediamine
50
Reduction of «#c<-Dicarbobanzoxyaminopropionic Acid
SL
d, lH?-Phenylal anlne from o^oc-Dicarbobenzoxyamlno-^-phenylpropionlc Acid
d, 1-0-Phenyla lanine from
52
Carbobenz-
oxyaminoclnnamlc Aold
54
Reduction of <<-Carbdbenzoxyamino-o*hydroxyglutaryl Laotone
55
Summary
56
Bibliography
59
1
IHTR0CT7CTI0H
The purpose of th is MNaroh la to extend the
•tody of the condensation of amides olth aldehydes
and alpha-keto acids to aald«i of th« bensyl
carbamate type, aod to investigate tho possibility
of converting tbaaa condensation products into
amines and alpha-amino aolda by the application of
suitable hydrogenation techniques.
This mould
provide a nee method for the synthesis of primary
amines and a Ipha-amino aolda from aldehydea and
alpha-keto aolds*
The alpha-earbobenxoxyamimo darlvatlTea of
alpha-hs to aolda synthealsed by msana of this type
of condenaation could be need In the preparation
of dipeptides of various types after coupling with
amino acids by the application of a similar hydrogenation technique*
These condensation products
may also be useful for the synthesis of acyl
derivatives of alpha-amino acids in which the acyl
group is an alpha-Into acid*
such derivatives are
important in the study of proteolytic ensynes.
CHAPTER I
INTRODUCTORY DISCUSSION
s
IHTROTOCTORY PISCUSSIQM
The eoadmuntlOD of awidea with Mrtooyl compounds
was A « m d ft a early as 1870, when Roth (1) succeeded
In obtaining benzylidene diaaatanida by boating benaaldehyde with aoetamide*
Too yaars lata r Taalldaroa (8)
eondanaad aeetaldehyde with aeatanida and obtained tha
oorra^ponding d a rln tlw , ethylidene diaaatanida*
Similar ea^omdf were subsequently prepared by other
workers*
PulTerwaoher (S) prepared nathylana diaaatanida,
Babal and Choay (4) synthesised obloral dlTomanida, and
Pinner (5) aaa able to Obtain methylene dlbonaamldlne*
In 1874 Blsehoff (6), ear king olth urethane, aaa
able to prepare the dSamldo derivatives of various
aldehyde a*
Fra■ bensaIdehyde, aeetaldehyde, and valer-
aldahyde ha obtained H,Xf^learbethoxyben^rlldenedlaulae,
8,It *«dlaarbeth03tyethylldenedlagine> and X,X'-dioarbathozyanylidanedia nixie respectively*
However, i t aaa found
that ehloral and braanl did not aariama in tha sane nannar
but raaatad with only one mole of urethane , to fern simple
addition oenpounds of the anide to tha earbonyl group*
Voohellea (7) deaaribad similar hydroxy derivatives of
ehloral with f crwamlde, aeatanida, azd benaamlde*
Be waa
able to dehydrate tha aa aubatanoaa to tha oorre upending
unaaturatad compounds*
In ter, alailar produata, famed by
the interaction of one mole of formaldehyde with one nolo
8
of aside r a n ebtalned by Unborn and Ladlaah (8)»
Mora rtMnbly loyes and Pormn (9) etudled tha
condensation of a aerlee of aldohydoa a 1th aeetaslde.
TTalng f ornaldehyde, aeetaldehyde, proplonaIdehyde,
butyrsldehyd©, lsovaleraldehyde, heptaldehyde an!
bcnsaldehyde, they obtained tha condensation products
with two sole a of aside In eaeh moo* The yields
ranged f*o* six to 54 per sent*
I t la seen, therefore, that one nolo of aldehyde
usually condenses with two soles of aside socording to
the following eohese:
RCHO +
2 R*COHHg
RCH
^RHCOR*
In ease oases, however, the reaction stope with tha
fontstlon of the primary addition product of the aside
to the carbonyl groupt
OH
RCHO +
R*CORHg
R CH — HHCCR *
4
This type of d a r l a a t l may undergo dehydration to tho
ofi rreqpcoding unnturattd ooQtooxidi
RCB-HHCCR * ------------------- RCH =
*CCfl*
Tho f i r s t example of tho condensation of m amide with
on alpha-keto mold, roportod by Orloaux (10), is tho
reaotlon betveon urea and pyruvic aoid to for* pyruril*
NHCONHg
CH.— C-----CO
8
i
i
NHCO-NH
Horo eenplex derivative e are also foraod daring tha re­
action*
Tha sim ilarity betveen the abora struotur a and
condonation products of anldoa vith aXdehydes la ap­
parent.
No derivatives of simple a*ldoo aith alpha-hsto
aeldo aara da scribed until Bergmann and Orafe (XX) in­
vestigated the reaction bataaan pyruvic aold and aoetaaldo to font a^oc-diaoatamlnopropionlo acid*
They ob­
served tba t a aaall amount of <*-aeetaminoacrylic acid
aaa also formed*
5
The investigatlon of condensations of alpha-keto
•elde elth aoetandde me
Herbet (12) •
extended by Shemln mad
Bensoylformle mold oondeneed la the norsnl
fashion to giro <*, <x-dlmeetanlnophenylmeet le meld*
Hoe-
ever, ehen phenylpyruvlo meld erne hemted e&th moetmmlde,
m-mootmainooIranmmlo meld erne formed, ehlle, ehea
«<-ketoglntarle meld ms condensed a llh aeetamlde, the
preduet erne the lmetone of <*-aeeta*ino-«*- hydroxyglutmrle meld*
Thus, I t mppemre the t the eondensmtlon of aeetamlde
el Hi alpha-tos to melde may lemd to m variety of product e*
If the remotion proeeede to completion, ooupounde
formed by the condensation of the keto aold elth tee
moles of the mmlde are obtained according to the fe l­
loe ing sohemet
M
HOOOR*
I
RCOCOOH+ 2 R * C 0 N H g -------------> RCCOOH
KHCOOR*
However, oertmln Intermediate etagee may be stabilised
by the formation of m lmetone or an unemturmted struc­
ture, me in the eases of a lpha-ketogLutmrle meld and
phenylpyrtrv le meld:
COOH
CBg
I
00
RCOHHg
CHg
0
CO
e
I
COO®
MHCOR
COOH
HHCCR
CgHgCHgCOOOOH+BCOM
H2 —^CgR6<ai:= C COO®
Tha oondanaat ion producta of cma nolo of aootamido with aIpha-kato soldo ana uooful In introducing
• nltrogan In tho position alpha to tha oarboxyl g r o u p ,
and nay therefore ho used to aynthoaiso amino aoide and
amino aold doriTatiToa.
Thua Bargmam and Orafo (11)
apntbm ai sad aoetyl-d, 1-alanlna by oatalytio hydra gonation of oc-aoetawlnoaerylie aoid.
Kora recently,
Shamin and Harbot (12,12) praparad d,1-glutamio aold
and d ,1-phenylalanine froai c<^oetamino-oc-hydroxyglutaryl laetona and oc-aeetaminocimnamie aold respec­
tively.
Sinoa tha amino aold derivatives mada by aondanslng
alpha-hsto aolda aith aoatamida contain aeetylated, or
"madced”, amino groups, thsy may ba converted into
dipaptida derivatives by tha elasaloal techniques de­
veloped by Flaohar and Bargmann»
Thua shamin and
7
Herbat (14) converted oc^cetamiao-o^hydroxyglutaryl
littw i to tho a xlaotone, ahleh «t» then tm t« d olth
glycine to give the lactone af cx-aeetamlno-o^hydroxyglutar yl-glyo laes
CO
CO
NHCOCH.
COOH
00
C
HHCOCHg
COHHCHgCOQH
Slnee the hydrolytic oendi t lone neoeaaary to re a m tho
oootyl group from euoh derivatives a l l l alao attack
tho peptide linkage, tha method described la not useful
for the synthesis of peptides*
Bargaonn (15), In working out a general soheme
far poptldo synthesis, fbund that beasyl ohloroearbooate
could bo ueed to aeylato and thue etoblllxo the amino
group, and took advantage of the oaoo with Uiioh tha
earbobensoxy group could be renewed by eetelytle hydro­
genation*
Dlpeptldee were aide by coupling an aad.no
acid with the meld chloride of an <*-earbobenaoxyamino
aold, followed by tha removal of the carbobenaoxy group
by catalytic hydrogenations
8
HHCOOCHgCgHg
HHg
I
* « e
, ~
RCHC0C1
+ RCHCOOH
^
BHOOQCHgCgHg
I
RCHCOHHCHOOOH
\
R
HHg
R*
RCHCOBHCHCOOH
This method of removal of tho acyl group boo no offoot
on the poptldo, linkage.
In the ligUb of the above inve eti gotion, i t nee
reoeonod that I f benayl carbamate oould he condensed
vlth alpha-keto aside , the resulting c*-earbdbenxoxyemlno eelds eoald he converted to tie corresponding
amino eelds hy simple oetelytio hydrogenstl on, end that
similar condonation products vlth aldehydes eoald he
consorted to the earrespending primary aalneo In the
aaae mmnor.
I t vaa proposed, therefore, to investigate
the possibility of synthealclng such oarbdbensoxy
derivatives of alpha-keto acids and various aromatic
and aliphatic aldehydes.
Catalytic reduction of sush
derivatives would afford a nev method for the prepara­
tion of certain amines and alpha-amino aelde.
CHAPTER II
DISCUSSION OF EXPERIMENTAL WORK
9
DISCUSSIQH OP THE KXFBRBCSTAL W
ORK
A number of aromatic and aliphatic aldehydea
were eoudeneed with benayl carbamate by heating the
aubatanoaa together without aolwent.
Whan poaslble,
redueed preaanre aaa need in order to remove the
aater formed*
In a ll oaaaa triad tao molea of the
carbamate eondanaad aith one mole of aldehyde*
The
reaction may be repreMinted a t folloe as
BHCOOCHgCggg
RCHO +
2 Hj>HC00CHs 0 6H8 ------- ,
rL
+
HHOOOCRgCgSg
The aame type of oondensatlon aaa obtained by Boyea
(9) , though in hi a eaae the yielda eere appraoiably
lower,
Benayl carbamate aaa oondensed a 1th leaaaler-
aldehyde, benxaldehyde, aniaaldehyde, plperonal, and
furfural*
The oondenaation product a were reepeetively
H,F*-dioarbobenaoxy-S-methylbutylidenedlamine, l t* 'diearbdbenxoxybensylldenedlamlne , B»B<«dioarbobenaonyp-methosybensylidenedlamina, H,H*-dioarboban»oaty-S,4methylenedloxybenaylidenedlamine and H,Nt-dloarbobensoxy~
furfttrylidened lamine•
The produet a were obtained aa
10
•o lirltita M d lti vlth tha exemption of tha d arlfttlv ai
of bencaldehyde and furfural, which oould be isolated
only aa oolorlaas amorphous powdera*
The Identity of
tha product a waa eatab 11ahad by elementary analyala
aod by hydrolyala with acid to benayl carbamate and tho
aldehyde*
In the oondenaatlon between benayl carbamate aid
alpha-keto aolda two type a of product a were formed*
In
acme case a one mole of carbonyl compound condeneed in
a normal faahlon with two molea of benayl carbamate*
In
other oaaea, when an Intermediate etaga waa atablllxed
by the elimination of water with the formation of a lac­
tone or an unaaturated compound, only one mole of amide
and one mole of keto acid were Involved In the reaction*
Pyruvic acid oondenaed with bensyl carbamate In
the normal fa ahIon, giving ocpc-dlcarbobenmencyamlnopropionic aold i
HHCOOCH2 C6 H5
I
CH5 COCOOH + 2H gN C00C H 2 C6R 5 - > C B 5 CC00H
n h o o g ch 2 c 6h 5
Thla la analagoua to the derivative obtained with
pyruvic acid and aeetamlde by Bergmann and Grafe (11)*
11
Hoeever, in contraat to their finding* In the ease
of aeetamlde, no acrylic cold derivative cm* fc m d
under the condition* employed here*
The condeneatlon of ofc»hetoglutarle add eith
benzyl
carbamate resulted In the format Ion of
oC^carbobonzozyamlno»o(rhydrozyglutary1 lactone*
Here
the product of the primary addition of one mole of
amid* to the carbonyl group ea* stab 111zed by the
formation of a lactone ring}
COOH
CO
00
COOH
This compound la analogous to that obtained by Shemln
and Herbst <18) from o<-ketoglutarla acid and aeetamlde*
Tbeae author* alao observed the formation of Yt r-diaoetamlnobutyrie acid when higher temperatures were employed
for the condensation#
The attenqpt to oarxy out a
similar condeneatlon eith benayl carbamate resulted
only in the formation of the asms product, the lactone
of oC-oarbobeneozy-o^hydrozyglutarlo add*
12
When phenylpyruvie sold was condensed elth
bensyl carbamate, the neture of the product ob­
tained depended on the conditions used*
At a
relatively lee temperature «,<x-dioarbobensosyamino-0 -phenylproplonie acid was formed, while
at a somewhat higher temperature <x-earbctoensojcy*aminocixxnamie acid was produced!
shCOOUHgCgBg
CeHfiC&sC-COOH
CgHgCHgCOCOOH
HgUCOOCH^eHg
r
OgHgCH^ C-OOOH
mhcooch 2 c 6 h 6
To test the mechanism involved in the formation of
these products bensyl carbamate was heated with
06-earbobexuEOxyaminoalnnaralo acid, but no reaction
occurred#
On the other hand when <*,oc*-dlearbebensoccy-
amino-£?-phenylpropionie acid waa heated, bezuqrl
carbamate was eliminated with the f orna tion of
33
q(-oarbobon»03tyaminocinnamio aold*
Atteapta to ooiadenee benaoylfomaie mold
olth benayl carbamate did not reeult in tha fornation of an aoylamlno derivative of phonylaoatio
aold*
However, a ana11 amount of a oondanaatlon
produet m i obtained aid identified aa oarbobenaoxybensa limine by analyala and by hydrolyala * I t
may have bean formed by dehydration and deoarbexy3atlon of the primary addition product aa followat
neco o ch 2 c6h 5
C
H
jl
|
C6 H 5 C 0C 00H + H 2 S C 0 q p 6H 5 ---------->
C gH g-C -C O O H
OR
NCOOCHjjCgHg
CgHgC-COOH
-------------^ C6 H 6 C R =rN C 00C H 2 Ce H5
Tho poaalbllity of an in itia l deoarboxylation of
benxoylfomio acid producing banmaldahyda* which in
turn might combine with benayl oarbamate to form
the product ia unlikely.
Tha faet that bensaldehyde
Invariably react a with two molea of amide aupporta
this contention*
14
The condensation products of bensyl carbonate
with alpha-keto adds were i scla ted aa eolorleaa
mediae having diarp melting points.
Their struc­
ture m s determined by elementary analysis, neutral
equivalent, and hydrolysis to benayl carbamate and
the aIpha-heto acid.
The hydrolysis of these de­
rivatives vlth sold ms more difficult than that of
the aldehyde derivatives, with the exception of the
<x-ketoglutarle acid condensation product which ms
completely hydrolysed by boiling a fee minutes vlth
vster.
The mechanism proposed for the condensation re­
actions of aldehydes and alpha keto aolda with bensyl
carbamate may be outlined as follows*
1
I
RC=0
HHGOOCHgCgRg
TL
R-C-X
MHCOOCHgCgHg
■> R-C-X
I
UHC00CHgC6H5
II
IV
III
MHCOOCHgCgHg
R*-C-X
I
u 0
X
SHCOOCHj C6H6
R *=C -X
VII
NCOOCHgCeHg
R -C -X
VI
V
H for aldehydes and -COOH for a.-keto acids.
R» R minus H.
15
The primary reaction i t an addition to tha
carbonyl group with the formation of compounds
of typo XXI.
This postulation is supported by tho
faet that such addition products of amidea to cer­
tain aldehydes and alpha-keto aoids hare been
Isolated in pure form.
described*
These hare already been
Further evidence for the existence of
III as an intermediate la found in the isolation
of oc-acylamino-cv*hydroxyglutaryl lactones (VII),
where the intermediate Is stabilised by la oton! sat ion.
This has been diown to take plaoe with both aoetamide (12) azd bensyl carbamate*
The
next step in tbs condensation is the re­
placement of the hydroxyl group by a second bensyl
carbamate residue to give tbs final product IV*
This
step may conceivably take plaoe by direct replacement
of the hydroxyl group or by a preliminary elimination
of water from the molecule with the formation of un­
sat urated intermediates such as V and VI*
Subsequent
addition of another mole of bensyl carbamate to sueh
an intermediate would lead to the fin al produet IV*
The formation of an unsaturated derivative was ob­
served in the oase of eC-oarbobensoxyaminoolnnamlo
acid*
It has been pointed out* however* that this
compound would not condense with a aeeond mole of
16
bensyl carbamate*
I t seems unlikely, t hi re fora,
that an unsaturated compound of type VI la an In­
ternedlate In thla condensation*
The faet that
o^*-di earbobenzoxyamino-tf-phenylpro pionio aeld
vas formed from Interact Ion ofbenayl oarbamate
and phenylpyruvlo aold, vhereas i t vas not formed
from benayl oarbamate and tt-oarbobensoxyajslnoelnnamlo aold Indicates that the second step in
the condensation vas moat likely a direct re­
placement of the hydroxyl group.
The addition of aeetamlde to <*-aeetamlnoaeryllo acid to fora «,<*-dlacetaminopropionle
acid (IS) seems a t f ir s t to oontradlot the evidenee nentioned above*
The acrylic acid deriva­
tive, hovever, is in tautomeric equilibrium vlth
the corresponding imino form, and the addition of
a second mole of amide nay take place by addition
to the oarbon-nltrogen double bond*
Thla type of
reaction vould be unlikely in the case of the
oInnamio acid derivatives vhere the tendency of
the double bond to conjugate vlth the bensene
ring favors the carbon-carbon unsaturated linkage,
and represses the tautomeric shift to the imino
form*
17
The e<-earbobensoxyaminoclnnasde acid nay have
been formed directly from the intermediate addition
produet III by the elimination of a mole of water,
or Indirectly by elimination of a mole of benzyl
carbamate from the dlaoylaoilno derivative IV*
The
available exporimenta 1 evidence does not permit a
decision between these alternative a*
Further evidence for the possible existence of
a structure such as V as an intermediate in this eon*
denset Ion may be found in the synthesis by Moehelles
(7) of analogous unsaturated derivatives of
aldehydes*
As already stated, suoh a derivative
was formed when bensoylfortnlc sold was heated with
bensyl carbamate*
The fact that this substance was
stable enougi to be isolated and characterized nay
be attributed to the fact that the unsaturated
linkage is here conjugated with the aromatic nucleus*
Other compounds of this type, such as
B-substltuted
lmines of aromatic aldehydes are known*
The isolation
of this product suggests the possibility that the for*
nation of the dlcarbdbensoxysmine derivatives of
aldehydes involves a direct replacement of the
hydroxyl group of Intermediate III by a oarbobensoxyamine
group*
This possibility has not been tested
18
experimentally due to look of sufficient material.
The reduction of these derivatives eaa carried
out in absolute alcohol vlth palladium oxide catalyst
in a Burgess-Parr loe pressure hydrogenation appar­
atus,
Bensylamlne, anlsylamina , and piperonylamlne
were obtained in good yield by the hydrogenation
of N,H•-dioarbobenxoxybenxylidensdiamina,
N,Nf-dioarbobenxoxy-p-methoxybensylidenedlamina,
and H,H*-dioarbobenxoxy-p-methylenedlaxybenxylidenedlamina,
The reduction of N, H1-dicarbdbenxoxy-5-
methylbut y1id ined lamine and N^N'-dloarbdbensoxyftrfurylldlnedlamina led to products vhoaa Identity
has not yet been established.
The oarbdb ensoxyamino derivative of pyrtar io
add aas c onverted into alanine by hydrogenation.
Both derivatives of phenylpyruvle acid, i,e , ,
o^,c*-di carbobenxoxymmlno-b-phsnylprop ionic acid and
owoarbobenxoxyaminoeinnamic acid gave d, 1 -phenylalanine
on hydrogenation.
The yields of amino acids, though
good, eere not as high as the yields of amines from
the aldehyde derivatives.
When similar reductions
of o(-oarbdb enxoxyaraino-<*-hydraxyglutaryl laetons
eere attempted, the nitrogen eas aplit off as am­
monia,
The same result eas obtained ebon the lactone
19
ring was opened with alcohol prior to reduction,
a technique successfully employed by Shemin (12)*
According to Bergmonn (IS) the hydrogenation
of the earbebensoocy group result a In the formation
of toluene* carbon dioxide* and th» corresponding
amino compound*
Thua the diearbobensoxyamlno com­
pounds probably undergo hydrogenation as follows*
^KHCOOCHgCgHg
----------------- >
RCHn ^
RGHUHg + 2 CgHgCHg
NHCOO C H gC gP g
+ 2 COg + HHS
The formation of carbon dioxide and anmonia during
the hydrogenation of substances of this type pre­
cluded accurate estimation of the hydrogen uptake*
The behavior of «<-earbdbensoxyamlno-oe>hydroacyglutaryl lactone upon catalytic hydrogenation was
unfortunate* but not surprising in view of the ease
with which this substance was hydrolysed*
Apparent­
ly the leotone ring is wery easily opened by such
reagents as
water and alcohol*
The resulting
20
structure is unstable due to the preeenoe of
hydroxyl and mtlno groups on the seas carbon atom
and readily loses the bensyl carbamate groups
CO
CO O CgPg
C % X Q
fv
CgHgOH
C— a e o o o v A
C 00C 2 H6
CH2
CBg
*T8O
T— v r*
COOR
y<«m oaW
.
COOH
?°
COOH
tt mt aaaw
^0h5wh2ow,w,2
Tala bahaTlor is in contrast to that of the corre­
sponding aoetamino derIra tire prepared by Shemin
and Herbst ( 1 2 ) which lost eater rather than aoetamlde upon reaction with alcohol and could then be
reduced to the glutamic acid derivative*
This behavior of <*-©arbobensoxy-«-hydroxyglutaryl lactone limits the usefulness of the com­
pound in the preparation of derivative a of glutamine
and peptides of glutamio acid*
On the other hand,
the ease eith which the lactone ring opens would be
an advantage in the preparation of alpha-koto
glutaryl derivatives of amino acids analogous to
the pyruvylaaino type*
CHAPTER III
EXPERIMENTAL W
ORK
SQL
gJPERXHBMTAL W
ORK
Preparation of Materiala
1* Benzyl Carbamate.
Benzyl ehlorocarbornate eas prepared by a
e lic it modiflcatlon of the method deearIbed by
Bergmann (15).
the
Conversion of the aald ehlorlda to
amide by the method of Thiele (16) aae fbund
to be inferior to the method deeeribed below•
Fhoegene «ai paeeed through 400 ml. of dry,
Ice-cooled toluene until 1 0 0 grame eas ebacrbed.
To the resulting solution 06 ml. of cold, redietille d benzyl alcohol eas added in one portion.
The resulting solution eas kept in the lee bath
for one half hour and then a Hosed to earn up to
room temperature.
The hydrogen chloride and
phosgene evolved by the toluene solution eere ab­
sorbed in 1 0 per eent. sodium hydroxide solution*
After allosing the reaction mixture to stand at
room temperature for three hours, the exoess of
hydrogen ehlorlda and phosgene eas removed by
passing a ourrent of dry nitrogen through the
system.
The toluene eas then removed by evaporation
88
outer
reduced pressure i t • both tm p in ta ri not
exceeding 60°, while dry nitrogen was passed through
the capillary of the d istillatio n apparatus.
The
almost colorlese bensyl ehloroearbonate thus ob­
tained welgied 160 grams and s t i l l contained a
snail amount of toluene.
The aold chloride was
then poured slowly with rapid stirring Into one
l i t e r of ice-cold concentrated aqueous ammonia.
The
amide quickly precipitated with the evolution of
considerable heat.
The reaction mixture was al­
lowed to stand at room temperature for one half hour,
after which the product mas filtered off and washed
four times with water.
The yield was 180 grams
(OS per cent, of the theoretical) of pure odorless
benzyl earbamate melting a t 8 6 °,
After reerystal-
llzat Ion from 800 ml. of toluene, 180 grams of
glistening rectangular platee melting ot 87° were
obtained.
The product may also be purified by reerystalllsatlon from water.
Anal.
Caled* for CgH^Ogllt
H, 0.8
Pounds
8 , 0.8
£3
2 . oioEita^atirli Aeld
ouKit^gSictariA told Mi prepared by • Mlbsd
alnllar to diet of lewberg and Ringer (IT).
The
description of tfao proportion given by thooo authoro m i found to to brief and Inoonplete.
For
this rooaon a description of the preparation of
thla notorial la lnduded*
Ton grama of sodium aoro addod to 200 ml. of
dry toluene.
Tho mixture was haatod to 105° and
tlmn rtiakan rigorously olth gradual ooollng until
the sodium had boon brokon up Into a fino ponder*
Then 21.0 grama of absolute ethyl aloohol vara
addod.
After the In itia l rigorous reaotion had
ai bolded the mlxtuao ana gradually heated and f i ­
nally boiled under reflux until a l l the sodium had
dlsselred.
The solution ms eooled to loo-bath
temperature and 64 grans of fredily-dletllled ethyl
oxalate oaa added to the rapidly-stirred suepenaion
of sodium ethyla to.
After aliasing the resulting
tar bid solution to stand fcr throe hours. 76 grama
of frodily-dlstillsd ethyl suoelnata mas addod mlth
rapid stirring*
The reaotion mixture mas nos aliened
to stand at room temperature under anhydrous eondltlons for four days*
The sodium derivative of ethyl oxalo sueelnate
mas extracted from the yellom toluene solution by
shaking mlth too 260 ml* portions of mater*
The
84
aqueous portion vai nd« aeld to Congo rod with
dilute sulphuric aeid and then extracted with teo
260 utl. portions of other*
The ether solution uaa
sashed onee ulth eater and then carefully evaporated.
The resulting Iceto ester eas the n heated on the
steam hath slth 400 ml. of
aeld.
4-nor*al hydrochloric
Hydrolysis eas complete and the o il had
dissolved in the course of four hours.
The hydro­
chloric aeld solution eas then evaporated to dryness
under reduced pressure.
The resulting solid eas
dissolved in 1 0 0 ml. of eater and again evaporated
to dryness.
After repeating this procedure once
more the product ms pulverised under 160 ml. of
dry ether to remove oily impurities.
The msterial
eas then filtered by suction and sashed slth a small
amount of dry ether.
62 grams (64 per cent, yield)
of <*-ketoglutarle sold eas obtained in the form of
nearly colorless crystals melting at 116°.
The product eas further purified by recrystal­
lization from ether.
86
3. Phanylpyruv1© Aeld
Phenylpyruvio aeld eas prepared aeeordlng to
the method described by Shomln and Herbet (18)*
I t eas found advantageous to reorystalllse the
material from bensens before use.
4* Bensoylfcrmle Acid
BenmoyIformic add eas prepared by tbs method
of Aeree (18).
It eas found that the purity of
the produet eould be greatly enhanoed by reorystalllsatlon from dry toluene.
N E W Y O R K U N I V E R S . TY
W
A
S
H
IN
G
T
O
NS
Q
U
A
R
E
®
LIBRARY
•
86
H.l '-DlcarbobenxQiXr-S-nsthylbutylldenod^-*™o
<*S
HHCOOGHgCgHg
CHjCHCRgCH
mhcooch 2 c 6 h 5
Ten grama of benzyl carbamate ess heated under
reflux at 1 0 0 ° a 1 th four grama of freshly-dlst tiled
isovaleraIdehyde in an atmosphere
of nitrogen.
After two houra the mixture began to solidify*
After
four hour* the reflux condenser was restored
the
reaotion vessel evacuated to a pressure of 16 am. to
remove excess aldehyde*
The produo1, a colorless
orystallIn* mass, eas purified by dissolving i t in
50 ml. of hot benzene and adding an eqpal volume of
petroleum ether.
On cooling, 6 . 6 grams ( 6 6 per eent.
yield) of long silky needles molting at 115° eere ob­
tained*
The material had no odor of 1sovaleraXSShyde
and eas pure enough fox* further* eork*
Further re-
crystallizations from ben sens and petroleum ether
gave 5 .0 grams of product melting at 184°
27
H,H«-Dioarbobenzoxy-3-met hylbutylldensdlamlne
la soluble la bonsens, toluens, ethyl alcohol, ethyl
aoetate, end ether, end is Insoluble In eater,
llgroln end petroleum ether*
Anal*
Celed* for
C, 68*1* H, 7*1} K, 7*6
Founds C, 68.2* H, 6 *8 * S, 7*4
Hydrolysis of K. H»-dlcarbobenzoxy-5-methylbutylidsnelewlao
One gram of S-methyl-dlearbobeneoxy-butylldenediamine ms boiled for 15 minutes li th 50 ml* of nor­
mal hy&roohlorlo sold in an atmosphere of nitrogen*
A solution of 0*65 grams of 2,4-dlnitrophenylhydraslne
In 10 ml* of ooneentrated hydrochloric acid and 15 ml*
of 95 per oent* alcohol eas then added, and the mix­
ture heated under reflux for flee minutes*
ture eas cooled and filtered*
The mix­
The product eelghed
0*64 grams (89 per cent* yield)*
On re crystallisa­
tion from alcohol the 2, 4-dinit rophenylhydra sone of
lsovaleraldehyde eas obtained in the form of orangeyell o s needles ehloh melted at 124°*
The loss on re­
cry stall leat ion did not exceed flee per oent*
There
eas no depression of the melting point when the deri­
vative was mixed with an authentic sample (SO)*
Upon evaporation of the mother liquor from the
hydrolysis 0 * 1 0 gram of benzyl carbamate smiting at
96° eas recovered*
£8
1 . 1 ^Pioarbdb enzoacybcnaylldanodlamina
.HHCOOCH2 C6 H6
IHOOOCHgCgBg
Ten g r m of benayl carbamate and four grama
of freahly-diatilled bensaldehyde eere baatod undor
reflux at 80° and 15 » • proaaura.
Tha raactlon
mixture oolldlfiod in about half an hour.
Aftor
ono hour tha axoaaa bensaldehyde aaa ramovad by
haating at 1 0 0 ° and IS on. preawre aith a daalinlng eondanaar.
Tha oolorlaaa produat aaa dia-
eoleed in 1 0 0 ml. of hat bensene, from #iich i t
aaparatad on cooling aa a galatinoua maaa9 whioh
aaa partially ooagulatad by alternately fraasing
and salting tha aoleant.
Tha produet aaa than
f i It arad aith auction and aartied aith 1 0 0 ml. of
oold banaana.
Tha yield aaa 8 . 6 grama ( 6 8 par eeflt.
of tha thaoratloal) of a ahita poadar malting at
175°,
After further purification by praoipitation
from athyl aeatata aith petroleum other tha produat
29
malted at 175°,
Dlaarbobenzoxybenzylldenedlamina is soluble
In ethyl acetate, bensene, toluene, and acetone*
It is daringly soluble in ethyl aleohol and ether,
Insoluble in eater, petroleum ether, and llgroin*
Ana1>
Calod* for
70*7} H,5*7j N,7*2
Pound*
C, 70,8| H,5*7j H,7.1
One gram of dIcarbobenzoxybenzylidenediamine
eas boiled for 15 minutes elth 50 ml, of normal
hydrochloric acid in an atmosphere of nitrogen*
A
solution of 0,60 gram of 2 , 4 -dinltrophenylhydrasine
in 1 0 ml* of concentrated hydrochloric acid and IS
ml. of 95 per cent, alcohol eas then added and the
mixture boiled for an additional fire minutes*
After
cooling the mixture the precipitate eas filtered and
washed elth a l i t t l e 50 per cent, alcohol*
low
The yel­
2,4-dlnltrophenylhydrasone of bensaldehyde
eeighed 7,50 grams (99 per cent* yield).
Recrystal­
lization from benzene produced yelloe needles molt­
ing at 240°.
When the hydrazone eas mixed with an
authentic sample (2 1 ), there eas no depression of
the melting point*
Evaporation of the alcohol from the mother liquor
yielded a snail amount (0*15 gram) of benzyl carbamate,
melting at 85°.
90
M.K *-PlcarbqibonsoxyH?-goth03Prbonsylldonodlanlno
COOCRgCgpg
HHCOOCHgCgHg
Ten grams of benzyloerbamat© and five grams
of freshly-distilled anlsaldehyde sere heated at
100® and IS am. pressure for four hours*
After two
hours the reaotion mixture began to solidfy and
gradually changed to a pale yellos oryatalline sees*
The product see crystallized from 800 ml. of hot
bensens, yielding 0 * 0 grams ( 6 6 per sent*) of long
colorless needles melting at 182-186®.
The produet
at this poind had no odor of anisaldehyde and see
purs enougi for further use*
After reerystallisatiom
from ethyl aoetate and petroleum ether 7*8 grams of
needles melting at 109° sere obtained*
V* 1 •-d ioarb dt>«nxoxy-p-methoxyben*ylidenediamine
is insoluble in eater, petroleum ether* and llgroln,
somewhat soluble in ethyl alcohol, benzene, and
81
toluene, end eeally aoluble in ethyl acetate*
Anal*
Caled. fer 0 2 4 8 2 4 0 5 8 2 :
C, 68*7) H,6 . 8 | 11,6.7
Found « C, 6 8 •6 ; Et 6*7| 1,6,5
Hvdrolysia of N.E'-dhtitobeiunxf-PHUttaoxibtAiTl*
One gram of V ,V *-diearbobensoxy-p-me thoxybenaylidene diamine vaa boiled for 16 minute a aith normal
hydroohlorio aeld in an btmoaphere
of nitrogen*
A
aolution of 0.60 gram of 2,4-dlnitrophenylhydrasine
in 1 0 ml. of concentrated hydrochloric aold and 15
ml. of 96 per oent. alcohol aaa then added and the
mixture boiled for fire minutes*
After eoollng, f i l ­
tering, and aaahlng aith dilute alcohol, 0*75 gram
(99 per cent* yield) of aniaal-2,4-dinitrophenylhydrasone melting at 250° aaa-', obtained.
By reery-
ata1 1 1 action from a mixture of ethyl aloohol and
bensene, orange-red needle a melting at 262° eere ob­
tained.
A mimed melting point aith an authentic
eemple (2 2 ) ahoaed no depreaslen*
A ana11 amount of benay1 carbamate aaa recovered
upon evaporation of the mother liquor from the
hydrolyala ,
52
VI
Idenediamlne
HHCOOCHgCgHg
/
—CH
ch2
\
Ten grams of bensyl carbamate erne heated
with five grama of fra shly-d 1 at Iliad piperonal
at 1 1 0 °
for fire hours under 15 mu pres aura*
Tha mixture began to solidify after two hours and
gradually ehanged to a colorleaa eryatalline mass*
The product sas reorystallised from 200 ml* of hot
toluene, producing 0,0 grams (65 per cent, yield)
of colorless needles.
This material had no odor
of piperonal and eas sufficiently pure for further
reactions.
Recryeta H i sat ion from toluene produced
needles melting at 204°.
H, N*-Dicarb obenzoxy-S, 4-methylen edi oxybenxylidenedlamlne is soluble in ethyl acetate, sparingly
soluble in benzene, toluene and ethyl alcohol, and
insoluble in eater, petroleum ether, and ligroln.
55
Anftl*'
Ctlod<for ^24^2^6%^
W«4| H,5*1) I|6«4
F«nA s C, 66*4} H,5*0| 1,6*4
Hydrolysis
On* gran of I fI»-dia«rbcib«nzoxy-8l 4-»thyl«nidloxybensylldenedlamina van boHad for 15 minutes
with 80 ml, of normal hydrochloric aold In an atmos­
phere of nitrogen*
A eolation of 0*55 gnus of 2,4—
dlnitrophw^lhydrasine In 1 0 ml* of ooneentrated
hydrochloric aeld and 15 ml. of 95 per cent* alcohol
vac added, and the mixture boiled for fixe minutea*
The piperona1-2, 4-dlnltrophenyIhydram na which separ­
ated from the reaotion mixture weighed 0.74 gram
(97 per oent* yield) and melted at 265°# After re­
cry at a 1 1 1 satIon from diosane tha hydra sona wae ob­
tained In the form of deep red needles melting at
266®,
a mixed melting point with an authentio sample
(2 2 ) showed no depression*
A small amount of bensyl carbamate was obtained
on evaporation of the alcohol from the mother liquor*
54
y.B **B lw b4 »n««»yfqrftgylldiB>dAiali>i
OH
G
H
.NHCOOCHgCgHg
CH
C—CH
XvHHC0 0 CHgC6 H6
Ten grams of bensyl carbamate eas tested at
100° under reflux with 4*0 grams of freahly-dlstllle d furfural at 15 ms* pressure In an atmosphere
of nitrogen*
The melt, at firs t oolor less, gradu­
ally solidified and assumed a dark brown oolor*
After one hour the reflux condenser was removed
and the heating was continued for two hours more*
The dark brown product was decolorised by boiling
with norite during three recrystallisations from
hot bensens*
A yield of 6*2 grams (49 per cent* of
theoretical) of almost colorless solid melting at
150° was obtained*
At th is stage the product had
no odor of furfural and was pure enough for synthetic
work*
I t separated from solution as a gelatinous
mass and farmed a white powder on drying*
Further
S6
recryat a 1 1 1 sat Ion from ethyl acetate and petroleum
ether aa wall aa from benaene produoad a whita
powder malting at 165°.
8 ,N«-dioarb6 ben*oxyforfurylidenedlamine la
soluble in athyl alcohol, ether, athyl acetate,
acetone, hot bansane and hot toluene •
I t la In­
soluble In water, llgrolm, and petroleum ether.
Anal*
Calod. foe* (gfgQOgKg*
c» 56»3| H,5.S| 11,7.4
Founds
C, 66.4; H,5.4| 1,7.5
Hydrolysis
One
of y .y >-djtoarbdbcnaoxyfurfiirylldansdiamlin
gram or H,H*-dIearboben7,o*yfurfwrylidene-
dlamina was boHad under reflux with C
D ml. of normal
hydroOhiorlo aeld for 15 mlnutaa In an atmoaphara of
nitrogen.
Than a aolution of 0.60 gram of 2,4-dinitro-
phenylhydra sine In 1 0 ml. of ooncantratad hydroohloric aeld and 15 ml. of 95 par cent. alebhol waa
added and tha mixture boiled for five mlnutaa.
Tha
raaulting rad precipitate of f urfural-2,4-dinitrophanylhydra sone waa filtered off and wa died with al­
cohol.
I t weighed 0.67 gram (95 par oerit • yield) and
malted at 2 0 0 - 2 1 0 ®.
Racryatalllsatlon from toluene
gave deep rad prisma melting at 210-215°.
An authen-
86
tie sample was prepared and separated into tvo
Isomers, one of vhioh crystallised from toluene
in the form of red prisms, d ills tbs other, being more
soluble, separated from the mother liquor in the form
of yellos needles*
Purification of the red form
gave soarlet-red prisms melting a t 225-2260.
Bredareek
(25) described two isoomrle forms of furfural-8,4din i t r ophenylhydra sone, a red variety melting at
250° and a yellow variety melting at 212-214®.
Theso isomers were reported to have a mixed melting
point of 185°.
Bredereek also mentioned that the
yellow fcrm was oonverted to the red fora by boiling
with alcoholic hydrogen ehlorlde.
When the
hydrasone obtained from the hydrolysate was sub­
jected to such treatment, the melting point was
raised
to 22Sr° # and a mixture of this substance
with the authentic sample prepared above had a melt­
ing point of 226°.
Anal*
Calod* for C^jHgOgH^:
H, 20*5
Found s
H, 20*1
m
olaOl-DlcarbcibenKoxyamlnoproplonlo Aeld
HHCOOCHgCgHg
CHS— C
L
COOH
COOCHgC^s
Ten grams of bensyl earbamate and four grama
of
fre Aily-distllled pyruvic acid eere heated
under reflux at 15 mm. pressure for two hours*
The bath temperature eas kept at 70° and nitrogen
eas passed through a capillary into the reaotion
mixture to prevent bumping*
The material began
to solidify after 50 minutes*
reflux condenser eas
After teo hours the
removed and the excess
pyruvic aeld eas distilled off at 80° and 15 m
m
*
pressure*
After an hour the colorless mass eas
ooeled, pulverised, and extracted three times slth
cold eater*
After reerystalllsation from ethyl
aeetate and petroleum ether the
,<x-diea rbobens-
oxyamlnoprOplonlc aeld eas obtained In very pure
form as colorless needles selghlng 10*5 grains
38
(85 per cent. yield) end melting at 139°.
*/*-dlearbobensoxyamlnopropionle aold le
very soluble in ethyl aloohol, ethyl aeetate,
acetone, bensens and toluene •
I t ie insoluble in
eater, petroleum ether, end ligroin*
Anal,
Calod* for CxpHaoOgVgs 0,61*5} H,5.4; 11,7,5
Keutral Equivalent ,572
Found) C, 61,4j H,5*6| 11,7*3
Keutral Equivalent,586
gydrolyola of <*j*—
dloarbqh enzozyamlnopro plonlo Aeld
One gram of c^ot-diearbobensootyamlnopropionie
acid eas hydrolyzed by bollix^
elth 1 0 0 ml, of
normal hydrochloric aeld for 50 minutes.
The solu­
tion eas filtered and upon cooling yielded 0*54
gram (€7 per oent*) of bensyl carbamate aa oolor leas
plates melting at 87°,
The f iltr a te eas treated elth a hot solution of
0*80 gram of 2 , 4 -dinit rophenylhydraxine in 150 ml, of
dilute aqueous hydrochloric add*
On ooAllng 0*70
gram (98 per cent* yield) of pyruvic acid 2,4-dlnltrophenylhydrazone eae obtained as yelloe crystals melt­
ing at 217®,
a mixed melting point elth an authentic
sasqple (24) shooed no depression.
30
IHCOOCHgCgHg
HHOOOCHgC^Ig
Ten g n u of bensyl carbonate end sin g n u
of phenylpyruv1c aeld freshly recrystallised from
benzene eere bested far
ms, pres sirs*
four hours s t 95° under 15
The slnost colorless crystalline nasa
produced use pulverised and extracted uith several
80 ml* portions of oold normal potsssiuai hydroxide
solution*
The oonblned alkaline extracts sere
acid i f led uith dilute hydroehlorlo sold*
The pre­
cipitate use filtered off and cashed uith cold cater*
The yield of cx,<x*-dioarbotoenzcacyunlno-<3-ph«nylpropianlc
aeld melting at 156° vas 7*2 grans (46 per cent* of
the theoretical)« On reoryslslllsation from ethyl
acetate and petroleum ether the product separated
as colorless xmedles malting a t 141°*
oc^oo-dlearbobenzoxyaminoW?-phenylpropionic acid
is soluble in ethyl acetate, ethyl alcohol, toluene,
40
and benaene.
I t is insoluble In water, petroleum
ether, and llgroln*
Andlj^ Gtlod* T o p O g ^ t | O g^g*
®# M*lj H,6«4f X,6«2
Ventral Equivalent,448
Found s
C, 6T7.1; H,5.4j 1,6*2
Vautral Equivalent, 465
Hydroly si a of oc.c*-dlearbdbenaoptjw«i mW3-phenylproplonlo AaM
L
(tea gram of o<,o<Hlioarbflfcenzo*yBmlnoW?-phenylpropionlc aeld *aa hydrolysed by boiling with 100 ml*
or normal hydroafaloric aeld far thrae houra*
To tha
resulting aolntion 0*80 gran of £,4-dlnitrophenylhydrazine dissolved In 100 il* of dilute hydrochloric
acid aaa addad and the mixture boiled for fire mlnutaa.
Tha 2,4-dlni trophenylhydra none of phenylpyrtnr ie aeld
praolpltatad aa a gunny orange material which aaa
filtered off and raeryatallisad from dilate aloohol*
The yield waa 0*75 gram (96 par sent* of the theorotleal) of sallow eryatals malting a t 190°*
a
melting point with an anthentle sample ahowed no de­
pression*
Beeauae of tha long time required for complete
hydrolyale of tha product no benzyl carbamate oould
be found in the hydrolysate •
41
A#Id
NHCOOCHgCgHg
y < m ~ c —c o o h
Ten ffmwm of bensyl cashomats and six grama
of f r e e ly reoryetaliized phanylpyrueic
aold
were hoatod for thrao hours a t 150* sudor 10 an*
presaare*
The yellow aemi-solld prodaet vas ex­
tracted with thrao SO-ml* portions of normal po­
tassium* hydroxide solution*
The product aas pro-
si pita tod from the alkaline extracts by aoidlfying
with dilate hydrochloric sold*
After filtering *
sashing s 1th cold water, and drying, 7*0 grams
(71 par cent* of theoretical.) of colorless
oc-oarhohcnmoxyaadnooixmamio ad d was obtained*
The product ass obtained in the form of odorless
needles melting at 100° on reorystalliaction from
ethyl aeetate and petroleum ether*
c<-Carbobonaoxyamlnoelnnamlc aold is sexy soluble
in ethyl alcohol and ethyl acetate, fairly soluble
in ether, and sparingly soluble i* bensene and toluene.
48
in the sold*
I t may be M tr y f ttllliii free benaene*
Zt is Insoluble in eater, petroleum ether, and
ligroin.
iB ilt
Caled. f«r C17HlgO^Ht
C, 68*9; H, 6*Of8,4. 7
Neutral tqalT., 297
Founds
0, 08,9; I,S *2|lf4i6
Ventral tiu lT ,f 891
Hydrolyela of o(»oirt)d>onaoxyaadnoo1nnamlo Aold
One g n a of °o»carbcben*oxyamlivooinnamlo aold
oaa hydrolysed by boiling for four hours with 100 ml.
of normal hydroehlorio aoid«
The resulting solution
see filtered sad 0.75 gran of 2,4-dinltrophanylhydrsslne dieeolTod in 150 n l. of dilute hydroehlorie
asid use
added.
The gussy orange precipitate of
phanylpyrtnrle aold 2,4-dinitropha nylhydrasono oas
filtered and reerystalliaed
from dilute aloohol.
The
yield use 1.09 grama (94 per oeait. of theoretical)
of yellow e¥ystala melting a t 191°.
a
mixed melting
point with an authentle sample Obcmed no depression.
45
Aot Ion of Benayl Carbanata mi oc-OarfeSbonsoaciMdaoitmoMto Aold
Bensyl oarbamata (0*15 gram) and <x~aeetanlno»
olzmaade mold (0*85 gram) mere heated together for
16 hours ot 96°.
Daring this tins tha roootlon
mixture remained partially crystalline and beeano
only slightly colored.
Whoa i t hod ooolod to soon
temperature, tha eryStallino aaai was pulrerlsed
and oxtraetod with throw 5 ml* portions of half
normal pota salon hydrosids solution*
Tha bensyl
oarbanato was than filtorod off and weighed 0*070
gran (47 par oont* recovery)•
Whan tha alkaline
fU trato was aoldifiad with diluto hydroohloria
•old, 0*85 gram (98 par oont*) of unehangad oeeaztobensoxyanlmooInnawlo aoid maltlng at 165° was
isolated.
Kecrystalllsatlon fron othyl aeotato and
potroloum othor gave naadlos molting a t 160°.
a
mixed molting point with an authsntio sample showed
no depression*
44
pi^arbobcnsoayamlnoolnnanlo Aold froa
tx.oc,p1carb oben»oxyamlno-/3^phsngrlproplonlo
Acid
<*,ot-Dioarbobensoxyandno«0-phenylpro plonlo
aold (1*00 gran) m i boated for one hour at 140°*
Tim reaction mixture assumed a brown oolor and
partially solidified on cooling.
The material
was extracted with two 10 ml* portions of half
normal potassium hydroxide solution*
uble o il remained, and was
An insol­
separated from the
alkaline solution by filtration*
On reerystal-
11sat Ion from water th is o il gave 0*06 gram of
bensyl carbamate melting at 85°*
filtra te
The alkaline
was acidified with dilute hydrochloric
aold and the nearly colorless precipitate which
formed was filtered off*
(hi
re crystallisation
from ethyl acetate and petrole an ether 0*46 gram
(68 per cent* of the theoretical) of o^.carbabensoxymmlnoclnnamlc ad d melting at 189° was obtained*
A mixed melting
point with an authentic sample
showed no depression*
46
oo-Carbobensoxyamlno-o^hydrojcyglutTyl Laotone
C
HHCOOCHgCgHg
COOH
Tan grama of
bensyl earbama te and 10 grama
ofowketoglutarie aold aere be ated at 80° and 16 am*
preaacire for four houra.
After one hour the re­
action mixture had solidified.
The produet was
reerystalllzed from hot ethyl acetate, yielding
16« 5 grams (90 per eent •) of hard, dense, oolor la aa
prisms melting at 175°.
The laetone la also quite soluble In aleehol,
acetone and chloroform, somewhat soluble In ether,
and lnaoluble In oold water, petroleum ether, and
llgroln.
The product crystallised from a mixture
of ethyl acetate and petroleum ether In the form of
oolories a needles melting at 178°*
Anal. Calcd. for CigH^gOgK:
C,55.9| H, 4*7} V, 6.0
Neutral equlw., 279
Founds C,55.7| H, 4.6| V, 5,0
Neutral eqclw., 340
Hydrolysis of <*-Carbdbensoxyan&no-oehydroocyglutaryl Lactone
One gran of c*-oarbd>ensoxyamino-o^-hydroxyglutaryl laotone was hydrolysed by boiling »ith
© ml. of water for fire minutes.
On eoollng 0.42
gram (78 per eertfc.) of bensyl carbamate melting at
S7° crystallised from the solution.
was heated almost to boiling and
The filtra te
treated with a
hot solution of 0.00 gram of 2, 4-dlnltropheny1hydraslne In 100 ml. of dilute hydreehlorle sold.
The mixture was oooled and the ye lion solid that
precipitated was filtered and washed with water.
The product, oc-ketoglutarie acid 2,4-dinitrophenylhydrasone, weighed 1.17 grams, representing a yield
of 100 per cent., and melted a t 117°,
a
mixed
melting point with an authentic sample (25,26) diowed
no depression.
4« (a)
Condensation of Bensyl Carbaante with
Bansoylformlo Aold
A tte sts were made to eendense bensyl car­
bamate and bensoylformlc aold by heating for vary­
ing lengths of time a t various temperatures ranging
up to 110° under reduced pressure.
All such at­
tempts resulted In the Isolation of much unchanged
bensyl oarbanate and a considerable quantity of an
orange-colored o il from which no crystalline material
could be obtained.
Ten grama of bensyl oarbamate and five grams o f
fredhly reorystalllsed bensoylformlc sold were heated
for 12 hours at 128° under a pressure of 20 sen.
Addition of ether and petroleum ether to the reddish
o il formed resulted In the separation of a yellow
solid, Ohloh, after reoryatalllsatl on from ethyl
acetate and petroleum ether, weighed 2.0 grams and
melted at 220-230°.
After further reorystalllsatlons
from ethyl acetate, petroleum ether and bensene-petroleum ether mixtures, the product was obtained In the
form of colorless needles which melted at 240°.
material had no aold properties.
It to be carbotoensoxybensallmine.
The
Analysis Indicated
46 <b)
Anal. Caled. for C^Hj^OgHx
C, 75.8f H,5.4f 11,6.9
Found: C, 75.6; H,5.4| H,6.8
Hydrolysis of Carbcfeanaoxybensallmins
A m all amount of the material was hydrolysed
by boiling with dilute hydrochloric aold for 10
minutes.
Bensaldehyde was isolated from the
hydrolysate as the 2,4-dinitrophenylhydrasons In
80 per cent* yield, melting at 230°.
a
mixed
melting point with an authentic sample diosed no
depression.
A snail amount o f bensyl oarban* te was also
Isolated from the hydrolysate •
47
Reduction of N.I^-Dloarbobensoaybansylldenadlaialno
A suspension of 2*5 grams of dloarbobensoxybenzylidenedlainine in 50 ml. of absolute alcohol
i t s reduced cetalytloally under a pressure of four
atmospheres of hydrogen in the presence of 0.1 gram
of palladium oxide*
The pressure dropped alowly
over the period of an hour during ehloh the com*
pound gradually dissolved.
After two hours the
clear color less alcoholic solution ess decanted
from the catalyst and acidified with hydrochlorlo
acid.
On evaporation to dryness a colorless product
was obtained which consisted of a mixture of bensylamine hydrochloride and ammonium chloride*
The
bensylamina hydrochloride was separated by its
solubility in absolute alcohol and reerystalllsed
from absolute alcohol and ether*
The yield was
0*86 gram (95 per cent*) of product melting at
260° with decomposition*
Its identity was established
by conversion to the bensoyl derivative (27) in
80 per cert* yield and to bensyl urea (28) in 65 per
cent* yield*
Klxed melting points of these deriva­
tives with authentic samples Showed no depression*
48
Heduotlon of H»K♦-I)loarbobensaxy-pmathojtybenaylldansd lamina
Thm
g n u of N,N*-die arbdbensoxy-p-aeth-
oxybensylldenedlamlne was suspended in SO ml* of
absolute alcohol and reduced ibder a pressure of
four atmospheres of hydrogen in tha presence of
o .l gram of palladium oxide*
Tha hydrogen praaaura
dropped slowly daring tha firs t hoar as tha substanea
gradually dissolved*
Aftar two hours tha elaar
oolorlaaa solution vaa daeantad and aoidifiad with
hydrochloric aoid.
ation was
Tha product obtainad by evapor­
separated from ammonium chloride in tha
usual manner and reoryatalllsed from ethyl alcohol,
from whldh. i t aeparatad in tha form of large oolor­
ies a plates*
malting a t
Tha yield of anlsylamine hydro chloride,
265° with deeomposltlon, was 1*10 grams
(89 per cent* of tha theoretical)•
The identity of
tbs amine was established by conversion to tha
plerate (29), which molted at 190°.
Anal* Calod* for
C14H14°8H4*
*» 18,8
Found i
16,2
Reduction of N.IP-Dloarbobanaoxy-S,4m
©
t hy1ened1oxyben*y1idsnodiamine
Two grams of N,H,-dloarbdb«n*oxy-3#4methylenedloxybensylidefnediamine was suspended
in 100 ml* of absolute alcohol and shaken for two
hours under a pro ssure of four atmospheres of
hydrogen In the presence of 0.1 gram of palladium
oxide oatalyst•
The pressure dropped slowly dur­
ing the firs t hour as the substance gradually dis­
solved*
The resulting clear, colorless solution
was decanted, acidified with hydrochloric acid,
and evaporated to dryness*
The piperonylamine
hydrochloride was purified by reorystalllsation
from abeelute alcohol*
The product crystallised
In the form of colorless plates, weighed 0*75
gram (90 per cent* yield) and melted at 260° with
decomposition*
The product was identified by con­
version to the pierate (SO) Milch melted at 200°,
Anal*
Calcd* for ci^ i2 °9 N4*
Found s
14*7
N, 14 .6
to
Reduction of H«N»~Dio>rt)ct)enK03y-^ractfa?l~
butylldenadlamina and N.M*-Dloarbobenaoatyfurfurylldoned ia nine
IfgN*-Die arb dbeneoacy-3-»met taylbuty 1ldene die mine
and H#H*-»Diearbdboncoxyfurfurylidane diamine cere
reduced by methods similar to those described above
for the reduction of the other aldehyde derivatives*
The product e obtained have not ae yet been identified*
51
Rcduct Ion of oi,ou»Dioarbobcnsaxyaralnoproplonlc Aold
Six grams of <*,c*-diearbobcnsoxyamlnopro plonlo
meld mere dissolved In 100 ml. of 95 per oent
aleohol containing teo ml. of aeetlo meld.
The
solution was shaken under a pressure of four at*
mospheres of hydrogen with 0.1 gram of palladium
oxide catalyst for four houre.
The pressure dropped
somewhat during the firs t hour and then became con­
stant a a a colorless solid crystallised on the sides
of the reaction vessel.
The mixture see filtered
and the catalyst waShed free of product mi Hi a
l i ttl e mater.
The solid obtained on evaporating
the aqueous solution to dryness mas dissolved in
10 ml. of mater, boiled mlth nor its , filtered aid
treated mlth 75 ml. of absolute alcohol.
The
slightly yeHorn product that crystallised on stand­
ing overnigit in the refrigerator weighed 0.85
gram (60 per cent, yield).
I t melted
at 275° mlth
rapid evolution of gas, maa very soluble inmater
but insoluble in alcohol and other organic solvents,
ant in general behaved like alanine.
Further reory-
atalllzation from 85 per cent, alcohol produced a l­
most oolorless crystals melting at 280° with decom­
position.
The loas on recrystallisation mas only alight.
Anal. Calcd. for CjHyOgN:
N, 15.7
Found:
N, 15.6
58
d *l-/S-»PhanyIala nine from
arboben «gy«
amlno-0-phenylpnsplonlo Aold
Two grams of <^°^learbdbenaoxya»liio-0phenylprcpionic aold was dlssolved in 100 ml*
of absolute alcohol and shaken for five hours
under a pressure four atmospheres of hydrogen
alth 0*1 gram of palladium oxide*
The product,
ehioh separated from the solution In the form of
snail oolorleas needles, was separated from the
catalyst by filtra tio n and watiling with water*
On reerystalllsation from dilute aloohol, 0*40
gram (68 per cent* yield) of colorless crystals
of d, 1-6-phenylalanlne melting with decomposition
at about 250° was obtained*
An alkaline solution of the product was treated
with phenylIsocyanate*
The dlphenylurea which pare**
oi pita ted was filtered off and
on acidification of
the filtra te 0*66 gram (94 per cent * yield) of
<**•(phenylure ido)-f3**phenylpropionic ad d ms Isolated*
Rsctrystallatlon from dilute alcohol gave
colorless
needles melting Sharply, with decomposition, at 177°#
A mixed melting point with an authentic sample (31)
tixowed no depression*
88
Tha uretfo aold was converted almost quanti­
tatively to 3-phm y1-5-bensyIhydantoin "by boiling
for SO minutes with 10 per cent, hydrochloric aold*
Beerysta111sation from dilute alcohol produced
colorless needles melting at 171°.
a mixed malt­
ing point with an authentic sample (52) showed no
depression.
54
dsl-flpFhmiylalanlne from <*»Carbdbensoxyaminoolnnamle Aold
Two grama of oC-oarbdbenzoxyamlnoclnnamlo aold
vaa dissolved In 100 ml* of 95 par oont* alcohol
and ahaken for five hour a with
oatalyat under
hydrogen*
palladium oxide
a preaaure of four atmoaphorea of
The preaaure dropped slowly during the
f ir s t hour and then beearns constant as d, l-/?-phenylalanlne began to crystallize.
isolated as
The product was
before in a yield of 0*950 gram (85
per cent* of the theoretical),
I t was converted
as In the previous case to oo»(phenylureldo)Hy­
phenylproplonic acid (m*p* 180° with decomposition)
and then to
5-phenyl-5-benzyIhydantoin (m*p* 172°),
Mixed melting points of these derivatives \?ith
authentic samples (31,52) showed no depression*
Reduct Ion of cx^arbobenxoacyainino-o*-
• W
M
M
g M
M
H H M
M
M
H lM
M
lM
M
a ilH W
M
M
M
H M
M
M
M
H M
M
M
n M
M
a M
M
hydroxyK lntaryl Iooton.
The reduction of ocr-carbobensoacyamlno--«*hydrcocyglutaryl laotone by method* similar to the
teohnique* already described resulted In the re*
eovery of 95 per eent. of the nitrogen in the fora
of ammonia•
Modification of the procedure by boiling elth
alcohol to open the lactone ring prior to reduction,
a method successfully applied by Shemin (12) on the
aeetandde analogue, led to the same result.
56
SUM
M
ARY
1«
listhods for tiis prspsrstl on or bensyl car­
bamate and «¥-ketoglutarie acid haTe bssn Im­
proved*
R«
Tbs condensation of bensyl carbamate with
laovaleraldehyde, bensaldehyde, anlsaldehyde,
piperanal and furfural has been studied,
in
each ease two moles of amide reset with one
mole of aldehyde forming respectively 8,3•dioarbobensoxy-3-methylbutylidenedJamine0
H,H'-dlearbobenzosybensylldenedlamina, 8,H'dlearbob ensosy*p*msthoxybensylldenediamlne p
3,3* -die arb obensoxy*3, 4-methylenedloxybensy1idened lamina and N,H*-dloarbdben»osyfurfury1ldenedlamlne*
5.
The oondensatlon of bensyl earbamate with alpha*
koto aoida leads to a variety of products*
Pyruvio aoid condenses with two moles of bensyl
earbamate to form o^oc-dloartodb• nscsyamlnopropionlo aoid*
In the ease of cx-kstoglutarlo aold,
the laotone of c<«*oarbcb*nso3yamlno*oc*hydroacyglutarlo aoid was obtained*
Bensyl earbamate
reacts with phenylpyruvlc sold, depending on the
m
temperature of reaction to giro two products,
o^ou-di©arbdbenzoxyainino-&*phenylproplonic
aoid and oc-oarbobtnmyaninoo tnnaml o aold*
On heating «;a-di5arbdbenxaBEya»lnow5-phenylpropionic aold a raoleoule of bensyl car­
bamate la eliminated resulting In the forma­
tion of the ot-carbobensoxyaminoeinnamle aold*
The reverse reaction does not take plaoe•
The reaction of bensoylformlc acid with bensyl
carbamate is abnormal and leads only to the
formation of m all amounts of oarbobenzoxybensallnine*
4*
A possible mechanism for the condensation of
aldehydes and alpha-keto aolde with bensyl
oarbamate la suggested.
Ihe reaction in­
volves a primary addition of benzyl carbamate
to the carbonyl group, followed either by a
direct replacement of the hydroxyl group by
another benzyl carbamate residue or by elimina­
tion of water with the formation of unsaturated
Intermediates to which the second mole of
bensyl earbamate subsequently adds*
5*
The hydrolysis of the condensation products
with aqueous ad d was studied, and found to
lead to the original aldehyde or alpha-ksto
m
•old and bensyl carbamate*
6.
The oondonMtlon product■ of bensyl oarbamate
•1th banaaIdehyde, anlaaIdehydef and plporonal
war* rodueod oatalytloally to bemaylamlne,
anl ayla mine, and ptperonylwnine respectively,
Thla constitutes a new method for the ayntheale
of primary amines,
7,
Tha condensation produot a of bensyl earbamate
with pyruvic aold and phenylpyruvio aold aero
oatalytloally hydrogenated to alanine and
phenylalanine.
Thla oonatltutea a nev method
for tha ayntheaia of alpha-amino aolda from
alpha-keto aelda.
59
BIBLIOGRAPHY
1. Roth, Ann. 15*. 72 (1870)
2. Tavlldarow,
Bar. 5, 477 (1872)
5. PulTermaohar. Bar. 25, 510 (1892)
4m Bahai and Choay, Ann.Chim. phya. (6) 27,
528 (1892)
—
5. Planar, Bar.. 25, 5821 (1890)
6. BlaohofY, Bar. 7, 654 (1874)
7. MochaUaa. Bar. 24, 1805 (1891)
8. Elnhom and Ladlaoh, Ann. 545. 264 (1905)
9. Hoyaa and Forman, J . An.Cham. Boo. 55,
5495 (1955)
10. Grlmaux, Ann. Chlm.phya. (5) 11. 57*
U . Bargmann and Orafa, Z. Phyalol. Cham.
187. 187 (1950)
12. Shaain and Harbat, J. Am. Cham.Soo. 60.
1954 (195B)
15* Harbat and Shaadn, Organic synthaaaa, XIX,
67 (1959)
14. Shamin and Harbat, J. An. Cham. Soo. 60.
1951 (1958)
—
16. Bargmann and Zarvaa , Bar. 65, 1192 (1952)
16. Thlala, Ann. 502. 258 (1898)
17. Haubarg and Rlngar, Bloeham. Z. 71, 226 (1915)
18. Harbat and Shamin, Organic Synthaala, XIX,
77 (1959)
19. Aoraa, Amar, Cham. J. 50, 591 (1935)
60
20* Allen, J. Am
* Chen* Soo* 62. 2955 (1950)
21. Shrlner and Fuaon, "Identification of Or­
ganic Compounds* (1955) p. 110
22. Brady, J. Chem. Boo* (1951), 756
25. Broderick, Bar. 65, 1855 (1952)
24* Strain, J* Am
* Chem. Soo* 57. 758 (1955)
25* Krebs,
Z. Physiol* Chem* 218. 157 (1955)
26. Knoop, Z* physiol* Chem. 259
27. Beckmann, Ber. 25
SO (1956)
5554 (1890)
28* Paterno and rploa, Ber* 9, 81 (1876)
29* IngeId and Shoppee, J* Chem* Soc* (1929),
1199
50* Melon and Robert eon, J* Chem. Soo* (1927)
2655
51* Abderhalden, "Bloohemlohes Handiexikon*
(1911), IV, p. 679
52. Mouneyrat, Bar* 55, 2595 (1900)
NEW YORK UNIVERSITY
WASfllf’GTOM SQUARE
•
LIBRARY
•
Документ
Категория
Без категории
Просмотров
0
Размер файла
2 334 Кб
Теги
sdewsdweddes
1/--страниц
Пожаловаться на содержимое документа