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Metalated Dialkyl N-Alkyliminocarbonates New Masked -Amino and -Thio Carbanions.

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A N,N',N",N"'-Tetramethylprphyrin~gen[~]
["I
By Burchard Franck and Christitrri Wegned']
N.N',N",N"'-Tetramethyl derivatives of porphyrinogens ( I )
and porphyrins (2) have long been viewed as a synthetic
goal',- 'I. They should provide valuable information about
deformability, aromaticity, complex formation, and structureactivity relations of these parents of biologically active natural
products. Using a simple route based on porphyrin biosynthesis we have now achieved the synthesis of compound ( 5 a )
as the first N,N',N",N"'-tetramethylporphyrinogen.
It is structurally related to uroporphyrinogen 111, the biosynthetic precursor of the blood pigment heme, from which it differs by
virtue of the four N-methyl groups.
assignment) 182.7 (s, CO,H), 127.9 (s, pyrrole a-C), 114.6 (s,
pyrrole b-C), 34.6 (t, CH, of side chains), 31.1 (9, CH,N), 22.3
(t. CH, bridges).
Contrary to previous thinkingt4],the colorless N,N',N",N"'tetramethylporphyrinogen (5a) and its ester ( 5 b ) have thus
proved to be readily accessible, in spite of steric hindrance
of the N-methyl groups. ( 5 b ) displays remarkable differences
in reactivity compared to the non-methylated compound. For
instance, while normal porphyrinogens [ ( I ), NH in place
of N-CH,]
are rapidly dehydrogenated to dark red fully
conjugated porphyrins by atmospheric oxygen or iodine, (5 b )
remains unchanged. The question whether it can be transformed into the aromatic bisquaternary porphyrin of type (2)
under energetic conditions is currently under study. According to model considerations, which suggest that ( 1 ) has a
conformation ( I a) with pronounced twisting of adjacent
pyrrole rings against each other, the completely dehydrogenated essentially planar molecule (2) should exhibit considerable strain.
Received: February 18. 1975 [ Z 202b IE]
German version: Angew. Chem. 87. 419 (1975)
CAS Registry numbers:
( 3 ) . 487-90-1; ( 4 ) . 54932-07-9: ( S a ) . 54932-08-0: ( S b ) , 54932-09-1
[I]
(Sa), R = CHz-COzH
( S b ) , R = CHZ-COzCH,
[?]
[3]
R
R
[4]
Of the two pathways deserving consideration for the preparation of N-methylated porphyrinogens-methylation of the
completed parent skeletonf3' and cyclotetramerization of Nrnethylpyrrole~~~~-only
the former has so far permitted partial
N-methylations. In order to exploit the latter synthetic pathway, N-methylnorporphobilinogen( 4 ) was prepared and subjected to acid-catalyzed condensation (0.5 N HCI, 100°C,
30 min), in analogy to the biogenetic-type synthesis of uroporphyrinogen from porphobilinogen (3)15]. The N,N',N",N"'tetramethylporphyrinogen ( 5 a ) , m.p. 233 "C, which crystallizes in 17% yield on cooling of the reaction mixture, was
converted by treatment with methanol/HCl into the crystalline
octamethyl ester ( 5 b ) ; m.p. 218 "C ; Ehrlich reaction negative :
FD-MS (8kV)'": m/e 9 4 8 k 1 (base peak, M@):UV (methyl
acetate): hm,,=252nm: 'H-NMR (D,-acetone): 6=3.80 (s.
8 H, CH, bridges), 3.50 (s, 16 H, CH, of side chains), 3.57 (s,
24 H, 8 CH,O), 2.60 (s, 12 H, 4 CH,N). The octacarboxylic acid
shows a base peak at m/e 484.3569 (Me - 8 CO,, calc. for
C32H44N4:484.3566) in its high resolution mass spectrum:
,C-NMR (NaOD): F (multiplicity in off-resonance spectrum.
['I
Prof. Dr. B. Franck [ +] and DipLChem. Ch. Wegner
Organisch-Chemisches Institut der Universitiit
44 Miinster. Orleans-Ring 23 (Germany)
[ + ] To whom correspondence should be addressed.
[**I Thls
work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie.
424
[5]
[6]
Tetrapyrrole Biosynthesis, Part 4.-Part 3: B. Franck and A. Rowold.
Angew. Chem. 87. 418 (1975); Angew. Chem. internal. Edit. 14. 423
( 1975).
W K . ,McEnoi. J. Amer. Chem. Soc. 68. 711 (1946): A. H. Corwtn
and W M . Quurrlehuum. ihid. 58. 1081 (1936): R. C . E//tri+soii and A
H . Corwin. ihid. 68. 1 1 I 2 ( 1946).
R. Grigg, A . Suernry. G. R. Drardiw. A. H . Jacksoii. and A. W Johnson.
Chem. Commun. 1970. 1273.
A. H. Jackson and G. R. Drarden. Ann. N. Y. Acad. Sci. 206. 151
( 1973).
G. H. Cookson and C. Rimingfon. Biochem. J. 57. 476 (1954).
We are grateful t o Dr. U . Rapp. Varian MAT, Bremen. for the field
desorption mass spectra (FD-MS).
Metalated Dialkyl N-Alkyliminocarbonates:
New Masked a-Amino and a-Thio Carbanions
By Dieter Hoppe"]
d
Masked a-amino carbanions
C-N
are becoming
increasingly important for the nucleophilic introduction of
a-aminoalkyl groups"]. We suspected the bis(alky1thio)methyleneamino group (RS),C=N in the open or cyclic[21dialkyl
N-alkyliminodithiocarbonates( I ), ( 2 ) , and (8) (representing
a masked amino function) to becapableofstabilizing neighboring carbanionic centers by allylic resonance. The compounds
( I ) . ( 2 ) . and (8) are readily accessible in high yields by
dithiocarboxylation of amines and subsequent bis- (or cyclo-)
alkylationf3!
We found that only those compounds of type ( I ) and
(2) which bear mesomeric electron-withdrawing groups in
the a-position can be metalated with potassium tert-butoxide
in tetrahydrofuran at -70°C to the anions (3) and ( 4 ) ,
respectively, whereas ( 8 a ) and (8c), for example, do not
>
[*I
<
Dr. D. Hoppe
Organisch-Chemisches lnstitut der Universitat
34 Gottingen. Tammannstrasse 2 (Germany)
A n g r n . Chrm. inrrmar. Edir.
/ R)/. 14 ( 1 9 7 5 ) / N o . 6
(la), R'
( l b ) , R'
(2a), R'
(2b), R'
R'-CH,-N=C(SR~)~
I
(CH))3COk
-7O'C
0
-
[R'-~H-N=C(SR~),
= C O ~ C ~ H ,R~
, = CH,
= C02C2H,, R2
R2 = -CH2-CH2-
+
= C,H,,
= C,H,,
R2 = CH3
Ra + R2 = -CH2-CHa-
0
R'-CH=N-C(SR2)2]K0
(3), R' = COzCzH,
(4). R' = C&5
react under these conditions. The ambidentate anions (3)
react regiospecifically with alkyl iodides or benzyl bromides
with chain-extension to form the carbonic acid derivatives
(5)141; ( 4 ) also yields the isomeric orthocarboxylic acid derivatives (6) (IR: 1640 cm- ')(seeTable 1).Apart from the carbonic
(2 b) addiacid derivative ( 5 e), 2-benzylimino-1,3-dithiolane
tionally gives the vinyl thioester (7) by base-induced ring
opening to the dithiocarbamateanion and subsequent benzylation.
was trapped as (10) with trimethylchlorosilane (see Table
1). Metalation in this position is apparently favored by chelation of the lithium by the basic imino nitrogen.
The lithium derivatives (9) readily add aldehydes and
ketones at - 70°C; for example, reaction of (9d) with benzaldehyde followed by neutralization at - 70°C affords an 80 %
yield of the P-hydroxyalkyl iminodithiocarbonate ( 1 1) [IR:
3380 (OH), 1570 cm-' (C=N)] which cyclizes slowly at room
temperature, and faster in boiling benzene, with elimination
Table 1. Metalation of dialkyl N-alkyliminodithiocarbonates (I), ( Z ) , and (8) and reaction with electrophiles R3X
Starting
compound
Base [a]
R3X
Products [b]
R'
R2
R3
Yield
B.p. ["C/torr]
[XI
K Ot Bu
KOtBu
KOtBu
KOtBu
KOtBu
LiN(iPr),
LiN(iPr),
LiN(iPr),
CHI
CHICH3
CHI
CHICH3
H
H
70
73 [.I
81 [dl
95 [dl
69 CCI
80 [dl
75
80
9410.5
12&28/0. I
78-8411.3
104--O8/1.O
[a]
[b]
[c]
[d]
[el
KOtBu = potassium trrt-butoxide (freshly sublimed); LiN(iPr), =lithium diisopropylamide.
'H-NMR spectra and IR spectra are in accord with the structures; the compounds gave correct CH analyses.
Purification by chromatography over silica gel (neutral) with light petroleum (40--60"C)/diethyl ether (1 :2).
Purification and separation by chromatography over silica gel (neutral) with light petroleum (40--60"C)/benzene (2: 1).
( 5 c ) : ( 6 c ) = 90:10 (NMR).
[fl ( 5 d ) : ( 6 d ) = 40:60 (NMR).
[g] ( 5 e ) : (7) = 65:35 (both products were isolated).
[h] ( 6 f ) : (9f) = 15:85 (both products were isolated).
[i] At room temperature (7) and ( 1 0 ) exist a s stable (on NMR time scale) E / Z mixtures. F. V6gtle. A. Mannschreck, and H. A. Staab, Liebigs Ann.
Chem. 708, 51 (1967).
@a),
R'-N=c, /S-CH2-R2
S-C H3
R'
f 8 b ) . R'
1 8 ~ ) R'
.
(8d), R'
= CH,,
(CtI,),,S,Cl
f
/s
r
=
c
,
R'
R2 = H
R2 = H
= c-C3H,,
= C,H,,
-
Li-CH,
R2 = H
= CH,, R Z = C,H,
S-kH-Si( CH,),
R~-N=c/
S-CH3
S-C HQ
R' = C,H5, R2 = H
~+C,H,CIIO
OH
I
C6H5-N=C,
/S-CH,-CH-C,H,
S-CH,
-
N-C&5
a
s o
H
(12)
Lithium diisopropylamide (in tetrahydrofuranln-hexane,
70°C) preferentially abstracts an u-proton of the S-alkyl group
from the iminocarbonic esters (8)-and also from (2a)-to
give [alkylimino(alkylthio)methylthio]alkyllithium ( 9 ) , which
Angebr. Chem. internat. Edit.
1 Vol. 14 (1975) J No. 6
Received: March 14, 1975 [Z 204a IE]
German version: Angew. Chem. 87.449 (1975)
CAS Registry numbers:
( l a ) , 54985-61-4;( l b j , 54985-62-5;(Za), 54985-63-6;(Zb), 2080-48-0;
( 5 a ) , 54985-64-7;(56). 54985-65-8;(Sc), 54985-66-9;( S d ) , 54985-67-0:
( 5 e ) . 54985-68-1; ( 6 c ) , 54985-69-2: ( 6 d ) . 54985-70-5;
(6 I'). 55012-66-3;(7). 54985-71-6;( 8 a ) . 18805-25-9;( 8 c ) . 54985-12-7:
(961. 54985-73-8;( 9 d ) , 54985-74-9:( 9 1 ) . 54985-75-0;(IOa). 54985-76-1
( l o b ) , 55012-67-4:( 1 1 ) . 54985-77-2;( 1 2 ) . 54985-78-3;
benzaldehyde, 100-52-7:4-benzyl-5,5-dimethyI-2-methylimino-1,3-oxathiolane. 54985-79-4
H-)4-C6H5
H
(llJ
of methanethiol to form 5-phenyl-2-phenylimino-l,3-oxathiolane (Z2)I5] (IR: 1650cm-' (C=N); 'H-NMR (CDCI,):
r=6.45,6.65 (4-H), 'v3J=10Hz; 4.4 (5-H), 1*4J,i,=6Hzand
1.4J1,,,=9Hz). In similar manner, (9b) and acetone give
4-benzyl-5,5-dimethyl-2-methylimino1,3-oxathiolane [78 %,
m.p. 91°C; IR: 1655cm-' (C=N)].
[i] Review: D. Srebach and D. Endrrs, Angew. Chem. 87, 1
(1975);Angew.
Chem. internat. Edit. 14,15(1975);for chemistry of metalated isocyanides,
see: U . SchiillkopS, Angew. Chem. 82,795(1970);Angew. Chem. internat.
Edit. 9, 763 (1970);D. Hoppe, Angew. Chem. 86, 878 (1974);Angew.
Chem. internat. Edit. 13, 784 (1974):for reactions of lithio-2-azaallyl
anions (metalated azomethines) see: Th. Kauffmann, Angew. Chem. 86,
715 (1974);Angew. Chem. internat. Edit. 13, 627 (1974).
[2] Systematic name: 2-Alkylimino-1,3-dithiolanes
425
[3] Prepared by analogy with: E. Fromm and M . Block, Ber. Deut. Chem.
Ges. 32, 2212 (1899); M . DelPpine, Bull. SOC. Chim. Fr. [3] 27, 48,
57 (1902); Y. Ueno, 7: Nakai, and M . Okawara, Bull. Chem. SOC.Jap.
43, 162 (1970).
[4] Use in amino acid synthesis: D. H o p p e . Angew. Chem. 87, 450 (1975);
Angew. Chem. internat. Edit. 14, 4261 1975).
[5] Compoundsoftype(l1) and(l2)decomposeon work-up in the presence
of bases to form episulfides.
Chain-Extended and a-Branched a-Amino Acids by
AlkYlation of Metdated a-[Bis(alkylthio)methyleneamino] Acid Esters
By Dieter Hoppe"]
As esters of iminodithiocarbonic acid['] N-[bis(methylthio)methylenel- and N-( 1,3-dithiolan-2-ylidene)glycine
ethyl esters
(I a) and (I b), respectively, are conveniently obtainable from
glycine ethyl ester hydrochloride. Their reaction with potassium tert-butoxide at -70°C leads to the a-amino carbanions
( 2 ) which afford chain-extended esters (3) on treatment with
alkyl iodides or benzyl bromides between -60 and 0°C (see
Table 1). The monoalkylated products (3) are formed almost
cut course of our new synthesis is a topic for further study.
On treatment at 5-2ooc with aqueous performic acid produced in situ, the esters (3) and ( 4 ) undergo oxidative-hydrolytic dedfuration to the amino acid esters ( 5 ) and ( 6 ) , respectively.
Ethyl 2-[bis(methylthio)methylene]amino-2-(p-bromobenzyl)butyrute (4a)
Compound (I a) (4.14g, 20 mmol) in THF (10ml) is added
dropwise at - 70 "C to freshly sublimed potassium tert-butoxide[31(2.24g, 20mmol) in dry THF under N2. Stirring is
continued for IOmin, and a solution of p-bromobenzyl bromide (5.0g, 20mmol) in THF (20ml) is then added. After
warming up to room temperature, the mixture is stirred for
another 15 min and recooled to - 70°C. Potassium tert-butoxide (2.36g,21 mmol) in THF (30ml) is added from a dropping
funnel cooled with dry icelacetone, and ethyl iodide (3.4g,
22mmol) is squirted in after 15min; the reaction mixture
is then treated as above. After removal of solvent under
vacuum, the residue is taken up in ether (50ml) and water
(30ml), the organic phase washed with water and dried over
Table I . a-[Bis(alkylthio)methyleneamino] acid ethyl esters ( 3 ) and ( 4 ) prepared.
RzX (+R3X)
Starting
compound
Product [a]
R'
R2
R3
Yield
[X]
B.p. ["C/torr]
[a] The IR and 'H-NMR spectra are in accord with the structures; the products gave correct CH analyses.
[b] Distillative work-up.
[c] Purified by chromatography over silica gel (neutral) with light petroleum (40-6O0C)/diethyl ether ( 1 :2; 3: 1 for ( 4 a ) ) .
exclusively (>97 %) with one equivalent of base and the alkylating agent; renewed metalation [without isolation of (311
and alkylation permits introduction of a second alkyl group
(which may differ from R2) to form the a-branched a-amino
acid derivatives ( 4 ) .
Selective monoalkylation of relatively stable carbanions
generally runs into dificulties[21.The reason behind the clear(R~s)~c=N-cH,-co~c~H,
(la), R'
{Ib), R'
-(CH,),COK
700~
= CH3
+ R'
2-Ethyl-p-bromophenylalanineethyl ester (6 a)
= -CH,-CH2-
0
R2\
(R~S)~C=N-CH-CO,C~H, K@
(2)
R2
( R'S)2C=N-&H-C02C2H,
1. (CH,),COK
P
2 . R'Y
T2
(R~s),c=N-c-co,c~H,
A3
(31
( 3 ) or
(4)
(4)
HCOzH, H201
H20
."
R2
I
H~N-C-CO,C,H,
I
R3
(5). R3 = H
(4). R3 = Alkyl
[*] Dr. D. Hoppe
Organisch-Chemisches Institut der Universitat
34 Gottingen, Tammannstrasse 2 (Germany)
426
sodium sulfate. The pale yellow oil (7.7g) left on removal
of the ether is chromatographed over silica gel (250g, neutral)
with light petroleum (40-6O0C)/diethyl ether (3 : 1) to give
( 4 a ) (6.80g, 84%) as a viscous colorless oil (Rf=0.40).-IR
(film): 1732 (C=O) and 1587cm-' (C=N). 'H-NMR (CCI,):
r=2.7 (d) and 3.1 (d), aromatic H ; 6.7 and 6.9 (AB part,
J = 13 Hz, diastereotopic benzyl H; 8.1 (9) and 9.2 (t), ethyl
H ; 5.9 (9)and 8.8 (t), ester ethyl H ; 7.6 (s) and 7.8 (s), S-methyl
H broadened by slow inversion.
+
2 R'SO~H
+ co,
30 % hydrogen peroxide (7.4g, 65 mmol) and p-toluenesulfonic acid (0.05g) are added with stirring to (4a) (4.05g,
IOmmol)in98-100% formicacid (15ml)at 0°C. The temperature is maintained at 10°C for 4 h by cooling (exothermic
reaction, evolution of carbon dioxide) and then allowed to
rise and kept at 20°C for 20h. The acid is drawn off under
vacuum in a rotary evaporator (bath temperature ~ 5 0 ° C )
and 50 % formic acid (10ml) added to the residue; the mixture
is then again evaporated to dryness[4! The (cold) residue
is covered with ether (30ml), 2 N sodium hydroxide solution
(IOml, 20mmol) cooled to 0°C is added, and the mixture
is stirred until dissolution is complete. After separation of
the ethereal phase the process is repeated with 5ml of 2~
sodium hydroxide. The united solutions are washed with a
small volume of water, dried over sodium sulfate, and the
ether drawn off under vacuum. (6a) (2.7g, 90%) is obtained
as a viscous colorless oil.-IR (film): 3350 and 1590 (NH2),
Angew. Chem. internat. Edit. 1 Vol. 14 ( 1 9 7 5 )
1 No. 6
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