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Isonitrile Syntheses.

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New M e t h o d s i n P r e p a r a t i v e O r g a n i c C h e m i s t r y IV
Isonitrile Syntheses
BY PRIV-DOZ. DR. I. UGI, DR. U. FETZER, DR. U. EHOLZER, DR. H. KNUPFER, AND
DR. K. OFFERMANN
WISSENSCWTLICHES HAUPTLABORATORIUM DER FARBENFABRIKEN BAYER AG.,
LEVERKUSEN (GERMANY)
In spite of the large number of reactions which involve the formation of isonitriles, the
only preparative routes to these compounds, until recently, were the classical isonitrile
syntheses discovered about one hundred years ago by Gautier and Hofmann. These methods
are not generally applicable, and give satisfactory yield$ only in exceptional cases. Isonitriles have recently become readily available by the elimination of water from N-substituted
formamides, using acyl halides of Group IV- VI elements in the presence of bases as dehydrating agents. A dehydrating system with a particularly wide range of application
consists of phosgene with tertiary amines. This system generally provides the easiest and
most productive route to isonitriles, particularly where large quantities (> 1 mole) are
to be prepared.
1. Introduction
5. Redox Reactions
2. T he Alkylation o f Cyanides
6. Abnormal Beckmann Rearrangements
3. T h e Reaction of Primary Amines with Dichlorocarbene
7. Ring-Cleavage Reactions of Heterocyclic Compounds
4. a-Eliminations f r o m Formic Acid Derivatives of
Primary Amines
8. Ring-Closure of a-Halogenoacylamines followed by
1-Cycloelimination
1. Introduction
The principal reason for the relatively small volume of
publications on the subject [3] is that convenient and
generally applicable methods for the preparation of isonitriles have only become available in the last few years
(cf. Section 4).
Almost one hundred years have passed since the discovery of isonitriles by Gautier [l -1 d] and Hofinann
[2-2b].
in
chemistry,
Such as the Problem of isomerism r1-41 and the question
of whether carbon can exist in the divalent state 15-91,
have at times stimulated investigations of the isonitriles,
littleexperimental efforthas been devoted to the &emistry of these compounds, in Spite Of their wide reactivity.
Organic
[ I ] A. Gautier, Liebigs Ann. Chem. 142, 289 (1867).
[la] A. Gautier, Liebigs Ann. Chem. 146, 119 (1868).
[IbI A. Gautier, Liebigs Ann. Chem. 149, 29, 155 (1869).
[Ic] A. Gautier, Liebigs Ann. Chem. 151, 239 (1869).
[Id] A . Gautier, Ann. Chimie (4), 17, 103, 203 (1869).
[2] A . W. Hofmann, C. R. hebd. Seances Acad. Sci. 65,484 (1867).
[2a] A . W. Hofmann, Liebigs Ann. Chem. 144, 114 (1867).
[2b] A. W. Hofmann, Liebigs Ann. Chem. 146, 107 (1868).
[3] Reviews: V. Migrdichian: The Chemistry of Organic Cyanogen Compounds, Reinhold Publ. Corp., New York 1947; p. 393;
P. Kurtr in Houben- W e y l : Methoden der Organischen Chemie.
Thieme, Stuttgart 1952, Vol. 8, p. 351 ; I. Ugi, Angew. Chem. 74,
9 (1962); Angew. Chem. internat. Edit. 1, 8 (1962); K. Sjoberg,
Svensk kem. Tidskr. 75,493 (1963); R . Oda and T . Shono, J. SOC.
org. synth. Chem., Japan 22, 695 (1964); I. Ugi, Jb. Akad. Wiss.
Gottingen, in the press; see also: I. Ugi, K. UfJerinann,and H .
Herlinger, Chimia 18, 278 (1964).
[4] M . H. Guillemard, Ann. Chimie (8), 14, 311 (1908).
[ 5 ] I. U. Nef, Liebigs Ann. Chem. 270, 267 (1892).
[5a] I. U. Nef, Liebigs Ann. Chem. 280, 291 (1894).
[5b] I. U . N e f , Liebigs Ann. Chem. 287, 265 (1895).
[Sc] 1. U. Nef, Liebigs Ann. Chem. 298, 2G2, 368 (1897).
472
Th e development of t h e chemistry of isonitriles has probably
suffered only little delay through the characteristic odor of
volatile isonitriles, which has been described by Hofmann
an d Gautier as “highly specific, almost overpowering”,
“horrible”, an d “extremely distressing”. It is true t h at many
potential workers in this field have been turned away by t he
odor, but this is heavily outweighed by t h e fact t h at isonitriles can be detected even in traces, an d t h at most of t he
routes leading t o t h e formation o f isonitriles were discovered
through the o d o r o f these compounds.
In the early days of isonitrile chemistry, the isonitriles
were formulated as compounds of divalent carbon
As the picture of the chemical bond became more refined,
this was replaced by a semipolar formula and by two
resonance structures [6].
R-NZC
{R-N=C
@a
R-N-CI}
[5d] I. U. Nef, Liebigs Ann. Chem. 309, 126 (1899).
[6] H. Litzdemann and L. Wiegrebe, Ber. dtsch. chem. Ges. 63,
1650 (1930).
[7] D.L. Hammick, R. G. A. New, N . V. Sidgwick, and L. E.
Surtun, J . chem. SOC.(London) 1930, 1876.
L8l N. V . Sidgwick, Chem. Reviews 9, 77 (1931).
[9] R. C. A . N ew an d L. E. Sutton, J. chem. SOC. (London) 1932,
1415.
Aiigrw. Client. ititernat. Edit.
Vol.4 (1965) / Nu. 6
Nevertheless, even modern quantum chemistry does not
oppose the continued use of the classical concept of the
formal divalence of the isonitrile carbon. This picture is
quite convenient, since it comprises the entire chemistry
of the isonitriles, which is ultimately reducible to aeliminations and a-additions [3].
Isonitriles were first prepared by Cautier [I -1 d], by the
reaction of silver cyanide with alkyl iodides; isonitrile
complexes are formed 115-181, from which the isonitriles are liberated by potassium cyanide. This method
gives yields of up to 55 %, based on the silver cyanide [17].
R--I+ [AgCNl
starting inaterials
precursors
}\
,X
R-N=C
‘y
J
a-E~irn.
C R-NZC
a-Add.
s t a b l e products
Apart from the alkylation of the cyanide ion or of hydrogen cyanide ( I ) , the tautomer (2) of which [lo] already
contains formally divalent carbon, reactions in which
0
CEN
H-CsN
+
H-NZC
0)
121
isonitriles are formed always involve the loss of two
monovalent groups or one divalent group from a compound containing formally tetravalent carbon, either by
a-elimination or by redox reactions.
2. The Alkylation of Cyanides
KCN
+ [R-NC.AgIl
4
R-NC
Considerable quantities of alkyl isonitriles are also
formed on decomposing the products of the reaction of
alkyl iodides and copper(1) cyanide [4,16a], whereas
very little isonitrile (about 3 %) is obtained when zinc,
cadmium, and nickel cyanides are treated in a similar
manner [4].
Alkyl isonitriles can be eliminated by heat [20] or by the
action of alkali metal hydroxides [19] or cyanides [4,
16a,21] on the alkylation products of alkali metal or silver
hexacyanoferrates(I1) [l9] or hexacyanocobaltates(II1).
When ethanolic solutions of hydrogen hexacyanoferrate(l1) containing hydrogen cyanide are heated to
120 OC,they yield up to 40 % of ethyl isonitrile [22]. The
partial “esterification” of the hydrogen hexacyanoferrate(I1) is followed by the replacement of isonitrile
ligands by hydrogen cyanide. Similar behavior is observed with hydrogen hexacyanocobaltate(II1) [22-241.
nCzHsOH
H4 [Fe(CN)61
Hydrogen cyanide is tautomeric with the parent compound of the isonitriles, i. e. hydrogen isocyanide [lo].
It reacts with diazomethane to form a mixture of acetonitrile and methyl isonitrile [l I].
CHzNz
+ HCN
+ CH3-CN
+ CH,-NC
+ H4- n [(C2 H s -N C)n Fe(C.N)6.. nl
n HCN
--f
nCzHS-NC
3. The Reaction of Primary Amines
with Dichlorocarbene
Hydrogen cyanide adds onto ethylene, under the action
of a silent electrical discharge, to yield ethyl isonitrile [ 121.
The carbylamine reaction, i. e. the reaction of primary
amines with chloroform [25] and strong bases, such as
ethanolic potassium hydroxide solution [2-2 b, 27-29],
solid alkali metal hydroxide [6,30-341, or potassium
The principal products of nucleophilic attack of the free
ambident cyanide ion [ 131 on alkylating agents, such as
alkyl halides, alkali monoalkyl sulfates, and dialkyl
sulfates, are nitriles. Isonitriles are formed only in small
quantities (< 25 %) [4,5 b, 14-15]:
[I61 E. G. J. Hartley, J. chern. SOC. (London) 109, 1296 (1916).
[16a] E. G. J. Hartley, J. chern. SOC.(London) 1928, 780.
[17] H . L. Jackson and B. C. McKusick, Org. Synth., Coil. Vol.
I V Wiley, New York 1963, p. 438.
[I81 Analogous reactions with halogenosilanes and halogenogermanes: T. A . Bittner, W. H. Knorh, R . V. Lindsey, and W. H .
Sharkey, J. Amer. chern. SOC. 80, 4151 (1958); J. J . McBride,
J.org. Chemistry 24,2029( 1959); D. Seyferth and N . Kahlen, J.org.
Chemistry 25, 809 (1960); A. D. Craig, J. V. Urenovitch, and A. G.
McDiarniid, J. chern. SOC.(London) 1962, 548.
[I91 F. Holzl, W.Hausrr,and M.Eckinaim, Mh.Chern.48,71(1927).
[20] I. Ugi a nd C. Sreinbriickner, Angew. Chern. 71, 386 (1959).
[21] L . Malatesta, Progr. inorg. Chern. I , 283 (1959).
[22] W. Z . Heldt, J. org. Chemistry 26, 3226 (1961).
[23] F. Holzl, T. Meier-Mohar, and F. Viditz, Mh. Chern. 53/54.
237 (1929); F. Holzl and J. Krakoro, ibid. 64, 97 (1934).
[24] F. Holzl, 2. E1ektrochern.angew. physik.Chem.43,319 (1937).
[25] Bromoform [26] and iodoform [27] are less suitable.
[26]T.L.Davisand W.E. Ye/land,J.Arner.chern.Soc.59,1998(1937).
[27] S. Bose, J. Indian chern. SOC. 35, 376 (1958).
[28] M . Pusserini, Gazz. chim. ital. 50 I l , 340 (192C).
[29] M . Passerini a nd G. Banri, Gazz. chirn. ital. 58, 636 (1928).
[30] F. A . Corton and F. Zingales, J. Arner.chern.Soc.83,35 1 (1961).
[31] H . C. Biddte, Liebigs Ann. Chem. 310, 1 (1900).
[32] L . Malatesta, Gazz. chirn. ital. 77, 238 (1947).
[33] P . A. S. Smith and N . W. Knlenda, J. org. Chemistry 23,
1599 (1958).
I341 D. Ross, Doctorate Dissertation, Universitlt Miinchen,
1957; A . Dellinoyer, Diploma Thesis, Universitiit Miinchen, 1959.
R
->(
+ CNo
+ R-CN+
R-NC
The alkylation of complexed or internally complexed
cyanides, on the other hand, occurs preferentially on the
nitrogen.
[lo] K. H . Meyer and H . Hoph Ber. dtsch. chern. Ges. 54, 1709
(1921); A. Dadieu, ibid. 64,358 (1931); L. Reiclietand 0. Strasser,
ibid. 64, 1997 (1931); G. Herzberg, J. chern. Physics8, 847 (1940);
C. R. McCrosky, F. W. Bergstrom, and G. Waitkins, J. Amer.
chern. Soc. 64, 722 (1942); F. Klages and K . Monkemeyer, Chern.
Ber. 83, 501 (1950); W . Briigel, G. Danmiller, and 0. Rotrimel,
Angew. Chern. 68, 440 (1956).
[ I l l A. Peraronerand F. C. Pa/azzo,Gazz.chim.ital.38,102(1908).
[I21 L. Francesconiand A . Ciurlo, Gazz. chim. ital. 53,327(1923);
P. M. AronoviC, N . K . Bel‘skij, and B. M. Michaiiov, Izvest. Akad.
Nauk SSSR, Otdel. khirn. Nauk 1956, 696.
[I31 Review: R . Goinpper. Angew. Chem. 76,412 (1964); Angew.
Chern. intern. Edit. 3, 560 (1964); W. P. Griffith, Quart. Rev. 16,
188 (1962).
[I41 F. Kaufler and C. Pomeranz, Mh. Chern. 22, 492 (1901).
[14a] R. Merckx, J. Verhiilst, and P. Bruvlants, Bull. S O C . chim.
Belgique 42, 177 (1933).
[IS] J. Wade, J. chern. SOC.(London) 81, 1596 (1902).
Angew. Chew. internot. Edit.
1 Vd. 4
(1965)
No. 6
473
t-butoxide [34- 361, has been recommended [84] for the
qualitative detection of primary amines, and was considered for a long time to be the most useful method for
the preparation of isonitriles [36-36f].
In 1897, Nef [5c, 371 interpreted the Hoffmann carbylamine reaction as the addition of dichlorocarbene [38]
to primary amines [39-411, followed by $-elimination
of one molecule of hydrogen chloride and welimination
of another.
K-NH2
CClz
---3
0
R--NH2-CC12
8-Elim
->
-+
R -NH-CHC12
R-N=CHCI
a-Elim
3
R-NC
A similar mechanism is followed in the formation of isonitriles (1 5-43 ”/, yield) by the thermal decomposition of
sodium trichloroacetate in the presence of arylamines,
such as aniline, p-toluidine, or p-anisidine [42],
3Ar-NH2
therefore be possible to prepare them by elimination of
water from N-monosubstituted formamides. However,
Gaufier’s attempts [ 1d] to achieve such dehydrations
did not have the desired result.
R-NH2
- u.n
.-’-
+ HCOOH
- H..,.O
R-NH-CHO
R-NC
+H,O
+H,O
Wegler [44] re-examined this idea in 1938. On treating Nmonosubstituted formamides with thionyl chloride, he found
traces of isonitriles amo n g t h e products. Th e low yields were
probably d u e t o the sensitivity of t h e isonitriles t o acids.
T h e reaction of a formamide with a dehydrating halide in the
presence o f a base was first carried o u t by Hogedorn and
Tonjes during a n attempt to elucidate the constitution of
xanthocillin (3) [45-47]. The starting material was “0,O‘dimethylxanthocillin dihydrate” (4) an d t h e dehydrating
agent used was benzenesulfonyl chloride in pyridine.
+ CC13-COZNa
+ Ar-NC
+ 2Ar -NH2.HCI + NaCl + COz
and possibly also in the reaction of primary amines (nbutylamine, aniline) and carbon tetrachloride with
copper [43].
C H & ~ C H - C - C = C H ~ O C H 3
-
I
t
C N NC
-
2 HlO
C,H,-S02CI. Py
4. a-Eliminations from Formic Acid Derivatives
of Primary Amines
4.1 The Elimination of Water from
N-Monosubstituted Formamides
Considering their hydrolysis products, Gautier [I b-1 d]
suggested that isonitriles might be regarded as formic
acid derivatives of primary amines, and that it should
[351 T . Shingakiand M . Takebayashi, Bull. chem. SOC.(Japan) 63,
617 (1963).
[36] The yields of the carbylamine reaction are: up to 20% with
ethanolic potassium hydroxide solution as the base, up to 45%
with solid alkali, and up to 5 5 7 , with potassium t-butoxide.
Higher yields claimed in the literature ([32,35,36a] inter a/ia),
probably relate to mixtures of isonitriles and primary amines.
[36a] W . Schneidewind, Ber. dtsch. chem. Ges. 21, 1323 (1888).
[36b] H. Rupe and If. Clem, Liebigs Ann. Chern. 436, 184(1924).
[36c] U S . Pat. 2342794 (Febr. 29th, 1944); U.S. Pat. 2347772
(May 2nd, 1944), Celanese Corp., inventor H . Dreyfus.
[36d] D . Samuel, B. Weinraub, and D.Ginsburg, J. org. Chemistry
21, 376 (1956).
[36el H. Feuer, H. Rubinstein, and A. T. Nieisen, J. org. Chemistry
23, 1107 (1958).
[36f] E. Jungermann and F. W . Smith, J. Amer. Oil Chemists’ SOC.
36, 388 (1959).
[37] V. Meyer and P . Jacobson: Lehrbuch der Organiqchen
Chemie. De Gruyter, Leipzip 1922, Vol. I / l , p. 419.
[38] J . Hine, J. Amer. chem. SOC.72, 2438 (1950); W . Y. E . Doering and A. K . Hofmann, ibid. 76, 6162 (1954).
[39] Secondary and tertiary amines add onto dichlorocarbene in a
similar manner, but no dehydrochlorination leading to isonitriles
occurs in these cases [4C,41].
[40] M . Saunders and R. W . Murray, Tetrahedron 6 , 88 (1959)
I I , 1 (1960); M . B. Frankel and H . Feuer, Tetrahedron Letters
1959, No. 7, p. 5; see also 1411 and Section 7.
[41] J . Ploquin, Bull. SOC.chim. France (9,14, 901 (1947).
1421 A. P. Krapcho, J. org. Chemistry 27, 1089 (1962).
[43] G . J. Beichl, I. E. Colwell, and J. G. Miller, Chem. and Ind.
1960, 203.
[44] R. Wegler, personal communication.
474
T h e antibiotic xanthocillin (3), which was discovered 1471 by
Rothe in I948 in cultures of Penicillium notatum Westling
an d Penicillium chrysogenum, is t h e only known naturally
occurring isonitrile. It presumably arises by oxidative dimerization of tyrosine, t h e isonitrile group being formed
from a formylamino group under t h e dehydrating action o f
an energy-rich phosphate [*] (see Section 4.14).
It has also been shown t h at many acylating agents (phosgene
(Section 4.1 l), cyanuric chloride (Section 4.12), benzenesulfonyl chloride an d toluenesulfonyl chloride (Section 4.13),
phosphorus tribromide [48], phosphorus trichloride [48],
phosphorus oxychloride (Section 4.14), phosphorus pentachloride [48], phosphorus pentoxide [48], an d thionyl chloride [48]) eliminate water from N-rnonosubstituted formamides in t h e presence of bases [trialkylarnines an d dialkylarylamines (Section 4.1 I), pyridine (Sections 4.13 an d 4.14),
quinoline (Sections 4.1 1 an d 4.13), potassium carbonate
(Section 4.12), an d potassium t-butoxide (Section 4.14)l.
Particularly suitable combinations for t h e preparation of
isonitriles are phosgene/triethylamine (Section 4.1 I), benzenesulfonyl chloride or toluenesulfonyl chloride/pyridine or
quinoline (Section 4.13), a n d phosphorus oxychloride/
pyridine or potassium t-butoxide (Section 4.14).
The reaction of N-monosubstituted formamides with
acylating agents and bases proceeds in two steps: the
base-catalyzed 0-acylation is followed by the nucleophilic ceelimination of a proton and an acid anion.
19
R-NH-C,
H
Acyl-X
Base
P-Acyl
R-N=C,
H
Base
R-NC
[45] I . Hagedarn and H . Tonjes, Pharmazie 11, 409 (1956).
[45a] 1. Hagedorn and H . Tonjes, Pharmazie 12, 561 (1957).
[46] I. Hagedorn et. a/.,Chem. Ber. 93, 1584 (1960).
[47] W . Rothe, Pharmazie 5, 190 (1950).
[*] Note added in proof: Recent investigations demonstrate a
more complex sequence ofreactions: H. Grisebach and H. Achenbach, Z . Naturforsch.‘2OB, 137 (1965).
[48] I. Ugi and R. Meyr, Chem. Ber. 93, 239 (1960); cf. 1491.
Angew. Chem. internnt. Edit. VoI. 4 (1965) 1 No. 6
The elimination of hydrogen sulfide from N-monosubstituted thioformamides with cyanogen bromide or
picryl chloride in the presence of bases [50] proceeds in
a similar manner.
phosphates) before treatment with phosgene, the reaction finally yields the isonitriles of the corresponding
esters (see Section 4.1 I2 k).
Acyl--C -i HO-A--NH.CHO
-I-
COCIz
Acyl-0-A-NC
4.11 T h e P h o s g e n e M e t h o d
4.111. G e n e r a l
The elimination of water from N-monosubstituted
formamides using phosgene in the presence of tertiary
amines (trimethylamine, triethylamine, tri-n-butylamine,
N,N-dimethylcyclohexylamine,N,N-diethylaniline, pyridine, quinoline) [51] has been found to be convenient,
economical 1523, and very versatile with regard to the
constitution of the starting materials. Most of the isoR-NH-CHO
+ C O C l z t 2R;N
I n a recently developed, preferred variant of the phosgene
method, a fast current of phosgene is, without external
cooling, led into a vigorously stirred solution or suspension
[53] of a n N-alkylformamide or N-arylformamide in triethylamine/methylene chloride, until the refluxing caused by the
heat of t h e reaction [51a] ceases (cf. Section 4.112). T h e
isonitrile is isolated by introducing a m m o n i a into the reaction
mixture, filtering t o remove t h e precipitated a m m o n i u m
chloride, a n d concentrating t h e filtrate in vocuo [51b,54]. T h e
residual c r u d e isonitrile is purified by distillation, recrystallization, reprecipitation, or chromatography. A particularly suitable method for t h e purification of crystalline
isonitriles which a r e thermally unstable is by treating them
(in a homogenizer [55]) with solvents which dissolve t h e
impurities from t h e suspended isonitrile, followed by suction
filtration.
For the preparation of low-boiling (b.p. < 100 “C/760 m m
Hg) isonitriles or of isonitriles which a r e unstable or sensitive towards ammonia, cf. t h e examples given in Section 4.1 12.
A variant of the phosgene method is the “one-step synthesis” of ester isonitriles. Hydroxyalkylformamides or
hydroxyarylformamides react with phosgene (for conditions, see Section 4.1 12e) to form isocyanodialkyl
carbonates or isocyanodiaryl carbonates.
+ 3COC12 + 6R3N
C N - A - 0 - - C O - - 0 - A-NC
+
C
2COz 4-6R3N-HCI
I f hydroxyalkylformamides or hydroxyarylformamides
are reacted with acylating halides (acyl chlorides, chloro[49] I. Ugi and R . M e y r , Angew. Chem. 70, 702 (1958).
[501 German Published Patent Application 1 158499 (Mar.Znd,
1962/Dec. 5th, 1963), Farbenfabriken Bayer AG., inventors. W.
Betz and I . Ugi.
[51] I . Ugi, W . Betz, U.Fetzer, and K . Oferinann, Chem. Ber. 94,
2814 (1961); German Published Patent Application I177 146
(Aug. 3nd, 1960/Sept. 3rd, 1964). inventors: I . Ugi and W. Betz.
[51a] German Patent Application, Farbenfabriken Bayer AG.,
inventors: H. Knripfer, I. Ugi, U . Fetrer, and U.Eholzer.
[51b] German Patent Application, Farbenfabriken Bayer AG.,
inventor: 1. Ugi.
[521 Even for large preparations (10-100 moles), the maximum
time required, including working up, is only 8-15 hours; yields
are up to 97% ; auxiliary materials are cheap.
[531 German Published Patent Application 1158500 (Apr. 6th,
(1962/Dec. 5th, 1963),Farbenfabriken BayerAG., inventor: I. Ugi.
1541 The triethylamine/methylene chloride distilled off can be
used again for similar preparations without prior purification.
I551 For example, “Ultra-Turrax” from Messrs. Janke & Kunkel
KG., Staufen i. Br. (Germany).
Angew. Chem. internut. Edit.
+
C 0 2 t 3 R3N.HCI
As can be seen from Table 1, it is possible with the aid of
the phosgene method to synthesize mono- and polyisonitriles [51-51 b, 53,561 of almost any constitution,
provided that structural elements which destabilize the
isonitrile [58] or which react with phosgene under the
reaction conditions used [59] are avoided.
4.1 12. P r o c e d u r e s [67]
(a) Ethyl Isonitrilc.
-+ R - N C + COz t- 2R;N.HCI
nitriles recorded in the present paper were obtained
by the phosgene method (cf. Table 1).
ZCHO--NH-A--OH
+
1 Vol. 4 (1965) 1 N o . 6
730 g (10.0 moles) of N-ethylformamide, 5.0 I of tri-n-butylamine, a n d 3.0 I of 1,2,4-trichlorobenzene a r e placed in a 10 I
three-necked flask, fitted with a stirrer, a wide gas inlet tube
~
[561 Even the N-isocyanodialkylamines, which cannot bee
obtained by the Hofmann method (see Section 3) [33], have been
prepared by the phosgene method [57].
[57] H . Bredereck e t . a t . , Angew. Chem. 74, 388 (1962); 76, 580
(1964); Angew. Chem. internat. Edit. I, 334 (1962); 3,647 (1964).
[SS] For example, 2,4-dinitrophenyl isonitrile and I ,4-dichloro2,5-diisocyanobenzene cannot be obtained.
[59] p-Amino-, p-carboxy-, and p-aminosulfonylphenyl isonitriles,
which can be prepared by the carbylamine reaction [9,36d1,
cannot be obtained by the phosgene method. Isonitriles are very
reactive towards phosgene [5-5b,61] in the absence of bases 1601.
[60] See also A. A. R . Sayigh and H . Ulrich, J. chem. SOC.(London) 1963, 3146.
1611 I. Ugi and U . Fetzer, Chem. Ber. 94, 1 1 16 (1961).
[62] We are grateful to Frau Dr. D.Lauerer and Prof. M . Pesleimr
for carrying out infrared measurements. Dr. E. Degener, Dr. H .
Eck, Dr. H. Herlinger, Dr. K . W. Schellhamrner, Dr. R . Schroter,
Dr. H. Tarnow, Dr. H . Wilrns, and Dr. W. Zecher kindly supplied
some of the starting materials. We should also like to thank K .
Holstein, H. Howey, U . Kretschmann, B. Luckas, H . Preikschat,
H . Wolf,and Frl. (1. Schliiter for experimental assistance.
[63] The substances are arranged according to the number of
C-, H-, Br-, CI-, F-, N-, 0-, P-, and S-Atoms present. “n.d.”
stands for “non-distillable oil”.
[64] The yields marked “a”-“p” were obtained under reaction
conditions corresponding to procedures 4.1 12 a-p.
[65a] R . Neidlein, Angew. Chem. 76, 440 (1964); Angew. Chem.
internat. Edit. 3, 382 (1964).
[65b] R. Neidlein, Angew. Chem. 76, 500 (1964); Angew. Chem.
internat. Edit. 3, 446 (1964).
[65c] R. Neidlein, Arch. Pharm. 297, 589 (1964).
[66] According to a personal communication from H . Herlinger,
[a]: = -49.5
for (S/-a-phenylethyl isonitrile (from is)-(-I-&phenylethylamine), cf. [36b].
[67] (a) The tertiary amines used must be free from water and
from amines which can undergo acylation. The hydrogen chloride
content of the phosgene should be low. N-Alkylformamides are
generally readily available from primary aliphatic amines and the
calculated quantity of commercial grade 70 to 95 per cent formic
acid, by refluxing in chlorobenzene, toluene, or xylene and removing the water formed with the aid of a water separator. N-Arylformamides are obtained by heating primary arylamines for 2--15
hours at 70 to 105 “C with 2-10 times their weight of 85 to 100
per cent formic acid. The formamides used as starting materials
must contain neither formic acid nor dimethylformamide. Sparingly soluble formamides are suspended and thoroughly stirred
in a homogenizer before the reaction. Suitable drying agents for
isonitrile solutions include anhydrous potassium carbonate or
magnesium sdfate. Bath temperatures higher than 50 “C should
be avoided for the concentration of isonitrile solutions.
(b) With a few exceptions, isonitriles exhibit no appreciable toxicity for mammals(cf. [lal).As has been found in the toxicological
laboratories a t Farbenfabriken Bayer AG., Elberfeld, oral and
subcutaneous doses of 500-5000 mg/kg can be tolerated by mice.
475
Table I . fsonitriles prepared by the phosgene method [62,631
C1-G:
Methyl isonitrile [la,71]
Methylene diisonitrile
[65a, cl
Ethyl isonitrile
Ila,17,711
Ethylene diisonitrile
[36c, 531
Ally1 isonitrile [41
Isopropyl isonitrile
[ l b, 36eI
Ethyl isocyanoacetate
N-Methyl-O-(F-isocyanoethy1)urethane
n-Butyl isonitrile
[26,36el
t-Butyl isonitrile 154,323
2-Furylmethyl isonitrile
1.4-Diisocyanobutane
[36c, 531
Ethyl p-isocyanopropionate
3-Dimethylaminopropyl isonitrile [33]
C,:
Pentachlorophenyl
isonitrile
2,4,6-Tribromophenyl
isonitrile
2.6-Dibromophenyl
isonitrile
2.6-Dichlorophenyl
isonitrile 1741
3,4-DichIorophenyl
isonitrile
3-Nitrophenyl isonitrile
r271
4- Nit rop hen yl isoni tri le
~271
Fhenyl isonitrile [2a, 511
Di-(2-isocyano- I -ethyl)carbonate
Cyclohexyl isonitrile
[34,51.73]
Methyl n-isocyanoisovalerate [51]
t-Butyl isocyanoacetate
~ 1 1
2-Pyrrolidinoethyl
isonitrile
N-Methyl-0-(2-methyl2-isocyano-lpropy1)urethane
-
-
25-30/150
n. d.
-
32-35/120
-.
65-6810.005
_.
-
-
82 -L3/750
-
76-7814
38-39
-
-
40-42/1 I
-
92-93/750
-
35- 37/0.02
70-75/0.00 1
-
39-40/0.001
-
32-36/0.003
188-191
-
113-115
-
208.- 209
-
98-100
-
32-33
-
97-99
-
119-120
-
-
50-51/11
56-59
-
-
57-72/ I3
-
37-38/15
-
38-40/0.1
-
16-48/0.02
63-65
-
63-65
-
188-189
decomp.
i.
d.
134- I36
92-93
1. d.
106- I07
1,4-Diisocyanobenzene
19,531
100
decomp.
4-Cyanophenyl isonitrile
I30
decomp.
476
117-118
-
34-35
-
129-1 30/0.01
95-96
.-
-
105/110/0.2
67-68/0.15
46-41
S8-60/0.005
95-97
-
75-76
-
103-104
78-80
-
81--56
-
75-77
-
158- 160
-
97-98
-
103-105
-
-
92-93/1 I
2- Methylphenyl
isonitrile 15,731
-
36-3810.6
4-Methylphenyl
isonitrile [2a, 51
4-Methylsulfonylphenyl
isonitrile
Tricyclo[2.2.1 .OZ-6]-2heptyl isonitrile
1,3-Diisocyanocyclohexane
1,4-Diisocyanocyclohexane I531
1-Cyanocyclohexyl
isonitrile
I ,2,3,6-Tetrahydrobenzyl isonitrile
1,6-Diisocyanohexane
[36c, 531
-
70-72/8
90-93
-
-
56-58/1
106-107
115-1 16/13
108-109
110- 115/0.1
36-38
-
-
48--50/0.01
-
92-94/0.003
-
40-42/0.004
3-Diethylaminopropyl
isonitrile [331
Cg:
Cg:
1.3-Diisocyanotetrachlorobenzene 1531
1.4-Diisocyanotetrachlorobenzene [53]
2-Trifluoromethyl-4chlorophenyl isonitrile
2,4,6-TrichlorobenzyI
isonitrile
2-Methoxy-3,5,6-trichlorophenyl isonitrile
1,2-Diisocyanobenzene
1531
I , 3-Diisocyanobenzene
[531
5-Chloro-2-methoxy-4nitrophenyl isonitrils
2,6-Dichlorobenzyl
isonitrile
3,4-DichIorobenzyl
isonitrile
4,5-Dichloro-2-methoxy
phenyl isonitrile
4-Chlorobenzyl isonitril
3-Chloro-Zmethylphenyl isonitrile
4-Chloro-3-methylphew1 isonitrile
4-Chloro-2-methoxyphenyl isonitrile
5-Chloro-2-methoxyphenyl isonitrile
4-Nitrobenzyl isonitrile
2-Methyl-5-nitrophenyl
isonitrile
2-Methyl-6-nitrophenyl
isonitrile
4-Methyl-3-nitrophenyl
isonitrile
2-Methoxy-Cnitrophenyl isonitrile
4-Methoxy-2-nitrophenyl isonitrile
2- Methoxy-5-nitrophenyl isonitrile
Benzyl isonitrile [32,36a
-
2,4-Diisocyano-2,5,6trichlorotoluene 1531
2-(Pentachlorophenylthio)ethyl isonitrile
2,4-Diisocyanotoluene
[531
2,6-Diisocyanotoluene
[531
2,5-Diisocyanotoluene
[531
2- Methoxycarbonyl-5nitrophenyl isonitrile
3-Acetylphenyl isonitrile
4-Chloro-2-methoxy-5methylphenyl
isonitrile
5-ChIoro-2,4-dimethoxy
phenyl isonitrile
4-Chloro-2,5-dimethoxy
phenyl isonitrile
I -(4-Fluorophenyl)ethy 1
isonitrile
i.4-Dimethyl-5-nitrophenyl isonitrile
112-116
113-114
88-89
84-86
154-155
68-70
45-49
93-94
109-1 10
150- 151
77--7L
Angew. Chem. internnt. Edit. 1 Vol. 4 (1965)
/ Nc. 6
Table 1 (continued)
Compound I631
M.p.
2,4-Dimethyl-6-nitrophenyl isonitrile
2-Methoxy-5-niethyl-4nitrophenyl isonitrile
2,5-Dimethoxy-4-nitrophenyl isonitrile
2-Chloro-4-(dirnethylaminosulfony1)phenyl
isonitrile
a-Phenylethyl
isonitrile [661
2.3-Dimethylphen yl
isonitrile
2,4-Dimethylphenyl
isonitrile
2,5-Dirnethylphenyl
isonitrile 1701
2,6-DimethyIphenyl
isonitrile
4-Methoxybenzyl
isonitrile
4- Methoxy-2-methylphenyl isonitrile
2,4-Dimethoxyphenyl
isonitrile
2,5-Dimethoxyphenyl
isonitrile
2-Phenylthioethyl
isonitrile
1,2,3,b-Tetrahydro-3,6methanobenzyl
isonitrile
I ,2,3,6-Tetrahydro-5methylbenzyl isonitrile
2-lsocyano-2-methylpropyl rnethacrylate
N,N-Eiis-(3-isocyanopropy1)-N-methylarnine
2,4,4-Trimethylpentyl
isonitrile 1511
Diethyl 2-isocyano-2methylpropyl
thionophosphate
clo:
I ,4-Bis(isocyanornethyl).
tetrachlorobenzene
8-Isocyanoquinoline
1,3-Diisocyano-4,6dimethylbenzene
p-Ethoxycarbonylphenyl
isonitrile
6-Nitro-2,4,5-trirnethylphenyl isonitrile
2-Phenyl-2-propyl
isonitrile
2,3,5-Trimethylphenyl
isonitrile
2,4,5-TrimethylphenyI
isonitrile
5-Ethylsulfonyl-2methoxyphenyl
isonitrile
4-Dimethylaminobenzyl
isonitrile
Ethyl a-isocyanoisovaleroylglycinate
1,6-Diisocyano-3dirnethylaminohexane
I -Diethylarnino-4-pentyl
isocitrile
50-52
I "C]
B.p. ["Cjmm]
[631
135-136
134- I37
98-101
-
50-54/0.001
-
62-6310.01
-
55-5610.03
-
56-5810.01
72-73
70-7510.3
-
90-95jO.05
-
68-69/0.000 I
67-68
-
64-65
-
-
85-9OjO.00 1
-
36-40/0.008
-
56-58/0.04
Angew. Chem. internot. Edit.
6-Isocyano-3methylquinoline
5,6,7,8-Tetrahydro- 1naphthyl isonitrile
2.5-Diethoxy-4-nitrophenyl isonitrile
2- Methyl-2-phenylpropyl isonitrile
I -(4-Tolyl)propyl
isonitrile
2,6-Diethylphenyl
isonitrile
2,4-Dimethyl&ethylphenyl isonitrile
Di-(2-methyl-Z-isocyanopropyl)
carbonate 1531
1 -(8-Isocyanoethyl)-3,6ethano-hexahydroazepine
Yield
1641
[%I
M.p.
[ T I
B.p. [ "C/mml
1631
114-1 15
-
-
119-12310.02
I40
decornp.
-
-
68-75/0.05
-
70-7310.00 1
-
70-72/0.40
-
72-74/0.002
114-115
120- I25j0.00 I
-
104- 10610. I
c12:
-
88-9210.02
-
131--13410.2
-
45-5013
-
70-75/0.004
1,4-Diisocyanonaphthalene 1531
1,s-Diisocyanonaphthalene 1531
2,FDiisocyanonaphthalene
-5-Cyano- I-naphthyl
isonitrile
N-(3,4-DichlorophenyI)0-(2-isocyano-2methy1propyl)urethane
4,6-dirnethylbenzene
I.3-Di(isocyanomethyl)4.6-dimethyl benzene
I ,3-Diisocyano-5-isoProPyl2-methylbenzene
1 ,4-Diisocyanodurene
2.6-Diet hyl-4isocyanotoluene
Tris-(3-isocyanopropy1)amine
110-1 12
150
decomp.
142- 144
150
decornp.
122-125
68-69
70-75
127- 128
-
-
72-74/0.002
-
n. d.
c13:
-
170
decomp.
69-70
105- 107
-
95-103
-
120- 126
-
-
62--6410.003
-
77-7910.04
29-31
77-80/0.05
108-109
-
-
40-4 1
-
n. d.
-
110--115/0.003
-
58-60/0. I
ci1:
2,CDichloro- I-naphthyl
ironitrile
4-Bromo- I-naphthyl
isonitrile
I-Naphthyl isonitrile 127
2-Naphthyl isonitrile[271
Compound [631
95-98
88-118
decomp.
-
59-60
VoI. 4(1965)
90-9510.005
100- 102/1
No. 6
2-Isocyano-2',4,4,5,5'pentachlorodiphenyl
ether
2-Phenoxy-3,5-dichIorophenyl isonitrile
3-Isocyanodibenzofuran
4-Isocyanodibenzofuran
5-Isocyano-2-phenylbenzotriazole
2-lsocyanobiphenyl
5-lsocyanoacenaphthene
4-lsocyanoazobenzene
(281
2-Isocyanodiphenyl
sulfide
2-Isocyanodiphenyl
sulfone
2-Ethoxy- I-naphthyl
isonitrile
5-Chloro-2,4-diethyl- I , 3diisocyano-6methylbenzene
2,4-Diethyl-l,3-diisocyano-6-methylbenzene [531
4-Cyclohexylphenyl
isonitrile
2.4-Diisopropyl-5-nitrophenyl isonitrile
3- Methyl- l-(4-tolyl)butyl isonitrile
2,4-Diisopropylphenyl
isonitrile
2,6-DiisopropylphenyI
isonitrile
63-64
120
decomp.
113-114
114-116
157- 159
116-118
70-72
102- I04
70
decomp.
78-80
50-62
-
-
108-1 1010.5
-
33-9SjO.005
70-71
-
-
38-100/0.02
-
7 1-72/0.02
-
34-9610.7
477
Table 1 (continued)
Compound 1631
n-Dodecyl isonitrile
[36f,68,721
Yield [ %]
"541
M.p. [ " C ]
-
C14:
1,3-Diisocyano-4-(penra
chloropheny1thio)benzene
4,V-Diisocyano2,2',5,5'-tetrachloroazoxybenzene
4,4'-Diisocyano2,2',6,6'-tetrachloroazoxybenzene
3,3'-Dichloro-4,4-diisocyanobiphenyl
6,6-Dichloro-3,3'-diisocyanoazobenzene
2',4'-Dichloro-2,4-diisocyanodiphenyl ether
3,3'-Dichloro-4,4-diisocyanoazoxybenzene
2-endo-(p-lsocyanophenyl). 1,4,5,6,7,7.
hexachlorobicyclot2.2.1 Ihept-5-ene
V-Chlor0-2,4-diisocyanodiphenyl ether
2,4,5-Trichlorobenzhydryl isonitrile
2,2'-Diisocyanobiphenyl
2,4'-Diisocyanobiphenyl
4,4'-DiisocyanobiphenyI
4,4'-Diisocyanoazobenzene
4,4'-Diisocyanodiphenylether
3,3'-Diisocyanoazoxybenzene
4,V-Diisocyanodiphenyl
sulfone
4,4'-Dichlorobenzhydry I
isonitrile
2-Isocyanoliuorene
4-lsocyanobenzophenon~
4-Isocyano-3-methoxydibenzofuran
Benzhydryl isonitrile
2-Isocyano-2'-methyldiphenyl ether
l-lsocyano-4'-methyldiphenyl sulfide
3-Isocyano-4-methoxydiphenyl sulfone
1,6,1 I-Triisocyanoundecane
160
decomp
I I6
decornp.
I54
decomp.
300
decomp.
152
decomp.
102
decomp.
132
decomp.
167-168
110
decomp.
63-64
101-I04
97-98
183-186
195
decomp.
136-1 37
96- 100
9 300
decomp.
73-74
58-59
79-84
172-173
35-36
37-40
3,3'-Dichloro-4,4'-diisocyanodiphenylmethane
4.4'-Diisocyanobenzophenone
4,V-Diisocyanodipheny 1
carbonate
2-(4-Isocyanophenyl)3,4-benzothiophene
1,l-dioxide
4.4'-Diisocyanodiphenylmethane [53]
2-(4-Isocyanophenyl)-6 methylbenzothiophene
l-PhenyI-2-(2,5-dich1orophenylthio)ethyl isonitrile
478
Compound [63]
M.p. ["C]
1-Phenyl-2-(3,4-di-
-
chloropheny1thio)ethyl isonitrile
1 -(4-Chlorophenyl)-2phenylethyl isonitrile
2-(4-Chlorophenylthio)I-phenylethyl
isonitrile
I -Isocyano-l,2diphenylethane
1-(4-Biphenylyl)ethyI
isonitrile
2',3-Dimethyl-4-isocyanoazobenzene
I-Phenyl-2-phenylthioethyl isonitrile
5-Benzylsulfonyl-2methoxyphenyl
isonitrile
B.P. I"C/rnm]
1631
68-69
-.
29-30
45-46
115-- I 1 8
156-157
c16:
I ,4,5,6,7,7-Hexachlorob1cyclo-[2.2. Ilhept-5ene-endo-dicarboxyh c
N-(p-isocyanophen yl)imide
2,2'.4,4'-Tetraisocyanobiphenyl
1.5-Diisocyanoanthraquinone I531
7-lsocyano-3-phenylcoumarine
3,3'-Dimethyl-4,4'diisocyanobiphenyl
4,4'-Diisocyano-3,3'dimethoxybiphenyl
3,3'-Diisocyano-4,4'-dimethylazoxybenzene
N-Ethyl-N-(p-isocyanobenzoy1)-aniline
4,4-Dimethoxybenzhydryl isonitrile
1-Phenyl-2-(2-tolylthio)ethyl isonitrile
1-Phenyl-2-(3-tolylthio)ethyl isonitrile
I -Phenyl-2-(4-tolylthio)ethyl isonitrile
> 260
decornp.
> 120
90-92
100
decomp.
147-149
240-243
,130
decomp.
72-14
127-128
-
-
c17:
68-71
115-116
-
CIS:
2.4.4-Triisocyanobiphenyl
2,4,4'-Triisocyanodiphenyl ether
I -1socyanoanthraquinone
B.p. [ "C/mml
[631
200
decornp.
110
decomp.
170
decomp.
116-118
120
deco m p.
107-128
162-163
131-133
175-176
-
4-(B-Naphthoxy)phenyI
isonitrile
4-(P-Naphthylthio)phenyl isonitrile
78-80
3,3'-Dichloro-4,4'-diiso-
208
decomp.
cyano-5,s-dimethyldiphenylmethane
3,3'-Diisocyano-4,4'dimethoxydiphenyl
carbonate [531
4,4-Diisocyano-3,3'-dimethyldiphenylmethane
5,7-Dimethyl-2-(4-iso cyano-3-toly1)benzothiazole
2,6-Diethyl-4-isocyano4'-nitroazobenzene
I ,3-Diisocyano-2,4,6-triisopropylbenzene [531
2,6-Di-t-butyl-4-(P-iso cyanoethy1)-phenol
cls--czO:
3,3'-Diethoxy-4,4'-diiso cyano bj phen yl15 3I
4,4'-Diisocyano3,3',5,5'-tetrarnethyldiphenyl sulfide
3,3'-Diethyl-4,4'-diisocyanodiphenylmethane
113-114
128-1 30
87-89
129-130
133- 136
59-61
114
decomp.
140-142
185-186
83--b4
Angew. Chem. internat. Edit.
1 Vol. 4 (1965) I No. 6
Table 1 (continued)
Compound 1631
1
4.4'-Diisocyano3,3',5,5'-tetramethyIdiphenylmethane 153 I
4-Lauroylphenyl
isonitrile
N-Benzyl-N-n-hutylN,N-di-(3-isocyanopropy1)ammonium
chloride
4-n-Dodecylphenyl
isonit rile
4-n-Dodecyloxyphenyl
isonitrile
n-Octadecyl isonitrile
[36a, 36c, 36e,681
5,5'-Diethyl-4,4'-diisocyano-3,3'-dimethyldiphenyl sulfide
N-n-Dodecyl-3-iso
cyanobenzamide
N,N-Di-(3-isocyanopropy1)-N-n-dodecylamine
C21-C33:
Tri-(4-isocyanophenyl)
thionophosphate
I-(4'-Chloro-4-biphenylyl)-2-(4-~hlorophenyl)ethyl isonitrile
2-(3,4-Dichlorophenylthio). 1-(4-biphenylyl)ethyl isonitrile
I -(4-Biphenyly1)-2phenylethyl isonitrile
4,4'-Diisocyano-3,3'-diisopropyldiphenylmethane
5,5''-Diethy1-4,4'-diisocyano-3,3'-dimethyldiphenylmethane 1531
2-(n-Dodecylthio)-lphenylethyl isonitrile
I,l-Bis-(4-isocyano-3methylpheny1)cyclohexane
4,4'-Diisocyano3,3',5, S-tetraethyldiphenyl sulfide
4,4'-Diisocyano3,3',5,5'-tetraethyldiphenylmethane I531
N,N'-Bis-(3-isocyano-4methylphenoxycarbony1)-I .6-diaminohexane
4,4'-Diisocyano2,2'.5,5'-tetramethyltriphenyl methane
2-Methoxy-S-(N-methylN-n-octadecyl aminosulfony1)phenyl
isonitrile
N-Benzyl-N,N-di-(3-isocyanopropy1)-N-noctadecylammonium
chloride
Yield 1%I
I641
M.p. [ "C]
B.p. 1"Cjmm]
I631
-
72 (0)
190
decornp.
85 (i)
37-43
-
84 (0)
-
n. d
55 (i)
39-55
72 (i)
29--34
9 5 (h)
-
6 6 (0)
81-82
54 (i)
62-76
decomp.
71 (0)
-
13 (n)
120-122
89 (i)
116- 118
9 2 (i)
74-15
31 (i)
102-103
4 5 (n)
102-106
9 0 (0)
68 (n)
128- 130
80 (0)
142
decomp.
7 2 (0)
69-7 I
71 (0)
47 (n)
98-99
4 2 (h)
115-119
5 5 (0)
102
decomp.
4 4 (i)
1 12- 120
decom p .
8 6 (m)
(c, d ) t-Butyl Isonitvile
(c) 1.00 kg (10.1 moles) of phosgene is led into a stirred
solution of 1.01 kg (10.0 moles) of N-t-butylformamide i n
1.30 kg of trimethylamine and 7.0 I of o-dichlorobenzene.
The heat of the reaction is dissipated with the aid of a reflux
condenser carrying cooling brine (-20 "C). Water is added,
the layers are separated, and the non-aqueous layer is dried
over anhydrous potassium carbonate or magnesium sulfate
and fractionated; b.p. 90-92"C/750 mm Hg, yield: 681 g
(82 %)(d) 1.00 kg (10.1 moles) of phosgene is added t o 1.01 kg
(10.0 moles) of t-butylformamide in 5.4 I of tri-n-butylamine
and 2.5 I of 1,2,4-trichlorobenzene at 10-20°C (cf. Section
4.112a). After the introduction of SO g of ammonia, the
reaction product is distilled at 120-150 mm Hg (bath
temperature 80-85 "C) and purified by fractionation, yield:
648 g (78 %).
(dl) If the product of a preparation according to 4.1 12d is
isolated by steam distillation, the yield is 413 g (SO %,).
(dz) If the tri-n-butylamine of 4.1 12 d is replaced by 3.50 kg of
N,N-diethylaniline, the yield of t-butylisonitrile is 582 g (70 ",)
(d3) If the tri-n-butylamine of 4.112d is replaced by 3.00 kg
of quinoline, the yield is 222 g (24 %,).
( e ) Di-(2-isocyanoethyl) Carbonate
300 g (3.03 moles) of phosgene is led into a boiling solution
of 178 g (2.00 moles) of 2-formylaminoethanol (prepared
from 2-aminoethanol and methyl formate) in 1.00 1 of
triethylamine and 1.50 1 of methylene chloride. The solution
is then cooled t o 20 "C, 110 g of ammonia is introduced,
and the mixture is filtered and concentrated. The residue
solidifies o n standing; m.p. 58-6OoC, yield: 145 g (86
x).
To prepare diisocyanodiaryl carbonates by a similar method,
it is recommended that the reaction mixture is worked up in
analogy t o the procedure given in Section 4.1 1211.
-
( f ) Cyclohexyl Isonitrile
Data regarding the fungicidal, acaricidal, and insecticidal properties of isonitriles are reported in Belg. Pat. 641 379 (June 12th,
1964; German priority: Dec. 17th, 1962), Farbenfabriken Bayer
AG., inventors: I. Ugi, U . Fetzer, F. Grewe, W. Behrenz, P. E.
Frohberger, B. Homeyer, H . Scheinpflug, and G . Unterstenhoyer;
Spanish Pats. 294587 and 294588 (Febr. 7th, 1964; German
priority: Dec. 17th, 1962) and Belg. Pats. 641309 and 641 31 I
(June 12th, 1964; German priority: Dec. 17th, 1962), Farbenfabriken Bayer AG., inventors: U . Fetzer, I. Ugi, G . Unrerstenhofer, W. Behrenz, P. E. Frohberger, and H . Scheinpflug; cf. also
168,741.
[68] U.S. Pat. 3012932 (Dec. 12th, 1961), Standard Oil of
Indiana, inventor: F. Busserr.
Angew. Chem. internat. Edit.
( b ) Ethyl Isocyanoacetate
105g(I.O6mole) of phosgene dissolved in 900 ml of methylene
chloride is added dropwise to a refluxing solution of 131 g
(1.00 mole) of the ethyl ester of formylglycine in 320 ml of
triethylamine and 500 ml of methylene chloride. The reaction
mixture is concentrated in v~zcuuand 200 ml of benzene is
added. The mixture is then filtered, concentrated once more,
and distilled in vncuo; b.p. 76-78 OC/4 mm Hg, yield: 87 g
(77 %)-
__
84 (i)
dipping deeply into the liquid, and a wide gas outlet. The
flask is cooled and stirred, and 1.00 kg (10.1 moles) of
phosgene is led in at 20-30°C over a period of 3-4 h,
followed 1 hour later by 100 g of ammonia. The rezction
product is distilled in vucuu (about 150 mm Hg) at 30-50 "C
and collected in traps cooled by dry ice. The crude product
(430 g) is distilled through a helix-packed column with reflux
control; b.p. 32-35 'C/120 mm Hg, yield: 358 g (65 %,).
1 Vol. 4(1965)
No. 6
1.27 kg (10.0 moles) of N-cyclohexylformamide, 3.20 I of
triethylamine, and 4.50 I of methylene chloride are placed
in the reaction vessel. The solution is stirred, and phosgene
is led in sufficiently rapidly (300-400 g/h) t o cause vigorous
refluxing.When the solution ceases t o boil (after about 1.04 kg
of phosgene has been introduced), the introduction of
phosgene is immediately stopped and the solution is cooled
to about 20'C. About 400 g of ammonia is led into the
solution over a period of 1-2 hours, and the mixture is
filtered and then concentrated in vncuo. The residue is
distilled; b.p. 67-72'C/14 mm Hg, yield: 955 g (88
x).
479
(9) t- Butyl Isocyanoaretato
100 g (1.01 mole) of phosgene is led into a boiling, stirred
solution of 159 g (1.00 mole) of the t-butyl ester of formylglycine I511 in 400 ml of triethylamine and 400 ml of methylene chloride over a period of one hour. The solution is cooled
in ice, saturated with ammonia (55 g in 50 min), and filtered.
'The residue is washed with methylene chloride, the solution
IS concentrated in vucuo, and the crude product is purified by
distillation in vncuo; b.p. 52-58 OCI0.3 mm Hg, yield: 106 g
(75 %I.
(h) p-Nitrobenzyl Isonitrile
36 g (0.364 mole) of phosgene dissolved in 300 ml of methylene chloride is added to a boiling solution of 60.0 g (0.333
moles) of N-formyl-p-nitrobenzylamine in 110 ml of triethylamine and 400 ml of methylene chloride. The solvent is
distilled off in vncuo, and the residue is taken up in 100 ml of
benzene. The resulting solution is concentrated, filtered, and
washed with cyclohexane; m.p. 103-104"C, yield: 45.3 g
(84 %I.
(i) p-Methylsulfonylphenyl Isonitrile
796 g (4.00 moles) of p-methylsulfonylformanilide, 1.30 1 of
triethylamine, and 3.0 of methylene chloride are placed in
the reaction vessel. 415 g (4.20 moles) of phosgene are led in
without external cooling. The solution is saturated with
ammonia at about 20"C, filtered, and Concentrated. The
residue is mixed with ether/isopropanol (1 : 3), stirred in a
homogenizer, and filtered; m.p. 88-89 OC, yield: 613 g (85 %).
(j) cc-PhenylethylIsonitrile
99 g (1 .OO mole) of phosgene is led into an ice-cooled, stirred
solution of 147 g (1.00 mole) of N-formyl-cc-phenylethylamine in 350 ml of triethylamine and 1.0 1 of methylene
chloride. Water is added, the layers are separated, and the
non-aqueous layer is dried and distilled in vncuo; b.p.
41-45 oC/O.OOl mm Hg, yield: 112 g (87 %,).
(k) 2-Methyl-2-isocyanopropyl Methacrylate
314 g (3.00 moles) of methacryloyl chloride is added to a
boiling solution of 351 g (3.00 moles) of 2-methyl-2-formylaminopropanoi and a spot of phenothiazine in 1.50 1 of
triethylamine and 2.50 1 of methylene chloride. 300 g of
phosgene is then passed into the solution. Ice water is
added ; the non-aqueous layer is separated, washed with
sodium bicarbonate solution, dried, and concentrated in
vucuo. The crude product (498 g) can be purified in portions
by distillation in vacuu; b.p. 65-7O0C/0.O08 mm Hg, yield:
I87 g (37 %).
the filtrate concentrated. The residue is stirred in isopropanol,
filtered, and washed with ether; m.p. 142-144"C, yield:
82 g (93 :<).
(n) 4-Isocyanoazobenzene
225 g (1.0 mole) of 4-formylaminoazobenzene, 320 ml of
triethylamine, and 2.50 1 of methylene chloride are placed in
the reaction vessel. The mixture is cooled in ice and stirred,
and 100 g (1.01 mole) of phosgene is led in. After one hour,
water is added, the layers is separated, and the nonaqueous layer is dried and distilled in vucuo. The residue is
washed with light petroleum; m.p. 102-104"C, yield: 151 g
(73 %).
(0)
4,4'-Diisocyanodiphenylmethane
254 g (1.00 mole) of 4,4'-diformylaminodiphenyimethane
is suspended in 650 ml of triethylamine and 1.0 1 of methylene chloride, and thoroughly mixed in a homogenizer. The
suspension is stirred and 200 g (2.02 moles) of phosgene is
led in, whereupon the reaction mixture refluxes owing t o the
heat of the reaction. The mixture is saturated with ammonia
at 20 OC, and the precipitated ammonium chloride is filtered
off and washed with methylene chloride. The filtrate is
concentrated in vucuo and the residue (219 g) is mixed with
150 ml of ether and 8 ml of isopropanol, stirred at 0 "C in a
homogenizer, and separated by suction filtration ; m.p.
131-133°C, yield: 181 g (83 %,).
(p) N, N-Di-(3-isocyanopropyl)-n-dodecyfamine
200 g (2.02 moles) of phosgene is led into a stirred, boiling
solution of 355 g (1.00 mole) of N,N-di-(3-formylaminopropyl)-n-dodecylamine, 650 ml of triethylamine, and 1.50 I
of methylene chloride. The solution is saturated with ammonia a t 20 OC, filtered, and concentrated. Steam is passed
through the residue for a short time (about 5 min) to remove
volatile impurities (mainly 3-chloropropyl isonitrile). Dark
resins are removed by making use of their insolubility in
ether. Concentration of the dried ether solution yields 218 g
(71 %,)of a light brown oil which cannot be distilled without
decomposition.
4.12 C y a n u r i c C h l o r i d e a s t h e D e h y d r a t i n g
Agent
The reaction of N-monosubstituted formamides with
cyanuric chloride ( 5) and potassium carbonate in acetone has only been used for the preparation of a few
simple isonitriles (n-butyl isonitrile, cyclohexyl isonitrile,
(1) N,N-Di-(3-isocyanopropyl)-methylamine
1.02 kg (1.03 mole) of phosgene is led into a stirred, boiling
solution of 1.015 kg (5.00 moles) of N,N-di-(3-formylaminopropy1)methylamine in 3.20 1 of triethylamine and 5.00 1 of
methylene chloride. The solution is saturated with ammonia
at 20"C, filtered, and concentrated. The residue (730 g) is
purified by molecular distillation; b.p. 131-1 34 'C/0.25 mm
Hg, yield: 445 g (54 %).
benzyl isonitrile) [69]. It may be a particularly mild
method in special cases.
4.13. T h e S u l f o c h l o r i d e M e t h o d
(m) 2,7-Diisocyanonaphthalrnc
107 g (0.50 mole) of 2,7 - diformylaminonaphthalene is
suspended in 320 mi of triethylamine and 1.20 1 of methylene
chloride, and thoroughly mixed in a homogenizer. 100 g
(1.01 mole) of phosgene is led into the boiling suspension,
followed by 35 g of ammonia. The suspension is filtered and
480
Benzenesulfonyl chloride and toluenesulfonyl chloride
in pyridine [45a, 701 are relatively mild dehydrating
[69] R . Wittmann, Angew. Chem. 73, 219 (1961).
1701 W. R . Hertler and E. J. Corey, J. org. Chemistry 23, 1221
(1958).
Angew. Chem. internat. Edit. / Vol. 4 (1965)
/
Nc. 6
agents, and are particularly suitable for the preparation
of small quantities of isonitriles.
R -NHCHO
+ Ar-SOzCI
12Py
+
R-NC
f
Py.ArSOxH
+ Py.HCI
Quinoline is a useful base and solvent for the preparation of low-boiling, aliphatic isonitriles, since its high
boiling point facilitates the isolation of the reaction
product [71] by distillation.
T h e phosphorus oxychloride method c a n also b e used for the
dehydration of N-formylhydrazones to f o r m isocyanamide
derivatives [77], a n d for t h e preparation of aliphatic @-0x0-,
6-hydroxy-, and $-chloro-isonitriles. a,P-Unsaturated isonitriles are accessible by dehydrochlorination of 3-chloroisonitriles [77,78]. T h e last steps in t h e recent synthesis
[77,79] of 0,O'-dimethylxanthocillin ( 6 ) (cf. Section 4.1)
correspond t o this type of reaction.
O H C - NH
Some examples of preparations by the sulfochloride
method are described in references [45 a, 70-723.
2 . I2
O H C- N H N H - CH O
(41
4.14 T h e P h o s p h o r u s O x y c h l o r i d e M e t h o d
The synthesis of isonitriles from N-monosubstituted
formamides using phosphorus oxychloride as the dehydrating agent requires more work and material than
when phosgene is used. This may be important in the
preparation of large quantities of isonitriles. Moreover,
the phosgene method generally gives higher yields.
Nevertheless, in laboratories where safety provisions are
inadequate for safe handling of the extremely poisonous,
volatile phosgene, the choice must fall on phosphorus
oxychloride, or even on a sulfochloride, as the dehydrating agent.
Aliphatic or araliphatic isonitriles can be prepared from
the corresponding formamide simply by a combination
of phosphorus oxychloride and pyridine [48,49,73,73a].
2 R - -N H C H O
+ POCI3 + 4Py
+
2 R-NC
+ Py'HPO, + 3Py.HCI
OHC-NH NH-CHO
POCL,
PY
T h e synthesis of 2-cyclohexenyl isonitrile (7) (57 "/, yield
[SO]) from N-( 1 -cyanocyclohexyl)formamide (8) represents
another variant of t h e phosphorus oxychloride method.
nCN
This method gives 58-95 % yields of aliphatic isonitriles
but only 7-54% of aromatic isonitriles [48,74].
The elimination of water from N-arylformamides by
phosphorus oxychloride proceeds satisfactorily, however, if potassium t-butoxide is used as the base. The
reason for this is probably that the anion formed from
N-arylformamides by the t-butoxide [75] is more readily
0-acylated by phosphorus oxychloride than the starting
material itself.
2[R-N - C H
O]OK"
--f
+ POCI3 + 2(CH,),COK
2RNC
+ K P 0 3 + 3 KCI + 2(CH3)3COH
It is possible in this way t o prepare mono- a n d diisonitriles
in 56-88
yield (48,761.
[71] J . Casanova, E. R . Schrrster, and N . D . Werner, J. chern. SOC.
(London) 1963, 4280.
[72] M . Lipp, F. Dallncker, and I . Meier zu Kocker, Mh. Chern.
90, 41 (1959).
1731 I. Ugi, R . M e y r , M . Lipinski,F. Badesheim. and F. K . Rosendahl, Org. Syntheses 4 1 , 13 (1961).
[73a] F. Lurrtenschliiger and G. F. Wright, Canad. J. Chem. 41,
863 (1963).
[741 Belgian Published Patent Application 625036 (Nov. I9th,
I962/May 20th, 1963), Philips' Gloeilampenfabrieken.
[751 1. Hine and M . Hine, J. Amer. chern. SOL 74, 5266 (1952).
(761 I. Ugi and R. Meyr, Org. Syntheses 4 / , 101 (1961).
Angew. C h e m . internat.
Edit. / Vol. 4(1965) / N o . 6
f7)
4.2. The Thermolysis of
N,N'-Diar yl-N-hydroxyformamides
In the course of his investigations on cycloadditions,
Ingold observed that nitrosobenzene and p-chloronitrosobenzene form stable adducts with N-methyleneaniline
or its p-bromo, p-chloro, or p-methyl derivatives [81].
These adducts were found to be N,N'-diaryl- N-hydroxyformamidines (9), instead of the expected 1,4-diaryl[77] I. Hagedorn, Angew. Chem. 75, 305 (1963).
[78] I. Hagedorn and H . Elting, Angew. Chem. 73, 26 (1961).
[79] I . Hagedorn and U . Eholzer, Angew. Chem. 7 4 , 215 (1962);
Angew. Chem. internat. Edit. 1 , 514 (1962); German Published
Patent Application 1167332 (July 6th, 1961/Apr. 9th, 1964),
Farbenfabriken Bayer AG., inventors: I. Hagedorn and H . Etling;
I. Hagedorn, (1. Eholzer, and H . Etling, Chem. Ber. 98, 193 (1965).
I. Hagedorn and U . Eholzer, ibid. 98, 202 (1965).
[80]I. Ugi and F. K . Rosendahl, Liebigs Ann. Chem. 666, 65
(1963).
[8 1 I C . K . Ingold, J. chern. SOC.(London) 125, 87 (1924).
48 1
I ,2,4-oxadiazetidines [82]. They decompose on heating
to form isonitriles, presumably by a-elimination via a
cyclic mechanism.
-
Ar-N=CHZ + ON-Ar'
Ar-N=CH-N-Ar'
OH
(12)
--t
Ar-NC
5. Redox Reactions
The reduction of readily available derivatives of iminocarbonic acid could provide a valuable addition to the
above methods for the preparation of isonitriles, if it
could be made to proceed under mild conditions and in
high yield. Usually, however, drastic reaction conditions
are required, and the yields are only moderate.
Isocyanates are reduced by heating with triethyl phosphite (17-57 % yield [83]), whereas isothiocyanates can
be reduced with triethylphosphine [84], triphenyltin
hydride [84b], copper [84a], or by photolysis [85].
R-N=C=Y
Red.
>-
R-NC
(Y=O,S)
Tertiary phosphines dehalogenate isonitrile dichlorides
1861.
R-NzCC12
+ RIP
+
R-NC
BrzC=N-N=CBrz
- ~y>- -
CN-NC
-+
9)
H
[Ar-N=Crk-Ar'j
!.I
I
H@"
change and subsequent cc-elimination. Tetrabromo-N,N'dimethylenehydrazine (12) cannot be reduced by metals
to diisocyanogen [89].
+ RiPC12
During the oxidation of l-cyclohexyl[34] and 1-phenyl
[90] thiosemicarbazides with sodium chlorite or hypochlorite or with mercuric oxide, small amounts of
isonitriles are formed.
Brackman and Snzit [90a] believe that the oxidation of
n-butylamine/methanol with oxygen, which is catalysed
by copper(I1) chloride, leads to n-butyl isonitrile. A reaction of this type would necessarily proceed via Nmethylene-n-butylamine, and would be a counterpart to
the reduction of iminocarbonic acid derivatives.
6. Abnormal Beckmann Rearrangements
According to Miiller and Narr [91], the 0-tosyl oximes
of 3,s-disubstituted 4-hydroxybenzaldehydes (13) and
of p-dimethylaminobenzaldehyde, which are obtained
from the sodium salts of the oximes and p-toluenesulfonyl chloride, give mixtures of the corresponding
nitriles (14) and isonitriles (15) in 40 to 92% yield on
elimination of p-toluenesulfonic acid. The formation of
the nitriles corresponds to nucleophilic $-elimination of
a proton and a tosylate anion 1921, whereas the isonitrile is formed from the syn-isomer by an abnormal
Beckmann rearrangement [93 -951.
Aliphatic isonitrile dichlorides are also reduced by
iodide. The intermediate isonitrile diiodide is unstable
and dissociates spontaneously into isonitrile and iodine
P71.
R-N=CClz
K1
+
[R-N=CIz]
+
R--NC+12
Isonitrile halides can also be converted to isonitriles by
organometallic compounds. Attempts to obtain di-tbutylamine by the reaction of t-butyl isocyanide di-
R
R
=
L
R
J
R
B r , C1, CH3, C(CH3)3
A similar interpretation can be given for the reaction of
the syn-oximes of benzaldehyde, p-methylbenzaldehyde,
chloride with methyl-lithium [88] led to the formation of
t-butyl isocyanide ( l l ) ,probably by halogen-metal ex[82] M . D. Farrow and C . K . Ingold, J. chem. SOC.(London) 125,
2543 (1924); cf. also G. N . Burkhardt, A. Lapworth and E. B .
Robinson, J. chern. SOC.(London) 127, 2234 (1925).
[83] T. Mukaiynma, H . Nambu, and M . Okamoto, J. org. Chemistry 27, 3651 (1962).
[84] A . W. Hofmann, Ber. dtsch. chern. Ges. 3; 766 (1870).
[84a] W . Weirh, Ber. dtsch. chern. Ges. 6,210 (1873).
[84b] D.H. Lorenz andE.1. Becker, J.org.Chernistry28,1707( 1963).
1851 U. Schmidf and K . H . Kabitzke, Angew. Chern. 76, 687
(1964); Angew. Chem. internat. Edit. 3, 641 (1964).
[86] German Published Patent Application 1158501 (May 23rd,
1962iDec. 5th, 1962), Farbenfabriken Bayer AG., inventors:
H . Malz and E. Kuhle.
1871 K . A . Petrov and A. A. NejmySeva, Zhur. obshch. Khim. 29,
2165 (1959).
482
[88l I. Ugi and F. K . Rosendahl, unpublished work.
1891 C . Grundmann, personal communication.
[90] K . Ley and 0: Eholzer, personal communication.
[9Oa] W. Brnckmnn and P. J . Smit, Recueil Trav. chim. Pays-Bas
82, 757 (1963).
[91] E. Miilfer and B. Nurr, Z. Naturforsch. 16 B, 845 (1961).
[92] Review: P . Kurtz in Houben- Weyl: Methoden der organischen Chemie. Thierne, Stuttgart 1952, Vol. 8, pp. 247, 325; cf.
also J. F. Bunnetr, Angew. Chem. 74,731 (1962); Angew. Chern.
internat. Edit. 1, 225 (1962).
[93] A . Werner and A. Piquet, Ber. dtsch. chern. Ges. 37, 4295
( 1904).
1941 See also: E. Beckmann and A. Koster, Liebigs Ann. Chem.
274, 1 (1893).
[95] A. H. Blatt and R . P . Barnes, J. Amer. chern. SOC. 56,
1148 (1934); J. org. Chemistry 24, 580 (1959); A. Ferris, ibid.
25, 12 (1960); A. F. Ferris, G. S . Johnson and F. E. Gauld,
ibid. 25, 1813 (1960); Reviews: C. A . Grob, Bull. SOC.chirn. France
1960, 1360; P. A. S . Smith in P . de Maya: Molecular Rearrangements. Interscience Publishers, New York 1963, p. 457.
Angew. Chem. internat. Edit. 1 Vol. 4 (1965) No. 6
(l3J
and p-nitrobenzaldehyde (16) with methyktene diethylacetal (17) 1961, which is catalysed by boron trifluoride/mercuric oxide.
C6H5-C-CHOH-Ca5
II
N-OH
C bH
o i 0S O S I
-
C&~-S-CHOH-C~~
N-O-SO2-Ca5
.-'
,.-
&-
Similar treatment of the anti-oximes yields only the
nitriles (60-80%) [92].
~CGH5-N=C-CHOH-Ca51
0 - s O 2 - c 6H5
---+
Ca5-NC
J.
+
C ~ ~ - C H O
+
c&s-so,o
7. Ring-Cleavage Reactions of
Heterocyclic Compounds
-
R
\ o
NC
+
R
(I-)
\ /
( 5 0 - 7 3%)
CN
+
( 0 - 23%)
CH3-C02C,H,
+
CzH50H
On attempting to carry out a Beckmann rearrangement
of y-bend monoxime (18) by the action of benzenesulfonyl chloride and alkali, Werner and Piquet [93] obtained products containing benzoic acid, phenyl isonitrile, and a sulfur compound which was decomposed
by alkali to yield benzoic acid and phenyl isonitrile. The
reaction was interpreted as a Beckmann rearrangement
of the y-benzil monoxime 0-benzenesulfonate to phenylglyoxyl anilide 0-benzenesulfonate (19), followed by
C,HsSOSI
CGH~-$-CO-CGHS
N-OH
OHo
C~H~-$-CO-C~HS
N-O-SOz-CsH5
-
i 18,
alkaline cleavage of the latter [93,94]. This interpretation
is supported by the cr-fragmentation of cc-ketocarboxylic
imide chlorides (20) by alkali [5-5 b, 61,971 and by
amines [61,97].
The cleavage of heteroaromatic rings to form isonitriles
may be regarded as a further indication of the strong
tendency of the isonitriles to be formed (i.e. isonitriles
are thermodynamically favorable and a large number of
reactions with suitable activation energies are available).
Quinazoline 3-oxide (21) is converted by acetic anhydride into 2-isocyanobenzonitrile (22) [99].
o::-[a,,1
C H =N- OAc
According to Ploquin, 2-methylpyridine (23) reacts with
dichlorocarbene, via the ylide (24), to form phenyl isonitrile by ring cleavage followed by ring closure in a new
arrangement [41].
Indole reacts with nitrosobenzene to form phenyl isonitrile [loo]. The reaction is assumed to proceed via
intermediates (25) and (26) [loll, corresponding to
those postulated by Grundmann to explain the tetramerization of phenyl isonitrile to indigo dianil (27) [103].
No investigations have as yet been carried out, to our
knowledge, to find whether indigo dianil can also be
prepared "directly" from indole and nitrosobenzene.
The anomalous Hofmann degradation of P-arylglycidarnides (28) is an example of the formation of isonitriles
by ring cleavage of nonaromatic heterocyclic systems.
It is not yet known whether the cc-fragmentation occurs
during or after the abnormal Beckmann rearragement of
p-benzoin oxime [98].
-
.
~
1961 T. Mukarjama, K . Tonooka, and K . Inoue, J. org. Chemistry
26, 2202 (1961); see also: T. Mukaijania and T . Haia, Bull. chem.
SOC.(Japan) 33, 1382 (1960).
[97] I. Ugi, F. Beck, and U . Ferzer, Chem. Ber. 9, 126 (1962).
[98] A. Werner and T. Detscheff, Ber. dtsch. chem. Ges. 38, 69
( 1905).
A n g e w . Chem. internat. Edit. 1 Vol. 4(1965)
No. 6
[99] T. Higashino, Chem. pharmac. Bull. (Tokyo) 9, 635 (1961).
[ 1001 W. Madelung and M . Tencer, Ber. dtsch. chem. Ges. 48,953
( 1915).
[I011 "Dimeric phenyl isocyanide", which may exist in small
quantities in equilibrium with phenyl isocyanide, can probably
also be regarded as an intermediate in the synthesis of 2-hydroxyI-naphthylglyoxal [102].
[I021 M . Passerini, Gazz. chim. ital. 54, 185, 633 (1924); 55, 555
(1925); M . Passerini and A. Neri, ibid. 64, 934 (1934).
[lo31 C. Grundmann, Chem. Ber. 91, 1380 (1958).
483
x-lactam is heated, it decomposes by isomerization to
(31/, followed by a-cycloelimination.
As an alternative to the mechanism proposed by ,46raham and Hajela [I041 an intermediate (28a) may be
assumed [ 1051 (a differentiation between these mechanisms could be made by labelling with 14C).
A similar course is followed in the conversion of N-tbutyl-a-bromoisobutyramide to l-t-butyl-2,2-dimethyIaziridin-3-one (54%) and the thermal dissociation of the
latter into acetone (12
t-butyl isonitrile (12
and
N-t-butylmethacrylamide (65%) [106a].
x),
x),
Reactions proceeding by related mechanisms are the
formation of small quantities of cyclohexyl isonitrile
from N-cyclohexyldichloroacetamideand potassium tbutoxide [lo71 and the formation of 4-chlorophenyl isonitrile from the sodium salt of N-(4-chlorophenyl)dichloromethylsulfonamide [108]. It is not yet known
whether, in the latter reaction, the intermediate a-sultam
(33) decomposes by a-cycloelimination followed by a-dehydrochlorination, or whether the opening of a threemembered carbene ring (34) [lo91 is followed by cleavage of the cumulative double-bond system.
8. Ring-Closure Reactions of a-Halogenoacylamines Followed by a-Cycloelimination
According to Sheehan and Lengyel[106],N-t-butyl-lbromocyclohexanecarboxamide (29) can be cyclized to
the a-lactam (30) by potassium t-butoxide. When the
r
t
J.
Received: November I l t h , I964
German version:
[A 4291226 I€]
Angea. Chem. 77, 492 (1965)
Translated by Express Translation Service, London
r
75oc
----+
(3I)
11041 N.A . Abraham and N. Hajela, C. R. hebd. Seances Acad
Sci. 255, 3192 (1962).
[I051 Cf. M . S. Newmanand C. Courdrrvelis, J. Amer. chem. SOC.
86, 2942 (1964).
[I061 J . C . Sheehan and I . Lengyel, J. Amer. chem. SOC.86, 746
( 1 964).
484
[106a] J. C. Sheehan and 1. Lengyel, J. Amer. chem. SOC.86, 1356
(1964).
[lG7] I . Ugi, unpublished work.
[I081 W. V. Farrar, J. chem. SOC.(London) 1960, 3058.
[ 1091 W. Y. E. Doering and P . M . L a Flamrne, Tetrahedron 2, 75
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Arrgew. C h e m . internat. Edit. Val. 4 (1965)
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