3114 J. Org. Chem., Vol. 42,No.19,1977
Oldenziel, van Leusen, and van Leusen
A General One-Step Synthesis of Nitriles from Ketones Using Tosylmethyl Isocyanide. Introduction of a One-Carbon Unit’ Otto H. Oldenziel, Daan van Leusen, and Albert M. van Leusen* Depa,ptment of Organic Chemistry, T h e University, Zernikelaan, Groningen, T h e Netherlands Received February 7,1977
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Ketones are converted efficiently, in one step, to nitriles (R2CO R2CHC=N) at temperatures between 0 and 45 O C by the use of TosMIC (tosylmethyl isocyanide) and base. This conversion is effectively a reductive cyanation, unlike the classical cyanohydrin reaction. The reaction is shown to be generally applicable.
Results and Discussion The synthesis of nitriles according to eq 1 is applicable to a wide variety of different ketones (Table I). The substrates range from simple aliphatic and aromatic ketones to sterically hindered ones, including camphor and P,p-dimethyl-a-tetralone (to give 2c and 2g, respectively). Also, the cyanation can be realized with 3-and 17-steroidal ketones (2h-k). So far only the severely hindered carbonyl of di-tert -butyl ketone has resisted reaction, whereas tert-butyl methyl ketone (pinacolone) and diisopropyl ketone are convertible (2q and 2P). Reaction Conditions. The conditions of reaction 1 were adapted to differences in reactivity of the ketones concerned. Typically, for ketones of normal reactivity t-BuOK was added at 0 “C to a solution of a ketone and 1.0-1.5 equiv of TosMIC in 1,2-dimethoxyethane (containing a little t-BuOH or EtOH). The reaction went to completion in 1-2 h at room temperature (2a,b,d,e,i-k,m-o). Under these mild conditions, however, camphor and diisopropyl ketone gave only trace amounts of nitrile (2c,p),and tert-butyl methyl ketone gave no more than 36% of 2-cyano-3,3-dimethylbutane (2q). The best way to convert camphor to 2-cyanocamphane (2c) was with 3 equiv of TosMIC in dimethyl sulfoxide (containing some MeOH) a t a slightly elevated temperature (45 “C). Thus, 80%of 2c was obtained after 70 h. In hexamethylphosphoric triamide (HMPT) the same reaction went faster (17 h), but the product was less pure. Comparable reaction conditions were used with success for other sterically hindered ketones (nitriles 2g,p,q). Benzophenone and a-tetralone,’O which did not react in DME, were also converted to the corresponding nitriles (21,f) in MezSO and HMPT, respectively. Reaction Scheme. A rationale for reaction 1 is given in
Tosylmethyl isocyanide (TosMIC, 1) is a synthon with diverse and steadily expanding applications. Thus far emphasis in the chemistry of TosMIC has centered mainly on heterocyclic synthesis. The preceding paper in this series deals with the synthesis of imidazoles from TosMIC and aldimines,2a and summarizes other azole (and azoline) syntheses.2 The present paper will show, however, that the application of TosMIC by no means is restricted to the domain of heterocyclic synthesis only. We here wish to concentrate on the use of TosMIC in an efficient, direct conversion of ketones to nitriles3
2
TosMIC adds one carbon unit to a ketone, as in the classical cyanohydrin r e a ~ t i o nbut , ~ without the simultaneous formation of an a-hydroxy group. In this sense the reaction of TosMIC is a “reductive cyanation”. Reaction 1is unique because it allows the ketone nitrile conversion to be carried out in a single operation.5~6 Obviously, the nitriles can be exploited further, for instance, by conversion to carboxylic acids or derivatives thereof.6,’ A reaction of TosMIC with aldehydes and ketones leading in two steps via N - (1-tosyl-1-alkeny1)formamides to carboxylic acids has been reported independently by Schollkopf et a1.P and this reaction has later been shown to proceed through nitriles (as in eq 1).8b Dehydration of aldoximes also leads to nitriles, however, with the same number of carbon atoms as in the starting ald e h y d e ~and , ~ therefore is a process quite different from reaction 1.
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Scheme I. Proposed Mechanism for Conversion of Ketones to Nitriles with TosMIC According to Equation 1 \c=o T ~ ~ C H ~ N = C
T~~CHN=C
1
-
c ;H*
4
R2’
To s
3
;%-- R’
7
TOS
5
6
P‘
-
171
,N-C
\c=c /
10s
7 R’
\
F12
+o
-HCOOR ___c
H
To s
R1\
-10s-
\
-
R2/
I
H ‘
8
I”
9
OR 10
-TosH
/O R 2 - L 0
Tos
’c=c
13
R2
R’ \
H‘
/
‘10s
,N-C/
CH-C/
R2
14
\
RO-
H ‘ To s
R’,
,N-C-H CH-CCd
R2’
LTos
15
pr AR 16
R’ I?’ \
+O
,N=C
c=c 172’
8 \Tos
Et0
17
R2,
c-c
.-?,+“
N
18
C,H,’
*O
12
19
-
12
TosH
CO
J.Org. Chem., Vol. 42, No. 19,1977
Synthesis of Nitriles from Ketones
3115
Table I. Nitriles Synthesized from Ketones and Tosylmethyl Isocyanide (TosMIC) According to Equation 1 Substrateo and product Adamantanone* 2-Cyanoadamantane (%a)
Registry no.
1.3 1.3
Lit. data
t-BuOK (2.4), DME t-BuOK (3.5), MezSO
1.5
35
93
17
20
84
t-BuOK (3.5), MezSO EtONa (1.3), DME
17
20
73
20
62
t-BuOK (7), Me2SO t-BuOK (7), HMPT t-BuOK (2), DME
70
45
80
17
45
73
1.5
20
CHC=N (35) R . W. Horobin, N. R . Kahn, and J. McKenna, Tetrahedron Lett., 5087 >F(OH)C=N was described recently: E. Vedejs and J. E. Telschow, (1966). ibid., 41, 740 (1976), and ref 6e. For the reversal of reaction 1 (i.e., (36) D. N. Jones, R. Grayshan, and K. J. Wyse, J. Chem. SOC.C, 2027 >CHC=N >C=O) see S. J. Selikson and D. S. Watt, ibid., 40, 267 (1970). (1975). (37) Beilstein, 9, E Ill, 2421. (8) (a) U. Schollkopf, R . Schroder, and E. Blume. Justus Liebigs Ann. Chem., (38) R. F. Brown and N. M. van Gulick. J. Am. Chem. SOC.,77, 1083 (1955); F. 766, 130 (1972); (b) U. Schollkopf and R. Schroder, Angew. Chem., lnt. C . B. Marshall, J. Chem. SOC., 2754 (1930). Ed. Engl., 12, 407 (1973) (39) C. G. Overberger and M. B. Berenbaum, J. Am. Chem. Soc., 74, 3293 (9) Recent leading references: E. Vowinkel and J. Bartel, Chem. Ber., 107, (1952). 1221 (1974); J. B. Hendrickson, K. W. Bair, and P. M. Keehn, Tetrahedron (40) M. S. Newman. A. Arkell, and T. Tukunaga, J. Am. Chem. SOC., 62,2498 Lett., 603 (1976); A. Antonowa and S. Hauptmann, Z.Chem., 16, 17 (1976); (1960).
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Aminations with Ammonia and Formamide. Synthesis of Terephthalamic Acid and of p -Nitroaniline Christian S . Rondestvedt, Jr. Research and Development Division Publication No. 548, Jackson Laboratory, Organic Chemicals Department, E. I. d u Pont de Nemours and Company, Wilmington, Delaware, 19898 Received March 23,1977 Ammonolysis of potassium m e t h y l terephthalate (2k) t o potassium terephthalamate (3k) is m a r k e d l y accelerate d by formamide solvent. N o corresponding acceleration i s seen w i t h other amides, such as mono- o r d i m e t h y l f o r m amide o r acetamide. Negligible hydrolysis t o a m m o n i u m terephthalate (4a) occurs. An efficient procedure f o r t h e H o f m a n n conversion o f potassium terephthalamate (3k) t o p-aminobenzoic acid is reported. Ammonolysis o f p nitrochlorobenzene occurs rapidly in formamide solvent a t 200-220 O C t o f u r n i s h high yields o f p-nitroaniline. p Chlorobenzotrifluoride a n d 1,2,4-trichlorobenzene are n o t aminated u n d e r these conditions.
W e sought to develop an economical synthesis of P-aminobenzoic acid from commercial dimethyl terephthalate (DMT, 1).1 Attempts to half-ammonolyze DMT to methyl
terephthalamate (38) were unsuccessful, since all conditions tried formed excessive amounts of terephthaldiamide. However, half-hydrolysis of DMT by potassium hydroxide in
