A new convenient synthesis of aroyl cyanides via the formation of cyanohydrin nitrate intermediates

Article abstract of DOI:10.1016/j.tetlet.2008.06.034

The treatment of α-bromoarylacetonitriles with AgNO₃ generates cyanohydrin nitrate intermediates, which easily eliminate nitrous acid with the formation of carbonyl bond to afford aroyl cyanides in good to high yields.

Full text of DOI:10.1016/j.tetlet.2008.06.034

Tetrahedron Letters 49 (2008) 5070–5072
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new convenient synthesis of aroyl cyanides via the formation
of cyanohydrin nitrate intermediates
*
Takuya Sueda , Masashi Shoji, Kiyoharu Nishide
Faculty of Pharmaceutical of Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure City, Hiroshima 737-0112, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The treatment of
a-bromoarylacetonitriles with AgNO3 generates cyanohydrin nitrate intermediates,
Received 20 May 2008
Revised 5 June 2008
Accepted 6 June 2008
Available online 12 June 2008
which easily eliminate nitrous acid with the formation of carbonyl bond to afford aroyl cyanides in good
to high yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
a
a
-Cyanohydrin nitrates
-Elimination
Aroyl cyanides
Organonitrates have been widely used in explosives, propel-
modifications have been reported and have led to some improve-
ments.6 An alternative method is the oxidation of cyanohydrins
with MnO2, PDC, and RuCl2(PPh3)3/tert-BuOOH.7 Our present
study provides a new and convenient synthetic route to aroyl
lants, and medications for heart conditions; however, there has
been little utilization of organonitrates in organic synthesis.1 On
the basis of similarities in the kinetics of alkyl nitrates and alkyl
halides, it has been proposed that the nitrate group acts as pseud-
ohalides.2 On the other hand, a reaction of special interest is the
cyanides 3 starting from
a-bromoarylacetonitriles 1, which are
easily available from the reaction of arylacetonitriles with N-
elimination of
halides but in carbonyl compounds for alkyl nitrates.3 We report
here that -hydrogen elimination of cyanohydrin nitrates 2 gener-
ated from the reaction of the corresponding -bromoarylacetonitr-
a-hydrogen, which results in carbenes for alkyl
bromosuccinimide.8
Acetone cyanohydrin nitrate has been synthesized from the
reaction of acetone cyanohydrin with fuming HNO3/Ac2O and used
as a nitrating reagent of amines.9 We tried to synthesize a hitherto
a
a
iles 1 with AgNO3 proceeds smoothly to give aroyl cyanides 3 in
high yields (Scheme 1).
unknown benzaldehyde cyanohydrin nitrate,
acetonitrile 2a, from the nucleophilic substitution reaction of
a-bromophenylacetonitrile 1a with AgNO3 in CH3CN at room tem-
perature. Surprisingly, benzoyl cyanide 3a was obtained in 59%
yield and a small amount of 2a was observed in the 1H NMR spec-
trum of the reaction crude product (Table 1, entry 1). Generally,
a-nitrooxyphenyl-
Acyl cyanides are versatile synthetic intermediates and have
been utilized in a variety of transformations of CO and CN func-
tions,4 and Sharpless recently reported that cycloaddition of azide
to aroyl cyanides gives aroyltetrazols in high yields.5 Generally,
acyl cyanides have been prepared from reactions of acid halides
with a variety of metal cyanides. These reactions often produce
acyl cyanide dimers as well as acyl cyanides in substantial quanti-
ties because of their strong carbonyl activities. Therefore, many
elimination of
a-hydrogen from organonitrates requires the use
of bases or strong acid.10 To the best of our knowledge, this is
the first report of the direct synthesis of aroyl cyanides 3 from
the corresponding
a
-bromoarylacetonitriles 1.11 Our efforts were
directed toward finding the optimal conditions for the direct con-
version of 1a into 3a. Increased equivalent of AgNO3 and prolonged
reaction times lead to no improvement in the yield of 3a (Table 1,
entries 2–3). Furthermore, when the reaction was performed under
basic conditions, no desired product was obtained at all (Table 1,
entries 4–6). Finally, this was settled by heating the reaction mix-
ture, and when 1a was treated with 1.3 equiv of AgNO3 in CH3CN at
50 °C for 5 h, 3a was obtained in 80% yield (Table 1, entry 8).
AgNO3
CH3CN
ONO2
Br
O
- HNO2
Ar
CN
Ar
CN
Ar
CN
1
2
3
Scheme 1. Aroyl cyanides from the reaction of
a-bromoarylacetonitriles with
AgNO3.
The scope and limitations of the reaction with
a-bromoaryl-
acetonitriles 1 were also examined, and the results are shown in
* Corresponding author. Tel./fax: +81 82 373 8933.
E-mail address: t-sueda@ps.hirokoku-u.ac.jp (T. Sueda).
Table 2.12 Various functional groups such as ether, alkyl, halogen,
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.034

T. Sueda et al. / Tetrahedron Letters 49 (2008) 5070–5072
5071
Table 1
Reactions of
Table 3
Selective formation of
-nitrooxyphenylacetonitrilea
a
a
-bromophenylacetonitrile (1a, Ar = Ph) with AgNO3
a
Entry
Equivalent
Additive
Conditions
Yieldsb (%)
Entry
1
Conditions
Yieldsb (%)
AgNO3
2a
3a
1ac
2
3
1c
1
2
3
4
5
6
7
8
9
1.1
1.5
2.0
1.3
1.3
1.3
1.1
1.3
1.5
—
—
—
rt, 2 h
rt, 24 h
rt, 2 h
rt, 5 h
rt, 5 h
3
7
59
57
39
0
0
0
62
80
76
39
14
0
0
55
0
4
0
0
1
2
3
4
1a
1a
1a
1b
ꢀ20 °C, 24 h
0 °C, 10 h
0 °C, 5 h
ꢀ20 °C, 2 h
2a (18)
2a (81)
2a (25d)
2b (93d)
3a (0)
3a (0)
3a (60)
3b (0)
1a (70)
1a (0)
1a (0)
1b (0)
48
0d
0
(i-Pr)2NEt (1.3)
K2CO3 (1.3)
Ag2O (1.3)
—
—
—
a
0d
4
Reactions were carried out using 1 (0.1 mmol) and AgNO3 (0.11 mmol) in
rt, 5 h
CH3CN (1 ml) under N2, except for entry 3 (10-fold scale) and entry 4 (50-fold scale).
50 °C, 5 h
50 °C, 5 h
50 °C, 5 h
Determined by analysis of the 1H NMR spectra of the reaction crude.
Recovered yield.
Isolated yield.
b
2
2
c
d
a
Reactions were carried out using 1a (0.1 mmol), AgNO3, and additive in CH3CN
(1 ml) under N2.
b
Determined by analysis of the 1H NMR spectra of the reaction crude.
Recovered yield.
Complex mixture.
Table 4
c
Conversion of cyanohydrin nitrate intermediates (2) into the corresponding aroyl
d
cyanides (3)a
Entry
2
Additive (equiv)
Yieldsb (%)
Table 2
3
2c
Aroyl cyanides (3) from the reaction of
a-bromoarylacetonitriles (1) with AgNO3 at
1
2
3
4
5
6
7
8
9
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
—
—
3a (51)
3b (17)
3b (18)
2a (35)
2b (64)
2b (82)
2b (0)
2b (0)
2b (4)
2b (5)
2b (60)
2b (23)
2b (0)
2b (0)
50 °Ca
Yieldb (%)
AgBr (1.0)
Entry
AgNO3
Time (h)
AgNO3 (0.3)
3b (100)
3b (100)
3b (84)
3b (80)
3b (37)
3b (50)
3b (100)
3b (83)
Ar
1
3
1c
Bu4NþNOꢀ3 (0.3)
K2CO3 (1.0)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Ph
1a
1b
1c
1d
1e
1e
1f
1g
1h
1h
1h
1i
1.3
1.3
1.3
1.3
1.3
2.0
1.3
1.3
1.3
1.3
2.0
1.3
2.0
1.3
1.3
5
5
5
5
5
5
5
5
5
10
10
5
5
5
3a (79)
3b (81)
3c (83)
3d (84)
3e (72d)
3e (82)
3f (84)
3g (75)
3h (65d)
3h (78d)
3h (75)
3i (71d)
3i (68)
0
0
0
0
p-MeOC6H4
p-MeC6H4
p-BrC6H4
p-MeOC(O)C6H4
p-MeOC(O)C6H4
m-MeOC6H4
m-MeC6H4
m-BrC6H4
m-BrC6H4
m-BrC6H4
m-MeOC(O)C6H4
m-MeOC(O)C6H4
o-MeOC6H4
o-MeC6H4
(i-Pr)2NEt (1.0)
Alumina, N (50 mg)
Alumina, B (50 mg)
Aluminam B (100 mg)
4 Å MS (50 mg)
1e (8d)
10
11
0
0
0
a
Reactions were carried out using 2 (0.1 mmol) in CH3CN (1 ml) at 50 °C for 5 h
1h (31d)
under N2.
Determined by analysis of the 1H NMR spectra of the reaction crude.
Recovered yield.
b
c
1h (12d)
0
1i (17d)
1i
1j
1k
0
0
0
3j (85)
3k (86)
similar conditions (Table 4, entry 2). Thus, heating at 50 °C did not
lead to complete conversion of cyanohydrin nitrates 2 to aroyl cya-
nides 3. Table 4 shows the reaction of cyanohydrin nitrates 2 under
various reaction conditions. No effect was observed for the addi-
tion of AgBr, which was produced in situ via nucleophilic substitu-
5
a
See Ref. 12.
b
c
Isolated yields.
Recovered yields.
Determined by analysis of the 1H NMR spectra of the reaction crude.
d
tion of
a-bromoarylacetonitriles 1 with AgNO3 (Table 4, entry 3).
On the other hand, addition of a catalytic amount of AgNO3 gave
aroyl cyanide 3b exclusively (Table 4, entry 4). A similar result
was obtained with tetrabutylammonium nitrate (Table 4, entry
5). These results suggest that there is a mechanism involving inter-
mediate formation of cyanohydrin nitrates 2 followed by elimina-
tion of nitrous acid to give aroyl cyanides 3. 3b was also obtained
from the reactions with various species listed in Table 4.
When benzyl nitrate was heated at 50 °C in CH3CN for 24 h in
the presence of AgNO3, benzaldehyde was not detected and the
starting nitrate ester was recovered quantitatively.10 Furthermore,
and ester on the phenyl ring survived under the reaction condi-
tions. The rate of reaction, however, was affected by the electronic
nature of the substituents. Electron-donating substituents such as
MeO and Me gave the corresponding aroyl cyanides in good yields,
which were independent of any position on the phenyl ring. On the
other hand, electron-withdrawing groups decreased the rate of the
reaction. For example, when bromo(3-bromophenyl)acetonitrile
1h was treated with 1.3 equiv of AgNO3 at 50 °C for 5 h, 31% of
1h was recovered (Table 2, entry 9). Since no nitrate intermediate
2h was observed, the decreased rate of the reaction is probably
caused by the lower reactivity of 1h toward AgNO3.
a
-nitrooxydecanenitrile was not converted into the corresponding
acyl cyanide under similar conditions.13 These differences in the
reactivity of nitrate esters for the elimination reactions of nitrous
We then turned our attention to isolation of a-nitrooxyphenyl-
acetonitrile. As shown in entry 1 of Table 3, the reaction at ꢀ20 °C
afforded 2a selectively, although a large amount of the starting 1a
was recovered. The selective formation of 2a was also performed at
elevated reaction temperature (Table 3, entry 2). However, it seems
that 2a is relatively unstable, which resulted in a low isolation
yield (Table 3, entry 3).12 The electron-donating substituents ap-
pear to accelerate the formation of cyanohydrin nitrates and stabi-
lize them. Thus, 2b was selectively synthesized at ꢀ20 °C in high
yield and no aroyl cyanide was observed (Table 3, entry 4).
acid should be due to the acidity of a
-proton.14 We computed
the proton affinity for the organonitrates examined in this study.15
The effects of the electron-withdrawing CN group and conjugating
aromatic substituents actually resulted in much lower proton
affinity (Table 5).
In conclusion, we have shown that various aroyl cyanides can
be prepared directly from a-bromoarylacetonitriles. Our procedure
involving the generation of organonitrates might be applicable to
the synthesis of reactive carbonyl compounds involving adjacent
electron-withdrawing and conjugating groups.
a-Nitrooxyphenylacetonitrile 2a was directly converted into
benzoyl cyanide 3a by heating at 50 °C in CH3CN for 5 h in 51%
yield (Table 4, entry 1). 2b was converted only in 17% yield under
Selected spectroscopic data. For 2a: mp = 68–70 °C; 1H NMR
(400 MHz, CDCl3) d 7.62–7.45 (m, 5H), 6.36 (s, 1H); 13C NMR

5072
T. Sueda et al. / Tetrahedron Letters 49 (2008) 5070–5072
7. For MnO2, see: (a) Corey, E. J.; Gilman, N. W.; Ganem, B. E. J. Am. Chem. Soc.
Table 5
Relative proton affinity (RR0CꢀONO2?RR0C(H)ONO2)a
1968, 90, 5616; For PDC, see: (b) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1980,
731; For RuCl2(PPh3)3/tert-BuOOH, see: (c) Murahashi, S.-I.; Naota, T.;
Nakajima, N. Tetrahedron Lett. 1985, 26, 925; Murahashi has also reported the
palladium-catalyzed decarbonylation of aroyl cyanides to give the
corresponding aromatic nitriles, see: (d) Murahashi, S.-I.; Naota, T.; Nakajima,
N. J. Org. Chem. 1986, 51, 898.
R
R0
B3LYP/6-311+G(2d,p)
MP2/6-311+G(2d,p)
Ph
Me
Ph
H
+34.59
+20.19
0
+31.82
+19.38
0
CN
CN
CN
8. Molina, P.; López-Leonardo, C.; Llamas-Botía, J.; Foces-Foces, C.; Fernández-
Castaño, C. Tetrahedron 1996, 52, 9629.
p-MeOC6H4
+4.17
+3.45
9. (a) Gonzalez, A.; Galvez, C. Synthesis 1983, 212; (b) Olah, G. A.; Malhotra, R.;
Narang, S. C. J. Org. Chem. 1978, 43, 4628; (c) Freeman, J. P.; McKusick, B. C..
Organic Synthesis Coll.. In Vol. V; Wiley: New York, 1973. p 839.
a
All values (in kcal/mol) are calculated for 298 K and 1 atm. Enthalpies were
calculated by using HF/6-31+G(d) optimized geometry.
10. Base-induced elimination of
J. Am. Chem. Soc. 1961, 83, 193; (b) Kornblum, N.; Frazier, H. W. J. Am. Chem. Soc.
1966, 88, 865; Base-induced -elimination reaction of benzyl nitrate is in
a-hydrogen, see: (a) Letsinger, R. T.; Jamison, J. D.
(150 MHz, CDCl3) d 131.6, 129.6, 128.7, 127.7, 114.2, 71.0; IR
(CHCl3) 1668, 1281, 1263, 827 cmꢀ1; HRMS Calcd for C8H6N2O3:
178.0378. Found: 178.0381; Anal. Calcd for C8H6N2O3: C, 53.94;
H, 3.39; N, 15.73. Found: C, 53.55; H, 3.51; N, 15.48. For 2b:
mp = 45–46 °C; 1H NMR (400 MHz, CDCl3) d 7.48 (d, J = 8.7 Hz,
2H), 6.99 (d, J = 8.7 Hz, 2H), 6.29 (s, 1H), 3.85 (s, 3H); 13C NMR
(150 MHz, CDCl3) d 162.1, 130.6, 119.4, 114.9, 114.4, 70.9, 55.5;
; HRMS Calcd for
C9H8N2O4: 208.0484. Found: 208.0482; Anal. Calcd for C9H8N2O4:
C, 51.93; H, 3.87; N, 13.46. Found: C, 52.08; H, 3.96; N, 13.36.
a
accordance with a concerted process, see: (c) Smith, P. J.; Bourns, A. N. Can. J.
Chem. 1966, 44, 2553; (d) Buncel, E.; Bourns, A. N. Can. J. Chem. 1960, 38, 2457;
Elimination of a-hydrogen under acidic conditions, see: (e) Ross, S. D.; Coburn,
E. R.; Finkelstein, M. J. Org. Chem. 1968, 33, 585.
11. Suzuki has reported the reaction of arylmalononitriles with nitric acid to afford
organonitrate intermediates, which are decomposed to aroyl cyanides, see:
Suzuki, H.; Koide, H.; Ogawa, T. Bull. Chem. Soc. Jpn. 1988, 61, 501.
12. General procedure for the synthesis of 3:
A
mixture of
a-
IR (CHCl3) 1665, 1283, 1256, 833 cmꢀ1
bromophenylacetonitrile 1a (196.0 mg, 1 mmol) and AgNO3 (220.8 mg,
1.3 mmol) in CH3CN (10 ml) was heated for 5 h at 50 °C under N2. After
cooling, the solvent was evaporated in vacuo, then hexane or CH2Cl2 was
added. Filtration and the filtrate was evaporated in vacuo to give a colorless
solid. The reaction crude was recrystallized from hexane at ꢀ78 °C to yield the
pure benzoyl cyanide 3a (103.9 mg, 79%) as a white solid. The 1H NMR, IR, and
GC–MS data of 3a were in good agreement with those of an authentic sample.
Acknowledgement
13.
a
-Nitrooxydecanenitrile was synthesized from the reaction of
a-
iododecanenitrile with AgNO3 at 50 °C. No reaction occurred when 2-
The present work was supported by a research grant from JSPS
KAKENHI (16790012).
bromodecanenitrile was used as
conditions.
a substrate under the same reaction
14. Baker, J. W.; Heggs, T. G. J. Chem. Soc. 1955, 616.
References and notes
15. All calculations reported here were performed using the Gaussian 98M
(revision A.11.). Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery Jr., J. A.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin,
K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.;
Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.;
Ayala, P. Y.; Cui, Q.; Morokuma, K.; Salvador, P.; Dannenberg, J. J.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.;
Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong,
M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A.
Gaussian, Inc., Pittsburgh PA, 2001.
1. For reviews, see: (a) Klamann, D. In Houben-Weyl Methoden der Organischen
Chemie; Georg Thime Verlag: Stuttgart, Germany, 1992; Vol. E16c, pp 23–66;
(b) Boschan, R.; Merrow, R. T.; van Dolah, R. W. Chem. Rev. 1955, 55, 485.
2. Baker, J. W.; Easty, D. M. J. Chem. Soc. 1952, 1208.
3. (a) Ross, S. D.; Coburn, E. R.; Finkelstein, M. J. Org. Chem. 1968, 33, 585; (b)
Kornblum, N.; Frazier, H. W. J. Am. Chem. Soc. 1966, 88, 865.
4. For review, see: Hunig, S.; Schaller, R. Angew. Chem., Int. Ed. Engl. 1982, 21, 36.
5. Demko, Z. P.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2113.
6. (a) Ando, T.; Kawate; Yamawaki, J.; Hanafusa, T. Synthesis 1983, 637; (b) Sukata,
K. Bull. Chem. Soc. Jpn. 1987, 60, 1085; (c) Koenig, K. E.; Weber, W. P. Tetrahedron
Lett. 1974, 2275.