Reaction of 2-alkynylbenzoyl cyanides with carboxylic acids producing functionalized indenones

Article abstract of DOI:10.1055/s-2008-1078501

2-Alkynylbenzoyl cyanides react with carboxylic acids via a cyclic allene intermediate to produce 2-acylamino-3-acylindenones in good yield. The high reactivity of the 2-acylamino moiety of the product for a substitution reaction can be utilized for the s

Full text of DOI:10.1055/s-2008-1078501

LETTER
1817
Reaction of 2-Alkynylbenzoyl Cyanides with Carboxylic Acids Producing
Functionalized Indenones
R
eaction of 2-Alky
i
nylben
r
zoyl
C
y
o
a
nides
w
ith C
s
arboxylic
h
A
cids i Shimizu, Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Kyoto 615-8510, Japan
Fax +81(75)3832748; E-mail: murakami@sbchem.kyoto-u.ac.jp
Received 17 April 2008
O
Abstract: 2-Alkynylbenzoyl cyanides react with carboxylic acids
1. (COCl)2, DMF (cat.),
CO2H
via a cyclic allene intermediate to produce 2-acylamino-3-acylinde-
nones in good yield. The high reactivity of the 2-acylamino moiety
of the product for a substitution reaction can be utilized for the syn-
thesis of fused heterocycles.
CH2Cl2, r.t.
CN
2. CuCN, MeCN, 70 °C
nBu
nBu
2a 79%
1a
Key words: cyclization, carboxylic acids, heterocycles, benzoyl
cyanides, indenones
Equation 1 Preparation of 2-(hexyn-1-yl)benzoyl cyanide (2a)
PhCH2CH2CH2NH2
(1.0 equiv)
The cyanocarbonyl group is an interesting ambident elec-
trophilic functionality; its cyano and carbonyl groups are
both electrophilic enough to accept nucleophiles, and their
electron-withdrawing nature reinforces the electrophilic
reactivities.1,2 As an extension of our previous studies on
the rhodium-catalyzed reaction of cyanoformate with
arylboronic acids,3 we prepared 2-alkynylbenzoyl cyanide
in order to develop a cascade reaction. Careful examina-
tion of its reactivity, however, disclosed an unexpected
acid-mediated cyclization reaction. In this paper, we re-
port the reaction of 2-alkynylbenzoyl cyanide with a car-
boxylic acid, which furnishes a functionalized indenone
as the cyclized product.
O
O
or
PhCH2CH2CH2OH
(1.0 equiv)
Et3N (1.2 equiv)
X
Ph
CN
dioxane, r.t., 1 h
nBu
nBu
X = NH 3a 97%
X = O 3b 88%
2a
Equation 2 Reaction of 2a with an amine and an alcohol
O
O
O
PhCO2H (4a)
(2.0 equiv)
Ph
CN
NH
2-(1-Hexyn-1-yl)benzoyl cyanide (2a) was readily pre-
pared from 2-(1-hexyn-1-yl)benzoic acid (1a);4 treatment
of 1a with oxalyl chloride in the presence of DMF in
CH2Cl2 and subsequent removal of volatile compounds
under reduced pressure afforded the corresponding acid
chloride as the crude product. The crude acid chloride was
directly reacted with CuCN in MeCN at 70 °C.5 Isolation
by column chromatography on silica gel afforded the de-
sired benzoyl cyanide 2a in 79% yield (Equation 1).
nBu
nBu
O
2a
5aa
in p-xylene 140 °C, 24 h
in toluene 100 °C, 48 h
in dioxane 100 °C, 48 h
84%
84%
87%
Equation 3 Reaction of 2a with benzoic acid 4a
The results obtained with other carboxylic acids 4 and 2a
are summarized in Table 1.7 Not only substituted ben-
zenecarboxylic acids (entries 1–5) but also heteroaromat-
ic (entries 6 and 7), cinnamic (entry 8), and aliphatic
(entries 9–11) carboxylic acids reacted with 2a to give the
corresponding 2-acylamino-3-pentanoylindenone (5aa–
ak) in yields ranging from 60% to 92%. Thus, a wide
range of carboxylic acids effectively mediated the cy-
clization reaction of 2a.
When 2-(1-hexyn-1-yl)benzoyl cyanide (2a) thus ob-
tained was treated with 3-phenylpropylamine, the amino
group attacked the carbonyl group of 2a, with the cyano
group acting as a leaving group to afford the correspond-
ing amide 3a in 97% yield. The related reaction between
3-phenylpropanol and 2a in the presence of Et3N proceed-
ed in a similar manner producing ester 3b (Equation 2).
Thus, relatively active nucleophiles attacked the carbonyl
group of 2a under basic conditions. In contrast, when 2a
was heated with benzoic acid 4a, a cyclization reaction
occurred to afford 2-benzoylamino-3-pentanoylindenone
5aa as shown in Equation 3.6
In order to further probe the scope of the reaction, benzoyl
cyanides possessing other alkynyl groups were also exam-
ined. 2-Alkynylbenzoyl cyanide 2b4 having an isopropyl
substituent was a suitable substrate, giving 5ba and 5bi at
120 °C (Equation 4). When the reaction of 2b with benzo-
ic acid 4a was carried out at a lower temperature (100 °C),
enol ester 6ba was isolated in 71% yield. Furthermore, on
SYNLETT 2008, No. 12, pp 1817–1820
x
x
.x
x
.2
0
0
8
Advanced online publication: 19.06.2008
DOI: 10.1055/s-2008-1078501; Art ID: U03808ST
© Georg Thieme Verlag Stuttgart · New York

1818
H. Shimizu, M. Murakami
LETTER
heating a mixture of 6ba and benzoic acid 4a at 120 °C, 2-
acylaminoindenone 5ba was produced in 65% yield
(Scheme 1). Unlike 2a and 2b, 2-alkynylbenzoyl cyanides
2c–e4 (Figure 1) failed to react with benzoic acid (4a), and
2c–e were recovered, suggesting the need for a hydrogen
at the propargylic position in order for the cyclization re-
action to occur. The attempted reaction of benzoyl cya-
nide 2f8 bearing a terminal alkyne resulted in the
formation of a mixture of intractable compounds.
Table 1 Reaction of 2a with Various Carboxylic Acids 4
O
O
O
R2CO2H (4a–k)
(2.0 equiv)
R
CN
NH
p-xylene, 140 °C, 24 h
nBu
nBu
O
2a
5aa–5ak
Entry
4
R2
Product 5 Yield
(%)a
In order to gain a further insight into the mechanism, we
treated 2a with acetic acid-d1 4i-D (5 equiv) in p-xylene at
120 °C for 7 hours. Under these conditions, 5ai-D which
incorporated a deuterium at the a-position of the carbonyl
group (67% D), was isolated in 83% yield (Equation 5).9
The deuterium incorporation also indicated the intermedi-
acy of an enol ester such as 6ba. On the basis of these re-
sults, we propose the pathway shown in Scheme 2 to
explain the formation of 2-acylamino-3-acylindenone 5
from 2. Initially, carboxylic acid 4 mediates isomerization
of 2-alkynylbenzoyl cyanide 2 to cyclic allene 7. Then,
carboxylic acid 4 attacks the sp-carbon of the allene moi-
ety to form enol ester 6. Finally, the acyl group migrates
to the amino group to afford 2-acylamino-3-acylindenone
5.
1
2
4a
4b
4c
4d
4e
4f
Ph
5aa
5ab
5ac
5ad
5ae
5af
5ag
5ah
5ai
84
64
89
88
60
62
83
87
92b
83
87
4-MeOC6H4
4-ClC6H4
4-BrC6H4
4-MeO2CC6H4
Pyrid-2-yl
Thien-2-yl
(E)-PhCH=CH
Me
3
4
5
6
7
4g
4h
4i
8
9
10
11
4j
i-Pr
5aj
5ak
We next examined the reactivities of the product. Treat-
ment of 5aa with a primary amine resulted in a facile sub-
stitution reaction of the acetylamino group to give 2-
alkylamino-3-pentanoylindenone 11 in high yield
(Equation 6).10 The substitution reaction probably pro-
ceeds via an addition–elimination mechanism. The substi-
tutive reactivity of the acylamino group with primary
amines was next utilized for construction of heterocyclic
structures.11 Treatment of 2-acetylamino-3-acylindenone
5ai and 5bi with amidine hydrochlorides 8 in pyridine at
100 °C afforded the corresponding indenopyrimidine 9 as
exemplified in Equation 7.12 When 5ai and 5bi were re-
acted with methylhydrazine, the primary amino group ini-
tially replaced the acetylamino group to furnish
indenopyrazole derivatives 12 possessing a methyl group
at the 2-position (Equation 8).13,14
4k
t-Bu
a Isolated yield.
b Reaction at 120 °C.
O
O
O
R
RCO2H (4)
CN
NH
Me
p-xylene, 120 °C
Me
O
Me
Me
5ba R = Ph 73%
5bi R = Me 91%
2b
Equation 4 Reaction of 2b with carboxylic acids
O
2c R = tBu
2d R = Ph
2e R = TMS
O
O
CN
PhCO2H (4a)
(2.0 equiv)
CN
NH2
2f R = H
dioxane, 100 °C, 19 h
Me
R
OBz
2
Me
2b
Me
Me
Figure 1 The substrates which failed to react with carboxylic acids
6ba 71%
O
O
O
AcOD (4i-D)
(5.0 equiv)
PhCO2H (4a)
(1.0 equiv)
CN
NHBz
NHAc
D
p-xylene, 120 °C, 7 h
p-xylene, 120 °C, 48 h
Me
O
O
Me
5ba 65%
2a
5ai-D
83% 67% D
Scheme 1 Formation of 5ba from 2b and 4a via enol ester 6ba
Equation 5 Deuterium experiment
Synlett 2008, No. 12, 1817–1820 © Thieme Stuttgart · New York

LETTER
Reaction of 2-Alkynylbenzoyl Cyanides with Carboxylic Acids
1819
O
acylamino-3-acylindenones could be utilized for the syn-
thesis of fused heterocycles with an indenone skeleton.
O
O
H
∆
R3
CN
NH
H
O
4
O
References and Notes
H
R2
O
R1
R3
R1
(1) For attack of carbon nucleophiles to the cyano group, see:
(a) Veronese, A. C.; Callegari, R.; Basato, M.; Valle, G.
J. Chem. Soc., Perkin Trans. 1 1994, 13, 1779.
R2
4
2
7
(b) Veronese, A. C.; Gandolfi, V.; Basato, M.; Corain, B.
J. Chem. Res., Synop. 1988, 8, 246. (c) Basato, M.; Corain,
B.; Cofler, M.; Veronese, A. C.; Zanotti, G. J. Chem. Soc.,
Chem. Commun. 1984, 23, 1593.
O
O
O
R3
NH2
NH
(2) For recent examples of attack of carbon nucleophiles to the
carbonyl group, see: (a) Ikeda, Z.; Hirayama, T.; Matsubara,
S. Angew. Chem. Int. Ed. 2006, 45, 8200. (b) Shen, Z.; Li,
B.; Wang, L.; Zhang, Y. Tetrahedron Lett. 2005, 46, 8785.
(c) Zhou, S.; Yan, B.; Liu, Y. J. Org. Chem. 2005, 70, 4006.
(d) Duplais, C.; Bures, F.; Sapountzis, I.; Korn, T. J.; Cahiez,
G.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 2968.
(e) Gohain, M.; Gogoi, B. J.; Prajapati, D.; Sandhu, J. S. New
J. Chem. 2003, 27, 1038. (f) Wiles, C.; Watts, P.; Haswell,
S. J.; Pombo-Villar, E. Chem. Commun. 2002, 1034.
(g) Wiles, C.; Watts, P.; Haswell, S. J.; Pombo-Villar, E.
Tetrahedron Lett. 2002, 43, 2945. (h) Yoo, B. W.; Hwang,
S. K.; Kim, D. Y.; Choi, J. W.; Ko, J. J.; Choi, K. I.; Kim, J.
H. Tetrahedron Lett. 2002, 43, 4813.
O
O
O
R2
R2
R3
R1
R1
5
6
Scheme 2 Proposed mechanism for the formation of 5 from 2 and 4
O
O
O
RNH2 (10)
(1.2 equiv)
Ph
NHR
nBu
R = CH2CH2CH2Ph 11aaa 95%
NH
DCE
nBu
O
O
(3) Shimizu, H.; Murakami, M. Chem. Commun. 2007, 2855.
(4) Representative Procedure for the Preparation of 2-
Alkynylbenzoyl Cyanide 2
5aa
R = CHMePh
11aab 97%
Oxalyl chloride (1.60 mL, 18.7 mmol) was added dropwise
to a mixture of 2-(1-hexyn-1-yl) benzoic acid (1a, 3.43 g,
17.0 mmol) and DMF (2 drops) in CH2Cl2 (35 mL). The
reaction mixture was stirred for 1.5 h at r.t. Then, volatile
components were removed in vacuo to give crude acid
chloride. A solution of the crude acid chloride in MeCN (20
mL) was added to a stirred suspension of CuCN (3.00 g, 33.5
mmol) in MeCN (20 mL) at r.t. After the mixture was stirred
for 1 h at 70 °C, the resulting clear solution was cooled to r.t.
and concentrated in vacuo. The residue was washed with
Et2O, filtrated and concentrated in vacuo again. The residue
was purified rapidly by silica gel column chromatography
(hexane and then hexane–Et2O, 50:1) to afford 2-(1-hexyn-
1-yl)benzoyl cyanide (2a) (2.83 g, 79%). 1H NMR (300
MHz, CDCl3): d = 0.96 (3 H, t, J = 7.2 Hz), 1.42–1.58 (2 H,
m), 1.58–1.72 (2 H, m), 2.51 (2 H, t, J = 7.2 Hz), 7.42–7.52
(1 H, m), 7.54–7.67 (2 H, m), 8.05–8.12 (1 H, m). 13C NMR
(75 MHz, CDCl3): d = 13.8, 19.8, 22.2, 30.4, 77.9, 101.6,
113.5, 125.9, 127.9, 132.6, 133.7, 135.2 (two signals
overlapping), 166.9. IR (neat): 2959, 2220, 1682, 1663,
1482, 1231 cm–1. HRMS (EI): m/z calcd for C14H13ON [M+]:
211.0997; found: 211.0997. Compounds 2b–e were
prepared by a similar procedure.
Equation 6 Reaction of 5aa with primary amines 10
NH
R2
· HCl (8)
O
O
NH2
(2.0 equiv)
N
NHAc
R1
R2
py, 100 °C
N
R1
O
R1 = nBu, R2 = Ph 9aia 89%
R1 = nBu, R2 = Me 9aib 68%
R1 = iPr, R2 = Ph 9bia 96%
5ai or 5bi
Equation 7 Synthesis of 9-oxoindenopyrimidines (9) from 2-ace-
tylamino-3-acylindenone (5ai and 5bi) and amidine hydrochlorides 8
O
O
MeNHNH2 (1.2 equiv)
N
NHAc
1,4-dioxane, 60 °C, 3 h
N
Me
R1
R1
O
(5) Normant, J. F.; Piechucky, C. Bull. Soc. Chem. Fr. 1972, 6,
2402.
(6) No reaction occurred at room temperature.
R1
=
nBu 12ai 52%
iPr 12bi 46%
5ai or 5bi
(7) Representative Procedure for the Cyclization Reaction
of 2 with 4
Equation 8 Synthesis of 2-methyl-8-oxoindenopyrazoles (12) from
2-acetylamino-3-acylindenone (5ai and 5bi) and methylhydrazine
A mixture of 2-(1-hexyn-1-yl)benzoyl cyanide (2a, 42.3 mg,
0.20 mmol) and benzoic acid (4a, 48.8 mg, 0.40 mmol) in
p-xylene (1.0 mL) was stirred at 140 °C for 24 h under an
argon atmosphere, and then the solvent was evaporated in
vacuo. The residue was purified by preparative thin-layer
chromatography (toluene–EtOAc, 10:1) to afford 2-
benzoylamino-3-pentanoylindenone 5aa (55.9 mg, 84%). 1H
NMR (300 MHz, CDCl3): d = 0.91 (3 H, t, J = 7.2 Hz), 1.38
(2 H, pseudo sext, J = 7.5 Hz), 1.74 (2 H, pseudo quin,
J = 7.5 Hz), 2.75 (2 H, t, J = 7.5 Hz), 7.14 (2 H, t, J = 7.5
In conclusion, we have found that 2-alkynylbenzoyl cya-
nides possessing a propargylic hydrogen react readily
with carboxylic acids to provide 2-acylamino-3-acylinde-
nones. The reaction proceeds via a cyclic allenyl interme-
diate, which is generated by assistance of the enhanced
electrophilic nature of the cyano group. The produced 2-
Synlett 2008, No. 12, 1817–1820 © Thieme Stuttgart · New York

1820
H. Shimizu, M. Murakami
LETTER
Hz), 7.35 (1 H, dt, J = 1.2, 7.5 Hz), 7.44–7.56 (3 H, m),
Hz), 3.13 (2 H, t, J = 7.5 Hz), 7.33–7.47 (1 H, m), 7.47–7.57
(3 H, m), 7.57–7.69 (2 H, m), 7.82 (1 H, d, J = 7.5 Hz), 8.47–
8.62 (2 H, m). 13C NMR (75 MHz, CDCl3): d = 14.2, 22.8,
29.4, 35.9, 123.7, 125.6, 128.6, 128.7, 129.7, 131.17,
131.23, 131.9, 136.3, 137.1, 141.8, 160.3, 165.3, 165.5,
193.4. IR (KBr): 2959, 1730, 1572, 1458, 1390, 1186 cm–1.
HRMS (EI): m/z calcd for C21H18ON2 [M+]: 314.1419;
found: 314.1422.
7.56–7.64 (1 H, m), 7.87–7.94 (2 H, m), 8.40 (1 H, br s). 13
C
NMR (75 MHz, CDCl3): d = 14.1, 22.6, 25.8, 44.1, 121.9,
124.4, 126.8, 127.3, 127.6, 127.9, 129.1, 132.5, 132.7,
133.0, 135.6, 145.5, 164.9, 193.0, 201.1. IR (KBr): 3312,
2959, 1726, 1678, 1662, 1512, 1277 cm–1. HRMS (EI): m/z
calcd for C21H19O3N [M+]: 333.1365; found: 333.1361.
(8) Compound 2f was prepared by the SnCl4-catalyzed reaction
of acid chloride with TMSCN: Olah, G. A.; Arvanaghi, M.;
Prakash, G. K. S. Synthesis 1983, 636.
(13) Representative Procedure for the Synthesis of
Indenopyrazole
(9) When 5ai was exposed to same reaction conditions, a
deuterium was incorporated only in 17% at the a-position of
the carbonyl group.
(10) No reaction occurred with secondary amines such as a
piperidine and N-benzylmethylamine.
(11) For cyclocondensation of b-enamino carbonyl compounds
with amidines and hydrazines, see: (a) Bredereck, H.; Sell,
R.; Effenberger, F. Chem. Ber. 1964, 97, 3407. (b) Kvita,
V. Synthesis 1986, 786. (c) Bredereck, H.; Herlinger, H.;
Schweizer, E. Chem. Ber. 1960, 93, 1208. (d) Plath, P.;
Rohr, W. Synthesis 1982, 318.
To a stirred solution of 5ai (27.2 mg, 0.10 mmol) in 1,4-
dioxane (0.5 mL) under an argon atmosphere was added a
solution of methylhydrazine (5.5 mg, 0.12 mmol) in 1,4-
dioxane (0.5 mL) at 60 °C over 5 min. After being stirred for
3 h, the reaction mixture was cooled and diluted with EtOAc
(5 mL) and H2O (5 mL). The organic layer was separated and
the aqueous layer was extracted with EtOAc (4 × 3 mL). The
combined extracts were washed with H2O and brine, and
dried over MgSO4. The solvent was evaporated in vacuo.
The residue was purified by preparative thin-layer
chromatography (CHCl3–EtOAc, 10:1) to afford 3-butyl-2-
methyl-8H-indeno[2,1-c]pyrazol-8-one (12ai, 12.4 mg,
52%). 1H NMR (300 MHz, CDCl3): d = 0.97 (3 H, t, J = 7.3
Hz), 1.39–1.49 (2 H, m), 1.63–1.73 (2 H, m), 2.74 (2 H, t,
J = 7.5 Hz), 3.83 (3 H, s), 7.09–7.14 (2 H, m), 7.35 (1 H, dt,
J = 1.1, 7.5 Hz), 7.52 (1 H, dd, J = 1.3, 7.7 Hz). 13C NMR
(75 MHz, CDCl3): d = 13.8, 22.3, 25.0, 30.7, 37.1, 120.2,
124.7, 126.8, 129.6, 134.4, 137.5, 138.0, 138.4, 152.3,
186.2. IR (KBr): 2939, 1714, 1603, 1491, 1317, 1169 cm–1.
HRMS (EI): m/z calcd for C15H16ON2 [M+]: 240.1263;
found: 240.1260. The position of the methyl group was
identified by NOE measurement.
(12) Representative Procedure for the Synthesis of
Indenopyrimidine
A mixture of 5ai (27.2 mg, 0.10 mmol) and benzamidine
hydrochloride (8a, 38.5 mg, 0.20 mmol) in pyridine (1.0
mL) was stirred at 100 °C for 24 h under an argon
atmosphere, and then the reaction mixture was cooled and
diluted with EtOAc (5 mL) and H2O (5 mL). The organic
layer was separated and the aqueous layer was extracted with
EtOAc (3 × 3 mL). The combined extracts were washed with
H2O and brine, and dried over MgSO4. The solvent was
evaporated in vacuo. The residue was purified by preparative
thin-layer chromatography (toluene–EtOAc, 20:1) to afford
4-butyl-2-phenyl-9H-indeno[2,1-d]pyrimidin-9-one (9aia,
28.1 mg, 89%). 1H NMR (300 MHz, CDCl3): d = 1.04 (3 H,
t, J = 7.5 Hz), 1.45–1.65 (2 H, m), 1.92 (2 H, quin, J = 7.7
(14) For selective formation of N-substituted pyrazoles from N-
methoxy-N-methyl-b-enaminoketoesters, see: Persson, T.;
Nielsen, J. Org. Lett. 2006, 8, 3219.
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