First synthesis of functionalized benzonitriles by formal [3+3] cyclocondensations of 1,3-bis(silyloxy)buta-1,3-dienes

Article abstract of DOI:10.1055/s-0028-1087395

A variety of functionalized benzonitriles were regioselectively prepared by formal [3+3] cyclocondensation of 1,3-bis(silyloxy) buta-1,3-dienes with 3-ethoxy- and 3-silyloxy-2-cyano-2-en-1-ones. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087395

LETTER
201
First Synthesis of Functionalized Benzonitriles by Formal [3+3] Cyclo-
condensations of 1,3-Bis(silyloxy)buta-1,3-dienes
S
ynthesis of Funct
l
ionalize
u
d Benzonitr
m
iles ide Fatunsin,a Mohanad Shkoor,a Abdolmajid Riahi,a,b Rüdiger Dede,a Helmut Reinke,a Peter Langer*a,b
a
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
Fax +049(381)4986412; E-mail: peter.langer@uni-rostock.de
b
Received 22 September 2008
ethyl acetone-1,3-dicarboxylate with 3-oxopentanedioic
acid diethyl ester.9 4-Amino-2-hydroxy-5-cyanoace-
tophenone is available by cyclization of malodinitrile with
2-acetyl-3-methoxyacrylic acid methyl ester.10 Benzoni-
triles have been prepared also based on Diels–Alder reac-
tions of cyano-substituted alkynes or buta-1,3-dienes.11
Recently, Pulido and Barbero have reported the synthesis
of methyl 3-cyano-4-hydroxy-2-methylbenzoate by [4+2]
cycloaddition of 3-cyano-2,4-bis(silyloxy)penta-1,3-di-
ene with propynoic acid methyl ester.12
Chan and co-workers were the first to report13 the synthe-
sis of salicylates by formal [3+3] cyclizations of 1,3-
bis(silyloxy)buta-1,3-dienes14 with 3-silyloxy-2-en-1-
ones. In recent years, this strategy has been applied to the
synthesis of various functionalized arenes.15 Herein, we
report what are, to the best of our knowledge, the first
[3+3] cyclocondensations of 1,3-bis(silyloxy)buta-1,3-
dienes with cyano-substituted 3-ethoxy- and 3-silyloxy-2-
en-1-ones. These reactions provide a convenient and
regioselective approach to a variety of functionalized 5-
cyanosalicylates, which are not readily available by other
methods.
Abstract: A variety of functionalized benzonitriles were regiose-
lectively prepared by formal [3+3] cyclocondensation of 1,3-bis(si-
lyloxy)buta-1,3-dienes with 3-ethoxy- and 3-silyloxy-2-cyano-2-
en-1-ones.
Key Words: arenas, benzonitriles, cyclizations, regioselectivity,
silyl enol ethers
Functionalized benzonitriles represent important building
blocks for the synthesis of natural products, pharmaceuti-
cals, agrochemicals, herbicides, and dyes. Their industrial
scale syntheses mostly rely on the ammoxidation of tolu-
enes. In addition, the reaction of aryl halides with cop-
per(I) cyanide (Rosenmund–von Braun reaction) and the
reaction of diazonium salts with copper(I) cyanide (Sand-
meyer reaction) are frequently used. In 2003, a catalytic
variant has been reported.1 In recent years, nickel- and
palladium-catalyzed cyanations of aryl halides have been
developed.2 5-Cyanosalicylates can be regarded as highly
functionalized benzonitrile derivatives containing an ad-
ditional ester and hydroxyl group. They have been pre-
pared by classic transformation of the corresponding
oximes into the nitriles,3 by application of the Rosen-
mund–von Braun reaction,4 by application of palladi-
um(0)-catalyzed reactions using Zn(CN)2 or KCN,5 and
by Grignard reaction of 4-hydroxy-3,5-diiodobenzonitrile
with carbon dioxide.6 Despite the recent progress in this
area, cyanation reactions often suffer from low catalyst
productivities (compared to other palladium-catalyzed
coupling reactions). In addition, reactions of ortho-substi-
tuted aryl halides are often problematic or not possible at
all or require the use of toxic thallium reagents.7 Last but
not the least, the regioselective synthesis of the required
starting materials, functionalized or highly substituted
aryl halides or triflates, can be a difficult and tedious task.
2-Cyano-3-ethoxy-2-en-1-ones 2a–e were prepared, fol-
lowing a known procedure,16 by reaction of ketonitriles
1a–e with ethyl orthoformiate and acetic anhydride. 1,3-
Bis(silyloxy)buta-1,3-dienes 3a–l were prepared from the
corresponding b-keto esters in two steps.13
The TiCl4-mediated cyclization of 2a with 3a afforded the
5-cyanosalicylate 4a (Scheme 1). The best yield was ob-
tained when the reaction was carried out in a highly con-
centrated solution.17 The cyclization proceeded with
excellent regioselectivity. The formation of product 4a
might be explained by TiCl4-mediated conjugate addition
of the terminal carbon atom of 3a to 2a to give intermedi-
ate A, cyclization via the central carbon of 3a to give
intermediate B (SN¢ reaction), and subsequent aromatiza-
tion.
An alternative strategy for the synthesis of functionalized
benzonitriles relies on the use of appropriate cyano-sub-
stituted building blocks in cyclization reactions. For ex-
ample, ethyl 4-amino-5-cyanosalicylate and related
compounds have been prepared by base-mediated cycliza-
tion of ethoxymethylenemalononitrile with b-keto esters.8
4-Amino-5-cyano-2-hydroxyisophthalic acid diethyl ester
has been synthesized by KOH-mediated cyclization of di-
The formal [3+3] cyclization of 2-cyano-3-ethoxy-2-en-
1-ones 2a–e with 1,3-bis(silyloxy)buta-1,3-dienes 3a–h
afforded the 5-cyanosalicylates 4a–l in 40–61% yields
(Table 1). The substituents R1, located next to the carbon-
yl group of 2a–e, have no significant influence on the
yields. Likewise, the substitution pattern of the diene has
no significant influence on the yield.
SYNLETT 2009, No. 2, pp 0201–0204
x
x.
x
x.
2
0
0
9
The configuration of all products was established by spec-
troscopic methods (2D NMR). The structure of 4a was in-
Advanced online publication: 15.01.2009
DOI: 10.1055/s-0028-1087395; Art ID: D33608ST
© Georg Thieme Verlag Stuttgart · New York

202
O. Fatunsin et al.
LETTER
TMSO
OTMS
O
OH
CN
OEt
TiCl4
3a
CH2Cl2
OEt
+
–78 to 20 °C
14 h
EtO
O
Me
Me
4a
CN
2a
– TMSCl
– TiCl3OH
O
O
O
TMSO
OEt
OTiCl3
Me
Figure 1 ORTEP plot of 4a (hydrogen at O3 found in the difference
map and refined freely)
OEt
– TMSOEt
OTiCl3
Me
EtO
CN
CN
Table 2 Synthesis of 6a–f: Products and Yields
A
B
TMSO
R1
OTMS
Scheme 1 Possible mechanism of the formation of 4a
OR2
O
OH
R1
TiCl4
3a, c, i–l
OR2
Table 1 Synthesis of 4a–l
CH2Cl2
+
–78 to 20 °C,
20 h
20 °C, 4 h
TMSO
R2
OTMS
OR3
TMSO
Me
O
Me
Me
CN
O
OH
CN
Me
TiCl4
R2
3a–h
4Å MS
OR3
CH2Cl2
6a–f
CN
+
–78 to 20 °C
14 h
5
EtO
O
R1
3
6
R1
H
R2
Yield of 6 (%)a
R1
4a–l
CN
2a–e
3i
6a
6b
6c
6d
6e
6f
Me
Et
34
41
40
8
2
3
4
R1
R2
R3
Yield
(%)a
3a
3j
H
H
i-Bu
t-Bu
Me
Et
2a
2a
2a
2a
2a
2b
2b
2b
2b
2c
2d
2e
3a
3b
3c
3d
3e
3b
3c
3f
4a
4b
4c
4d
4e
4f
Me
H
Et
33
41
40
42
40
43
42
41
40
61
57
50
3k
3l
H
Me
Me
Me
Et
Et
Et
44
58
Me
Et
3c
Me
n-Hex
n-Hept
Me
Me
Me
Me
Et
a Yields of isolated products.
Me
Ph
3-Cyano-4-(trimethylsilyloxy)pent-3-en-2-one (5) was
prepared by silylation of known19 3-cyano-acetylacetone.
The TiCl4-mediated [3+3] cyclocondensation of 5 with
3a,c,i–l afforded the 5-cyanosalicylates 6a–f in moderate
yields (except for 6d, Table 2).20 The best yields were
again obtained when the reactions were carried out in a
highly concentrated solution. The low yield of 6d can be
explained by TiCl4-mediated cleavage of the tert-butyl
ester.
4g
4h
4i
Ph
Et
Ph
n-Bu
n-Oct
Me
Me
Me
Me
Me
Me
3g
3b
3h
3g
Ph
4j
4-ClC6H4
4-BrC6H4
4-MeOC6H4
4k
4l
n-Non
n-Oct
In conclusion, we have reported a convenient and regiose-
lective synthesis of functionalized benzonitriles by what
are, to the best of our knowledge, the first formal [3+3] cy-
clizations of 1,3-bis(silyloxy)buta-1,3-dienes with cyano-
substituted enones. The products are not readily available
by other methods. The reactions are easy to be carried out,
a Yields of isolated products.
dependently confirmed by X-ray crystal structure analysis
(Figure 1).18
Synlett 2009, No. 2, 201–204 © Thieme Stuttgart · New York

LETTER
Synthesis of Functionalized Benzonitriles
203
(8) (a) Schmidt, H.-W.; Junek, H. Liebigs Ann. Chem. 1979,
2005. (b) Schmidt, H.-W.; Klade, M. Liebigs Ann. Chem.
1988, 257.
(9) Leaver, D.; Vass, J. D. R. J. Chem. Soc. 1965, 1629.
(10) Baker, S. R.; Crombie, L.; Dove, R. V.; Slack, D. A.
J. Chem. Soc., Perkin Trans. 1 1979, 677.
and the starting materials are readily available. We cur-
rently study the preparative scope of the methodology and
applications to the synthesis of pharmacologically active
products.
(11) See, for example: (a) Dilthey, W.; Schommer, W.; Trösken,
O. Ber. Dtsch. Chem. Ges. 1933, 66, 1627. (b) Noland,
W. E.; Kuryla, W. C.; Lange, R. F. J. Am. Chem. Soc. 1959,
81, 6010. (c) Boulton, A. J.; Mathur, S. S. J. Org. Chem.
1973, 38, 1054. (d) Ciganek, E. J. Org. Chem. 1969, 34,
1923. (e) Hopf, H.; Lenich, T. Chem. Ber. 1974, 107, 1891.
(f) Sasaki, T.; Ishibashi, Y.; Ohno, M. J. Chem. Res.,
Miniprint 1984, 7, 1972.
(12) Barbero, A.; Pulido, F. J. Synthesis 2004, 401.
(13) (a) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980,
102, 3534. (b) Brownbridge, P.; Chan, T.-H.; Brook, M. A.;
Kang, G. J. Can. J. Chem. 1983, 61, 688.
(14) For a review of 1,3-bis(silyloxy)buta-1,3-dienes, see:
Langer, P. Synthesis 2002, 441.
(15) Feist, H.; Langer, P. Synthesis 2007, 327.
(16) Salon, J.; Milata, V.; Pronayova, N.; Lesko, J. Monatsh.
Chem. 2000, 131, 293.
(17) Typical Experimental Procedure for the Synthesis of 4a–l
To a stirred solution of CH2Cl2 (3 mL per 1.0 mmol of 2a–e)
of 2a–e was added 3a–h (1.1 mmol) and, subsequently,
TiCl4 (1.1 mmol) at –78 °C under argon atmosphere. The
temperature of the reaction mixture was allowed to rise to
20 °C over 14 h with stirring. To the solution was added HCl
(10%, 20 mL) and the organic and the aqueous layer were
separated. The latter was extracted with CH2Cl2 (3 × 20
mL). The combined organic layers were dried (Na2SO4),
filtered, and the filtrate was concentrated in vacuo. The
residue was purified by column chromatography (SiO2,
heptanes–EtOAc) to give 4a–l. Starting with 2a (0.209 g, 1.5
mmol) and 3a (0.446 g, 1.65 mmol), 4a was isolated as a
colorless solid (101 mg, 33%), mp 86–87 °C. 1H NMR (250
MHz, CDCl3): d = 1.39 (t, 3J = 7.1 Hz, 3 H, OCH2CH3), 2.72
(s, 3 H, CH3), 4.42 (q, 3J = 7.1 Hz, 2 H, OCH2CH3), 6.84 (d,
3J = 8.8 Hz, 1 H, Ar), 7.53 (d, 3J = 8.8 Hz, 1 H, Ar), 11.78 (s,
1 H, OH). 13C NMR (75 MHz, CDCl3): d = 13.1 (CH3), 20.8
(OCH2CH3), 61.7 (OCH2), 104.8 (CCN), 112.6 (CCO2Et),
116.0 (CH), 117.4 (CN), 136.7 (CH), 145.5 (CCH3), 164.8
(COH), 169.6 (C=O). IR (neat): n = 3072 (w), 2991 (w),
2923 (w), 2851 (w), 2777 (w), 2692 (w), 2589 (w), 2224 (w),
1660 (s), 1588 (m), 1570 (w), 1476 (m), 1450 (w), 1398 (m),
1375 (s), 1348 (m), 1318 (m), 1302 (m), 1231 (s), 1182 (w),
1146 (m), 1108 (w), 1057 (w), 1021 (m), 996 (w), 909 (w),
856 (m), 831 (m), 723 (w), 632 (w), 609 (w), 558 (w) cm–1.
MS (GC-MS, 70 eV): m/z (%) = 205 (26) [M+], 159 (100),
130 (22), 103 (8), 77 (12), 51 (6). HRMS (EI): m/z calcd for
C11H11NO3: 205.07334; found: 205.073572.
Acknowledgment
Financial support by the State of Mecklenburg-Vorpommern
(scholarship for M. S.) is gratefully acknowledged.
References and Notes
(1) Zanon, J.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 2890.
(2) (a) Ellis, G. P.; Romney-Alexander, T. M. Chem. Rev. 1987,
87, 779. (b) Sundermeier, M.; Zapf, A.; Beller, M. Eur. J.
Inorg. Chem. 2003, 3513. (c) Cassar, L.; Foà, M.;
Montanari, F.; Marinelli, G. P. J. Organomet. Chem. 1979,
173, 335. (d) Sakakibara, Y.; Okuda, F.; Shimoyabashi, A.;
Kirino, K.; Sakai, M.; Uchino, N.; Takagi, K. Bull. Chem.
Soc. Jpn. 1988, 61, 1985. (e) Sakakibara, Y.; Ido, Y.;
Sasaki, K.; Sakai, M.; Uchino, N. Bull. Chem. Soc. Jpn.
1993, 66, 2776. (f) Takagi, K.; Okamoto, T.; Sakakibara, Y.;
Oka, S. Chem. Lett. 1973, 471. (g) Sekiya, A.; Ishikawa, N.
Chem. Lett. 1975, 277. (h) Takagi, K.; Okamoto, T.;
Sakakibara, Y.; Ohno, A.; Oka, S.; Hayama, N. Bull. Chem.
Soc. Jpn. 1975, 48, 3298. (i) Dalton, J. R.; Regen, S. L.
J. Org. Chem. 1979, 44, 4443. (j) Akita, Y.; Shimazaki, M.;
Ohta, A. Synthesis 1981, 974. (k) Chatani, N.; Hanafusa, T.
J. Org. Chem. 1986, 51, 4714. (l) Takagi, K.; Sasaki, K.;
Sakakibara, Y. Bull. Chem. Soc. Jpn. 1991, 64, 1118.
(m) Anderson, Y.; Långström, B. J. Chem. Soc., Perkin
Trans. 1 1994, 1395. (n) Anderson, B. A.; Bell, E. C.;
Ginah, F. O.; Harn, N. K.; Pagh, K. M.; Wepsiec, J. P.
J. Org. Chem. 1998, 63, 8224. (o) Okano, T.; Kiji, J.;
Toyooka, Y. Chem. Lett. 1998, 425. (p) Maligres, P. E.;
Waters, M. S.; Fleitz, F.; Askin, D. Tetrahedron Lett. 1999,
40, 8193. (q) Jin, F.; Confalone, P. N. Tetrahedron Lett.
2000, 41, 3271. (r) Sundermeier, M.; Zapf, A.; Beller, M.;
Sans, J. Tetrahedron Lett. 2001, 42, 6707. (s) Ramnauth, J.;
Bhardwaj, N.; Renton, P.; Rakhit, S.; Maddaford, S. Synlett
2003, 2237. (t) Sundermeier, M.; Zapf, A.; Mutyala, S.;
Baumann, W.; Sans, J.; Weiss, S.; Beller, M. Chem. Eur. J.
2003, 9, 1828. (u) Sundermeier, M.; Zapf, A.; Beller, M.
Angew. Chem. Int. Ed. 2003, 42, 1661. (v) Sundermeier, J.;
Mutyala, S.; Zapf, A.; Spannenberg, A.; Beller, M. J.
Organomet. Chem. 2003, 684, 50. (w) Schareina, T.; Zapf,
A.; Beller, M. Chem. Commun. 2004, 1388.
(3) Houben, J.; Fischer, W. Ber. Dtsch. Chem. Ges. 1933, 66,
339.
(4) (a) Takashi, Y.; Shigeki, N.; Toshiyuki, O.; Toyoo, N.;
Masateru, K. Chem. Pharm. Bull. 1984, 32, 4466.
(b) van Zandt, M. C.; Sibley, E. O.; McCann, E. E.; Combs,
K. J.; Flam, B.; Sawicki, D. R.; Sabetta, A.; Carrington, A.;
Sredy, J.; Howard, E.; Mitschler, A.; Podjarny, A. D. Bioorg.
Med. Chem. 2004, 12, 5661.
(5) (a) Nelson, P. H.; Carr, S. F.; Devens, B. H.; Eugui, E. M.;
Franco, F. J. Med. Chem. 1996, 39, 4181. (b) Srivastava,
R. R.; Collibee, S. E. Tetrahedron Lett. 2004, 45, 8895.
(6) Kopp, F.; Wunderlich, S.; Knochel, P. Chem. Commun.
2007, 20, 2075.
(18) CCDC-703181 contains all crystallographic details of this
publication and is available free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the following address: Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
UK; fax: +44 (1223)336033; or deposit@ccdc.cam.ac.uk.
(19) Buttke, K.; Niclas, H.-J. Synth. Commun. 1994, 24, 3241.
(20) Typical Experimental Procedure for the Synthesis of 6a–f
To a CH2Cl2 solution of 5 was added TiCl4 at –78 °C in the
presence of MS (4 Å). The appropriate bis(silyl enol ether) 3
was subsequently added. The reaction mixture was allowed
to warm to 20 °C during 20 h and was stirred for further 4 h.
To the solution was added CH2Cl2, the MS were removed,
and a sat. aq soln of NaHCO3 was added. The organic layer
was separated, and the aqueous layer was repeatedly
(7) (a) Taylor, E. C.; Katz, A. H.; McKillop, A. Tetrahedron
Lett. 1984, 25, 5473. (b) Sargent, M. V. J. Chem. Soc.,
Perkin Trans. 1 1987, 231.
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204
O. Fatunsin et al.
LETTER
extracted with CH2Cl2. All organic extracts were combined,
dried (Na2SO4), and filtered. The filtrate was concentrated in
vacuo. The residue was purified by column chromatography
(SiO2) to give salicylates 6. Starting with 5 (188 mg, 0.95
mmol), CH2Cl2 (3.0 mL), MS (4 Å, 0.4 g), TiCl4 (0.11 mL,
1.0 mmol), and 3i (356 mg, 1.4 mmol), compound 6a was
isolated by column chromatography (SiO2; n-heptane–
EtOAc, 10:1) as a colorless solid (67 mg, 34%), mp 109–
110 °C; Rf = 0.21 (n-heptane–EtOAc, 10:1); reaction time
21 h. 1H NMR (250 MHz, CDCl3): d = 2.48 (d, 4J = 0.9 Hz,
3 H, ArCH3), 2.75 (s, 3 H, ArCH3), 3.98 (s, 3 H, OCH3), 6.76
(s, 1 H, CHAr), 11.72 (s, 1 H, OH). 13C NMR (75 MHz,
CDCl3): d = 21.4, 21.8 (ArCH3), 52.7 (OCH3), 107.0, 111.0,
117.3 (2 × CAr, CN), 117.4 (CHAr), 146.6, 148.4 (CAr), 165.1,
171.0 (CArOH, CO). IR (KBr): n = 3431 (br, m), 2957 (m),
2217 (s), 1668 (s), 1601 (s), 1581 (s), 1442 (s), 1368 (s),
1358 (s), 1319 (s), 1241 (s), 810 (s) cm–1. MS (EI, 70 eV):
m/z (%) = 205 (83) [M+], 174 (76), 173 (100), 145 (66), 144
(37), 116 (20), 91 (14). Anal. Calcd for C11H11NO3 (205.21):
C, 64.38; H, 5.40; N, 6.83. Found: C, 64.64; H, 5.52; N, 6.65.
Synlett 2009, No. 2, 201–204 © Thieme Stuttgart · New York

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