A novel three-component coupling reaction of arynes, isocyanides, and cyanoformates: A straightforward access to cyano-substituted iminoisobenzofurans

Article abstract of DOI:10.3987/COM-12-S(N)77

Iminoisobenzofuran derivatives have been prepared in moderate yields by the palladium-catalyzed three-component coupling reaction of arynes, isocyanides, and cyanoformates.

Full text of DOI:10.3987/COM-12-S(N)77

HETEROCYCLES, Vol. 86, No. 2, 2012
933
HETEROCYCLES, Vol. 86, No. 2, 201, pp. 933 - 940. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 30th June, 2012, Accepted, 16th August, 2012, Published online, 23rd August, 2012
DOI: 10.3987/COM-12-S(N)77
A NOVEL THREE-COMPONENT COUPLING REACTION OF ARYNES,
ISOCYANIDES, AND CYANOFORMATES: A STRAIGHTFORWARD
ACCESS TO CYANO-SUBSTITUTED IMINOISOBENZOFURANS
Jing Li,1 Shintaro Noyori,1 Masayuki Iwasaki,1 Kiyohiko Nakajima,2 and
Yasushi Nishihara1*
Division of Earth, Life, and Molecular Sciences, Graduate School of Natural
Science and Technology, Okayama University, 3-1-1 Tsushimanaka, Kita-ku,
Okayama 700-8530, Japan. Department of Chemistry, Aichi University of
Education, Igaya, Kariya 448-8542, Japan. E-mail: ynishiha@okayama-u.ac.jp
Abstract – Iminoisobenzofuran derivatives have been prepared in moderate
yields by the palladium-catalyzed three-component coupling reaction of arynes,
isocyanides, and cyanoformates.
This paper is dedicated to Professor Ei-ichi Negishi on the occasion of his 77th
birthday.
Arynes are versatile and useful tools in synthetic organic chemistry, notably for the construction of
multi-substituted arenes which are hard to access by conventional methods.1 We have reported the
palladium-catalyzed cyanoesterification of norbornene derivatives via carbon-carbon bond cleavage of
cyanoformates.2 In the course of our attempts to find a new route for cyanoesterification of benzyne, a
benzyne precursor, 2-(trimethylsilyl)phenyl triflate (1a), was treated with a fluoride ion (KF/18-crown-6)3
in conjunction with a palladium catalyst and 1,1,3,3-tetramethylbutyl isocyanide (2a: tOctNC) as a ligand.
Using this system as an approach to ethyl 2-cyanobenzoate by using ethyl cyanoformate (3a), we
observed that N-[3-cyano-3-ethoxy-1(3H)-isobenzofuranylidene]-2,4,4-trimethyl-2-pentanamine (4a) was
formed as a minor byproduct in 5% yield (Scheme 1). Independent studies by the groups of Yoshida
and Kunai (aldehydes, ketones, and sulfonylimines)4 and Stoltz (phenyl esters)5 in the three-component
coupling reactions of arynes with isocyanides provided the direct synthesis of benzoannulated
iminofurans.6 Herein we disclose the use of a variety of cyanoformates as the third coupling partners in
such three-component assemblies with arynes and isocyanides, affording five-membered
iminoisobenzofuran derivatives with structural diversity.

934
HETEROCYCLES, Vol. 86, No. 2, 2012
PdCl2(MeCN)2 (5 mol%)
NtOct
t
2a
OctNC ( : 75 mol%)
O
OTf
KF/18-crown-6
O
+
EtO
CN
THF, 50 ºC, 18 h
5%
TMS
OEt
NC
1a:
3a:
4a
0.1 mmol
0.1 mmol
Scheme 1. Palladium-Catalyzed Three-Component Coupling.
As seen in Table 1, a variety of catalysts and solvents were exploited to improve the product yield of 4a.
We began our study on the three-component coupling by using 1a, 2a, and 3a in the presence of
potassium fluoride/18-crown-6 in THF without transition metal catalyst at 50 ºC for 18 h. However,
none of the desired product 4a was formed (entry 1). This result is in contrast to the results obtained by
Yoshida and Kunai,4 and Stoltz,5 in which iminoisobenzofuran derivatives were synthesized by adding
only a fluoride ion (KF or TBAT) in the three-component coupling reactions. When PdCl2(PhCN)2 was
added as the catalyst, the formation of product 4a was observed in 56% GC yield (entry 2). Initial
screening for prospective catalysts revealed that various Pd and Rh catalysts such as
[Pd(η-C3H5)(cod)]BF4,7 [Rh(cod)2]BF4,8 [Cp*Rh(MeCN)3](PF6)2,9 or [Cp*RhCl2]2,10 could catalyze this
reaction to some extent (entries 3-6). Further investigation has shown that the 68% GC yield of the
11
product 4a was obtained when [Pd(PhCN)2(dppf)](BF4)2 was employed as the catalyst (entry 7). We
investigated to use other solvents such as n-butyl ether or benzonitrile (entries 8 and 9), however, lower
yields were generally observed and the reaction would not proceed at all in 1,4-dioxane (entry 10).
Finally, we defined the optimized ratios of the substrates as the standard conditions: 2 equiv of benzyne
precursor 1a and isocyanide 2a to 3a in the presence of 4 equiv of KF/18-crown-6 under 10 mol% of
[Pd(PhCN)2(dppf)](BF4)2. To the best of our knowledge, this synthetic method provides the first
example of an alkoxy- and cyano-substituted iminoisobenzofuran.
Under the optimized reaction conditions, we then employed a variety of isocyanides 2 and cyanoformates
3 in order to examine the scope of this transformation. As described in Table 2, the three-component
coupling reactions proceeded smoothly to form the corresponding cyano-substituted iminoisobenzofurans
4. The reactions of cyanoformates 3b-3f bearing different substituents efficiently occurred to give the
desired products 4b-4f in good yields (entries 2-6).12 The structure of 4a was unambiguously confirmed
through careful NMR spectroscopy, MS, and X-ray diffraction analysis. As shown in Figure 1, the
imine moiety in the product 4a was found to have the Z configuration.13

HETEROCYCLES, Vol. 86, No. 2, 2012
935
Table 1. Three-Component Coupling of Benzyne Precursor 1a, 1,1,3,3-Tetramethylbutyl Isocyanide (2a)
and Ethyl Cyanoformate (3a).a
NtOct
catalyst (10 mol%)
NC
O
OTf
KF/18-crown-6
O
+
+
EtO
CN
(tOctNC)
THF, 50 ºC, 18 h
TMS
OEt
NC
1a
2a
3a
4a
entry
catalyst
solvent
THF
THF
yield (%)b
1
2
none
0
56
PdCl2(PhCN)2
3
4
[Pd(η-C3H5)(cod)]BF4
[Rh(cod)2]BF4
THF
THF
52
45
5
6
[Cp*Rh(MeCN)3](PF6)2
[Cp*RhCl2]2
THF
THF
47
16
7
8
9
10
[Pd(PhCN)2(dppf)](BF4)2
[Pd(PhCN)2(dppf)](BF4)2
[Pd(PhCN)2(dppf)](BF4)2
[Pd(PhCN)2(dppf)](BF4)2
THF
68(44)c
31
24
0
nBu2O
PhCN
1,4-dioxane
a The reaction was carried out using 1a (0.15 mmol), 2a (0.15 mmol), 3a (0.075 mmol), KF (0.3
mmol), 18-crown-6 (0.3 mmol), and a catalyst (10 mol%) in a solvent (0.5 mL) at 50 ºC for 18
b
h.
Yields were determined by GC using tetradecane as an internal standard, based on
cyanoformate 3a. c An isolated yield. Tf = trifluoromethanesulfonyl, TMS = trimethylsilyl.
In the case of the aromatic cyanoformate 3g, the desired product 4g was not generated because the
cationic Pd catalyst gave diphenyl carbonate as a by-product (entry 7). Except for 2a, the aliphatic
substituted isocyanides such as tert-butyl isocyanide (2b) participated in the three-component coupling
reaction to afford 4h in 42% (entry 8). In all cases, the unidentified by-products showed the same
molecular weight as 4, indicating structural isomers; these products were observed by GC-MS.
Figure 1. Structure of complex 4a determined by X-ray crystallography with 30% thermal ellipsoidal
plotting. Hydrogen atoms are omitted for simplicity.

936
HETEROCYCLES, Vol. 86, No. 2, 2012
Table 2. Pd-Catalyzed Three-Component Coupling of 1a, Isocyanides 2, and Cyanoformates 3.a
NR1
[Pd(PhCN)2(dppf)](BF4)2 (10 mol%)
OTf
O
KF/18-crown-6
R1NC
+
O
+
R2
CN
THF, 18 h, 50 ºC
TMS
R2
NC
1a
2
3
4
entry
isocyanide
cyanoformates
product
yield (%)b
(R1 = )
(R2 = )
OEt (3a)
OMe (3b)
OnPr (3c)
OiPr (3d)
OnBu (3e)
OBn (3f)
OPh (3g)
3a
t
1
2
3
4
5
6
7
8
CMe2CH2 Bu (tOct) (2a)
4a
4b
4c
4d
4e
4f
44
47
44
46
40
51
0
2a
2a
2a
2a
2a
2a
4g
4h
tBu (2b)
42
a
The reactions were carried out using 1a (1 mmol), 2 (1 mmol), 3 (0.5 mmol), KF (2 mmol) and
18-crown-6 (2 mmol), Pd catalyst (10 mol%) in THF (3.3 mL) at 50 ºC for 18 h. b Isolated yields, based
on cyanoformate 3.
To understand the effect of substituents on the benzyne moiety in the present reaction, substituted
benzyne precursors 1b and 1c were tested (Scheme 2). Under the optimized reaction conditions,
compound 1b, containing 4,5-dimethyl substitution, reacted smoothly with 2b and 3a to give the
three-component coupled product 4i in 18% yield. When 1-(trimethylsilyl)naphth-2-yl triflate (1c) was
subjected to the reaction, a 72:28 mixture of isomers 4j was obtained in 48% combined yield. We
presume that the major product was formed by the attack of the isocyanide on the 2-position due to the
steric congestion.4b
NtBu
[Pd(PhCN)2(dppf)](BF4)2 (10 mol%)
Me
Me
Me
TMS
OTf
KF/18-crown-6
O
+
2b + 3a
Me
THF, 18 h, 50 ºC
OEt
NC
1b
4i: 18%
NtOct
NtOct
O
TMS
OTf
as above
O
+
+
2a + 3a
OEt
NC
OEt
NC
1c
4j
48% (72:28)
Scheme 2. Three-Component Coupling with Arynes (1b and 1c).

HETEROCYCLES, Vol. 86, No. 2, 2012
937
The reaction was also found to be applicable to benzoyl cyanide (5). As shown in Scheme 3, benzoyl
cyanide (5) reacted with 1a and 2a to afford product 6 in 20% yield.
NtOct
PdCl2(PhCN)2 (10 mol%)
TMS
O
KF/18-crown-6
O
2a
+
+
NC
Ph
THF, 18 h, 50 ºC
20%
OTf
Ph
NC
1a
5
6
Scheme 3. Three-Component Coupling of Benzyne, Benzoyl Cyanide, and 1,1,3,3-Tetramethylbutyl
Isocyanide.
The desired final products 4 can be used as intermediates to generate products containing functionality via
further reaction with the cyano group. A simple transformation for an amide prepared by the treatment
of 4a with potassium hydroxide to form 7 in 91% yield, while leaving the C=N bond intact, is shown in
Scheme 4.
NtOct
NtOct
KOH
O
O
tBuOH
60 ºC, 6 h
91%
OEt
OEt
NC
4a
H2NC
O
7
Scheme 4. Transformation of 4a into the Corresponding Amide 7.
Arynes are known to exhibit high electrophilic character, and even neutral nucleophiles facilely add to
arynes to produce zwitterions, which act as key intermediates in the construction of complex organic
molecules.14 Thus the use of a suitable combination of nucleophiles and electrophiles allows arynes to
serve as connectors between these two components, leading to a variety of three-component coupling
reactions of high synthetic significance.15 We propose a mechanism for this reaction which is presented
in Scheme 4. First, the nucleophilic attack of the carbon atom of isocyanide 2 to the aryne, formed from
1 occurs to generate zwitterions I.
Meanwhile, a cationic palladium(II) complex activates
cyanoformates 3 (or benzoyl cyanide (5)). The resulting zwitterions I then adds to the cyanoformate
activated by cationic palladium species II, and a subsequent intramolecular cyclization affords the
product 4 (or 6). Because the amides derived from the protonation of I were observed in some cases,
the reaction between I and II would be the rate-determining step. We suspect that the added cationic
palladium catalyst might have an interaction with 3 or 5 to increase their electrophilicity. However,

938
HETEROCYCLES, Vol. 86, No. 2, 2012
other Lewis acids such as BPh3 and BF3·OEt2 did not promote the reaction, resulting in the recovered
starting materials.
O
TMS
R1
NC
3, 5
R2
N
OTf
O
1
Pd(II)
R2
CN
F-
4, 6
R1
N
Pd(II)
C N R1
O
2
R2
O
NC
Pd(II)
II
R2 CN
R1
N
I
Scheme 4. A Plausible Reaction Pathway of the Palladium-Catalyzed Three-Component Coupling.
In conclusion, we have demonstrated that arynes can be utilized in a three-component coupling reaction
with a suitable combination of isocyanides and cyanoformate to produce iminoisobenzofuran derivatives.
Further studies on the new three-component coupling via carbon-carbon bond cleavage of cyanoformates
using arynes are now in progress.
ACKNOWLEDGEMENTS
This work was partially supported by a Grant-in-Aid for Scientific Research (KAKENHI) (No.
24550119) from JSPS. The authors gratefully thank Ms. Megumi Kosaka and Mr. Motonari Kobayashi
at the Department of Instrumental Analysis, Advanced Science Research Center, Okayama University for
the measurements of elemental analyses and the SC-NMR Laboratory of Okayama University for the
NMR spectral measurements.
REFERENCES
1. (a) R. W. Hoffmann, Dehydrobenzene and Cycloalkynes, Academic Press, New York, 1967; (b) H.
Hart, The Chemistry of Triple-Bonded Functional Groups, Supplement C2 (ed. by S. Patai), Wiley,
Chichester, 1994, chap. 18; (c) H. Pellissier and M. Santelli, Tetrahedron, 2003, 59, 701; (d) H. H.
Wenk, M. Winkler, and W. Sander, Angew. Chem. Int. Ed., 2003, 42, 502; (e) D. Peña, D. Pérez, and

HETEROCYCLES, Vol. 86, No. 2, 2012
939
E. Guitián, Angew. Chem. Int. Ed., 2006, 45, 3579; (f) S. S. Bhojgude and A. T. Biju, Angew. Chem.
Int. Ed., 2012, 51, 1520; (g) F. Sha, L. Wu, and X. Huang, J. Org. Chem., 2012, 77, 3754.
2. (a) Y. Nishihara, Y. Inoue, M. Itazaki, and K. Takagi, Org. Lett., 2005, 7, 2639; (b) Y. Nishihara, Y.
Inoue, S. Izawa, M. Miyasaka, K. Tanemura, K. Nakajima, and K. Takagi, Tetrahedron, 2006, 62,
9872; (c) Y. Nishihara, M. Miyasaka, Y. Inoue, T. Yamaguchi, M. Kojima, and K. Takagi,
Organometallics, 2007, 26, 4054.
3. Y. Himeshima, T. Sonoda, and H. Kobayashi, Chem. Lett., 1983, 1211.
4. (a) H. Yoshida, H. Fukushima, J. Ohshita, and A. Kunai, Angew. Chem. Int. Ed., 2004, 43, 3935; (b)
H. Yoshida, H. Fukushima, T. Morishita, J. Ohshita, and A. Kunai, Tetrahedron, 2007, 63, 4793; (c)
H. Yoshida and K. Takaki, Heterocycles, 2012, 85, 1333.
5. K. M. Allan, C. D. Gilmore, and B. M. Stoltz, Angew. Chem. Int. Ed., 2011, 50, 4488.
6. (a) Y. Ito, H. Kato, and T. Saegusa, J. Org. Chem., 1982, 47, 741; (b) A. I. Meyers, M. A. Hanagan,
L. M. Trefonas, and R. J. Baker, Tetrahedron, 1983, 39, 1991; (c) V. Nair and A. U. Vinod, Chem.
Commun., 2000, 1019; (d) A. Fayol and J. Zhu, Angew. Chem. Int. Ed., 2002, 41, 3633; (e) N.
Chatani, M. Oshita, M. Tobisu, Y. Ishii, and S. Murai, J. Am. Chem. Soc., 2003, 125, 7812; (f) A.
Fayol and J. Zhu, Org. Lett., 2004, 6, 115; (g) A. V. Lygin and A. de Meijere, J. Org. Chem., 2009,
74, 4554; (h) K. Kobayashi, S. Fujita, D. Nakai, S. Fukumoto, S. Fukamachi, and H. Konishi, Helv.
Chim. Acta, 2010, 93, 1274; (i) K. Kobayashi, Y. Shirai, S. Fukamachi, and H. Konishi, Synthesis,
2010, 666; (j) Z.-Y. Yan, C.-M. Tan, X. Wang, F. Li, G.-L. Gao, X.-M. Chen, W.-S. Wu, and J.-J.
Wang, Synlett, 2011, 1863; (k) D. Chen, G.-Y. Song, A. Jia, and X.-W. Li, J. Org. Chem., 2011, 76,
8488; (l) K. Kobayashi, K. Matsumoto, and H. Konishi, Heterocycles, 2011, 83, 99.
7. G. Carturan, M. Biasiolo, S. Daniele, G. A. Mazzocchin, and P. Ugo, Inorg. Chim. Acta, 1986, 119,
19.
8. H.-B. Qiu, Y. Inoue, and S.-N. Che, Angew. Chem. Int. Ed., 2009, 48, 3069.
9. T. Hirakawa, K. Ikeda, H. Ogasa, M. Kawatsura, and T. Itoh, Synlett, 2010, 2887.
10. Y. Du, T. K. Hyster, and T. Rovis, Chem. Commun., 2011, 47, 12074.
11. S. Oi, K. Kashiwagi, E. Terada, K. Ohuchi, and Y. lnoue, Tetrahedron Lett., 1996, 37, 6351.
12. Typical procedure for the synthesis of cyano-substituted iminoisobenzofurans by
three-component coupling reactions (Table 2, entry 1). A flame-dried 25 mL Schlenk tube with
a magnetic stir bar was charged with KF (116 mg, 2.0 mmol), 18-crown-6 (529 mg, 2.0 mmol), and
[Pd(PhCN)2(dppf)](BF4)2 (52 mg, 0.05 mmol, 10 mol%) in THF (3.3 mL) under argon. To this
solution were added 2-(trimethylsilyl)phenyl triflate (1a) (243 μL, 1.0 mmol), t-octylisocyanide (2a)
(175 μL, 1.0 mmol), and ethyl cyanoformate (3a) (49 μL, 0.5 mmol) sequentially via syringe. The
reaction mixture was heated to 50 ºC for 18 h, then cooled to ambient temperature, quenched with

940
HETEROCYCLES, Vol. 86, No. 2, 2012
water, and extracted with Et2O (20 mL × 3). The combined extracts were washed with brine and
dried over anhydrous sodium sulfate. The volatiles were removed under reduced pressure to give
crude product, which was purified by silica gel column chromatography (eluent: hexane/EtOAC,
19:1). Further purification with HPLC (eluent: CHCl3) gave N-[3-cyano-3-ethoxy-1(3H)-
isobenzofuranylidene]-2,4,4-trimethyl-2-pentanamine (4a) (69 mg, 0.22 mmol, 44%) as yellow solid.
1H NMR (300 MHz, CDCl3, rt): δ 1.01 (s, 9H), 1.34 (t, J = 7.2 Hz, 3H), 1.46 (s, 6H), 1.76 (d, J = 2.4
Hz, 2H), 4.01 (m, 2H), 7.55-7.62 (m, 3H), 7.76-7.79 (m, 1H); 13C NMR (75 MHz, CDCl3, rt): δ 14.9,
30.4, 30.5, 31.7, 32.0, 55.3, 58.4, 63.6, 98.8, 114.8, 122.5 (× 2), 123.9, 131.7, 132.1, 139.2, 147.6.
IR (KBr, cm-1): 2239 (w, C≡N), 1715 (s, C=N). MS (EI, m/z (relative intensity)): 314 (M+, 2), 299
(71), 253 (28), 243 (86), 197 (54), 159 (31), 158 (100), 157 (67), 148 (31), 130 (71), 102 (43).
Anal. Calc for C19H26N2O2: C 72.58; H 8.33; N 8.91. Found: C 72.22; H 8.42; N 8.75.
13. Crystallographic data for the structure of 4a have been deposited with The Cambridge
Crystallographic Data Centre as the deposition number CCDC 886033. This data can be obtained
free of charge from on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44
(0)1223 336033 or www.ccdc.cam.ac.uk/data_request/cif.
14. (a) S. V. Kessar, Comprehensive Organic Synthesis, Vol. 4 (ed. by B. M. Trost and I. Fleming),
Pergamon, Oxford, 1991, pp. 483-515; (b) E. R. Biehl and S. P. Khanapure, Acc. Chem. Res., 1989,
22, 275.
15. (a) E. Yoshikawa and Y. Yamamoto, Angew. Chem. Int. Ed., 2000, 39, 173; (b) N. Chatani, A.
Kamitani, M. Oshita, Y. Fukumoto, and S. Murai, J. Am. Chem. Soc., 2001, 123, 12686; (c) H.
Yoshida, H. Fukushima, J. Ohshita, and A. Kunai, Tetrahedron Lett., 2004, 45, 8659; (d) T. T.
Jayanth, M. Jeganmohan, and C.-H. Cheng, Org. Lett., 2005, 7, 2921; (e) J. L. Henderson, A. S.
Edwards, and M. F. Greaney, J. Am. Chem. Soc., 2006, 128, 7426; (f) M. Jeganmohan and C.-H.
Cheng, Chem. Commun., 2006, 2454; (g) H. Yoshida, H. Fukushima, J. Ohshita, and A. Kunai, J.
Am. Chem. Soc., 2006, 128, 11040; (h) I. Larrosa, M. I. Da Silva, P. M. Gómez, P. Hannen, E. Ko, S.
R. Lenger, S. R. Linke, A. J. P. White, D. Wilton, and A. G. M. Barrett, J. Am. Chem. Soc., 2006,
128, 14042; (i) F. Sha and X. Huang, Angew. Chem. Int. Ed., 2009, 48, 3458; (j) E. Yoshioka, S.
Kohtani, and H. Miyabe, Angew. Chem. Int. Ed., 2011, 50, 6638.