Lewis acid-promoted imine synthesis by the insertion of isocyanides into C-H bonds of electron-rich aromatic compounds

Article abstract of DOI:10.1021/ol071314v

The Lewis acid-promoted insertion of isocyanides into aromatic C-H bonds is reported. An imine functionality containing an array of N-substituents can be introduced directly into electron-rich aromatics in good yields.

Full text of DOI:10.1021/ol071314v

ORGANIC
LETTERS
2
007
Vol. 9, No. 17
351-3353
Lewis Acid-Promoted Imine Synthesis
by the Insertion of Isocyanides into C
Bonds of Electron-Rich Aromatic
Compounds
3
−H
†
Mamoru Tobisu, Seiji Yamaguchi, and Naoto Chatani*
Department of Applied Chemistry, Faculty of Engineering, Osaka UniVersity,
Suita, Osaka 565-0871, Japan
chatani@chem.eng.osaka-u.ac.jp
Received June 4, 2007
ABSTRACT
The Lewis acid-promoted insertion of isocyanides into aromatic C
−H bonds is reported. An imine functionality containing an array of
N-substituents can be introduced directly into electron-rich aromatics in good yields.
Due to the presence of a formally divalent carbon atom,
isocyanides occupy a unique position in the field of organic
chemistry, and have enjoyed widespread use in organic
synthesis, especially in multicomponent transformations.
The chemistry of isocyanides is dominated by the nucleo-
philicity of the isocyano carbon atom as a result of the
an electron from the nucleophile (Figure 1, b). However,
this type of reactivity of isocyanides has only been observed
3a
in case of strong nucleophiles, such as organolithium,
1
2
3a
3b
4
-magnesium, and -zinc reagents. Obviously, broadening
the range of nucleophiles used in this R-addition reaction
should further increase the synthetic utility of isocyanides.
A simple strategy toward achieving this goal would be to
enhance the electrophilicity of isocyanides by Lewis acid
complexation (Figure 1, c). Although several Lewis acid-
π
interaction of the vacant p orbital with the lone pair of
electrons on the nitrogen atom (Figure 1, a). It should also
5
isocyanide complexes have been reported to date, such
species, to our surprise, have rarely been exploited in organic
(
1) Suginome, M.; Ito, Y. In Science of Synthesis; Murahashi, S.-I. Ed.;
Thieme, Stuttgart, 2004, Vol. 19; pp. 445-530.
2) For recent reviews, see: Bienaym e´ , H.; Hulme, C.; Oddon, G.;
Schmitt, P. Chem. Eur. J. 2000, 6, 3321. Zhu, J. Eur. J. Org. Chem. 2003,
133. Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu. S.; Sreekanth, A. R.;
(
1
Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36, 899. D o¨ mling, A.
Chem. ReV. 2006, 106, 17.
Figure 1. Ambiphilic reactivity of isocyanide serving (a) as
nucleophile, (b) as electrophile, and (c) as electrophile in which
isocyanide is activated by Lewis acid (M).
(3) (a) Niznic, G. E.; Morrison, W. H.; Walborsky, H. M. J. Org. Chem.
1974, 39, 600. (b) Murakami, M.; Ito, H.; Ito, Y. J. Org. Chem. 1988, 53,
4158.
(4) Reversible addition of weak nucleophiles to isocyanides has been
proposed in the intramolecular cyclization of 2-alkynylisocyanobenzenes:
be noted that isocyanides could serve as an electrophile as
well, in which the π* orbital of the isocyano group accepts
Suginome, M.; Fukuda, T.; Ito, Y. Org. Lett. 1999, 1, 1977.
(5) B: Jacobsen, H.; Berke, H.; Doring, S.; Kehr, G.; Erker, G.; Frohlich,
R.; Mayer, O. Organometallics 1999, 18, 1724. Al: Fisher, J. D.; Wei,
M.-Y.; Willett, R.; Shapiro, P. J. Organometallics 1994, 13, 3324. Zr:
Brackemeyer, T.; Erker, G.; Frohlich, R. Organometallics 1997, 16, 531.
Ti: Carofiglio, T.; Floriani, C.; Chiesi-Villa, A.; Guastini, C. Inorg.
Chem.1989, 28, 4417.
†
Present address: Frontier Research Base for Global Young Researchers,
Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871,
Japan.
1
0.1021/ol071314v CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/17/2007

6
7
synthesis, except for the polymerization of isocyanides.
Herein, we report that Lewis acids promote the addition of
weak nucleophiles, specifically, electron-rich aromatic com-
pounds, onto isocyanides.
3
Table 1. AlCl -Promoted Insertion Reaction of Isocyanide 2a
into C-H Bonds of Aromatic Compoundsa
During investigations into the reactivity of isocyanides in
the presence of Lewis acids, we found that 1-methylindole
(
1) can be added to 2,6-xylyl isocyanide (2a) effectively,
8
furnishing the 3-iminoindole 3a (Scheme 1). Lewis acids
containing group 13 elements proved to be excellent promot-
ers for this R-addition with indoles: BF
3
‚OEt
2 3
(68%), AlCl
9
.10
(
88%), GaCl (86%), and In(OTf) (90%). The transfor-
3
3
mation shown in eq 1 represents the insertion of isocyanides
into an aromatic C-H bond. Although such a process has
been reported to proceed in the presence of a rhodium
11
complex under photochemical conditions or when applied
1
2
to an intramolecular reaction of one specific substrate,
thermal intermolecular Variants are unprecedented. Under
the influence of inexpensive AlCl , the R-addition with indole
appears to be quite general in the context of isocyanide
3
1
architecture. The presence of two ortho substituents in
aromatic isocyanides, as in 2a, is not essential for the present
insertion reaction (Scheme 1). Electron-rich (2c) and -defi-
cient (2d) phenyl isocyanides, as well as alkyl isocyanides
(2e), all furnished the corresponding 3-imino indoles in good
yields. It is noteworthy that the byproducts arising from the
addition of indole 1 to the imine 3 were not observed in any
case, although such aza-Friedel-Crafts reactions of indoles
are well-known processes.13
a
Reaction conditions: indole (1.0 mmol), 2,6-dimethylphenyl isocyanide
b
(
1.1 mmol), AlCl3 (1.2 mmol) in toluene (2 mL) at rt, 15 h. Ar ) 2,6-
dimethylphenyl. NMR yields. d Run at 60 °C. e The 3-substituted isomer
c
was also observed as a minor product (6%).
Scheme 1
than a methyl group, benzyl and aryl groups are suitable as
N-substituents of indoles (entries 2 and 3), while electron-
withdrawing groups, such as benzoyl and p-toluenesulfonyl,
are not. These results indicate the importance of the
π-nucleophilicity of indoles in the present isocyanide inser-
tion to proceed. Notably, the free indole exhibited a
comparable reactivity, resulting in the formation of 3-imino
indole without competing with the N-H insertion (entry 4).14
The introduction of both electron-donating and -withdrawing
substituents, including alkyl and aryl groups, ethers, bro-
mides, and esters, was well tolerated (entries 5-9), whereas
no insertion products were obtained when highly electron-
deficient 5-cyano- and 5-nitroindoles were used. In addition,
by applying this methodology to 2-substituted indoles, imino
groups can be installed effectively at the sterically congested
positions (entries 10 and 11). It is important to note that the
reaction can successfully be extended to other electron-rich
aromatics, including pyrroles and thiophenes, which furnish
The scope of the reaction with respect to indoles was next
investigated by employing isocyanide 2a (Table 1). Other
(6) For recent examples of Lewis acid-promoted reactions of isocyanides,
see; Chatani, N.; Oshita, M.; Tobisu, M.; Ishii, Y.; Murai, S. J. Am. Chem.
Soc. 2003, 125, 7812. Bez, G.; Zhao, C.-G. Org. Lett. 2003, 5, 4991. Oshita,
M.; Yamashita, K.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2005, 127,
61. Yoshioka, S.; Oshita, M.; Tobisu, M.; Chatani, N. Org. Lett. 2005, 7,
697. Winkler, J. D.; Asselin, S. M. Org. Lett. 2006, 8, 3975. Korotkov,
7
3
(11) Tanaka, M.; Sakakura, T.; Tokunaga, Y.; Sodeyama, T. Chem. Lett.
1987, 2373. Jones, W. D.; Foster, G. P.; Putinas, J. M. J. Am. Chem. Soc.
1987, 109, 5047. Jones, W. D.; Hessell, E. T. Organometallics 1990, 9,
718.
(12) Kobayashi, K.; Matoba, T.; Irisawa, S.; Matsumoto, T.; Morikawa,
O.; Konishi, H. Chem. Lett. 1998, 551.
measurement of the crude reaction mixture after an aqueous workup. The
imines can be isolated by chromatography (Al2O3), but with reduced yields.
For example, the isolated yield of entry 12 in Table 1 was 65%.
(13) Xie, W.; Bloomfield, K. M.; Jin, Y.; Dolney, N. Y.; Wang, P.
G.Synlett 1999, 498.
(14) Transition metal-mediated insertion of isocyanides into the N-H
bond in indoles: Jones, W. D.; Kosar, W. P. J. Am. Chem. Soc. 1986, 108,
5640.
(10) Yields with other acids; TiCl4 (24%), HCl (26%), TfOH (51%),
and TFA (0%).
3352
Org. Lett., Vol. 9, No. 17, 2007

19
the corresponding C-H insertion products in a regioselective
manner (entries 12-14). Moreover, an electron-rich benzene
ring can serve as a good nucleophile for the R-addition with
isocyanides (Scheme 2).
example, the [4+2] cycloaddition with Danishefsky’s diene
provides dihydropyridone 4, which is a versatile intermediate
for the synthesis of indole alkaloids and analogues thereof
2
0
(Scheme 4).
Scheme 4
Scheme 2
To gain insights into the reaction mechanism, NMR
15
In summary, we report on the first R-addition of isocya-
nides with aromatic compounds, promoted by inexpensive
Lewis acids, such as AlCl . The method can provide a direct
3
and practical access to a wide array of imines via aromatic
C-H bond functionalization. Ongoing work seeks to explore
the new isocyanide insertion process into other chemical
bonds.
experiments were carried out with GaCl
soluble in nonpolar solvents. Upon treatment of 2,6-xylyl
isocyanide (2a) with 1 equiv of GaCl in C , the resonance
3
,
which is more
3
6 6
D
corresponding to the methyl group in 2a immediately shifted
upfield from 2.06 to 1.62 ppm, indicating the formation of
5
isocyanide-Lewis acid adduct, as in A (Scheme 3). When
Acknowledgment. This research has been carried out on
the Program of Promotion of Environmental Improvement
to Enhance Young Researchers’ Independence, the Special
Coordination Funds for Promoting Science and Technology,
Japan Ministry of Education, Culture, Sports, Science and
Technology. M.T. also acknowledges Mitsubishi Chemical
Corporation Fund. We also thank the Instrumental Analysis
Center, Faculty of Engineering, Osaka University, for
assistance in obtaining MS, HRMS, and elemental analyses.
Scheme 3
3
a solution of the isocyanide-GaCl adduct was treated with
Supporting Information Available: Detailed experi-
mental procedures and the characterization of products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
indole 1, the formation of the insertion product 3a was
observed after an aqueous workup. In addition, labeling
studies revealed that the hydrogen atom originally located
at the 3-position of indole is transferred to the imino
15
OL071314V
hydrogen of the product. On the basis of the above results,
we propose a mechanism that involves (i) the nucleophilic
attack of indoles to the isocyanide-Lewis acid adduct A to
generate intermediate B and (ii) aromatization via deproto-
nation and protonolysis of the carbon-metal bond, leading
to the inserted product (Scheme 3).1 A preliminary initial
rate measurement exhibited no significant kinetic isotope
(
17) An alternative mechanistic possibility would be the intermediacy
18
of a 3-indolylmetal species, such as D (see below). We observed the
interaction between indole 1 and GaCl3 by H NMR. However, no such
1
interaction was observed when a 1:1 mixture of 1 and 2a was treated with
GaCl3, and only the resonance of 2a was shifted. Thus, we currently believe
that the dominant species in our reaction is the isocyanide-Lewis acid
adduct, as in A, and the insertion proceeds through A.
6,17
1
5
effect, indicating that the formation of the intermediate B
is rate-limiting.
The imines synthesized through the isocyanide insertion
reaction are amenable to further synthetic elaboration. For
(
18) Ottoni, O.; de V. F. Neder, A.; Dias, A. K. B.; Cruz, R. P. A.;
(15) See the Supporting Information for details.
Aquino, L. B. Org. Lett. 2001, 3, 1005.
(
16) A crossover experiment indicates that the major part of the proton
(19) Yuan, Y.; Li, X.; Ding, K. Org. Lett. 2002, 4, 3309.
(20) Tasber, E. S.; Garbaccio, R. M. Tetrahedron Lett. 2003, 44, 9185.
Kuethe, J. T.; Comins, D. L. J. Org. Chem. 2004, 69, 2863.
migration occurs intramolecularly, although an intermolecular process can
be operating as a minor path. See Supporting Information for details.
Org. Lett., Vol. 9, No. 17, 2007
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