Bronsted acid catalyzed formal insertion of isocyanides into a C-O bond of acetals

Article abstract of DOI:10.1021/ja073286h

The Bronsted acid catalyzed formal insertion of an isocyanide into a C-O bond of an acetal is described. A diverse array of acyclic and cyclic acetals can be applied to the catalytic insertion to form α-alkoxy imidates. Functional groups, such as nitro, c

Full text of DOI:10.1021/ja073286h

Published on Web 08/24/2007
Brønsted Acid Catalyzed Formal Insertion of Isocyanides into
a C-O Bond of Acetals
Mamoru Tobisu,† Aki Kitajima, Sachiko Yoshioka, Isao Hyodo,
Masayuki Oshita, and Naoto Chatani*
Contribution from the Department of Applied Chemistry, Faculty of Engineering,
Osaka UniVersity, Suita, Osaka 565-0871, Japan
Received May 17, 2007; E-mail: chatani@chem.eng.osaka-u.ac.jp
Abstract: The Brønsted acid catalyzed formal insertion of an isocyanide into a C-O bond of an acetal is
described. A diverse array of acyclic and cyclic acetals can be applied to the catalytic insertion to form
R-alkoxy imidates. Functional groups, such as nitro, cyano, halogen, ester, and alkoxy groups, are tolerant
to the reaction conditions employed. The course of the reaction is highly dependent on the structure of the
isocyanide. The use of an electron-deficient aryl isocyanide, such as 2c and 2d, is required to selectively
obtain the monoinsertion product. When aryl isocyanides containing alkyl substituents, such as 2a and 2b,
are employed, two molecules of the isocyanide are incorporated, and the double-insertion product is
obtained. The reaction of tert-octyl isocyanide also induces a double incorporation, but the subsequent
acid-mediated fragmentation leads to the 2-alkoxy imidoyl cyanide. The monoinsertion products, R-alkoxy
imidates, can readily be hydrolyzed to R-alkoxy esters, realizing the formal carbonylation of an acetal.
Introduction
when they are tethered to an acetal substrate at a suitable position
(1,2-insertion, an intramolecular variant of eq 2).6,7
Since Mukaiyama’s report on the Lewis acid mediated
reaction of enol silyl ethers with acetals, the first efficient Aldol-
type reaction of acetals, in 1974,1 acetals have enjoyed
widespread use as an electrophile in organic synthesis.2 As
exemplified in Mukaiyama’s work, the overall process for the
reactions of acetals with nucleophilic reagents is substitution,
in which one of the alkoxy groups in the acetal is eliminated
(eq 1). In contrast to the significant progress in the substitution
processes of acetals, insertion reactions3 into a C-O bond of
an acetal remain largely unexplored despite their attractiveness
as a synthetic transformation: two new bonds are formed in an
atom-economical manner (eqs 2 and 3). To date, such inter-
molecular insertion reactions of acetals have been reported but
have been restricted to two families of molecules, ketenes (1,2-
insertion, eq 2)4 and carbenes generated from diazo compounds
(1,1-insertion, eq 3).5 It has also been reported that alkynes can
be inserted into a C-O bond of an acetal catalytically but only
To develop the 1,1-insertion reaction into a C-O bond of
acetals as depicted in eq 3, isocyanides represent promising
candidates as an inserting molecule, since it is known that they
can be inserted into a variety of chemical bonds, including
O-H,8 N-H,9 P-H,10 S-H,11 Si-H,12 C-H,13 C-Si,14 Si-
Si,15 S-S,16 and Si-B17 bonds. As a part of our program
† Frontier Research Base for Global Young Researchers, Graduate School
of Engineering, Osaka University, Suita, Osaka 565-0871, Japan.
(1) Mukaiyama, T.; Hayashi, M. Chem. Lett. 1974, 15.
(8) Saegusa, T.; Ito, Y.; Kobayashi, S.; Hirota, K. Tetrahedron Lett. 1967, 8,
521. Saegusa, T.; Ito, Y.; Kobayashi, S.; Takeda, N.; Hirota, K. Tetrahedron
Lett. 1967, 8, 1723. Saegusa, T.; Ito, Y.; Kobayashi S.; Takeda, N.; Hirota,
K. Can. J. Chem. 1969, 47, 1217.
(2) Mukaiyama, T.; Murakami, M. Synthesis 1987, 1043. Alexakis, A.;
Mangeney, P. Tetrahedron: Asymmetry 1990, 1, 477.
(9) Saegusa, T.; Ito, Y.; Kobayashi, S.; Hirota, K.; Yoshioka, H. Tetrahedron
Lett. 1966, 7, 6121. Saegusa, T.; Ito, Y.; Kobayashi, S.; Hirota, K.;
Yoshioka, H. Bull. Chem. Soc. Jpn. 1969, 42, 3310.
(3) The term “insertion” is intended to describe the formal reaction pattern of
the overall transformation and not to imply any mechanistic claim.
(4) Mulzer, J.; Trauner, D.; Bats, J. W. Angew. Chem., Int. Ed. Engl. 1996,
35, 1970 and references therein.
(5) Scho¨nberg, A.; Praefcke, K. Tetrahedron Lett. 1964, 30, 2043. Scho¨nberg,
A.; Praefcke, K. Chem. Ber. 1966, 99, 196. See also: Doyle, M. P.; Griffin,
J. H.; Chinn, M. S.; van Leusen, D. J. Org. Chem. 1984, 49, 1917.
(6) Nakamura, I.; Bajracharya, G. B.; Mizushima, Y.; Yamamoto, Y. Angew.
Chem., Int. Ed. 2002, 41, 4328. Nakamura, I.; Bajracharya, G. B.; Wu, H.;
Oishi, K.; Mizushima, Y.; Gridnev, I. D.; Yamamoto, Y. J. Am. Chem.
Soc. 2004, 126, 15423. Nakamura, I.; Mizushima, Y.; Gridnev, I. D.;
Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 9844. Nakamura, I.;
Mizushima, Y.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 15022.
(7) Fu¨rstner, A.; Davies, P. W. J. Am. Chem. Soc. 2005, 127, 15024.
(10) Saegusa, T.; Ito, Y.; Kobayashi, S. Tetrahedron Lett. 1968, 9, 935. Hirai,
T.; Han, L.-B. J. Am. Chem. Soc. 2006, 128, 7422.
(11) Saegusa, T.; Kobayashi, S.; Ito, Y.; Hirota, K.; Okumura, Y. Bull. Chem.
Soc. Jpn. 1968, 41, 1638.
(12) Saegusa, T.; Kobayashi, S.; Ito, Y.; Hirota, K. J. Am. Chem. Soc. 1967,
89, 2240.
(13) Barnea, E.; Andrea, T.; Kapon, M.; Berthet, J.-C.; Ephritikhine, M.; Eisen,
M. S. J. Am. Chem. Soc. 2004, 126, 10860. Komeyama, K.; Sasayama,
D.; Kawabata, T.; Takehira, K.; Takai, K. J. Org. Chem. 2005, 70, 10679.
Jones, W. D.; Foster, G. P.; Putinas, J. M. J. Am. Chem. Soc. 1987, 109,
5047. Tanaka, M.; Sakakura, T.; Tokunaga, Y.; Sodeyama, T. Chem. Lett.
1987, 2373.
9
10.1021/ja073286h CCC: $37.00 © 2007 American Chemical Society
J. AM. CHEM. SOC. 2007, 129, 11431-11437
11431

A R T I C L E S
Tobisu et al.
directed toward developing new Lewis acid catalyzed reactions
using isocyanides as a C1 component, we found that isocyanides
can indeed be inserted into a C-O bond of cyclic acetals in
the presence of a catalytic amount of GaCl3 (eq 4).18
(3,3-dimethyl-1,4-dioxan-2-ylidene)-2,6-dimethylphenylamine
(3a) in 47% yield, along with the double insertion pro-
duct 4a in 5% yield (eq 5, Ar ) 2,6-Me2C6H3). We next
examined the importance of the structure of the isocyanide on
this reaction. Increasing the steric demand of the isocyanide
had little effect on the efficiency of the reaction (eq 5, Ar )
2,6-i-Pr2C6H3). On the other hand, the introduction of electron-
withdrawing atoms, such as chlorine and bromine, on the
benzene ring of the aryl isocyanide led to a marked improve-
ment in both yield and selectivity for the monoinsertion prod-
uct 3c and 3d (eq 5, Ar ) 2,6-Cl2C6H3 and 2,6-Br2C6H3).
The use of tert-butyl isocyanide did not afford the insertion
product.
Although such an insertion reaction has been reported by Ito
and Saegusa prior to our work, the reaction, as described in
their work, requires the use of a stoichiometric amount of TiCl4,
and the scope has not been investigated extensively (two
examples).19 In this paper, we disclose the full details of our
work, including the discovery of a new Brønsted acid catalyst,
the extension to an unprecedented insertion into acyclic acetals,
and the control over the three different reaction pathways by
the nature of N-substituents of isocyanides.
By employing isocyanide 2d, we next explored the scope of
the catalytic insertion reaction (Table 1). The reaction proceeded
effectively with 1,3-dioxolanes derived from a range of aliphatic
ketones (entries 2-4). The yields were lowered, when acetals
derived from aromatic (entry 5) and R,â-unsaturated (entry 6)
ketones were employed; however, in the latter case, the use of
2 equiv of isocyanide increased the yield. 1,3-Dioxolanes
derived from aldehydes are significantly less reactive compared
to those derived from ketones (entries 7-9). 1,3-Dioxane
furnished diminished yields of the insertion product, presumably
due to the requirement of the demanding seven-membered ring
formation (entry 10).
Results and Discussion
Insertion into Cyclic Acetals. Our continuing interests in
the unique catalytic behavior of GaCl318,20-26 led us to discover
that a combination of GaCl3 and an isocyanide is a useful system
for cycloaddition reactions with R,â-unsaturated carbonyl
compounds.26 In the course of further examination of the GaCl3/
isocyanide system with other oxygenated compounds, we found
that isocyanides can be inserted into the C-O bond in cyclic
acetals (eq 5).
Catalyst Screening for the Insertion into Acyclic Acetals.
Although we established the first catalytic protocol for
the insertion of an isocyanide into a C-O bond of an acetal, as
mentioned above, several limitations associated with the
GaCl3-catalyzed reaction restricted the potential utility of the
reaction. First, the applicable substrates are strictly limited
to cyclic acetals. Moreover, within the cyclic acetals, only
those derived from aliphatic ketones afforded the insertion
product in good yields. Second, polar functional groups, such
as nitro and cyano groups, are not compatible due to catalyst
deactivation by complex formation. To overcome these draw-
backs, we decided to reexamine the reaction conditions for the
insertion of an isocyanide into an acyclic acetal. Despite the
apparent similarity, cyclic and acyclic acetals pose very different
synthetic challenges when applied to such reactions. The
difficulty associated with acyclic acetals is not surprising
considering the proposed stepwise insertion mechanism il-
lustrated in Scheme 1. For cyclic acetals, the once cleaved
alkoxy group (ROM) remains in the substrate. As a result, the
recombination (B f C) proceeds via a facile intramolecular
process.18 In contrast, in the case of acyclic acetals, the
recombination of the ROM competes with other undesired
intermolecular processes, such as the nucleophilic attack of
the second molecule of an isocyanide or contaminated water.
Indeed, acyclic acetals are not applicable to insertion reactions
of isocyanides reported for cyclic acetals, resulting in the
formation of a substitution product rather than an insertion
product.18,27 Thus, insertion into acyclic acetals represents a
formidable challenge in view of the lack of precedent for such
a process.
Thus, the reaction of 2,2-dimethyl-1,3-dioxolane (0.4 mmol, 1)
with 2,6-xylylisocyanide (0.44 mmol, 2a) in the presence of
GaCl3 (0.04 mmol) in toluene (1.5 mL) at 80 °C for 12 h gave
(14) Nguyen, P. T.; Palmer, W. S.; Woerpel, K. A. J. Org. Chem. 1999, 64,
1843.
(15) Murakami, M.; Suginome, M.; Matsuura, T.; Ito, Y. J. Am. Chem. Soc.
1991, 113, 8899.
(16) Kuniyasu, H.; Sugoh, K.; Su, M. S.; Kurosawa, H. J. Am. Chem. Soc. 1997,
119, 4669.
(17) Suginome, M.; Fukuda, T.; Nakamura, H.; Ito, Y. Organometallics 2000,
19, 719.
(18) Yoshioka, S.; Oshita, M.; Tobisu, M.; Chatani, N. Org. Lett. 2005, 7, 3697.
(19) Ito, Y.; Imai, H.; Segoe, K.; Saegusa, T. Chem. Lett. 1984, 937.
(20) Reviews on the use of gallium salts in organic synthesis: (a) Yamaguchi,
M.; Tsukagoshi, T.; Arisawa, M. Chemtracts 2000, 13, 431. (b) Kellog, R.
M. Chemtracts 2003, 16, 79.
(21) For recent examples of gallium(III)-catalyzed reactions by other groups,
see: (a) Surya, P. G. K.; Yan, P.; To¨ro¨k, B.; Bucsi, I.; Tanaka, M.; Olah,
G. A. Catal. Lett. 2003, 85, 1. (b) Yuan, F.; Zhu, C.; Sun, J.; Liu, Y.; Pan,
Y. J. Organomet. Chem. 2003, 682, 102. (c) Bez, G.; Zhao, C.-G. Org.
Lett. 2003, 5, 4991. (d) Usugi, S.; Yorimitsu, H.; Shinokubo, H.; Oshima,
K. Org. Lett. 2004, 6, 601. (e) Amemiya, R.; Fujii, A.; Yamaguchi, M.
Tetrahedron Lett. 2004, 45, 4333. (f) Amemiya, R.; Nishimura, Y.;
Yamaguchi, M. Synthesis 2004, 1307. (g) Yadav, J. S.; Reddy, B. V. S.;
Padmavani, B.; Gupta, M. K. Tetrahedron Lett. 2004, 45, 7577. (h) Sun,
P.; Hu, Z.; Huang, Z. Synth. Commun. 2004, 34, 4293. (i) Winkler, J. D.;
Asselin, S. M. Org. Lett. 2006, 8, 3975.
(22) Chatani, N.; Inoue, H.; Kotsuma, T.; Murai, S. J. Am. Chem. Soc. 2002,
124, 10294.
(23) Inoue, H.; Chatani, N.; Murai, S. J. Org. Chem. 2002, 67, 1414.
(24) Oshita, M.; Chatani, N. Org. Lett. 2004, 6, 4323.
(25) Oshita, M.; Okazaki, T.; Ohe, K.; Chatani, N. Org. Lett. 2005, 7, 331.
(26) Chatani, N.; Oshita, M.; Tobisu, M.; Ishii, Y.; Murai, S. J. Am. Chem.
Soc. 2003, 125, 7812. Oshita, M.; Tobisu, M.; Yamashita, K.; Chatani, N.
J. Am. Chem. Soc. 2005, 127, 761.
(27) (a) Mukaiyama, T.; Watanabe, K.; Shiono, M. Chem. Lett. 1974, 1457. (b)
Pellissier, H.; Meou, A.; Gil, G. Tetrahedron Lett. 1986, 27, 2979. (c)
Pellissier, H.; Gil, G. Tetrahedron Lett. 1988, 29, 6773.
9
11432 J. AM. CHEM. SOC. VOL. 129, NO. 37, 2007

Insertion of Isocyanides into a C
−
O Bond of Acetals
A R T I C L E S
Scheme 1. Possible Mechanism for the Catalytic Insertion of
Table 1. GaCl3-Catalyzed Reaction of Acetals with
2,6-Dibromophenylisocyanide (2d)a
Isocyanides into Acetals
Table 2. Survey of Acid Catalysts for the Insertion of Isocyanide
2c with Acetal 5
entry
catalyst
yield (%)
entry
catalyst
yield (%)
1
2
3
4
GaCl3
InCl3
Cu(OTf)2
Sc(OTf)3
<10
trace
38
5
6
7
8
Me3SiOTf
TfOH
Tf2NH
TFA
80
89
58a
3
48a
a 8-10% of the double insertion product was also obtained.
by the reaction of triflate salts and residual water.29 To our
delight, TfOH proved to be an excellent catalyst for this reaction,
affording 6c in 89% isolated yield at ambient temperature within
2 h (entry 6), while other Brønsted acids, such as Tf2NH and
TFA, were less effective (entries 7 and 8). It is noteworthy that
only a 1:1 mixture of 5 and 2c was needed to obtain the insertion
product 6c in a good yield, demonstrating the efficiency of the
new catalytic system.
The new Brønsted acid catalyst system can also effect the
insertion of an isocyanide into a cyclic acetal, affording the
corresponding cyclic imidates in yields comparable to those
obtained when GaCl3 is used as a catalyst (eq 6).
a Reaction conditions: ketal or acetal (0.4 mmol), 2,6-dibromophenyl-
isocyanide (0.44 mmol), GaCl3 (0.04 mmol, 1 M in methylcyclohexane) in
toluene (1.5 mL) at 80 °C, 18 h. bAr ) 2,6-dibromophenyl. cIsolated yields.
d2,6-Dibromophenylisocyanide (0.8 mmol) was used.
Effect of N-Substituents of Isocyanides. Having identified
the catalyst for the insertion into acyclic acetals, we next
investigated the effect of isocyanide structure on the TfOH-
catalyzed reaction. As was observed in the GaCl3-catalyzed
insertion into cyclic acetals, the use of aromatic isocyanides
containing alkyl substituents, such as 2a and 2b, afforded a
mixture of mono- and double-insertion products (eq 7). Ac-
cordingly, the use of the electron-deficient isocyanide 2c again
appears to be essential for the selective formation of the mono-
insertion product.
With this difficulty in mind, we initially investigated the
reaction of acyclic acetal 5 with isocyanide 2c in the presence
of Lewis acid catalysts (Table 2). After screening a variety of
catalysts,28 we were pleased to find that triflate salts exhibited
promising catalytic activity, furnishing the desired insertion
product 6c (entries 3-5). We next examined the catalytic
activity of TfOH, a compound that could be generated in situ
(28) Other less active catalysts that were examined: ZrCl4, HfCl4, ReCl(CO)5,
FeCl3, PtCl2, AuCl3, MgI2, Zn(OTf)2, Yb(OTf)3, Hf(OTf)4, Sn(OTf)2, and
B(C6F5)3.
(29) Le Roux, C.; Dubac, J. Synlett 2002, 181. Dumeunier, R.; Marko´, I. E.
Tetrahedron Lett. 2004, 45, 825.
9
J. AM. CHEM. SOC. VOL. 129, NO. 37, 2007 11433

A R T I C L E S
Tobisu et al.
Table 3. TfOH-Catalyzed Insertion Reaction of Isocyanide 2c into
Acetalsa
Although our prime objective was to develop a selective
monoinsertion process, we briefly pursued the possibility of
leading the double-insertion in a major reaction pathway. As a
result, the preferential formation of the double-insertion product
7b was observed, when acetal 5 and 2 equiv of 2b were treated
with a catalytic amount of TfOH in dioxane (eq 8).
The selective double-insertion of isocyanides is normally
successful when the cyclic product is formed, since the amount
of isocyanide incorporated can be controlled to lead to a
favorable five- or six-membered ring formation.21c,i,26,30a,b
Regarding the selective double-insertion of isocyanides in an
acyclic system, we found only two reports.16,30c In this context,
the result demonstrated in eq 8 is noteworthy.
We also examined several alkyl isocyanides for use in the
TfOH-catalyzed insertion into acetals. When benzyl and cyclo-
hexyl isocyanides were treated with acetal 5 under standard
conditions, no insertion products were obtained. On the other
hand, the reaction of 5 with tert-octyl isocyanide afforded
2-methoxy imidoyl cyanide 8 in 22% yield (eq 9).
a Reaction conditions: acetal (1.0 mmol), 2,6-dichlorophenyl isocyanide
It is interesting to note that Ito and Saegusa previously reported
that the reaction of 5 with 1 equiv of tert-butyl isocyanide in
the presence of a stoichiometric amount of TiCl4 resulted in
the formation of 2-methoxy-2-phenylacetonitrile,19 the com-
pound which was not observed in our catalytic system. Since 2
equiv of isocyanides are incorporated into the compound 8, we
conducted the reaction using the excess amount of isocyanide,
increasing the yield of 8 significantly. Optimization of the
solvent further improved the yield up to 78%. Although this
type of reaction has been reported to be promoted by a
stoichiometric amount of Et2AlCl,27c this represents the first
catalytic variant.
b
(1.0 mmol), TfOH (0.1 mmol) in toluene (6 mL) at 30 °C, 2h. Ar ) 2,6-
dichlorophenyl. cIsolated yields. dStereoisomeric ratio ) 1:1. eStereoisomeric
ratio ) 20:1.
Substrate Scope. Having identified the optimal isocyanide
for the selective monoinsertion process, we next explored the
scope of the reaction with respect to acetals. As illustrated in
Table 3, TfOH efficiently catalyzes the insertion of isocyanide
2c into a variety of acetals. In all cases, the reaction reached
completion within 2 h at ambient temperature. Unlike the GaCl3-
catalyzed insertion reaction, acetals derived from both aldehydes
and ketones containing aliphatic and aromatic substituents all
afforded the corresponding insertion products in good yields.
Moreover, the large functional group compatibility is another
advantage of the Brønsted acid catalysis. Functional groups,
including ethers, esters, halides, nitro, and cyano groups (entries
(30) (a) Nair, V.; Menon, R. S.; Deepthi, A.; Devi, R.; Biju, A. T. Tetrahedron
Lett. 2005, 46, 1337. (b) Masdeu, C.; Go´mez, E.; Williams, N. A. O.;
Lavilla, R. Angew. Chem., Int. Ed. 2007, 46, 3043. (c) Whitby, R. J.; Saluste,
C. G.; Furber, M. Org. Biomol. Chem. 2004, 2, 1974.
9
11434 J. AM. CHEM. SOC. VOL. 129, NO. 37, 2007

Insertion of Isocyanides into a C−O Bond of Acetals
A R T I C L E S
Table 4. TfOH-Catalyzed Insertion Reaction of Isocyanide 2c into
2-8), as well as heteroaromatic groups (entries 18 and 19) were
tolerated under the reaction conditions employed. Interestingly,
electronic properties of the aromatic ring had little impact on
the yield of the insertion product in reactions of a series of
p-substituted benzaldehyde-derived acetals (entries 1-8). An
allylic rearrangement was not involved when an acetal derived
from 2-hexenal was employed (entry 13). The presence of a
R-stereogenic center did not regulate the stereochemical course
of the reaction, affording a 1:1 diastereomeric mixture (entry
16). On the other hand, excellent stereoselectivity was observed
for the reaction of 4-tert-butylcyclohexanone dimethyl acetal:
isocyanide 2c is selectively inserted into the axial C-O bond
(entry 17). A similar stereoselectivity was previously observed
in the reaction of this acetal with isocyanides and related
nucleophiles.19,31
Tetrapyranyl Ethersa
isolated yields (%)
entry
R
9
10
1
2
3
4
5
6
7
8
Me
Et
i-Pr
t-Bu
allyl
benzyl
Ph
70 (9a)
57 (9b)
32 (9c)
0 (9d)
37 (9e)
0 (9f)
6
7
14
91
25
94
4
75 (9g)
0 (9h)
acetyl
52
We next examined the catalytic insertion into tetrahydrofura-
nyl ethers, wherein two nonequivalent C-O bonds are present.
As reported in the literature,32 Lewis acid mediated substitution
reactions of such compounds often afford a mixture of products
via the nonselective cleavage of both C-O bonds (Scheme 2).
a Reaction conditions: acetal (1.0 mmol), 2,6-dichlorophenyl isocyanide
(1.0 mmol), TfOH (0.1 mmol) in toluene (6 mL) at 30 °C, 2 h. Ar ) 2,6-
dichlorophenyl.
the R group, and amide 10 was formed exclusively when tert-
butyl ether was employed (entries 1-4). A significantly larger
amount of the amide product was formed with an allyl ether,
compared to the primary alkyl substituents (entry 5). In the case
of a benzyl ether, amide 10 was obtained in 94% yield without
the formation of the insertion product 9f (entry 6). A phenoxy
group, which possesses a better leaving ability relative to an
alkoxy substituent, efficiently afforded the insertion product 9g
(entry 7), whereas the use of an acetate, a much better leaving
group, resulted in the exclusive formation of the amide 10 (entry
8). The mechanism for the formation of amide 10 will be
discussed below.
To further expand the scope of the reaction, we examined
the catalytic insertion into N,O-acetals. The reaction of 2-meth-
oxypyrrolidine derivatives with isocyanide 2c in the presence
of a catalytic amount of TfOH cleanly furnished the insertion
products into a C-O bond (eqs 12 and 13). These reactions
represent a new C1 introducing method for cyclic amines, and
the products should be useful precursors for amino acid
derivatives.
Scheme 2. Possible Pathways for the Substitution Reactions of
Tetrahydrofuranyl Ethers
Interestingly, the reaction of 2-ethoxytetrahydrofuran with 2c
induces a selective insertion into the exocyclic C-O bond, and
products derived from the cleavage of the endocyclic C-O bond
were not detected at all (eq 10). The ring size of such mixed
acetals sometimes affects the selectivity between the cleavage
of endo- and exocyclic C-O bonds.32 However, in our catalytic
system, the insertion occurred exclusively at the exocyclic C-O
bond when the six-membered analogue was applied, providing
the tetrahydropyranyl imidate in good yield (eq 11).
Another factor that affects the selectivity of the reaction
shown in Scheme 2 is the nature of the R group.32 Thus, we
investigated the TfOH-catalyzed reaction of tetrapyranyl ethers
bearing a variety of alkoxy substituents (Table 4). Interestingly,
insertion into the exocyclic C-O bond did not occur in any
cases, but instead, the Passerini-type amide 1033 was obtained
in varying yields depending on the substituents. The yield of
amide 10 was increased by increasing the steric bulkiness of
Mechanistic Considerations. In the TfOH-catalyzed reac-
tions of acetals with isocyanides, we observed three different
products depending on the structure of the isocyanide employed.
The formation of each of the products observed can be explained
by assuming the formation of the common nitrilium ion
intermediate B′, which can be generated by the reaction of the
protonated acetal A′ and isocyanides via an oxocarbenium cation
or by the classical SN2 mechanism34 (Scheme 3). When the
nitrilium cation B′ was trapped by MeOH dissociated from acetal
A′, the monoinsertion product C′ was obtained. The attack by
(31) Noyori, R.; Suzuki, M. Tetrahedron 1981, 37, 3899.
(32) Uchimoto, K.; Wakabayashi, Y.; Horie, T.; Inoue, M.; Shishiyama, Y.;
Obayashi, M.; Nozaki, H. Tetrahedron 1983, 39, 967. Hojo, M.; Ushioda,
N.; Hosomi, A. Tetrahedron Lett. 2004, 45, 4499.
(33) For the Passerini-type reactions of acetals that lead to R-alkoxy amide,
see: Barrett, A. G. M.; Barton, D. H. R.; Falck, J. R.; Papaioannou, D.;
Widdowson, D. A. J. Chem. Soc., Perkin Trans. 1 1979, 652. See also ref
28a.
(34) Dilman, A. D.; Ioffe, S. L. Chem. ReV. 2003, 103, 733.
9
J. AM. CHEM. SOC. VOL. 129, NO. 37, 2007 11435

A R T I C L E S
Tobisu et al.
Scheme 4. TfOH-Catalyzed Reactions of Tetrahydropyranyl
Scheme 3. TfOH-Catalyzed Diverse Pathways in the Reactions of
Benzaldehyde with Isocyanides
Ethers with Isocyanides
while the phenyl ether, a much better leaving group, resulted
in the exclusive formation of the monoinsertion product. An
alternate mechanism leading to 10 is the proton-mediated
fragmentation of the monoinsertion product (9 f I f 10). In
this mechanism, amide 10 would be expected to be formed more
favorably when the R group contains a cation stabilizing
structure, such as a tertiary alkyl or a benzyl group. This is in
good agreement with the experimental results. Moreover, in the
case of the reaction of a benzyl ether substrate, we observed an
isomeric mixture of benzylmethylbenzenes (68% isolated yield)
which is presumably formed by the Friedel-Crafts type
alkylation of the solvent toluene with the postulated benzyl
cation.36
Application to a Formal Carbonylation Process of Acetals.
Carbonylation chemistry offers one of the most straightforward
methodologies for introducing carbonyl functionalities into
organic molecules.37 To date, a variety of substrates have been
reported to be carbonylated with the aid of transition metal
catalysts. However, acetals have not been exploited in such
carbonylation processes, although the insertion of carbon
monoxide into a C-O bond of acetals would provide a new
pathway to R-alkoxy esters, an important class of compounds38
(eq 14). The lack of such carbonylation processes is partly due
to the reluctance of acetals to oxidatively add to transition metal
complexes.39 We envisaged that this challenging class of
transformation shown in eq 14 should be achieved formally by
combining our catalytic isocyanide insertion and the hydrolysis
of the imidates (eq 15).
Table 5. 13C NMR Chemical Shifts of the Formally Divalent
Carbon Atoms of Isocyanides Used in This Study
chemical shift
isocyanide
(ppm)a
2,6-Me2C6H3NC: (2a)
2,6-i-Pr2C6H3NC: (2b)
2,6-Cl2C6H3NC: (2c)
2,6-Br2C6H3NC: (2d)
t-OctNC:
167.3
168.3
173.7
172.4
154.2
a
13C NMR in CDCl3. The chemical shifts of the formally divalent carbon
atoms are shown.
a second molecule of isocyanide, instead of MeOH, on cation
B′ affords intermediate D, which is then trapped by MeOH to
furnish the double-insertion product E. The selectivity between
these two pathways (i.e., B′ f C′ and B′ f D) is determined
by the structure of isocyanides. Isocyanides containing electron-
withdrawing groups, such as 2c and 2d, afforded monoinsertion
products exclusively, while the competitive double-insertion
process was observed with isocyanides containing alkyl sub-
stituents, such as 2a and 2b. These results indicate that the
cationic intermediate B′ reacts with a weak nucleophile MeOH
more efficiently than with a second molecule of the isocyanide
due to the low nucleophilicity of the electron-deficient isocya-
nides 2c and 2d. The relative nucleophilicity of isocyanides35
can be deduced from the 13C NMR chemical shifts of the
nucleophilic carbon atoms (Table 5). As expected, the signals
for 2c and 2d appeared at the lowest field among the isocyanides
examined. In the reaction with tert-octyl isocyanide, 2-methoxy
imidoyl cyanide F was obtained. The formation of F can be
explained by the elimination of the tert-octyl cation from
intermediate D.27c Since tert-octyl isocyanide would be expected
to be highly nucleophilic from the data shown in Table 5, the
second attack (B′ f D) should be faster than the trapping of B′
by MeOH or the fragmentation of B′,19 therefore selectively
affording F.
To establish the two-step protocol shown in eq 15, the
hydrolysis of the imidates synthesized through the TfOH-
catalyzed reaction was examined. As a result, the acid hydrolysis
of the insertion products proceeded smoothly as expected with
the efficient recovery of 2,6-dichloroaniline, which can be
recycled by converting it to isocyanide 2c (eq 16).
To further demonstrate the utility of the catalytic insertion,
we examined a one-pot protocol based on the three sequential
In the reactions of tetrahydropyranyl ethers with isocyanide
2c, we observed the formation of amide 10 in addition to the
monoinsertion product 9 (Table 4). Two possible pathways
leading to amide 10 can be considered (Scheme 4). One is the
addition of the contaminated water to the nitrilium cation H, in
which the selectivity between 9 and 10 should depend on the
relative nucleophilicity of water and the eliminated alcohol
(ROH). Thus, this pathway cannot account for the observation
that the benzyl ether afforded an amide as the sole product,
(36) Benzyl alcohol did not give benzylmethylbenzenes under the reaction
conditions, excluding the pathway H f 10.
(37) Colquhoun, H. M.; Thompson, D. J.; Twigg, M. V. Carbonylation: Direct
Synthesis of Carbonyl Compounds; Plenum Press: New York, 1991.
Catalytic Carbonylation Reactions; Beller, M., Ed.; Springer: Heidelberg,
Germany, 2006.
(38) R-Alkoxy carboxylic acid derivatives exhibit biological activities. For recent
examples, see: McDonnell, P. A.; Constantine, K. L.; Goldfarb, V.;
Johnson, S. R.; Sulsky, R.; Magnin, D. R.; Robl, J. A.; Caulfield, T. J.;
Parker, R. A.; Taylor, D. S.; Adam, L. P.; Metzler, W. J.; Mueller, L.;
Farmer, B. T., II. J. Med. Chem. 2006, 49, 5013. Cai, Z.; Feng, J.; Guo,
Y.; Li, P.; Shen, Z.; Chu, F.; Guo, Z. Bioorg. Med. Chem. 2006, 14, 866.
Usui, S.; Fujieda, H.; Suzuki, T.; Yoshida, N.; Nakagawa, H.; Miyata, N.
Bioorg. Med. Chem. Lett. 2006, 16, 3249. Kuhn, B.; Hilpert, H.; Benz, J.;
Binggeli, A.; Grether, U.; Humm, R.; Ma¨rki, H. P.; Meyer, M.; Mohr, P.
Bioorg. Med. Chem. Lett. 2006, 16, 4016.
(35) The relative nucleophilicity of isocyanides has been estimated based on
the rate constant of the reaction with benzhydrylium ions, although the
data for isocyanides 2c and 2d are not available. Tumanov, V. V.; Tishkov,
A. A.; Mayr, H. Angew. Chem., Int. Ed. 2007, 46, 3563.
(39) Jones, G. S.; Scott, W. J. J. Am. Chem. Soc. 1992, 114, 1491.
9
11436 J. AM. CHEM. SOC. VOL. 129, NO. 37, 2007

Insertion of Isocyanides into a C−O Bond of Acetals
A R T I C L E S
acetals that contain a wide range of functional groups, such as
nitro, cyano, halogen, ester, and alkoxy groups. Particularly
noteworthy is that the insertion into acyclic acetals is unprec-
edented. The key to success is the use of electron-deficient
isocyanides 2c and 2d, highlighting a valuable feature of
isocyanides: their reactivity can be readily controlled by the
nature of the substituents on the nitrogen atom. The use of
relatively nucleophilic aryl isocyanides 2a and 2b induced the
incorporation of two molecules of isocyanide, affording the
double-insertion product. The use of tert-octyl isocyanide
resulted in the double incorporation of the isocyanide, followed
by acid-mediated fragmentation with the selective formation of
an imidoyl cyanide. Since the imidate functionality in the
monoinsertion products can be hydrolyzed into an ester, we
formally established the carbonylation reaction of acetals, a
challenging transformation. Further efforts are being directed
toward the application of the catalytic insertion of an isocyanide
in the synthesis of more complex molecules and the development
of asymmetric variants.
reactions, i.e., acetal formation/catalytic isocyanide insertion/
hydrolysis. The treatment of a mixture of benzaldehyde,
isocyanide 2c, and ethoxytrimethylsilane40 with a catalytic
amount of TfOH followed by the acid hydrolysis furnished an
R-alkoxy ester in 67% isolated yield (eq 17).41 The aniline
derived from isocyanide 2c was recovered quantitatively.
Experimental Procedures
General Procedure for the TfOH-Catalyzed Insertion of Isocya-
nides into Acetals. A 30 mL two-necked flask was heated for several
minutes with a heat gun under flowing nitrogen. After cooling the flask
to 30 °C, the acetal (1 mmol), isocyanide (1 mmol), and toluene (6
mL) were added under a gentle stream of nitrogen. To the stirred
mixture TfOH (0.1 mmol, 8.9 uL) was added, and the mixture was
stirred at 30 °C under a N2 atmosphere. After 2 h, the mixture was
quenched by the addition of Et3N (3 mL). The product was isolated by
silica gel column chromatography.
Conclusion
Acknowledgment. This work is dedicated to the memory of
Professor Yoshihiko Ito (1937-2006). 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. This work was supported, in part, by
grants from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan. We also thank the Instrumental Analysis
Center, Faculty of Engineering, Osaka University, for assistance
in obtaining MS, HRMS, and elemental analyses.
In summary, we report on the development of the Brønsted
acid catalyzed insertion reaction of isocyanides into a C-O bond
of an acetal, leading to the production of R-alkoxy imidates.
The reaction is applicable to a diverse array of cyclic and acyclic
(40) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21, 1357.
(41) For a recent example of the one-carbon homologation of aldehydes using
isocyanides, see: Bonne, D.; Dekhane, M.; Zhu, J. J. Am. Chem. Soc. 2005,
127, 6926.
(42) For recent examples of Brønsted acid catalyzed reactions, see: Connon,
S. J. Angew. Chem., Int. Ed. 2006, 45, 3909. Mahoney, J. M.; Smith, C.
R.; Johnston, J. N. J. Am. Chem. Soc. 2005, 127, 1354. Inanaga, K.; Takasu,
K.; Ihara, M. J. Am. Chem. Soc. 2005, 127, 3668. Anderson, L. L.; Arnold,
J.; Bergman, R. G. J. Am. Chem. Soc. 2005, 127, 14542. Rowland, G. B.;
Zhang, H.; Rowland, E. B.; Chennamadhavuni, S.; Wang, Y.; Antilla, J.
C. J. Am. Chem. Soc. 2005, 127, 15696. Boxer, M. B.; Yamamoto, H. J.
Am. Chem. Soc. 2006, 128, 48.
Supporting Information Available: Detailed experimental
procedures and the characterization of products. This material
is available free of charge via the Internet at http://pubs.acs.org.
(43) For recent reviews of multicomponent transformations using isocyanides,
see: Bienayme´, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000,
6, 3321. Zhu, J. Eur. J. Org. Chem. 2003, 1133. Do¨mling, A. Chem. ReV.
2006, 106, 17.
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