[5 + 1]Cycloaddition of C,N-cyclic N′-acyl azomethine imines with isocyanides

Article abstract of DOI:10.1021/ol2034542

A catalyst-free [5 + 1] cycloaddition reaction between isocyanides and C,N-cyclic N′-acyl azomethine imines as the "isocyanophile" leading to novel heterocycles has been developed. These reactions proceeded quickly and cleanly to afford the corresponding

Full text of DOI:10.1021/ol2034542

ORGANIC
LETTERS
[5 þ 1] Cycloaddition of C,N-Cyclic N0-Acyl
2012
Vol. 14, No. 5
1226–1229
Azomethine Imines with Isocyanides
Takahiro Soeta,* Kaname Tamura, and Yutaka Ukaji*
Division of Material Sciences, Graduate School of Natural Science and Technology,
Kanazawa University, Kakuma, Kanazawa 920-1192, Japan
soeta@se.kanazawa-u.ac.jp; ukaji@se.kanazawa-u.ac.jp
Received December 26, 2011
ABSTRACT
A catalyst-free [5 þ 1] cycloaddition reaction between isocyanides and C,N-cyclic N0-acyl azomethine imines as the “isocyanophile” leading to
novel heterocycles has been developed. These reactions proceeded quickly and cleanly to afford the corresponding imin-1,3,4-oxadiazin-6-one
derivatives in high to excellent yields. A wide range of C,N-cyclic N0-acyl azomethine imines and isocyanides were applicable to this reaction.
Isocyanides are powerful for constructing polyfunc-
tional molecules with increased molecular diversity for
drug discovery and natural product synthesis.1 Histori-
cally, an isocyanide was synthesized by Lieke in 1859 as an
allyl isocyanide by alkylation of silver cyanide.2 These
compounds remained laboratory curiosities for decades,
as their strong repulsive smell prevented most chemists
from working with them. In 1921, a breakthrough with
isocyanides was achieved by Passerini to synthesize
R-hydroxyamides using aldehydes and carboxylic acids.3
Forty years later, Ugi developed multicomponent reac-
tions using aldehydes, amines, carboxylic acids, and iso-
cyanidesto affordR-amino amides.4 The Passerini and Ugi
reactions are the most important multicomponent reac-
tions in organic and medicinal chemistry.5 In addition,
isocyanides are used as two-electron donating ligands in
organometallic chemistry,6 as well as in oligo- and poly-
merizations.7 Furthermore, the most important applica-
tion of isocyanides is the synthesis of versatile hetero-
cycles,8 suchasintheBartonꢀZardand the Leusen pyrrole
syntheses,9a,b as well as the Fukuyama and SaegusaꢀItoh
indole syntheses.9c,d Zhu and others reported that the
reactionofR-isocyanoacetamides with aldehydesorimines
led to the corresponding oxazoles, including asymmetric
versions.10 Recently, Chatani and co-workers reported the
GaCl3-catalyzed [4 þ 1] cycloaddition of R,β-unsaturated
carbonyl compounds with isocyanides to afford the corre-
sponding five-membered heterocycles in good to high
yields.11 As far as we know, there are no examples of
[5 þ 1] cycloadditions of isocyanides to afford the six-
membered heterocycles. Herein, we describe the first ex-
ample of novel six-membered heterocycle construction
based on the nucleophilic addition of an isocyanide.
The Passerini and Ugi reactions generally require a
carboxylic acid, which activates an aldehyde or imine
(1) Ito, Y. J. Synth. Org. Chem. Jpn. 2010, 68, 1239–1248.
(2) Lieke, W. Justus Liebigs Ann. Chem. 1859, 112, 316–321.
(3) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126–129. (b) Passerini,
M. Gazz. Chim. Ital. 1921, 51, 181–189. (c) Banfi, L.; Riva, R. Org.
React. 2005, 65, 1–140.
€
(4) (a) Ugi, I.; Steinbruckner, C. Angew. Chem. 1960, 72, 267–268. (b)
€
Ugi, I.; Meyr, R.; Fetzer, U.; Steinbruckner, C. Angew. Chem. 1959, 71,
386.
(7) Suginome, M.; Ito, Y. Adv. Polym. Sci. 2004, 171, 77–136.
(8) (a) Lygin, A. V.; Meijere, A. Angew. Chem., Int. Ed. 2010, 49,
9094–9124. (b) Marcaccini, S.; Torroba, T. Org. Prep. Proced. Int. 1993,
25, 141–208.
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46, 7587–7598. (b) van Leusen, D.; van Leusen, A. M. Org. React. 2001,
57, 417–666. (c) Tokuyama, H.; Fukuyama, T. Chem. Rec. 2002, 2, 37–
45. (d) Ito, Y.; Kobayashi, K.; Seko, N.; Saegusa, T. Bull. Chem. Soc.
Jpn. 1984, 57, 73–84.
(5) Recent reviews: (a) Banfi, L.; Riva, R.; Basso, A. Synlett 2010,
23–41. (b) El Kaim, L.; Grimaud, L. Tetrahedron 2009, 65, 2153–2171.
(c) Domling, A. Curr. Opin. Chem. Biol. 2002, 6, 306–313. (d) Domling,
A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210. (e) Armstrong,
R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc.
Chem. Res. 1996, 29, 123–131.
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22, 209–310. (b) Treichel, P. M. Adv. Organomet. Chem. 1973, 11, 21–86.
(c) Yamamoto, Y.; Yamazaki, H. Coord. Chem. Rev. 1972, 8, 225–239.
€
€
r
10.1021/ol2034542
Published on Web 02/10/2012
2012 American Chemical Society

and traps a nitrilium ion to form an acyloxylated inter-
mediate. Subsequent acyl transfer leads to the correspond-
ing R-acyloxy amides or R-amino amides. In our previous
studies, silanol or borinic acid acted as a carboxylic acid in
the Passerini-type reaction (eq 1).12
Table 1. Reaction Conditions for [5 þ 1] Cycloaddition Reac-
tion
entry
solvent
time/m
yield / %
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
AcOEt
THF
10
10
30
180
15
30
30
30
30
40
10
30
95
85
62
83
80
82
82
83
85
75
96
70
In these reactions, a nitrilium intermediate formed from
the aldehyde and isocyanide was intermolecularly trapped
by the hydroxyl group on the silicon or boron atom to
afford the corresponding products. We sought to expand
this concept to the intramolecular trapping of the nitrilium
intermediate in the Ugi-type reaction. Thus, if a molecule
contains both an electrophile (CdN) and a potential
nucleophilic group (Nuꢀ), intramolecular trapping of the
nitrilium intermediate could be readily realized relative to
the intermolecular version (eq 2).13 Based on this hypothesis,
we chose N0-acyl azomethine imine as an “isocyanophile”,14
whichisanextendedconjugated1,3-dipole and could function
as a “1,5-dipole”15 to afford the corresponding heterocycles
(eq 3).
2a
3b
4c
5
6
7
8
MeCN
MeOH
toluene
CH2Cl2
CH2Cl2
9
10
11d
12e
a 30 mol % of Mg(OTf)2 was used. b 30 mol % of Zn(OTf)2 was used.
c Reaction was conducted at ꢀ20 °C. d Isocyanide 2a (1.2 equiv) was
used. e Isocyanide 2a (1.0 equiv) was used.
an isocyanide as a C1 source to afford the corresponding
imin-1,3,4-oxadiazin-6-one derivatives (Table 1).
Our initial study began using the well-known C,N-cyclic
N0-acyl azomethine imine 1a16,17 as a 1,5-dipolar com-
pound as shown in Table 1. To our delight, 2.0 equiv of
tert-butyl isocyanide (2a) cleanly reacted with the N0-acyl
azomethine imine 1a in dichloromethane at room tem-
perature to afford the corresponding iminoxadiazinone
derivative 3aa in 95% yield (entry 1). Surprisingly, we
found that the reaction proceeded very quickly, and 1a was
consumed within 10 min at room temperature. In this
reaction, activation by some Lewis acids did not appear to
be significant, i.e., the reaction of the azomethine imine 1a
and the isocyanide 2a in the presence of Mg(OTf)2 or
Zn(OTf)2 gave the product in 85% or 62% yield, respec-
tively (entries 2 and 3). When the reaction was conducted
at ꢀ20 °C, it was complete within 180 min to afford 3aa in
83% yield (entry 4). This reaction proceeded smoothly in
At first, we examined whether the N0-acyl azomethine
imine could act as a 1,5-dipolar equivalent, which can trap
(10) (a) Yue, T.; Wang, M.-X.; Wang, D.-X.; Masson, G.; Zhu, J. J.
Org. Chem. 2009, 74, 8396–8399. (b) Mihara, H.; Xu, Y.; Shepherd,
N. E.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 8384–
8385. (c) Scheffelaar, R.; Paravidino, M.; Muilwijk, D.; Lutz, M.; Spek,
A. L.; de Kanter, F. J. J.; Orru, R. V. A.; Ruijter, E. Org. Lett. 2009, 11,
125–128. (d) Elders, N.; Ruijter, E.; de Kanter, F. J. J.; Groen, M. B.;
Orru, R. V. A. Chem.;Eur. J. 2008, 14, 4961–4973. (e) Pirali, T.; Tron,
G. C.; Masson, G.; Zhu, J. Org. Lett. 2007, 9, 5275–5278. (f) Wang,
S.-X.; Wang, M.-X.; Wang, D.-X.; Zhu, J. Org. Lett. 2007, 9, 3615–3618.
(g) Wang, S.-X.; Wang, M.-X.; Wang, D.-X.; Zhu, J. Eur. J. Org. Chem.
2007, 4076–4080. (h) Pirali, T.; Tron, G. C.; Zhu, J. Org. Lett. 2006, 8,
(12) (a) Soeta, T.; Kojima, Y.; Ukaji, Y.; Inomata, K. Tetrahedron
Lett. 2011, 52, 2557–2559. (b) Soeta, T.; Kojima, Y.; Ukaji, Y.; Inomata,
K. Org. Lett. 2010, 12, 4341–4343.
(13) (a) Rahmati, A.; Kouzehrash, M. A. Synthesis 2011, 2913–2920.
(b) Zhang, J.; Coqueron, P.-Y.; Vors, J.-P.; Ciufolini, M. A. Org. Lett.
2010, 12, 3942–3945. (c) Deyrup, J. A.; Killion, K. K. J. Heterocycl.
Chem. 1972, 9, 1045–1048.
ꢀ
~
4145–4148. (i) Cuny, G.; Gamez-Montano, R.; Zhu, J. Tetrahedron
ꢀ
2004, 60, 4879–4885. (j) Janvier, P.; Bois-Choussy, M.; Bienayme, H.;
Zhu, J. Angew. Chem., Int. Ed. 2003, 42, 811–814. (k) Janvier, P.; Sun, X.;
(14) “Isocyanophile” is herein defined as a substrate which is subject
to nucleophilic attack of an isocyanide.
ꢀ
Bienayme, H.; Zhu, J. J. Am. Chem. Soc. 2002, 124, 2560–2567. (l)
ꢀ
~
Gamez-Montano, R.; Zhu, J. Chem. Commun. 2002, 2448–2449. (m)
(15) Taykor, E. C.; Turchi, I. J. Chem. Rev. 1979, 79, 181–231.
(16) (a) Hashimoto, T.; Omote, M.; Maruoka, K. Angew. Chem., Int.
Ed. 2011, 50, 8952–8955. (b) Hashimoto, T.; Omote, M.; Maruoka, K.
Angew. Chem., Int. Ed. 2011, 50, 3489–3492. (c) Hashimoto, T.; Maeda,
Y.; Omote, M.; Nakatsu, H.; Maruoka, K. J. Am. Chem. Soc. 2010, 132,
4076–4077.
(17) We have already revealed that 1a functions as an electrophile
toward cyanide ion in the Strecker-type reaction. Sakai, T.; Soeta, T.;
Inomata, K.; Ukaji, Y. Bull. Chem. Soc. Jpn. 2012, 85, 231–235.
ꢀ
Sun, X.; Janvier, P.; Zhao, G.; Bienayme, H.; Zhu, J. Org. Lett. 2001, 3,
877–880.
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Oshita, M.; Yamashita, K.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc.
2005, 127, 761–766. (c) Chatani, N.; Oshita, M.; Tobisu, M.; Ishii, Y.;
Murai, S. J. Am. Chem. Soc. 2003, 125, 7812–7813. They also reported
the GaCl3-catalyzed insertion of isocyanides into the CꢀO bond of
acetals to form the iminoether derivatives; see: (d) Yoshioka, S.; Oshita,
M.; Tobisu, M.; Chatani, N. Org. Lett. 2005, 7, 3697–3699.
Org. Lett., Vol. 14, No. 5, 2012
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corresponding heterocycles in high yields, although the
reactivities were lower than for the aliphatic isocyanides
(entries 6ꢀ9).
Table 2. Scope of Isocyanides and Azomethine Imines
The reactivity toward various azomethine imines using
tert-butyl isocyanide (2a) was next examined by treatment
of 1.0 equiv of azomethine imines 1aꢀi and 1.2 equiv of 2a.
Regarding the substitution pattern of the C,N-cyclic N0-
acyl azomethine imines, the 5-, 6-, and 7-methyl substitu-
ents were all tolerated, furnishing the corresponding het-
erocycles (entries 10ꢀ12). The only exception was the
incorporation of the 8-methyl substituent wherein the
reaction was very sluggish (entry 13). The C,N-cyclic
azomethine imine 1f having an electron-donating group
was utilized as well (entry 14). In addition, the C,N-cyclic
azomethine imine 1g with an electron-withdrawing group
on the aromatic ring reacted slowly to afford the product
3ga in 96% yield (entry 15). The influence of the substit-
uent of the benzoyl group on the nitrogen was also
examined. We found that a methyl group on the aromatic
moiety was more effective than a chloride to afford the
products in 94% and 64% yields, respectively (entries 16 and
17). From these results, it was determined that the electron
density of the N0-acyl moiety played an important role in
trapping the nitrilium intermediate for the cyclization.
This study prompted us to examine structurally dis-
tinct azomethine imines. The reaction of a C,N-cyclic
azomethine imine not fused to the aromatic ring, which
was generated in situ from 1j in the presence of 2,6-di-
tert-butyl-4-methylpyridine (DTBMP) as a base,16c
was conducted with tert-butyl isocyanide (2a) to afford
the product 3ja in 81% yield (eq 4). On the other hand, a
N,N0-cyclized azomethine imine 1k, which geometri-
cally could not afford the iminoxadiazinone deriva-
tives, did not react with tert-butyl isocyanide (2a) even
under dichloromethane reflux conditions (eq 5). These
results suggested that the direction of the amidocarbo-
nyl oxygen was crucial to promote the nucleophilic
addition of isocyanide.
a 1.5 equiv of 1a and 1.0 equiv of 2bꢀi were used (entries 2ꢀ9) and 1.0
equiv of 1aꢀi and 1.2 equiv of 2a were used (entries 1, 10ꢀ17). b R2 = H
otherwise mentioned. c R2 = Me. d R2 = Cl.
polar, cyclic ether and protic solvents to afford 3aa in high
yields (entries 1, 5ꢀ9). The reactivity was slightly less when
toluene was used as a solvent likely due to the solubility of
the substrate 1a (entry 10). We have found that 1.2 equiv of
isocyanide was enough to afford the product in high yield
(entry 11), although fewer equivalents of isocyanide
(1.0 equiv) were also applicable to this reaction (entry 12).
We then examined the scope of isocyanides and azo-
methine imines applicable to the present [5 þ 1] cyclization
reaction as shown in Table 2. For the scope of isocyanides,
the optimal amounts of the azomethine imine 1a
(1.5 equiv) and isocyanides 2aꢀi (1.0 equiv) were used in
dichloromethane because it was difficult to separate the
products and unreacted isocyanides (entries 2ꢀ9). From
these results, we found that the conditions were applicable
to a wide variety of isocyanides. Most of the reactions were
complete within 1 h. The reaction of the aliphatic isocya-
nides (R3 = t-Bu, t-Oct, c-Hex, and Bn) with 1a gave the
iminoxadiazinone derivatives in high yields (entries 1ꢀ4).
The azomethine imine 1a was consumed in 16 h when tert-
octyl isocyanide (2b) was used, giving 3ab in 95% yield
(entry 2). In the case of cyclohexyl isocyanide (2c) and
benzyl isocyanide (2d), reactivities were higher to afford
the products in 99% yields (entries 3 and 4). The chiral
isocyanide 2e, which was prepared from the corresponding
amino acid, gave the product in 85% yield; however, no
chiral induction was observed (entry 5). Phenyl isocyanide
(2f) and aromatic isocyanides bearing electron-withdrawing
or -donating groups at the para position also afforded the
In conclusion, we have developed the catalyst-free [5 þ 1]
cycloaddition reaction of isocyanides and C,N-cyclic N0-
acyl azomethine imines as an “isocyanophile”. These reac-
tions proceeded quickly and cleanly to afford the imin-1,3,4-
oxadiazin-6-one derivatives in high yields. A wide range of
C,N-cyclic N0-acyl azomethine imines and isocyanides were
applicable to this reaction.
Acknowledgment. The present work was financially sup-
ported in part by the Adaptable and Seamless Technology
1228
Org. Lett., Vol. 14, No. 5, 2012

Transfer Program through target-driven R&D (221Z03585)
from the Japan Science and Technology Agency, a Grant-
in-Aid for Young Scientists from Kanazawa University,
and a Grant in-Aid for Scientific Research from the Japan
Society for the Promotion of Science (JSPS).
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 5, 2012
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