One-pot three-component sysnthesis of α-iminonitriles by IBX/TBAB-mediated oxidative strecker reaction

Article abstract of DOI:10.1021/ol800199b

The reaction of aldehydes, amines, and TMSCN in the presence of 2-iodoxybenzoic acid (IBX) and tetrabutylammonium bromide (TBAB) afforded α-iminonitriles in good to excellent yields under mild conditions. The presence of TBAB is essential for this transformation. The methodology was applied to a two-step synthesis of indolizidine via a microwave-assisted intramolecular cycloaddition of α-iminonitrile.

Full text of DOI:10.1021/ol800199b

ORGANIC
LETTERS
2008
Vol. 10, No. 8
1509-1512
One-Pot Three-Component Synthesis of
-Iminonitriles by IBX/TBAB-Mediated
Oxidative Strecker Reaction
r
Patrice Fontaine, Ange`le Chiaroni, Ge´raldine Masson,* and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-YVette Cedex,
France
masson@icsn.cnrs-gif.fr; zhu@icsn.cnrs-gif.fr
Received January 7, 2008
ABSTRACT
The reaction of aldehydes, amines, and TMSCN in the presence of 2-iodoxybenzoic acid (IBX) and tetrabutylammonium bromide (TBAB)
afforded -iminonitriles in good to excellent yields under mild conditions. The presence of TBAB is essential for this transformation. The
methodology was applied to a two-step synthesis of indolizidine via a microwave-assisted intramolecular cycloaddition of -iminonitrile.
r
r
The R-iminonitriles, also known as imidoyl cyanides, are
an important class of densely functionalized compounds that
could serve as precursors for R-ketoacids, amides, N-alkyl-
ketene-imines, cyanoenamides, amidines, etc.1 Furthermore,
they function as reactive components in cycloadditions,
providing a rapid access to nitrogen-containing heterocycles.2-4
Many synthetic methodologies have been developed.1a,5-11
However, most of them are multistep processes and have
limited application scope. Surprisingly, the direct oxidation
of R-aminonitriles has rarely been employed and only
aromatic R-iminonitriles were accessible by this method
using either manganese dioxide12 or air as oxidants.13 One
of the most general methods involves the chlorination of an
aminonitrile, followed by the base-promoted dehydrochlo-
rination of the resulting N-chloroaminonitrile.1a,7 The incon-
venience associated with this two-step sequence is the
instability of some N-chloroaminonitriles. It has been
reported that they decomposed violently and often explo-
sively even at 0 °C.1a As a continuation of our interest in
the development of oxidative multicomponent reactions
(1) (a) De Corte, B.; Denis, J. -M.; De Kimpe, N. J. Org. Chem. 1987,
52, 1147. (b) Roychowdhury, A.; Kumar, V. V.; Bhaduri, A. P. Synth.
Commun. 2006, 36, 715.
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React. 2005, 65, 141.
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Huu Dau, M.-E.; Riche, C.; Fowler, F. W.; Grierson, D. S. J. Org. Chem.
1996, 61, 3715. (b) Sisti, N. J.; Zeller, E.; Grierson, D. S.; Fowler, F. W.
J. Org. Chem. 1997, 62, 2093. (c) Motorina, I. A.; Fowler, F. W.; Grierson,
D. S. J. Org. Chem. 1997, 62, 2098. (d) Tarver, J. E.; Terranova, K. M.;
Joullie´, M. Tetrahedron 2004, 60, 10277.
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Boyer, J. H.; Kooi, J. J. Am. Chem. Soc. 1976, 98, 1099. (c) De Kimpe,
N.; Verhe´, R.; De Buyck, L.; Chys, J.; Schamp, N. Synthesis 1978, 895.
(d) Ksander, G.; Bold, G.; Lattmann, R.; Lehmann, C.; Fru¨h, T.; Xiang,
Y.-B.; Inomata, K.; Buser, H.-P.; Schreiber, J.; Zass, E.; Eschenmoser, A.
HelV. Chim. Acta 1987, 70, 1115. (e) Drenkard, S.; Ferris, J.; Eschenmoser,
A. HelV. Chim. Acta 1990, 73, 1373.
(8) Smith, J. G.; Irwin, D. C. Synthesis 1978, 894.
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Commun. 1985, 15, 335. (b) Konwar, D.; Goswami, B. N.; Borthakur, N.
J. Chem. Res. Synop. 1999, 242.
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Org. Chem. 1968, 33, 3625. (b) Amos, D. T.; Renslo, A. R.; Danheiser, R.
L. J. Am. Chem. Soc. 2003, 125, 4970. (c) Maloney, K. M.; Danheiser, R.
L. Org. Lett. 2005, 7, 3115.
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Hattori, K.; Yamamoto, H. J. Am. Chem. Soc. 1983, 105, 2831.
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1978, 892. Takahashi, K.; Rimura, S.; Ogawa, Y.; Yamada, K.; Iida, H.
Synthesis 1978, 892.
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(b) Pellissier, H.; Gil, G. Tetrahedron Lett. 1989, 30, 171. (c) Tobisu, M.;
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Soc. 2007, 129, 11431.
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5, 152.
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Lett. 2002, 43, 5361.
10.1021/ol800199b CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/18/2008

(MCRs),14,15 we describe herein a one-pot synthesis of
R-iminonitriles by reaction of aldehydes, primary amines and
TMSCN using 2-iodoxybenzoic acid (IBX) as oxidant in
conjunction with a catalytic amount of tetrabutylammonium
bromide (TBAB). We also document a rapid construction
of indolizidine skeleton by applying this new synthetic
methodology.
Table 1. Three-Component Synthesis of R-Iminonitriles,
Optimization of Reaction Parametersa
To achieve the projected transformation, the oxidant has
to satisfy the following criteria: (a) to be compatible with
the conditions of the Strecker reaction or, in an ideal case,
to be capable of promoting the Strecker reaction; (b) to be
able to selectively oxidize the aminonitrile in the presence
of two oxidizable starting materials. On the basis of this
consideration, we selected 2-iodoxybenzoic acid (IBX)16 as
IBX
(equiv)
additive
(equiv)
yield
(%)
entry
X
conditions
1
2
3
4
5
6
7
8
K
K
THF/rt/72 h
MeCN/rt/24 h
2
2
2
2
1
1
1
1
-
-
-
-
40b
18b
35b
28c
90c
90c
37c
87c
TMS MeCN/rt/24 h
TMS MeCN/40 °C/4 h
TMS MeCN/rt/1 h
TMS MeCN/rt/1 h
TMS MeCN/rt/4 h
TMS MeCN/rt/1 h
TBAB (1)
an oxidant for its intrinsic acidity (pKaH2O ) 2.4, pKaDMSO
)
TBAB (0.05)
TBAI (0.05)
TBAC (0.05)
6.65)17 that would be beneficial to the Strecker reaction18
and for its ability to oxidize amines to imines.19,20 The
condensation of benzaldehyde (2a), phenethylamine (3a), and
cyanide (4) in the presence of IBX was examined as a test
reaction, and the results are summarized in Table 1. The
R-iminonitrile was indeed produced using KCN or TMSCN
as a cyanide source, in either THF or acetonitrile as a solvant;
however, the yield was low even after prolonged reaction
periods (entries 1-3). Heating the reaction mixture to 40
°C reduced the reaction time but had adverse effect on the
product yield (entries 4 vs 3). A control experiment indicated
that the Strecker reaction of 2a, 3a, and TMSCN in
acetonitrile under Ramo´n-Yus’s catalyst-free conditions21 was
almost instantaneous, leading to aminonitrile in nearly
quantitative yield. The low efficiency observed in the
production of iminonitrile is thus due to the slow oxidation
step. Much to our delight, adding tetrabutylammonium
bromide (TBAB, 1 equiv) to the reaction mixture accelerated
significantly the reaction, leading to the desired R-iminoni-
trile in 90% isolated yield (entry 5, Table 1).22 A very similar
result was obtained when the reaction was performed in the
presence of a catalytic amount of TBAB (0.05 equiv, entry
6). We have also briefly examined the halide effect. Whereas
tetrabutylammonium chloride (TBAC) is as efficient as
a General conditions: molar ratio 2a/3a/4 ) 1:1:1.1. b Determined based
on the 1H NMR spectrum of the crude material. c Isolated yields after
column chromatography on the silanized silica gel.
TBAB, tetrabutylammonium iodide (TBAI) was found to be
far less effective in mediating the present transformation.
The scope of this novel synthesis of R-iminonitriles was
next examined by varying the structures of aldehydes and
amines. As shown in Table 2, electron-neutral, -rich, and
-poor aromatic aldehydes, as well as R,â-unsaturated alde-
hydes (cinnamaldehyde, entry 3) were all compatible with
these oxidative conditions, leading to the respective adducts
in good to excellent yields. A heteroaromatic aldehyde, such
as pyridinecarboxaldehyde (entry 4), was converted into the
corresponding R-iminonitrile (1e) in 79% yield. The (S)-1-
phenylethanamine participated in the reaction to afford 1f
in almost quantitative yield without racemization as evi-
denced by chiral HPLC analyis of 1f and (()-1f′ (entry 5,
Table 2). When bulky amines (t-butyl, entry 6) or aromatic
amines (entries 7 and 8) were subjected to the same
conditions, the reaction was slowed down significantly.
However, by adding a catalytic amount of iodine, which is
known to catalyze the Strecker reaction,23 the desired
iminonitrile was isolated in excellent yields (entries 6-8,
Table 2). The three-component reaction is also applicable
(14) (a) Ngouansavanh, T.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46,
5775. (b) Ngouansavanh, T.; Zhu, J. Angew. Chem., Int. Ed. 2006, 45, 3495.
(15) For a recent overview, see: Taylor, R. J. K.; Reid, M.; Foot, J.;
Raw, S. A. Acc. Chem. Res. 2005, 38, 851.
(16) (a) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J.
Org. Chem. 1995, 60, 7272. (b) Richardson, R. D.; Zayed, J. M.; Altermann,
S.; Smith, D.; Wirth, T. Angew. Chem., Int. Ed. 2007, 46, 6529 and
references therein. (c) Moorthy, J. N.; Singhal, N.; Senapati, K. Org. Biomol.
Chem. 2007, 5, 767. (d) Moorthy, J. N.; Singhal, N.; Senapati, K.
Tetrahedron Lett. 2008, 49, 80.
(17) Gallen, J.; Goumont, R.; Clark, T.; Terrier, F.; Williams, C. M.
Angew. Chem., Int. Ed. 2006, 45, 2929.
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(b) Groger, H. Chem. ReV. 2003, 103, 2795. (c) Enders, D.; Shilvock, J. P.
Chem. Soc. ReV. 2000, 29, 359. (d) Strecker, A. Ann. Chem. Pharm. 1850,
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Chem., Int. Ed. 2003, 42, 4077. (b) Nicolaou, K. C.; Mathison, C. J. N.;
Montagnon, T. J. Am. Chem. Soc. 2004, 126, 5192.
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2812. (b) Wirth, T.; Angew. Chem., Int. Ed. 2006, 45, 4402.
(21) (a) Martinez, R.; Ramo´n, D. J.; Yus, M. Tetrahedron Lett. 2005,
46, 8472. (b) Zhu, J.; Bouillon, J.-P.; Singh, G. P.; Chastanet, J.;
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R.; Bourdet, S.; Chastanet, J.; Roussi, G. J. Org. Chem. 1995, 60, 6389.
(22) Quaternary ammonium salt were known to be beneficial in some
IBX-mediated transformations, see: (a) Tohma, H.; Takizawa, S.; Watanabe,
H.; Fukuoka, Y.; Maegawa, T.; Kita, Y. J. Org. Chem. 1999, 64, 3519. (b)
Tohma, H.; Takizawa, S.; Morioka, H.; Maegawa, T.; Kita, Y. Chem.
Pharm. Bull. 2000, 48, 445. (c) Shukla, V. G.; Salgaonkar, P. D.;
Akamanchi, K. G. J. Org. Chem. 2003, 68, 5422. (d) Zhu, J.; Germani, A.
G.; Porco, Jr. J. A. Angew. Chem., Int. Ed. 2004, 43, 1239. (e) Shukla, V.
G.; Salgaonkar, P. D.; Akamanchi, K. G. Synlett 2005, 1483. (f) Kuhakarn,
C.; Kittigowittana, K.; Pohmakotr, M.; Reutrakul, V. Tetrahedron 2005,
61, 8995. (g) Kuhakarn, C.; Kittigowittana, K.; Ghabkham, P.; Pohmakotr,
M.; Reutrakul, V. Tetrahedron 2005, 61, 8995. (h) Ozanne-Beaudenon, A.;
Quideau, S. Tetrahedron Lett. 2006, 47, 5869. (i) Bhalerao, D. S.; Mahajan,
U. S.; Chaudhari, K. H.; Akamanchi, K. G. J. Org. Chem. 2007, 72, 662.
(j) Potassium iodide as additive: Pan, Z.-L.; Liu, X.-Y.; Liang, Y.-M.
Tetrahedron Lett. 2004, 45, 4101.
(23) (a) Royer, L.; De, S. K.; Gibbs, R. A. Tetrahedron Lett. 2005, 46,
4595. (b) Masdeu, C.; Go´mez, E.; Williams, N. A. O.; Lavilla, R. Angew.
Chem., Int. Ed. 2007, 46, 3043.
1510
Org. Lett., Vol. 10, No. 8, 2008

NMR studies. This assignment was corroborated in the case
of 1i by X-ray analysis (cf. Supporting Information).27
Table 2. R-Iminonitriles from Aromatic and Aliphatic
Aldehydea
Grierson et al.3 have demonstrated the utility of 2-cyano-
1-aza dienes in the synthesis of indolizidines.28 The literature
methods for the access to these dienes are nevertheless long
and low yielding. On the other hand, by applying the present
methodology, a two-step synthesis of indolizidine was
developed. The reaction of penten-1-amine (3b) with cin-
namaldehyde (2b) and TMSCN in CH3CN at room temper-
ature, followed by addition of IBX/TBAB, gave rise to
2-cyano-1-aza-1,3-butadiene (1p) in 71% yield (Scheme 1).
The thermal intramolecular hetero-Diels-Alder reaction of
Scheme 1. Two-Step Synthesis of Indolizidines Involving a
Key Three-Component Synthesis of R-Iminonitriles.
a All reactions were run in acetonitrile at room temperature in the
presence of the TMSCN, IBX, and TBAB. For the alphatic aldehydes, IBX
was added after the completion of the Strecker reaction. b Yields refer to
the mass isolated after silanized silica gel chromatography. c General
condition using iodine to catalyze Strecker reaction: molar ratio 2/3/4/I2/
IBX/TBAB ) 1:1:1.1:0.1:1.1:1.1. d All reagents were mixed at once.
e Isolated as a mixture of two diastereomers in a 4:1 ratio.
1p failed to produce the desired cycloadduct. Gratefully, the
cycloaddition of 1p took place smoothly under microwave
irradiation conditions (300 W for 6 h, toluene) to afford the
indolizidine in 99% yield as a mixture of two diastereomers
5 and 6 (5/6 ) 1:1) (Scheme 1).
On the basis of the literature precedents, it is reasonable
to hypothesize that the role of TBAB is to activate the IBX
via the formation of a pentacoordinated 12-I-5 species 7,
which was then more susceptible to nucleophilic attack by
amine, leading to 8. The syn elimination of a molecular of
water via transition state 9b, which was less sterically
congested than 9a, would lead to the formation of the
observed Z-iminonitrile and IBA (Scheme 2). Conceivably,
a single electron transfer (SET) mechanism leading to 10
followed by dehydration could also be operating, as dem-
onstrated by Nicolaou and co-workers.29
to the synthesis of R-iminonitriles derived from aliphatic
aldehydes, far less accessible than their aromatic counterparts
(Table 2). Aliphatic aldehydes whether linear or R-branched,
participate effectively in oxidative condensation process in
the presence of a stoichiometric amount of TBAB. In
addition, chiral nonracemic N,N-dibenzyl-O-TBS-serinal24
was successfully transformed into the corresponding R-imi-
nonitrile in excellent yield (entry 13, Table 2). However,
partial epimerization occurred as the union of a chiral
aldehyde and a chiral amine (entry 14, Table 2) provided
1o as a mixture of diastereomers (dr ) 4:1).25 The formation
of R-cyanoenamines resulting from the tautomerization of
corresponding iminonitriles was not observed in these cases.26
Higher yields were generally obtained, especially in the case
of aliphatic aldehydes, when IBX was introduced to the
reaction mixture after the completion of the Strecker reaction
(entry 9, Table 2). Except for 1h, only one stereomer was
produced and was assigned as the Z isomer according to
To verify this possibility, a three-component condensation
of benzaldehyde (2a), cyclopropylamine (3c), and TMSCN
was carried out under our standard conditions. As shown in
Scheme 3, the expected R-iminonitrile (1q) was isolated in
91% yield. Since cyclopropylamine cation radicals are known
(27) CDC-668053 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge via www.ccdc-
.can.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic
Center, 12 Union Road, CambridgeCB21EZ, UK; Fax: (+44)1223-336033;
or deposit@ccdc.cam.ac.uk.
(28) For leading references on the biological activity of indolizidine
alkaloids, see: (a) Michael, J. P. Nat. Prod. Rep. 2007, 24, 3001. (b)
Takahata, H.; Momose, T. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press, Inc.: San Diego, 1993; Vol. 44, Chapter 3.
(24) (a) Andre´s, J. M.; Barrio, R;, Martinez, M. A.; Pedrosa, R.; Pe´rez-
Encabo, A. J. Org. Chem. 1996, 1, 4210. (b) La¨ıb, T.; Chastanet, J.; Zhu,
J. Tetrahedron Lett. 1997, 38, 1771. (c) Andres, J. M.; Pedrosa, R.
Tetrahedron 1998, 54, 5607. (d) La¨ıb, T.; Chastanet, J.; Zhu, J. J. Org.
Chem. 1998, 63, 1709.
(25) The formation of the minor product results from partial epimerization
of N,N-dibenzyl serinal. The chiral amine is configurationally stable as
shown in the formation of 1f.
(29) (a) Nicolaou, K. C.; Zhong, Y-L.; Baran, P. S. Angew. Chem., Int.
Ed. 2000, 39, 625. (b) Nicolaou, K. C.; Baran, P. S.; Kranich, R.; Zhong,
Y-L.; Sugita, K.; Zou, N. Angew. Chem., Int. Ed. 2001, 40, 202.
(26) De Kimpe, N.; Verhe´, R.; de Buyck, L.; Hasma, H.; Schamp, N.
Tetrahedron 1976, 32, 3063.
Org. Lett., Vol. 10, No. 8, 2008
1511

Scheme 2. Postulated Mechanism for IBX-Mediated
Scheme 3. Synthesis of N-Cyclopropyliminonitrile.
Oxidation of Aminonitrile.
corresponding cyanoiodinanes.32 However, preliminary ex-
periments indicated that the reaction rate of the Strecker
reaction was not affected by the presence of IBX-TBAB.
In summary, we have described a novel IBX-TBAB-
promoted three-component synthesis of R-iminonitrile from
readily accessible starting materials. Operational simplicity
and good-to-excellent chemical yields are key features of
the present protocol. To the best of our knowledge, this
represented the first one-pot procedure that is applicable to
a wide range of aldehydes, amines including aromatic and
aliphatic ones. The ready accessibility of the R-iminonitrile
should pave the way for the development of novel transfor-
mations based on this highly functionalized molecule. This
potential was illustrated by developing a two-step synthesis
of indolizidine via a microwave-assisted intramolecular
cycloaddition of R-iminonitrile.
to undergo fragmentation leading to ring-opened products,30
this observation might suggest the ionic mechanism on the
way to iminonitriles. Furthermore, the clean formation of
1m (entry 12, Table 2) and 1p (Scheme 1) without concurrent
generation of pyrrolidine derivatives is also supportive of
the ionic mechanism.31 Finally, it has also to be noted that
the oxidation is highly regioselective, presumably due to the
high acidity of Ha vs Hb (cf. intermediate 8).
Acknowledgment. Financial support from CNRS and this
institute are gratefully acknowledged. P.F. (ICSN) thanks
this institute for doctoral fellowships. We also thank M. V.
Guerineau (ICSN) for Maldi mass analysis.
Supporting Information Available: Experimental pro-
1
It is also reasonable to hypothesize that the IBX-TBAB
system could influence the Strecker reaction since TMSCN
is known to react with polyvalent iodines to afford the
cedures, product characterization, and copies of the H and
13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL800199B
(30) (a) Lee, J.; U, J. S.; Blackstock, S. C.; Cha, J. K. J. Am. Chem.
Soc. 1997, 119, 10241. (b) Itoh, T.; Kaneda, K.; Teranishi, S. Tetrahedron
Lett. 1975, 2801.
(31) 5-Exo-cyclization of δ,ω-unsaturated aminium cation radical, see:
Newcomb, M.; Deeb, T. M. J. Am. Chem. Soc. 1987, 109, 3163.
(32) Zhdankin, V. V.; Kuehl, C. J.; Krasutsky, A. P.; Bolz, J. T.;
Mismash, B.; Woodward, J. K.; Simonsen, A. J. Tetrahedron Lett. 1995,
36, 7975.
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Org. Lett., Vol. 10, No. 8, 2008