Convenient synthesis of α-amino amides using low-valent tantalum prepared from TaCl5 and Zn

Article abstract of DOI:10.1016/j.tetlet.2005.08.131

We have developed a general preparation method of α-amino amides from imines and isocyanates using low-valent tantalum prepared from TaCl₅ and Zn in situ. This method was successfully applied to various imines derived from benzaldehyde derivati

Full text of DOI:10.1016/j.tetlet.2005.08.131

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7593–7595
Convenient synthesis of a-amino amides using low-valent
tantalum prepared from TaCl5 and Zn
*
ꢀ
Haruka Shimizu and Shu Kobayashi
Graduate School of Pharmaceutical Sciences, The University of Tokyo, The HFRE Division, ERATO, Japan Science and
Technology Agency (JST), Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 20 June 2005; revised 24 August 2005; accepted 25 August 2005
Available online 15 September 2005
Abstract—We have developed a general preparation method of a-amino amides from imines and isocyanates using low-valent
tantalum prepared from TaCl5 and Zn in situ. This method was successfully applied to various imines derived from benzaldehyde
derivatives with electron-withdrawing or electron-donating substituents, heteroaromatic aldehydes, and an aliphatic, a-branched
aldehyde, giving the corresponding a-amino amides in high yields.
Ó 2005 Elsevier Ltd. All rights reserved.
a-Amino acids and their analogues are among the most
important, numerous and diverse families of natural
products. They are not only used as building blocks
for living things but also show biological activities by
themselves. Therefore, many chemists have concen-
trated their efforts on the development of more efficient
synthetic methods of natural and unnatural amino acid
analogues.1
They also disclosed its characteristic structure and reac-
tivity toward carbonyl compounds. On the other hand,
it was reported that tantalum–imine complex 1 reacted
with cyclohexyl isocyanate to afford a mixture of an a-
amino amide and a urea in almost 2:1 selectivity
(Scheme 1).4 We thought that this type of reaction might
provide an interesting synthetic method of a-amino
amides, if the reactions proceeded regioselectively.
Whereas tantalum–imine complexes2 have attracted
much attention in the area of organometallic chemistry,
their use in organic synthesis has been rather limited.3 In
1998, Takai et al. reported the first example of direct
synthesis of tantalum–imine complex (1) from an imine
and low-valent tantalum prepared from TaCl5 and Zn.4
First, we used phenyl isocyanate instead of cyclohexyl
isocyanate (Table 1). It was found that the use of an ex-
cess amount of the isocyanate decreased the yield of the
desired product and led to an increase of unknown
insoluble by-products (entries 1 and 2). We thought that
the weakly basic work up using saturated aqueous
Ph
NCO
NaOH
H2O
N
Ph
N
TaCl5, Zn
TaCl3(dme)
H
Ph
H
Ph
Toluene-DME
1
O
Ph
NH
H
N
+
Ph
N
N
Ph
H
O
Ph
48%
28%
Scheme 1. The reaction of a Ta–imine complex with cyclohexyl isocyanate.
Keywords: a-Amino amides; Tantalum–imine complex; Isocyanate.
*
Corresponding author. Fax: +81 3 5684 0634; e-mail: skobayas@mol.f.u-tokyo.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.131

7594
Table 1. Optimization of the reaction conditions
Ph
H. Shimizu, S. Kobayashi / Tetrahedron Letters 46 (2005) 7593–7595
TaCl5 (1 equiv)
Zn (1.2 equiv)
Ph
NH
N
quench
H
+
R
NCO
N
Ph
R
Ph
H
benzene-DME
Entry
Imine (equiv)
R–NCO (equiv)
Time (h)
Quench
Yield (%)
1
2
3
4
5
6
7
1.0
1.0
1.0
1.2
1.2
1.2
1.2
PhNCO (1.2)
PhNCO (2.4)
PhNCO (1.2)
PhNCO (1.0)
PhNCO (1.0)
PhNCO (1.0)
BnNCO (1.0)
18
18
18
18
24
48
24
Satd NaHCO3 aq
Satd NaHCO3 aq
10% KOH aq
10% KOH aq
10% KOH aq
10% KOH aq
10% KOH aq
37
Complex mixture
78
82
90
82
90
NaHCO3 resulted in by-product formation, because the
unreacted isocyanate would remain after adding satu-
rated aqueous NaHCO3 and react with the desired prod-
uct to give undesired compounds. We then decided to
change the work up procedure by using aqueous 10%
KOH. As expected, the yield was improved (entry 3)
although a by-product, which was thought to be a urea
derivative of the product was still obtained. Further
optimization of the reaction conditions revealed that
the use of a slight excess of the imine led to an increased
yield, up to 90% in 24 h (entry 5). Benzyl isocyanate also
gave a promising result (entry 7). In these cases, isocya-
nates inserted mainly into the Ta–C bond of cyclotant-
alacycle to give the a-amino amides in high yields.
Encouraged by these results, we next investigated the
substrate scope of this reaction (Table 2). In the cases
of N-(4-substituted-benzylidene)benzylamine deriva-
tives, the reactions proceeded smoothly to give the
desired products in high yields (entries 1–3, 9–11),
although longer reaction times were needed to form
Ta–imine complexes when benzylamine derivatives with
electron-withdrawing substituents were used. N-Benzyl-
ideneaniline and aldimines prepared from hetero-
aromatic aldehydes and benzylamine also required
longer reaction times to form the corresponding
Ta–imine complexes in good yields (entries 4 and 12).
Even the aliphatic imine derived from cyclohexanecarb-
oxyaldehyde afforded the corresponding product in
Table 2. Substrate scope
R2
R1
R2
N
TaCl5 (1 equiv)
Zn (1.2 equiv)
NH
10% KOH aq.
benzene-DME, rt, 24 h
H
R3 NCO
+
N
R3
R1
H
O
Entry
R1
R2
R3
Yield (%)
1
2
3a
4a,b
5a
6
7
8
9
10
11a
12a
13a
14a
15a
16a
17a
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-Pyridyl
Ph
Ph
Ph
Ph
4-MeOC6H4
4-MeC6H4
4-ClC6H4
2-Furyl
Ph
Cyclohexyl
Ph
Ph
Bn
Bn
Bn
Bn
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
85
82
85
80
Ph
84
(R)-1-Phenylethyl
(R)-1-(a-Naphthyl)ethyl
(R)-1-(b-Naphthyl)ethyl
Bn
Bn
Bn
Bn
Ph
78c
72d
74e
93
86
86
74
85
Ph
59
(R)-1-Phenylethyl
(R)-1-(a-Naphthyl)ethyl
(R)-1-(b-Naphthyl)ethyl
83f
67g
88h
Ph
a Ta–imine complex formation time; 3 h.
b DCM–DME was used as a solvent.
c Major/minor = 68/32.
d Major/minor = 79/21.
e Major/minor = 66/34.
f Major/minor = 66/34.
g Major/minor = 75/25.
h Major/minor = 65/35.

H. Shimizu, S. Kobayashi / Tetrahedron Letters 46 (2005) 7593–7595
7595
Cajigal, M. L.; Abboud, K. A. Organometallics 1996, 15,
1905–1912; (c) Clark, J. R.; Franwick, P. E.; Rothwell, I. P.
Organometallics 1996, 15, 3232–3237; (d) Neithamer, D. R.;
Ph
Ph
TaCl5 (1.5 equiv)
Zn (1.8 equiv)
N
NH
10% KOH aq.
H
+
Ph NCO
N
Ph
benzene-DME,
50 ºC, 36 h
´
´
Parkanyi, L.; Mitchell, J. F.; Wolczanski, P. T. J. Am.
Chem. Soc. 1988, 110, 4421–4423; (e) Stricker, J. R.; Bruck,
M. A.; Wigley, D. E. J. Am. Chem. Soc. 1990, 112, 2814–
2816; (f) Smith, D. P.; Stricker, J. R.; Gray, S. D.; Bruck,
M. A.; Holmes, R. S.; Wigley, D. E. Organometallics 1992,
11, 1275–1288.
O
48% yield
Scheme 2. The reaction of a ketimine with an isocyanate.
good yield (entry 14), whereas an aliphatic imine with-
out a branch at the a-position such as hydrocinnamalde-
hyde resulted in the formation of a complex mixture. In
addition, it was found that aldimines derived from chiral
amines moderately influenced the stereochemical out-
come of subsequent additions of Ta–imine complexes
to isocyanates (entries 6–8, 15–17). These preliminary
results suggested that stereoselective synthesis of a-ami-
no amides using low-valent tantalum–imine complexes
might be possible. The ketimine derived from cyclohex-
anone and aniline reacted with low-valent tantalum fol-
lowed by phenyl isocyanate to give the desired product
in moderate yield (Scheme 2). This result suggests that
this method is useful for the preparation of a-amino-
a,a-disubstituted amide derivatives.1,5,6
3. (a) Takahashi, Y.; Onoyama, N.; Ishikawa, Y.; Motojima,
S.; Sugiyama, K. Chem. Lett. 1978, 525–528; (b) Mayer, J.
M.; Curtis, C. J.; Bercaw, J. E. J. Am. Chem. Soc. 1983,
105, 2651–2660; (c) Chamberlain, L. R.; Rothwell, I. P.;
Huffman, J. C. J. Chem. Soc., Chem. Commun. 1986, 1203–
´
´
´
´
1205; (d) Gomez, M.; Gomez-Sal, P.; Jimenez, G.; Martın,
´
A.; Royo, P.; Sanchez-Nieves, J. Organometallics 1996, 15,
3579–3587.
4. Takai, K.; Ishiyama, T.; Yasue, H.; Nobunaka, T.; Itoh, M.
Organometallics 1998, 17, 5128–5132.
5. Recent reports about the synthesis of a-amino-a,a-disub-
stituted acids, see: (a) Miyabe, H.; Asada, R.; Takemoto, Y.
Tetrahedron 2005, 61, 385–393; (b) Belokon, Y. N.;
´
ˇ
´
Bespalova, N. B.; Churkina, T. D.; Cısarova, I.; Ezernits-
kaya, M. G.; Harutyunyan, S. R.; Hrdina, R.; Kagan, H.
B.; Kocˇovsky´, P.; Kochetkov, K. A.; Larionov, O. V.;
´ˇ
Lyssenko, K. A.; North, M.; Polasek, M.; Peregudov, A. S.;
Prisyazhnyuk, V. V.; Vyskocˇil, S. J. Am. Chem. Soc. 2003,
125, 12860–12871; (c) Ellis, T. K.; Martin, C. H.; Tsai, G.
M.; Ueki, H.; Soloschonok, V. A. J. Org. Chem. 2003, 68,
6208–6214; (d) Clark, J. S.; Middleton, M. D. Org. Lett.
2002, 4, 765–768; (e) Fu, Y.; Hammarstro¨m, G. J.; Miller,
T. J.; Froncezek, F. R. J. Org. Chem. 2001, 66, 7118–
7124.
In summary, we have shown that a-amino amides were
readily prepared from imines and isocyanates using low-
valent tantalum generated from TaCl5 and Zn. A wide
variety of imines and isocyanates were applicable, and
various a-amino amides were synthesized in high yields.
Further investigations to develop an asymmetric version
of this reaction are now in progress.
6. Typical experimental procedure (Table 1, entry 6): Under
argon atmosphere, DME (0.25 mL) was added to a
suspension of TaCl5 (144 mg, 0.40 mmol) and Zn (32 mg,
0.49 mmol) in benzene (0.25 mL), and the mixture was
stirred at room temperature for 1 h. N-Benzylidenebenzyl-
amine (93 mg, 0.48 mmol) in benzene (0.50 mL) was added
to the resulting green-brown suspension at the same
temperature and the mixture was stirred for 1 h. The color
of the suspension changed to dark red. Phenyl isocyanate
(48 mg, 0.40 mmol) in benzene (0.50 mL) was then added
and the mixture was stirred at room temperature for 24 h.
The reaction was stopped by addition of aqueous 10%
KOH (5 mL) and ether (5 mL), and the mixture was stirred
vigorously for 30 min until the brown mixture became
white suspension. The white solid was filtered off through
CeliteÒ and the residue was washed with ether (10 mL,
three times). The filtrate and the washes were combined and
extracted with ether (10 mL, two times). The organic layer
was combined and washed with brine and dried over
Na2SO4. The crude product was purified by P-TLC
(CH2Cl2–EtOH, 30:1) to afford 2-(benzylamino)-N,2-diphen-
ylacetamide (115 mg, 90%). Off-white solid; Mp: 80–
82 °C; 1H NMR (400 MHz, CDCl3): d 3.85 (s, 2H), 4.33
(s, 1H), 7.01–7.60 (m, 15H), 9.47 (br s, 1H); 13C NMR
(400 MHz, CDCl3): d 52.7, 67.5, 119.4, 124.1, 127.2, 127.5,
128.1, 128.7, 128.8, 128.9, 137.6, 138.8, 170.0; IR (KBr)
3303, 3261, 1672, 1603, 1533, 1495, 1443, 1119, 924, 739,
694 cmÀ1; ESIMS m/z 317 ([M+H]+). Anal. Calcd for
C21H20N2O: C, 79.44; H, 6.00; N, 9.26. Found: C, 79.50; H,
6.20; N, 9.22.
Acknowledgements
This work was partially supported by a Grant-in-Aid for
Scientific Research from Japan Society for the Promo-
tion of Science (JSPS). The authors thank Ms. Miho
Ohsumi for her technical support.
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´
´
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