Double nucleophilic addition of trimethylsilyl cyanide to α,β-unsaturated aldimines promoted by aluminum chloride: Preparation of 2-aminopentanedinitrile

Article abstract of DOI:10.1246/cl.2005.1456

In the presence of AlCl₃, trimethylsilyl cyanide underwent 1,4- and subsequent 1,2-additions with α,β-unsaturated imines to give 2-aminopentanedinitriles in good yields. An asymmetric version of this type of bis-cyanation was successfully conducted using a chiral α,β- unsaturated imine possessing a phenylglycinol derivative as a chiral auxiliary. Copyright

Full text of DOI:10.1246/cl.2005.1456

1456
Chemistry Letters Vol.34, No.10 (2005)
Double Nucleophilic Addition of Trimethylsilyl Cyanide to ꢀ,ꢁ-Unsaturated Aldimines
Promoted by Aluminum Chloride: Preparation of 2-Aminopentanedinitrile
Makoto Shimizu,ꢀ Makiko Kamiya, and Iwao Hachiya
Department of Chemistry for Materials, Mie University, Tsu, Mie 514-8507
(Received August 8, 2005; CL-051029)
Table 1. Comparison of reaction conditionsa
In the presence of AlCl3, trimethylsilyl cyanide underwent
1,4- and subsequent 1,2-additions with ꢀ,ꢁ-unsaturated imines
to give 2-aminopentanedinitriles in good yields. An asymmetric
version of this type of bis-cyanation was successfully conducted
using a chiral ꢀ,ꢁ-unsaturated imine possessing a phenylglyci-
nol derivative as a chiral auxiliary.
R3
R3
TMSCN (3.0 equiv.)
Lewis Acid (equiv.)
R2
N
R2 HN
NC
R1
R1
H
CN
CH2Cl2, −78 °C−rt
2
1
Entry R1 R2
R3
LA(equiv.) 2/%b drc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
H
H
H
H
H
H
H
H
H
H
H
PMP
PMP
PMP
PMP
PMP
PMP
Bn
AlCl3(0.2)
AlCl3(0.5)
AlCl3(1.0)
EtAlCl2(0.5) 57
Et2AlCl(0.5) 28
Me3Al(0.5) 50
AlCl3(0.5)
AlCl3(0.5)
AlCl3(0.5)
34
83
65
88:12
51:49
79:21
56:44
65:35
51:49
65:35
50:50
—
56:44
52:48
—
—
52:48
—
One of the most important reactions for the synthesis of ꢀ-
amino acids involves the Strecker reaction.1 Several methods
have been reported involving their asymmetric versions.2 We
have introduced 1,4- and 1,2-double nucleophilic addition reac-
tions to ꢀ,ꢁ-unsaturated aldimines, which avoids unnecessary
isolation process of relatively unstable imino intermediates to
give secondary amines in good yields.3 Very recently, trimethyl-
silyl cyanide was successfully used as a second nucleophile to
give the Strecker-type products in good yields (Scheme 1, Eq
1).4 We have now found that trimethylsilyl cyanide is an excel-
lent nucleophile for both the 1,4- and 1,2-additions to ꢀ,ꢁ-unsat-
urated aldimines to give 2-aminopentanedinitriles.5 This paper
reports a facile double nucleophilic addition of trimethylsilyl cy-
anide as well as its asymmetric version (Scheme 1, Eq 2).
58
77
0
51
79
69
51
80
70d
CHPh2
p-Ts
2,4-(MeO)2C6H3 AlCl3(0.5)
PMP
PMP
CHPh2
PMP
CHPh2
AlCl3(0.5)
AlCl3(0.5)
AlCl3(0.5)
AlCl3(0.5)
AlCl3(0.5)
Me Me
Me Me
n-Pr
H
H
15 TMS
aReaction was carried out according to the typical procedure.6
bIsolated yield. cIsomer ratio determined by 1H NMR. dDesilylated
product (R1 ¼ H) was obtained.
R2 OTMS
R3 R2
HN
PMP
PMP
TMSCN
R4OC
N
N
R4
R3
(1)
(2)
Table 2. Effects of chiral auxiliariesa
R1
R1
H
R3
AlCl3, CH2Cl2
R1
CN
R3
Ph
Ph
R2 HN
R2
OR1
TMSCN
OR1
OR1
NC
R1
2R2 HN
N
R
(R,S)-5
AlCl3, CH2Cl2
CN
H
TMSCN (3.0 equiv.)
AlCl3 (0.5 equiv.)
NC
CN
Ph
H
Ph
2
1
3
4
+
OR1
or
CH2Cl2
−78 °C−rt
Scheme 1.
HN
R2
N
R2
NC
(R,R)-5
CN
TMS
H
First, the effect of Lewis acids for the double nucleophilic
addition of TMSCN to imine 1 was investigated, and the results
are summarized in Table 1.
Entry 3 or 4
R1
R2 Yield/%b (R,S):(R,R)c
1
2
3
4
5
6
7
8
3
3
3
3
3
4
4
4
Me
CH2CH=CH2
(E)-CH2CH=CHMe Me
(E)-CH2CH=CHPh Me
CH2(Me)C=CH2 Me
CH2CH=CH2
(E)-CH2CH=CHMe
CH2CꢁCH
Me
Me
76
71
68
50
73
54
64
47
93:7
96:4
86:14
90:10
92:8
91:9
81:19
79:21
Among the Lewis acids tested, AlCl3 was found to be the
most efficient promoter (Entries 1–6). In particular, the reaction
in the presence of 0.5 equivalent of AlCl3 promoted the double
nucleophilic addition most effectively to give the pentanedi-
nitrile in 83% yield, whereas the use of 1 equivalent of AlCl3 in-
duced the hydrolysis of the imine to some extent, resulting in the
decrease in the product yield (Entries 2 and 3). Use of other
Lewis acids such as AlBr3, TiCl4, TiI4, TMSI only gave 1,2-ad-
dition products. Regarding the substituent at the nitrogen atom,
diphenylmethyl, 2,4-dimethoxyphenyl, and benzyl groups could
also be used, whereas the electron-withdrawing p-tosyl substi-
tuted imine did not give the desired addition product (Entries
7–10). It is noteworthy that use of the TMS derivative gave
the desilylated dinitrile in good yield, indicating that this partic-
ular compound acted as an equivalent of the imine derived from
acrolein, most of whose imino derivatives were readily polymer-
H
H
H
aReaction was carried out according to the typical procedure.6
bIsolated yield. cIsomer ratio determined by 1H NMR and/or
HPLC. Determination of the absolute configuration. See Ref. 7.
ized during preparation (Entry 15). We next investigated an
asymmetric version of these processes using chiral imines
possessing a chiral auxiliary at the nitrogen atom, and Table 2
summarizes the results.
Under the optimum conditions found for the present double
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.10 (2005)
1457
References and Notes
nucleophilic addition, chiral imines 3 and 4 possessing chiral
auxiliaries derived from (R)-phenylglycinol8 underwent dia-
stereoselective addition. Regarding the derivatives, methyl,
allyl, and methallyl ethers induced good diastereoselectivities
(Entries 1, 2, 5, and 6). In particular, using the allylated chiral
auxiliary, the TMS derivative 4 gave the dinitrile 5 in a good
diastereoselective manner (Entry 6). In these instances where
the TMS derivative 4 was used, the desilylated dinitrile 5
(R2 ¼ H) was obtained as in the case of the entry 15 in
Table 1. The dinitrile obtained was converted into aminodiacid.7
In order to check the diastereoselectivity in the first conju-
gate addition reaction, the tert-butyldimethylsilylated derivative
6 was subjected to the present double addition conditions. In this
case, however, three peaks of the adducts were detected by
HPLC, indicating that the first conjugate addition was not dia-
stereoselective. The use of the (R)-phenylethylimino derivative
8 resulted in decrease in the product yield as well as in the dia-
stereoselectivity (Scheme 2).
1
a) A. Strecker, Liebigs Ann., 75, 27 (1850); A. Strecker, Liebigs
Ann., 91, 349 (1854). b) For a review: G. C. Barrett, ‘‘Chemistry
and Biochemistry of the Amino Acids,’’ Chapman and Hall, New
York (1985), p 251 and 261.
2
a) F. A. Davis, R. E. Reddy, and P. S. Portonovo, Tetrahedron
Lett., 35, 9351 (1994). b) F. A. Davis, P. S. Portonovo, R. E.
Reddy, and Y.-h. Chiu, J. Org. Chem., 61, 440 (1996). c) M. S.
Iyer, K. M. Gigstad, N. D. Namdev, and M. Lipton, J. Am. Chem.
Soc., 118, 4910 (1996). d) M. S. Sigman and E. N. Jacobsen,
J. Am. Chem. Soc., 120, 5315 (1998). e) M. S. Sigman and
E. N. Jacobsen, J. Am. Chem. Soc., 120, 4901 (1998). f) H.
Ishitani, S. Komiyama, and S. Kobayashi, Angew. Chem., Int.
Ed., 37, 3186 (1998). g) C. A. Krueger, K. W. Kuntz, C. D.
Dzierba, W. G. Wirschun, J. D. Gleason, M. L. Snapper, and
A. H. Hoveyda, J. Am. Chem. Soc., 121, 4284 (1999). h) J. R.
Porter, W. G. Wirschun, K. W. Kuntz, M. L. Snapper, and
A. H. Hoveyda, J. Am. Chem. Soc., 122, 2657 (2000). i) M.
Takamura, Y. Hamashima, H. Usuda, M. Kanai, and M.
Shibasaki, Angew. Chem., Int. Ed., 39, 1650 (2000). j) E. J. Corey
and M. J. Grogan, Org. Lett., 1, 157 (1999).
Ph
3
a) M. Shimizu, A. Morita, and T. Kaga, Tetrahedron Lett., 40,
8401 (1999). b) M. Shimizu, T. Ogawa, and T. Nishi, Tetrahedron
Lett., 42, 5463 (2001). c) M. Shimizu and T. Nishi, Chem. Lett.,
31, 46 (2002). d) M. Shimizu, T. Nishi, and A. Yamamoto, Syn-
lett, 2003, 1469. e) M. Shimizu, C. Yamauchi, and T. Ogawa,
Chem. Lett., 33, 606 (2004).
Ph
OAllyl
TMSCN (3.0 equiv.)
AlCl3 (0.5 equiv.)
HN
TBS
NC
OAllyl
N
CN
7
CH2Cl2, −78 °C−rt
TBS
H
65% (dr = 38:45:17)
Ph
6
Ph
TMSCN (3.0 equiv.)
AlCl3 (0.5 equiv.)
4
5
M. Shimizu, M. Kamiya, and I. Hachiya, Chem. Lett., 32, 606
(2003).
HN
N
For conjugate addition of cyanides, see for example; a) K.
Higuchi, M. Onaka, and Y. Izumi, Bull. Chem. Soc. Jpn., 66,
2016 (1993). b) G. M. Zhdankina, G. V. Krystal, V. S. Bogdanov,
V. I. Kadentsev, L. A. Yanovskaya, Izv. Akad. Nauk SSSR, Ser.
Khim., 1982, 346; Chem. Abstr., 96, 180736 (1982).
NC
CN
H
CH2Cl2, −78 °C−rt
9
8
44% (dr = 76:24)
Scheme 2.
On the basis of these results and the reaction in the presence
of an added proton source9 as well as the deuterium incorpora-
tion ratio previously reported,4 we propose a plausible reaction
mechanism as shown in Scheme 3. The initial AlCl3-promoted
1,4-addition reaction of cyanide produces the metalloenamine
11, which after isomerization into the imine 12 and/or a hydro-
lyzed species with a certain proton source, is attacked by
TMSCN to afford the 1,4–1,2-adduct (R,S)-5.
6
A typical experimental procedure for the addition reaction: To a
suspension of AlCl3 (13.3 mg, 0.10 mmol) in CH2Cl2 (1.0 mL)
was added a solution of the imine 4 (R1 = allyl) (57.5 mg,
0.20 mmol) in CH2Cl2 (1.5 mL) at ꢂ78 ꢃC and the mixture was
stirred at ꢂ78 ꢃC for 15 min. A solution of TMSCN (59.5 mg,
0.60 mmol) in CH2Cl2 (1.5 mL) was added to the resulting
mixture. The mixture was gradually warmed to room temperature
during 24 h. Saturated aqueous NaHCO3 (10 mL) was added to
quench the reaction. The mixture was extracted with ethyl acetate
(15 mL ꢄ 3). The combined extracts were dried over Na2SO4 and
concentrated in vacuo to give the crude product. Purification on
silica gel TLC (hexane:ethyl acetate = 5:1 as an eluent; devel-
oped three times) gave the 1,4–1,2-adduct 5 (29.3 mg, 54%) as
a colorless oil. 1H NMR (270 MHz, CDCl3) ꢂ 2.06–2.16 (m,
2H), 2.33 (d, J ¼ 13:2 Hz, 1H), 2.57 (t, J ¼ 7:3 Hz, 2H), 3.27–
3.57 (m, 3H), 4.02–4.06 (m, 2H), 4.23 (dd, J ¼ 4:0, 9.9 Hz,
1H), 5.20–5.33 (m, 2H), 5.84–5.99 (m, 1H), 7.28–7.40 (m, 5H).
IR (neat) 3317, 2859, 2248, 1494, 1454, 1421, 1361, 1134,
R2
R2
Cl2Al
R1
Met
R1
R1
N
R2
H
N
TMSCN, AlCl3
N
TMSCN, AlCl3
NC
R1
R1
H
R1
CN
3 or 4
10
11
Ph
Ph
O
R1
N
O
1) TMSCN
AlCl3
R1
NC
R1
HN
NC
R1
H
CN
2) H2O
Met
(H)
(R,S)-5
12
1092, 932, 804, 763 cmꢂ1
.
Scheme 3.
7
The adduct was transformed into glutamic acid, and comparison
of the optical rotation to that reported established the absolute
stereochemistry.
In conclusion, we have found an efficient method for 2-
aminopentanedinitrile synthesis by double nucleophilic addition
of trimethylsilyl cyanide to ꢀ,ꢁ-unsaturated aldimines. A chiral
version realizes a diastereoselective synthesis of amino diacid
precursors. The present reaction has an advantage that ꢀ-amino
nitriles derived from relatively unstable imines can be obtained
owing to in situ generation of imino species as intermediates.
1) 20% Pd(OH)2/C, H2
Ph
NH2
O
EtOH, 100 atm, rt
HN
HOOC
21
COOH
2) 6 M HCl, 100 °C
20% yield, (2 steps)
[α] D +30 ° (c 0.044, 2 M HCl)
NC
CN
8
9
For the use of phenylglycinol as a chiral auxiliary, see for exam-
ple; a) Y. Ukaji, T. Watai, T. Sumi, and T. Fujisawa, Chem. Lett.,
1991, 1555. b) A. I. Meyers, G. S. Poindexter, and Z. Brich, J.
Org. Chem., 43, 892 (1978).
When the reaction (Entry 3, Table 1) was carried out in the
presence of molecular sieves 4A containing 1 equiv. of H2O,3b
the dinitrile 2 was obtained in 37% yield.
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technolgy, Japan, and a grant from the Chugai
Pharmaceutical Co. is also gratefully acknowledged.
Published on the web (Advance View) September 24, 2005; DOI 10.1246/cl.2005.1456