Synthesis of N-allylideneamines and their use for the double nucleophilic addition of ketene silyl (thio)acetals and trimethylsilyl cyanide

Article abstract of DOI:10.1021/ol8014539

(Chemical Equation Presented) N-Allylideneamines 1a,b were prepared from acrolein and diphenylethyl or trityl amine in the presence of Ti(OEt) ₄. Double nucleophilic addition of various ketene silyl (thio)acetals and trimethylsilyl cyanide to t

Full text of DOI:10.1021/ol8014539

ORGANIC
LETTERS
2008
Vol. 10, No. 18
3977-3980
Synthesis of N-Allylideneamines and
Their Use for the Double Nucleophilic
Addition of Ketene Silyl (Thio)acetals
and Trimethylsilyl Cyanide
Isao Mizota, Yuri Matsuda, Iwao Hachiya, and Makoto Shimizu*
Department of Chemistry for Materials, Graduate School of Engineering,
Mie UniVersity, Tsu, Mie 514-8507, Japan
mshimizu@chem.mie-u.ac.jp
Received June 27, 2008
ABSTRACT
N-Allylideneamines 1a,b were prepared from acrolein and diphenylethyl or trityl amine in the presence of Ti(OEt)4. Double nucleophilic addition
of various ketene silyl (thio)acetals and trimethylsilyl cyanide to these imines proceeded efficiently to give, after workup with TFA, homoglutamic
acid derivatives 3 and valerolactam 5.
N-Allylideneamines 1 derived from acrolein are expected
to be important intermediates for the preparation of amino
acid derivatives, when these imines 1 are used as acceptors
of nucleophiles in a 1,4- and 1,2-double nucleophilic
addition. However, difficulties have been always reported
for their syntheses, and therefore, there are only a few reports
available for the synthesis of this type of imines 1.1 Colvin
and co-workers prepared a variety of N-silylimines for
ꢀ-lactam synthesis. Although the N-allylideneamine 1 pro-
tected with a TBS group at the nitrogen was synthesized as
one of the examples, it was not used for further reactions.1d,2
The imine having an electron-withdrawing substituent at the
nitrogen was prepared from acrolein1a but did not work as
an effective acceptor in a 1,4- and 1,2-nucleophilic addition.3
Yamamoto reported another example, where the formation
of this particular imine was only confirmed by GC analysis.1c
Since there is no substituent at the ꢀ-position, the imine 1
has high reactivity and readily undergoes polymerization,
which calls for a tedious isolation process.1
(1) (a) Davis, F. A.; Deng, J. Org. Lett. 2005, 7, 621. (b) Bachrach,
S. M.; Liu, M. J. Org. Chem. 1992, 57, 6736. (c) Uyehara, T.; Chiba, N.;
Suzuki, I.; Yamamoto, Y. Tetrahedron Lett. 1991, 32, 4371. (d) Colvin,
E. W.; Mcgarry, D.; Nugent, M. J. Tetrahedron 1988, 44, 4157. (e) Bock,
H.; Dammel, R. Chem. Ber. 1987, 120, 1971. (f) Boyd, D. R.; Coulter,
P. B.; Hamilton, R.; Thompson, N. T.; Sharma, N. D.; Stubbs, M. E.
J. Chem. Soc., Perkin Trans. 1 1985, 2123. (g) Hakiki, A.; Ripoll, J.;
Thuillier, A. Tetrahedron Lett. 1984, 25, 3459. (h) Guillemin, J.; Denis, J.
Angew. Chem. 1982, 94, 715. (i) Earl, R. A.; Vollhardt, K. P. C.
Heterocycles 1982, 19, 265. (j) Arques, A.; Molina, P.; Soler, A. Synthesis
1980, 702. (k) Boyd, D. R.; Hamilton, R.; Thompson, N. T.; Stubbs, M. E.
Tetrahedron Lett. 1979, 3201. (l) Tamura, Y.; Matsushima, H.; Minami-
kawa, J.; Ikeda, M.; Sumoto, K. Tetrahedron 1975, 31, 3035. (m) Ben-
Efraim, D. A. Tetrahedron 1973, 29, 4111. (n) Levine, R.; Fernelius, W. C.
Chem. ReV. 1954, 54, 449.
We have introduced a double-nucleophilic addition reac-
tion of R,ꢀ-unsaturated imines with several nucleophiles such
as ketene silyl acetals, trimethylsilyl cyanide, trimethylsilyl
(2) Although we examined the 1,4- and 1,2-double nucleophilic addition
using the imine 1 N-substituted with a TBS group, 1,4- and 1,2-double
addition products were not obtained
.
(3) When 1,4- and 1,2-double nucleophilic addition was carried out using
the R,ꢀ-unsaturated imine having an electron-withdrawing group at the
nitrogen, a 1,4-addition product was obtained instead of 1,4- and 1,2-adducts.
10.1021/ol8014539 CCC: $40.75
Published on Web 08/15/2008
2008 American Chemical Society

azide, and thiols.4 A recent result also shows a short synthesis
of 2,3,5-trisubstituted pyrroles using these reactions.4a We
would like to report herein a practical synthesis of N-
allylideneamines 1a,b and the subsequent double nucleophilic
addition reactions with them.
Although we attempted the synthesis of N-allylideneamine
1, e.g., deprotection of the 3-trimethylsilyl-protected imine,
oxidation of the allylamines using various oxidants,5 and
condensation of acrolein with amines in the presence of MS
4Å, the imine 1 was not obtained at all. When the condensa-
tion of acrolein with the amine was carried out in the
presence Ti(OEt)4, the reaction proceeded smoothly to afford
N-allylideneamine 1a,b having a diphenylethyl or trityl group
(Scheme 1).
Figure 1. LUMO coefficients of acrolein and N-allylideneamine.
regioselectivity for 1,4- and 1,2-addition. Both acrolein and
N-allylideneamine 1a have larger coefficients at the 4-posi-
tion, and the major reaction course based on the HOMO-
LUMO interaction would be the 1,4-addition. The involve-
ment of the steric factors suggests that it would be easier
for N-allylideneamines to be attacked at the 4-position than
for acrolein.
Scheme 1. Preparation of N-Allylideneamines
We next carried out 1,4- and 1,2-double nucleophilic
additions of ketene silyl acetals and trimethylsilyl cyanide
to N-allylideneamines 1a,b. The N-allylideneamines 1b was
decomposed upon treatment with Lewis acids such as AlCl3,
TiCl4, and Ti(OiPr)4. The N-allylideneamine 1a was also
decomposed under the influence of AlCl3 and TiCl4. In
contrast to the case with 1b, however, when Ti(OiPr)4 was
used as a Lewis acid, formation of the 1,2-addition product
with TMSCN was confirmed by 1H NMR (Scheme 2). These
In order to study the characteristics of these N-allylide-
neamines, we caluculated the LUMO coefficients of the
carbonyl (or imino) carbons and ꢀ-carbons, which would
suggest regioselectivities on the addition of nucleophiles.6
Based on molecular orbital calculations, electronic and steric
effects of the substituent at the imino nitrogen atom should
be rationalized (Figure 1).7
Scheme 2. Double Nucleophilic Additions to N-Allylideneamine
Structures were fully optimized with HF/6-31G* level
using geometry optimization. Calculations were shown to
be comparable with the ab initio (HF/STO-3G) method.8 The
values of LUMO coefficients at each reaction site (2- and
4-positions) and the absolute value differences between these
coefficients for the optimized geometries are summarized for
comparison (Figure 1). Comparison of LUMO coefficients
of acrolein and N-allylideneamine 1a gave an estimation of
(4) (a) Shimizu, M.; Takahashi, A.; Kawai, S. Org. Lett. 2006, 8, 3585.
(b) Shimizu, M.; Kamiya, M.; Hachiya, I. Chem. Lett. 2005, 34, 1456. (c)
Shimizu, M.; Kurokawa, H.; Takahashi, A. Lett. Org. Chem. 2004, 1, 353.
(d) Shimizu, M.; Yamauchi, C.; Ogawa, T. Chem. Lett. 2004, 33, 606. (e)
Shimizu, M.; Nishi, T. Synlett 2004, 889. (f) Shimizu, M.; Nishi, T.;
Yamamoto, A. Synlett 2003, 1469. (g) Shimizu, M.; Kamiya, M.; Hachiya,
I. Chem. Lett. 2003, 32, 606. (h) Shimizu, M.; Nishi, T. Chem. Lett. 2002,
46. (i) Shimizu, M.; Ogawa, T.; Nishi, T. Tetrahedron Lett. 2001, 42, 5463.
(j) Shimizu, M.; Morita, A.; Kaga, T. Tetrahedron Lett. 1999, 40, 8401.
(5) For example, benzophenone was obtained from the reaction below.
results suggested that use of a weak acid and a proton source
would promote the double-nucleophilic addition.4i Indeed,
the reaction in the presence of Ti(OiPr)4 and molecular sieves
4Å containing 1 equiv of water gave the desired 1,4- and
1,2-addition product 2aa in 63% yield.
Among the promoters examined, silica gel was found to
be the most effective.9 The double-nucleophilic addition
reactions were next carried out using various ketene silyl
acetals under the optimized conditions, and the results are
summarized in Table 1. The use of ketene silyl acetals
(6) (a) Tomioka, K.; Shioya, Y.; Nagaoka, Y.; Yamada, K. J. Org. Chem.
2001, 66, 7051. (b) Tomioka, K.; Okamoto, T.; Kanai, M.; Yamataka, H.
Tetrahedron Lett. 1994, 35, 1891.
(7) Calculations were carried out using the SPARTAN pro program and
optimization with 6-31G*.
(8) The difference in the method of calculation (HF/STO-3G, and PM3)
has little influence on a qualitative conclusion.
3978
Org. Lett., Vol. 10, No. 18, 2008

also gave the desired 1,4- and 1,2-addition adduct 2a in 56%
yield (entry 7). Further examples using ketene silyl thioac-
etals are summarized in Table 2.
Table 1. Examination of 1,4-Nucleophile and Deprotection
Table 2. Double Nucleophilic Addition Using Ketene Silyl
Thioacetal and Transformation into Valerolactam
with 1a
with 1b
entry
R1
R2
R3
2aa (3)b (%)
2ba (3)b (%)
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
OEt
OMe
OnPr
OiPr
OMe
OEt
StBu
OtBu
OEt
OEt
Ph
83 (78)
87 (57)c
- (47)
- (27)
87 (76)
- (40)
56
80 (56)
64 (67)
58 (54)
68 (59)
59 (61)
51 (12)
22 (-)d
59 (61)
24f
Z/E
R3 (KSTA)
condns B 4 condns B/TFA
entry R1
R2
(%) (dr)
5 (%) (dr)
1
2
3
4
5
6
7
H
H
H
H
H
H
Me Cy
Me Et
92/8
89/11
Me tBu 94/6
Me iPr 94/6
75 (50:50)
69 (71:29)
65 (55:45)
68 (58:42)
85 (53:47)
76a (50:50)
71 (47:53)
35b, c (66:34)
-(CH2)5-
OEt OEt
H
Me
SMe
H
H
e
Me
Me
Me
Me
-
-
-
Me Ph
Me nPr 88/12
73/27
55d (55:45) 64d (42:58)
e
9
10
11
45 (51:49)
39 (-)
40c (46:54)
53 (-)
e
0
0
e
Me Me Et
-
H
-
a Ketene silyl thioacetal (Z/E ) 91/9) was used. b Ketene silyl thioacetal
(Z/E ) 92/8) was used. c Treatment with TFA at rt for 10 min. d Reaction
time was 24 h.
a Under the conditions A. b Under the conditions A followed by TFA
treatment. c Formation of the cyclized valerolactam (17%) was observed.
d Although formation of valerolactam was confirmed by 1H NMR; isolation
was not successful. e Not examined, see ref 10. f dr ) 53:47.
When the trisubstituted ketene silyl thioacetal derived from
S-cyclohexyl propanethioate was used under the conditions
B/TFA, cyclized valerolactam 5 was obtained in high yield as
a result of the good leaving ability of the alkylthio group (entry
1). Valerolactams are often found in various natural products
and many of them are of great current interest because of their
unique biological activities.11 The trisubstituted ketene silyl
thioacetals studied here gave 1,4- and 1,2-double-nucleophilic
addition products 4 or 5 in moderate to good yields (entries
1-6). Use of a tetrasubstituted analogue also gave the product
4 or 5 in moderate yield (entry 7).
derived from ethyl isobutyrate and methyl isobutyrate gave
the desired 1,4- and 1,2-adducts 2a in high yields (entries 1
and 2). Due to the instability of some 1,4- and 1,2-addition
products arising from the imine 1a,10 the in situ transforma-
tion into amino nitrile was next examined. Upon quenching
with TFA after double-nucleophilic addition, the reaction
gave the amino nitrile 3 in 78% yield (entry 1). Using the in
situ hydrolysis, the reaction gave amino nitriles 3 in moderate
to high yields (entries 2-6). Use of the ketene silyl acetal
derived from isopropyl isobutyrate with the imine 1b gave
amino nitrile 3 in good yield, which contrasts to the result
with 1a (entry 4). Use of ketene silyl thioacetal (KSTA)4g
A proposed reaction mechanism is shown in Scheme 3.
First, the N-allylideneamine was activated with silica gel
(9) Use of other promoters such as MeOH, PhOH, AcOH, Na2SO4·
10H2O, Amberlyst 15DRY, and Florisil gave 1,4- and 1,2-addition products
2aa in low yields. The amount and the shape of silica gel were also
examined. See the Supporting Information. Examples using silica gel as a
reaction promoter, see: Shimizu, M.; Tanaka, M.; Itoh, T.; Hachiya, I. Synlett
2006, 1687.
Scheme 3. Proposed Mechanism
1
(10) We confirmed by H NMR that 1,4-1,2-adduct products 2a were
changed to 1,4-adducts via retro-Strecker reaction (Table 1, entries 3, 4,
6). Since the adducts were not stable, the addition reactions were not
examined with 1a in detail (Table 1, entries 8-11).
(11) (a) Maio, W. A.; Sinishtaj, S.; Posner, G. H. Org. Lett. 2007, 9,
2673. (b) Taylor, P. J. M.; Bull, S. D.; Andrews, P. C. Synlett 2006, 1347.
(c) Bower, J. F.; Svenda, J.; Williams, A. J.; Charmant, J. P. H.; Lawrence,
R. M.; Szeto, P.; Gallagher, T. Org. Lett. 2004, 6, 4727. (d) Lautens, M.;
Tayama, E.; Nguyen, D. Org. Lett. 2004, 6, 345. (e) Cellier, M.; Gelas-
Mialhe, Y.; Husson, H.; Perrin, B.; Remuson, R. Tetrahedron: Asymmetry
2000, 11, 3913. (f) Kobayashi, S.; Akiyama, R.; Moriwaki, M. Tetrahedron
Lett. 1997, 38, 4819. (g) Ezquerra, J.; Pedregal, C. Tetrahedron Lett. 1995,
36, 3247. (h) Paulvannan, K.; Stille, J. R. Tetrahedron Lett. 1993, 34, 8197.
(i) Bailey, P. D.; Wilson, R. D.; Brown, G. R. Tetrahedron Lett. 1989, 30,
6781. (j) Angle, S. R.; Arnaiz, D. O. Tetrahedron Lett. 1989, 30, 515.
Org. Lett., Vol. 10, No. 18, 2008
3979

followed by 1,4-addition of ketene silyl (thio)acetal to give
an intermediary enamine species 6. Then isomerization to
imine was promoted by silica gel followed by 1,2-addition
of TMSCN to give the 1,4- and 1,2-product.
Moreover, hydrolysis of the nitrile moiety of amino nitrile
3a gave amino acid 7 in high yield (Scheme 4).
scope and limitation of the present reaction is currently under
way, amino nitriles and valerolactams are also respectively
synthesized using ketene silyl acetals and ketene silyl
thioacetals in good yields under the influence of TFA which
effects removal of the diphenylethyl and trityl groups. Since
weak acids can promote the present addition, this reaction
may be used in an asymmetric version with chiral protic
acids.
Scheme 4. Hydrolysis of Amino Nitrile
Acknowledgment. This work was supported by Grant-
in-Aids for Scientific Research (B) and Priority Areas from
MEXT and JSPS.
Supporting Information Available: Experimental details
and characterization data for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
In conclusion, it was found that the isolation of N-
allylideneamines having sterically demanding substituents
was possible in good yields using Ti(OEt)4. Although the
previous double-nucleophilic addition needed strong Lewis
acids such as TiCl4 or AlCl3, even the use of silica gel, a
weak acid, promoted the double nucleophilic addition to
N-allylideneamines.12 Although detailed examination into the
OL8014539
(12) Regioselectivity on the addition of nucleophiles to R,ꢀ-unsaturated
aldimimes has been studied previously, see ref 4c. Examples using R,ꢀ-
unsaturated aldimimes for the ꢀ-lactam synthesis, see: (a) Fleming, I.;
Kilburn, J. D. J. Chem. Soc., Perkin Trans. 1 1998, 2663. (b) Ha, D.-C.;
Hart, D. J.; Yang, T.-K. J. Am. Chem. Soc. 1984, 106, 4819.
3980
Org. Lett., Vol. 10, No. 18, 2008