Use of N-allylidene-1,1-diphenylethanamine as a latent acrolein synthon in the double nucleophilic addition reaction of ketene silyl (Thio)acetals and allylborolanes

Article abstract of DOI:10.1021/ol101061t

In the presence of silica gel and water, a mixture of ketene silyl acetals and 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane underwent 1,4-and subsequently 1,2-addition with N-allylidene-1,1-diphenylethanamine to give δ-hydroxyesters in good yields, where the allylideneamine was successfully used as an acrolein equivalent.

Full text of DOI:10.1021/ol101061t

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3571-3573
Use of N-Allylidene-1,1-diphenylethanamine
as a Latent Acrolein Synthon in the
Double Nucleophilic Addition Reaction
of Ketene Silyl (Thio)acetals and
Allylborolanes
Makoto Shimizu,* Mami Kawanishi, Isao Mizota, and Iwao Hachiya
Department of Chemistry for Materials, Graduate School of Engineering,
Mie UniVersity, Tsu, Mie 514-8507, Japan
mshimizu@chem.mie-u.ac.jp
Received May 13, 2010
ABSTRACT
In the presence of silica gel and water, a mixture of ketene silyl acetals and 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane underwent 1,4- and
subsequently 1,2-addition with N-allylidene-1,1-diphenylethanamine to give δ-hydroxyesters in good yields, where the allylideneamine was
successfully used as an acrolein equivalent.
Although acrolein has received considerable attention as
a useful unit for the synthesis of a variety of novel and
functional materials as well as biologically important
molecules, it is not always easy to use this particular
compound as a conjugate addition acceptor of carbon
nucleophiles.1 This is due in part to the high reactivity of
the carbonyl and olefin functional groups to induce 1,2-
addition and/or polymerization. During an investigation
into double nucleophilic addition to R,ꢀ-unsaturated
imines,2 two practical methods were developed for the
preparation of N-allylideneamines 1a,b, which in turn were
used as efficient substrates for 1,4- and 1,2-double
nucleophilic additions.2a Several years ago, we also found
that the aldimines 2 and 3 derived from enals and alkynals
acted as latent unsaturated aldehydes to promote the 1,4-
addition of thiolates or azide and 1,2-addition of tetraal-
lyltin to the parent unsaturated aldehydes under the
influence of SnCl4·5H2O, where in situ hydrolysis of the
imino moieties to the parent aldehydes was crucial for
the success of the double addition.3 However, in contrast
to these results using heteroatom nucleophiles for the 1,4-
(1) (a) He, R.; Ding, C.; Maruoka, K. Angew. Chem., Int. Ed. 2009, 48,
4559. (b) Wakabayashi, K.; Aikawa, K.; Mikami, K. Heterocycles 2009,
77, 927. (c) Srinivas, B.; Kumar, V. P.; Sridhar, R.; Reddy, V. P.; Nageswar,
Y. V. D. R.; Kakulapati, R. HelV. Chim. Acta 2009, 92, 1080. (d) Jana, R.;
Tunge, J. A. Org. Lett. 2009, 11, 971. (e) Bates, R. W.; Snell Robert, H.;
Winbush, S. Synlett 2008, 1042. (f) Kawatsura, M.; Aburatani, S.; Uenishi,
J. Tetrahedron 2007, 63, 4172. (g) Imachi, S.; Onaka, M. Chem. Lett. 2005,
34, 708. (h) Liu, G.; Lu, X. Tetrahedron Lett. 2002, 44, 127. (i) Uehira, S.;
Han, Z.; Shinokubo, H.; Oshima, K. Org. Lett. 1999, 1, 1383. (j) Ohgomori,
Y.; Ichikawa, S.; Sumitani, N. Organometallics 1994, 13, 3758. (k)
Sawamura, M.; Hamashima, H.; Ito, Y. Tetrahedron 1994, 50, 4439. (l)
Grisso, B. A.; Johnson, J. R.; Mackenzie, P. B. J. Am. Chem. Soc. 1992,
114, 5160. (m) Matsuzawa, S.; Horiguchi, Y.; Nakamura, E.; Kuwajima, I.
Tetrahedron 1989, 45, 349.
(2) (a) Mizota, I.; Matsuda, Y.; Hachiya, I.; Shimizu, M. Eur. J. Org.
Chem. 2009, 4073. (b) Shimizu, M.; Hachiya, I.; Mizota, I. Chem. Commun.
2009, 874. (c) Mizota, I.; Matsuda, Y.; Hachiya, I.; Shimizu, M. Org. Lett.
2008, 10, 3977. (d) Shimizu, M.; Takahashi, A.; Kawai, S. Org. Lett. 2006,
8, 3585. (e) Shimizu, M.; Kamiya, M.; Hachiya, I. Chem. Lett. 2005, 34,
1456. (f) Shimizu, M.; Kurokawa, H.; Takahashi, A. Lett. Org. Chem. 2004,
1, 353. (g) Shimizu, M.; Yamauchi, C.; Ogawa, T. Chem. Lett. 2004, 33,
606. (h) Shimizu, M.; Kamiya, M.; Hachiya, I. Chem. Lett. 2003, 32, 606.
(i) Shimizu, M.; Nishi, T. Chem. Lett. 2002, 46. (j) Shimizu, M.; Ogawa,
T.; Nishi, T. Tetrahedron Lett. 2001, 42, 5463. (k) Shimizu, M.; Morita,
A.; Kaga, T. Tetrahedron Lett. 1999, 40, 8401.
(3) (a) Shimizu, M.; Nishi, T. Synlett 2004, 889. (b) Shimizu, M.; Nishi,
T.; Yamamoto, A. Synlett 2003, 1469.
10.1021/ol101061t  2010 American Chemical Society
Published on Web 07/21/2010

addition reaction, difficulties were always encountered for
the use of carbon nucleophiles in the initial conjugate
addition reaction. The accessibility of the allylideneamine
recently developed,2a,c coupled with the need to use acrolein
as conjugate addition acceptor, has prompted us to report
an efficient method for the use of N-allylidene-1,1-diphe-
nylethanamine 1a as a latent acrolein (Scheme 1).
Table 1. Double Nucleophilic Addition to the Latent Acrolein
under Various Conditionsa
entry
solvent
additive (equiv)
4a yield (%)
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
CH2Cl2
SnCl4·5H2O (0.24)
SnCl4·5H2O (0.24)b
SnCl4·5H2O (0.24)c
SnCl4·5H2O (0.20)
Cu(OAc)2·H2O (1.00)d
Na2SO4·10H2O (1.00)
Al2Cl3·6H2O (0.20)
CeCl3·7H2O (0.14)
SmCl3·6H2O (0.20)
none
67
52
79
68
41
58
54
65
53
38
51
69
73
81
Scheme 1. 1,4- and 1,2- Double Addition Reactions
9
10
11
12
13
14
H2O (2.80)
MS 4A/H2O (2.80)
H2O (2.80)e
H2O (2.80)e
a The reaction was carried out according to the typical procedure.
b Ketene silyl acetal (1.0 equiv) was used. c Ketene silyl acetal (1.5 equiv)
was used. d The reaction was carried out for 38 h. e Water was added after
1.5 h of the initial reaction.
yield, while addition of water increased the formation of the
double addition product in moderate yields (entries 10 and
11). The presence of a limited amount of water absorbed in
molecular sieves 4Å as previously reported2j increased the
product yield (entry 12). The best result was obtained when
the reaction was conducted by initially mixing all of the
reagents in dichloromethane at -78 °C for 1.5 h and then
adding water (2.8 equiv) at -78 °C followed by allowing
the whole mixture to stand at room temperature for 15.5 h
to give the desired adduct in 81% yield (entry 14). Under
the best conditions a variety of ketene silyl acetals or ketene
silyl thioacetals and 2-allyl-4,4,5,5-tetramethyl-1,3,2-diox-
aborolane4 underwent the 1,4- and 1,2-double addition
reaction to give the adduct in good yields. Table 2 sum-
marizes the results.
The initial examination was carried out to check the use
of the allylideneamine 1a to act as a latent acrolein synthon
to accept a carbon nucleophile in the initial 1,4-addition under
similar conditions previously reported.3
Scheme 2. Double Addition Reaction to the Latent Acrolein
As shown in Table 2, among the tetrasubstituted ketene
silyl acetals, ethoxy and benzyloxy derivatives provided good
yields of the adducts (entries 1-5 and 12-14), whereas the
cyclohexylthio derivative gave better results regarding the
tri- and disubstitued analogues (entries 6-11). When cro-
tylboronates 3c,d were used as the second nucleophile, the
reaction proceeded with good to excellent diastereoselec-
tivities with respect to the C5-C6 carbons, where the (E)-
derivative 3c gave anti-adducts and (Z)-isomer 3d effected
the formation of the syn-isomers (entries 13, 14, 16, 17, 19,
and 20). However, the diastereoselectivities regarding the
C2-C5 carbons were not high.
As shown, the 1,4-addition of the ketene silyl acetal
actually proceeded followed by hydrolysis of the imino
moiety and the subsequent 1,2-allylation to give the adduct
4a in 61% yield. However, the recent need to use more
environmentally benign reagents induced us to investigate
other conditions, e.g., without the use of SnCl4·5H2O and
tetraallylstannane. Table 1 summarizes the results.
As can be seen from Table 1, regarding the solvent, both
dichloromethane and toluene gave comparable results (entries
1-4). Among the metal salt hydrates, SnCl4·5H2O and
CeCl3·7H2O promoted the desired double addition to give
the adduct 4a in moderate yields (entries 4 and 8). In the
absence of added water the reaction gave the adduct in poor
(4) (a) Sugiura, M.; Hirano, K.; Kobayashi, S. Org. Synth. 2006, 83,
170. (b) Bubnov, Y. In Science of Synthesis, Houben-Weyl Methods of
Molecular Transformations; George Thieme Verlag: Stuttgart, Germany,
2004; Vol. 6, pp 945-1072, and earlier references therein.
(5) For determination of the relative stereochemistry, see: Yamamoto,
Y.; Asao, N. Chem. ReV 1993, 93, 2207, and references therein.
3572
Org. Lett., Vol. 12, No. 16, 2010

give the 1,4- and 1,2-double addition products in only low
yields, indicating that the present procedure offers a conve-
nient acrolein source for the double addition reactions
(Scheme 3).
Table 2. Double Nucleophilic Addition to the Latent Acrolein
with Various Nucleophilesa
Scheme 3. Control Experiments Using Acrolein
entry
R1
R2
R3
R4
R5
4 yield (%) (anti:syn)b
1
2
3
4
5
6
7
8
Me Me OEt
Me Me OBn
Me Me OPh
Me Me SEt
Me Me SCy
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
81
72c
0
17
8
H
H
H
H
H
H
Me OCy
Me SCy
Me SPh
8d
73e f
,
13d
9
H
H
H
OCy
SCy
SCy
0
10
11
12
13
14
15
16
17
18
19
20
40
54g
Me Me OEt
Me Me OEt
Me Me OEt
Me Me
Me
H
Me Me
Me
H
Me Me
Me
H
75
H
Me
79 (94:6)
70 (<1:>99)
58e f
,
In conclusion, we have found that the use of N-allylide-
neamine as a latent acrolein can be successfully carried out
in the presence of silica gel and a limited amount of water
to effect the 1,4- and 1,2- double nucleophilic addition of
two different kinds of nucleophiles. Since the N-allylidene-
amine used for the present study is readily prepared by the
previously published method2a,c and the double addition
reaction is readily carried out, the present method offers a
convenient and useful procedure for the use of a conjunctive
C3 unit.
H
H
H
H
H
H
Me SCy
Me SCy
Me SCy
H
Me
62e (>99:<1)
63e (<1:>99)
52g
H
H
H
SCy
SCy
SCy
H
Me
67g (>99:<1)
54g (<1:>99)
a The reaction was carried out according to the typical procedure. b Ratio
regarding C5/C6 diastereomers.5 c Ketene silyl acetal (5.0 equiv) was used.
d Diastereomer ratio was not determined. e Ketene silyl acetal (E/Z )
55/45) was used. f 1:1 ratio of diastereomers was obtained. g Ketene silyl
acetal (2.0 equiv) was used.
Although more experimental results are needed to propose
a plausible reaction mechanism, facile hydrolysis of an
intermediary 1,4-addition product A or an iminium salt B6
to the aldehyde C7 is responsible for the success of the
present tandem addition (Figure 1).
Acknowledgment. This work was supported by Grant-
in-Aids for Scientific Research (B) and on Innovative Areas
from JSPS and MEXT.
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.
OL101061T
(6) For related addition to iminium salts, see: (a) Niwa, Y.; Shimizu,
M. J. Am. Chem. Soc. 2003, 125, 3720. (b) Shimizu, M.; Itou, H.; Miura,
M. J. Am. Chem. Soc. 2005, 127, 3296.
Figure 1. Possible intermediates for hydrolysis to aldehyde.
(7) (a) Tang, L.; Choi, S.; Nandhakumar, R.; Park, H.; Chung, H.; Chin,
J.; Kim, K. M. J. Org. Chem. 2008, 73, 5996. (b) Angelova, V. T.; Vassilev,
N. G.; Koedjikov, A. H.; Pojarlieff, I. G. Org. Biomol. Chem. 2007, 5,
2835. (c) Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2006, 128, 5604. (d) Hartley, J. H.; James, T. D. Tetrahedron Lett. 1999,
40, 2597. (e) Sola, R.; Commeyras, A. J. Chem. Res., Synop. 1992, 180.
Control experiments were carried out using acrolein under
essentially the same conditions used in the present study to
Org. Lett., Vol. 12, No. 16, 2010
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