Tandem N -alkylation/vinylogous aldol reaction of β,γ-Alkenyl α-iminoester

Article abstract of DOI:10.1021/ol5007983

This report describes a highly regioselective tandem N-alkylation/ vinylogous aldol reaction of β,γ-alkenyl α-iminoesters. The sulfur group improves the regioselectivity of the directed vinylogous aldol reaction, providing a new synthetic method of 3-amino-2-pyrones.

Full text of DOI:10.1021/ol5007983

Letter
pubs.acs.org/OrgLett
Tandem N‑Alkylation/Vinylogous Aldol Reaction of β,γ-Alkenyl
α‑Iminoester
Hirotaka Tanaka, Isao Mizota, and Makoto Shimizu*
Department of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu, Mie 514-8507, Japan
S
* Supporting Information
ABSTRACT: This report describes a highly regioselective
tandem N-alkylation/vinylogous aldol reaction of β,γ-alkenyl
α-iminoesters. The sulfur group improves the regioselectivity
of the directed vinylogous aldol reaction, providing a new
synthetic method of 3-amino-2-pyrones.
Table 1. Optimization of N-Alkylation of β,γ-Alkenyl α-
Iminoester
ldol reactions using metal enolates formed from the 1,4-
Aaddition of organometallic reagents to α,β-unsaturated
carbonyl compounds are very useful in organic chemistry
because they facilitate three-component assembly reactions that
can build complex molecules.1 However, the reported examples
of the vinylogous aldol reactions2 have used allenic esters as
starting materials.3d The directed vinylogous aldol reaction,3 via
in situ formation of the enolate, benefits from atom economy
compared to the Mukaiyama vinylogous aldol reaction.4
However, steric factors related to the substrates have affected
its regioselectivity3b,c and the use of excess amounts of bulky
Lewis acids has often been required.3a,f,g
An umpolung reaction of an α-iminoester involving
nucleophilic addition to the nitrogen atom is difficult due to
the electronegativity of the imino group.5 We have developed
umpolung reactions of α-iminoesters followed by C−C bond
formation using the metal enolate produced by N-alkylation.6
Nonetheless, constructing C−C bonds via subsequent reactions
of the resulting enolates remains of interest. Recently, we
reported the N-alkylation of β,γ-alkynyl α-iminoesters followed
by regioselective acylation through the formation of magnesium
yne-enolates.6a This report focuses on the synthesis of
dienolates by N-alkylation of β,γ-alkenyl α-iminoesters7 and
describes a new tandem N-alkylation/vinylogous aldol reaction
via in situ formation of these dienolates. In particular, the sulfur
moiety on the alkene portion of the substrate controls the
regioselectivity of the directed vinylogous aldol reaction.
In the initial N-alkylation step, the β,γ-alkenyl α-iminoester
1a underwent reaction under the N-alkylation conditions
optimized for the β,γ-alkynyl α-iminoester (1.1 equiv of
EtMgBr, THF, −78 °C to rt, 30 min), to give the desired N-
adduct isomers 2 and 3 in a low combined yield of 24% (Table
1, entry 1). Other organometallic reagents and reaction
conditions were examined to improve this step, but the yields
could not be improved (see Tables S1 and S2 in Supporting
Information (SI)). All the reaction byproducts could not be
a
time
(min)
smr
c
b
entry
1
temp (°C)
yield (%)
2:3
(%)
1
2
3
4
5
6
7
1a
1a
−78 to rt
−78
30
2a, 3a
2a, 3a
2b
24
33
32
61
85
58
91
83:17
67:33
100:0
100:0
100:0
100:0
100:0
0
50
49
0
30
1b −78
30
1b −78 to rt
1b −78 to 40
1b −78 to 40
2.5 h
30
2b
2b
0
10
2b
15
0
1c
−78 to 40
30
2c
a
The reaction was carried out according to the typical procedure.
Isolated yield. Recovery of the starting material.
b
c
isolated, but 1,4-addition to the conjugate imine might be
occurring as a side reaction, explaining the low yields.
Substrates containing a bulky substituent, such as 2,6-
Me2C6H3, on their alkene portion 1b provided the desired,
N-adducts with almost the same yields as in the case of 1a at
low temperature (entries 2 and 3). When the reaction was
performed from −78 °C to rt, the starting material was
completely consumed without noticeable side reactions, and
the desired product 2b was obtained as the sole product in 61%
yield (entry 4). Furthermore, when the reaction temperature
rose from −78 to 40 °C, the reaction proceeded more rapidly
to produce the N-adduct in the best yield (85%) (entry 5). The
use of substrates bearing three substituents on their alkene
Received: March 17, 2014
Published: April 10, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
portion completely prevented side reactions, giving the desired
product in 91% yield (entry 7). The N-alkylation hinges on the
geometry of the imine (Table S3 in SI) and is assumed to
proceed through reaction of the more reactive isomer (E)-1,
which is obtained by isomerization of the (Z)-isomer by heating
above room temperature. Optimization of reaction solvents
showed that THF resulted in the best yield (Table S5 in SI).
Under these optimized conditions (Table 1, entry 7), the
scope of Grignard reagents was examined (Table 2). Linear
Table 3. Optimization of Tandem N-Alkylation/Vinylogous
Aldol Reaction
a
b
b
entry
equiv
temp
time
4a (%)
2c (%)
1
2
3
4
5
6
7
8
9
5.0
5.0
5.0
5.0
5.0
5.0
5.0
2.5
10.0
0 °C
rt
15 min
15 min
15 min
15 min
15 min
1.5 h
0
19
46
58
73
77
63
69
56
79
73
49
20
20
22
20
23
29
a
40 °C
50 °C
reflux
reflux
reflux
reflux
reflux
Table 2. Scope of Grignard Reagents for N-Alkylation
9.0 h
1.5 h
1.5 h
a
The reaction was carried out according to the typical procedure.
Isolated yield.
b
γ-adduct. However, the yield of 4a did not increase (Tables S7
and S8 in SI), suggesting that the magnesium α-aldolate may be
stabilized by a strong chelation between the magnesium and the
nitrogen atoms.
The scope of substrates, Grignard reagents, and aldehydes
was evaluated under the optimized conditions (Table 4). When
2-thienyl, an electron-donating substituent such as 4-MeO-
a
Table 4. Scope of Substrates
a
The reaction was carried out according to the typical procedure.
Isolated yield.
b
primary alkyl Grignard reagents gave the desired N-adducts in
excellent yields (Table 2, entries 1−5), while a branched
counterpart afforded the desired product in good yield (entry
6). In contrast, methyl and secondary alkyl Grignard reagents
produced the desired compounds in low yields (entries 7 and
8) and the phenyl and allyl derivatives did not produce the N-
alkylation products (entries 9 and 10). However, primary
Grignard reagents with functional groups, such as cyclic acetals
(entries 11 and 12), terminal alkene (entry 13), and halogen
(entry 14), did not affect this reaction. In most cases where low
yields were observed, nucleophilic addition to the ethoxycar-
bonyl group occurred as the side reaction.
Next, the tandem N-alkylation/vinylogous aldol reaction was
investigated (Table 3). After N-alkylation under the optimized
conditions, 5.0 equiv of benzaldehyde were added to the
reaction mixture for the subsequent vinylogous aldol reaction.
In this case, the intramolecular cyclization proceeded to give δ-
lactone 4a. Examination of reaction temperature effects
demonstrated that reactions run at higher temperatures gave
the desired products in better yields (entries 1−5). Further
optimization of the reaction conditions indicated that the best
yield was obtained in reactions conducted with 5.0 equiv of
benzaldehyde for 1.5 h (entries 5−9). Although the N-
alkylation followed by hydrolysis of the resulting enamine
provided 2c as a byproduct, this compound may also result
from the retro aldol reaction of the unstable aldol product
formed by α-addition. Based on this hypothesis, we studied the
ester portion of the substrates, the addition of a Lewis acid to
improve aldehyde reactivity, and the effect of a Lewis base3d on
the retro aldol reaction of the α-aldolate that can reproduce the
a
The reaction was carried out according to the typical procedure.
b
Yields refer to pure isolated compounds, and yields of 2 are in the
c
d
parentheses. The diastereomer ratio is 54:46. The diastereomer ratio
is 62:38. The diastereomer ratio is 56:44.
e
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a
Table 5. Tandem Reaction of β,γ-Alkenyl α-Iminoesters Bearing Sulfenyl Groups
c
yield (%)
b
entry
R1
R2
temp
A (cis/trans)
4 + 6 (4:6)
d
e
1
2
3
4
Ph
Ph
Me
Me
Me
tBu
refl
nd
4r, 6a
4r, 6a
4s, 6b
4t, 6a
98
96
89
85
(86 :14)
(33:67)
(26:74)
(56:44)
40 °C
refl
71:29
76:24
2-thienyl
Ph
d
refl
nd
a
b
c
d
The reaction was carried out according to the typical procedure. Temperature for the addition of the aldehyde. Isolated yield. Not determined.
e
A 67:33 mixture of cis- and trans-isomers. Purification of the compund A was carried out by deactivated silica gel TLC.
C6H4, an electron-withdrawing substituent such as 4-F-C6H4,
and 2,6-Me2C6H3 (R1 and R2) were introduced on the alkene
portion of β,γ-alkenyl α-iminoesters, the desired δ-lactones 4
were obtained in moderate-to-good yields. The use of primary
Grignard reagents (R3) that readily underwent N-alkylation
allowed the desired tandem reaction to proceed in moderate-to-
good yield. Aromatic and heteroaromatic aldehydes afforded
the desired products in moderate-to-high yields. On the other
hand, aliphatic aldehydes produced only N-adducts 2 instead of
the desired products. The unsaturated aldehyde, cinnamalde-
hyde, was effective in this reaction, and alkynyl aldehyde
afforded the desired product, albeit in low yield.
several ways. (1) The first N-alkylation step proceeds selectively
because of steric hindrance. (2) Anion stability allows the
second aldol reaction with the dienolate to occur via γ-addition.
(3) The 3-amino-2-pyrone is produced via anti-elimination of
the thiolate. To the best of our knowledge, this example is the
first directed vinylogous aldol reaction promoted by sulfur-
containing groups.
A proposed reaction mechanism is shown in Scheme 2. β,γ-
Alkenyl α-iminoester 1 is a mixture of Z and E diastereomers.
Scheme 2. Assumable Reaction Mechanism
Higher temperatures enhanced the γ-selectivity of the
tandem reaction. Nonetheless small amounts of N-adducts 2
were still obtained. The use of substrates bearing sulfenyl
groups on the alkene part may improve γ-selectivity (Table 5).
In fact, substrates containing t-BuS or MeS effectively
underwent N-alkylation (see also Table S6 in SI), and the
subsequent vinylogous aldol reaction was more selective in
producing δ-lactones 4 in excellent yields (Table 5, entries 1−
4).8 Remarkably, the crude products only consisted of δ-lactone
4 but silica gel TLC chromatography purification produced 2-
pyrone 6. The ratios between δ-lactones 4 and 2-pyrones 6
matched the diastereomeric ratios of the δ-lactones in the crude
products. In addition, the stereochemistry of isolated δ-lactone
4s was determined to be trans by nuclear Overhauser effect
(NOE) measurements. This suggests that 2-pyrones 6 may
arise from the anti-elimination of the thiols. 3-Amino-2-pyrones
are valuable in organic synthesis because of their biological
activity such as selective cyclooxygenase-1 (COX-1) inhibitors.9
Furthermore, 2-pyrone can be readily transformed into other
heterocyclic compounds such as pyridine and 2-pyridone.10
The isolated anti-isomer 4r could also be converted into 3-
amino-2-pyrone 6a via syn-elimination of the sulfoxide (Scheme
1). Notably, the sulfenyl groups impact this tandem reaction in
The inert (Z)-1 isomerizes into its reactive form (E)-1 by
heating above room temperature. The N-alkylation proceeds
with the Grignard reagent to give magnesium dienolate A
through formation of a five-membered intermediate composed
of the imino nitrogen, the carbonyl oxygen, and the magnesium
atom.6m The α- and γ-protonations of dienolate A afford the N-
adducts 2 and 3, respectively. After γ-addition of dienolate A to
the aldehyde to form magnesium aldolate B, an intramolecular
cyclization proceeds with a concomitant formation of MgOEt
to provide δ-lactone 4. The α-adduct C may undergo a retro
aldol reaction followed by protonation to produce N-adduct 2.
Finally, we studied a tandem reaction of β,γ-alkenyl α-
iminoester bearing a phenyldimethylsilyl group on its alkene
part (Table 6). After the vinylogous aldol reaction, the Peterson
Scheme 1. Transformation of the trans-Isomer 4r
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Organic Letters
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a
Table 6. Tandem Reaction of β,γ-Alkenyl α-Iminoesters Bearing a Silyl Group
b
yield (%)
entry
R1
R2
8 (dr)
2
1
2
3
Ph
Ph
Ph
8a
8b
8c
61
49
71
(87:13)
(93:7)
2y
2z
2y
14
2-thienyl
Ph
4
(E)-PhCHCH
(64:36)
trace
a
b
The reaction was carried out according to the typical procedure. Isolated yield.
olefination11 proceeded faster than the intramolecular cycliza-
tion to provide dienamines 8 in moderate yields (entries 1 and
2). Cinnamaldehyde also produced trienamine 8c (entry 3).
Hence, we have developed a highly regioselective tandem N-
alkylation using the umpolung/directed vinylogous aldol
reaction of β,γ-alkenyl α-iminoesters. Sulfenyl substituents on
the alkene part of the substrates notably enhanced the
selectivities of both steps and induced the formation of 3-
amino-2-pyrones via anti-elimination.
(f) Saito, S.; Shiozawa, M.; Yamamoto, H. Angew. Chem., Int. Ed. 1999,
38, 1769. (g) Saito, S.; Shiozawa, M.; Ito, M.; Yamamoto, H. J. Am.
Chem. Soc. 1998, 120, 813.
(4) For a general review of the Mukaiyama vinylogous aldol reaction:
Denmark, S. E.; Heemstra, J. R., Jr.; Beutner, G. L. Angew. Chem., Int.
Ed. 2005, 44, 4682.
(5) For the N-alkylation to α-imino esters: (a) Dickstein, J. S.;
Kozlowski, M. C. Chem. Soc. Rev. 2008, 37, 1166. (b) Dickstein, J. S.;
Fennie, M. W.; Norman, A. L.; Paulose, B. J.; Kozlowski, M. C. J. Am.
Chem. Soc. 2008, 130, 15794. (c) Chiev, K. P.; Roland, S.; Mangeney,
P. Tetrahedron: Asymmetry 2002, 13, 2205. (d) Mae, M.; Amii, H.;
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Feray, L.; Nouguier, R.; Perfetti, P. Synlett 1999, 1148. (f) Yoo, S.-e.;
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(h) Yamamoto, Y.; Ito, W. Tetrahedron 1988, 44, 5415. (i) Fiaud, J.-
C.; Kagan, H. B. Tetrahedron Lett. 1971, 12, 1019.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and characterization data for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(6) For N-alkylation to α-imino esters in our laboratory: (a) Mizota,
I.; Matsuda, Y.; Kamimura, S.; Tanaka, H.; Shimizu, M. Org. Lett.
2013, 15, 4206. (b) Sano, T.; Mizota, I.; Shimizu, M. Chem. Lett. 2013,
42, 995. (c) Shimizu, M.; Kurita, D.; Mizota, I. Asian J. Org. Chem.
2013, 2, 208. (d) Shimizu, M.; Takao, Y.; Katsurayama, H.; Mizota, I.
Asian J. Org. Chem. 2013, 2, 130. (e) Nishi, T.; Mizota, I.; Shimizu, M.
Pure Appl. Chem. 2012, 84, 2609. (f) Mizota, I.; Tanaka, K.; Shimizu,
M. Tetrahedron Lett. 2012, 53, 1847. (g) Shimizu, M.; Hachiya, I.;
Mizota, I. Chem. Commun. 2009, 874. (h) Shimizu, M. Pure Appl.
Chem. 2006, 78, 1867. (i) Shimizu, M.; Itou, H.; Miura, M. J. Am.
Chem. Soc. 2005, 127, 3296. (j) Niwa, Y.; Shimizu, M. J. Am. Chem.
Soc. 2003, 125, 3720. (k) Niwa, Y.; Takayama, K.; Shimizu, M. Bull.
Chem. Soc. Jpn. 2002, 75, 1819. (l) Niwa, Y.; Takayama, K.; Shimizu,
M. Tetrahedron Lett. 2001, 42, 5473. (m) Shimizu, M.; Niwa, Y.
Tetrahedron Lett. 2001, 42, 2829.
(7) (a) Vicario, J.; Aparicio, D.; Palacios, F. Tetrahedron Lett. 2011,
52, 4109. (b) Palacios, F.; Vicario, J.; Aparicio, D. J. Org. Chem. 2006,
71, 7690. (c) Palacios, F.; Vicario, J.; Aparicio, D. Eur. J. Org. Chem.
2006, 2843. (d) Palacios, F.; Vicario, J. Org. Lett. 2006, 8, 5405.
(8) When the substrate (R1 = 2-thienyl, R2 = tert-butyl) was used, a
crude cyclized product A was obtained in ca. 59% yield. However, this
starting material was unstable upon purification by silica gel TLC, and
the product A could not be separated from the decomposed starting
material.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mshimizu@chem.mie-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Grants-in-Aid for Scientific
Research (B) and Scientific Research on Innovative Areas
“Organic Synthesis Based on Reaction Integration. Develop-
ment of New Methods and Creation of New Substances” from
JSPS and MEXT.
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