Aza-Morita-Baylis-Hillman reactions and cyclizations of conjugated dienes activated by sulfone, ester, and keto groups

Article abstract of DOI:10.1021/jo062655+

(Chemical Equation Presented) The?aza-Morita-Baylis-Hillman reactions of aldimines 2 with several activated conjugated dienes were found to proceed smoothly in DMF in the presence of 3-hydroxyquinuclidine (HQD). Imines 2 reacted with 1-(p-toluenesulfonyl)

Full text of DOI:10.1021/jo062655+

Aza-Morita-Baylis-Hillman Reactions and Cyclizations of
Conjugated Dienes Activated by Sulfone, Ester, and Keto Groups
Jovina M. Sorbetti, Kristen N. Clary, Danica A. Rankic, Jeremy E. Wulff,
Masood Parvez, and Thomas G. Back*
Department of Chemistry, UniVersity of Calgary, Calgary, Alberta T2N 1N4, Canada
tgback@ucalgary.ca
ReceiVed December 26, 2006
The aza-Morita-Baylis-Hillman reactions of aldimines 2 with several activated conjugated dienes were
found to proceed smoothly in DMF in the presence of 3-hydroxyquinuclidine (HQD). Imines 2 reacted
with 1-(p-toluenesulfonyl)-1,3-butadiene (3), methyl 2,4-pentadienoate (6), hexa-3,5-dien-2-one (7), and
1-phenylpenta-2,4-dien-1-one (8) to afford adducts 4, 13, 14, and 15, respectively. While products 4, 13,
and 15 were formed as E,Z mixtures, adducts 14 were obtained as essentially pure E-isomers. Cyclization
of the E-isomers of the products derived from the dienyl sulfone 3 and the dienoate ester 6 occurred via
intramolecular conjugate addition under base-catalyzed conditions to afford functionalized piperidines 5
and 16, respectively. The aza-Morita-Baylis-Hillman reaction and subsequent cyclization of the imine
2a with 3 were also carried out as a one-pot reaction, while the reaction mixture was simultaneously
irradiated at 300 nm to effect the photoisomerization of the unreactive Z-adduct of the corresponding 4
to the more reactive E-isomer.
Introduction
SCHEME 1
The Morita-Baylis-Hillman reaction1,2 is a useful synthetic
method that results in carbon-carbon bond-formation between
the R-position of a suitably activated alkene and the carbonyl
group of an aldehyde or related compound to afford the
corresponding allylic alcohol. In its simplest form, a nucleophilic
1a,1b
1c
catalyst such as a tertiary phosphine
or amine first adds
to an alkene that is activated by a suitable electron-withdrawing
group (EWG) to produce the corresponding zwitterion. Addition
of the latter to the aldehyde, followed by proton transfer and
elimination of the catalyst, affords the coupled product 1
(Scheme 1).
Since the reaction was first discovered, considerable variation
has been reported with respect to the nucleophilic catalyst, the
activating group on the alkene, and the carbonyl compound.2
Several recent studies have provided additional insight into the
mechanism of the Morita-Baylis-Hillman reaction.3 The
cooperative effects of added water, alcohols or phenols, or other
*
To whom correspondence should be addressed. Phone: (403) 220-6256.
Fax: (403) 289-9488.
1) (a) Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968,
4
6
1
(
1, 2815. (b) Morita, K. Japan Patent 43003364, 1968; Chem Abstr. 1968,
9, 58828s. (c) Baylis, A. B.; Hillman, M. E. D. Ger. Offen. 2,155,113,
972; Chem. Abstr. 1972, 77, 34174q.
(2) For recent reviews, see: (a) Basavaiah, D.; Rao, A. J.; Satyanarayana,
T. Chem. ReV. 2003, 103, 811-891. (b) Basavaiah, D.; Rao, P. D.; Hyma,
3e,4
hydrogen-bonding solvents or additives, have been investigated,
R. S. Tetrahedron 1996, 52, 8001-8062. (c) Ciganek, E. Org. React. 1997,
5
as well as temperature effects. Byproducts or atypical products
5
(
1, 201-350. (d) Langer, P. Angew. Chem., Int. Ed. 2000, 39, 3049-3052.
e) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653-4670.
that are formed under certain conditions include dioxanes, ethers,
10.1021/jo062655+ CCC: $37.00 © 2007 American Chemical Society
3
326
J. Org. Chem. 2007, 72, 3326-3331
Published on Web 03/24/2007

Aza-Morita-Baylis-Hillman Reactions
dimers, and other species.6 Catalysis with Lewis acids,
4a,7
SCHEME 2
8
5c,9
irradiation with microwaves or ultrasound, the use of ionic
liquids1 or supercritical carbon dioxide as solvents, and
0
6g
3
f,11
high pressure
Asymmetric
reported.
have proved advantageous in some cases.
2
d,12
3k,13
and intramolecular
variations have also been
The use of imines in place of carbonyl compounds (generally
referred to as the aza-Morita-Baylis-Hillman reaction) was
14
first reported by Perlmutter amd Teo and extends the process
to the preparation of allylic amines.15 Although activated allenes
and acetylenes have been investigated in place of alkenes in
aza-Morita-Baylis-Hillman reactions,16 the similar use of
conjugated dienes was neglected until very recently, when we
17
reported that aldimines 2 react with dienyl sulfone 3 to produce
the corresponding adducts 4. This was followed by intramo-
lecular conjugate addition, thus affording functionalized pip-
eridines 5 (Scheme 2). Subsequently, as part of their study of
the aza-Morita-Baylis-Hillman reactions of crotonates, Shi and
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1
8
Shi also included several examples where phenyl 2,4-penta-
dienoate was employed. The corresponding adducts were
obtained in variable yield, but their further cyclization was not
observed. We now describe the expanded results of our
1
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17
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J. Org. Chem, Vol. 72, No. 9, 2007 3327

Sorbetti et al.
TABLE 1. Aza-Morita-Baylis-Hillman Reaction of Aldimines 2
Although dienyl sulfone 3 was prepared and used as the
E-isomer, adducts 4 were obtained as E,Z mixtures, presumably
because of free rotation in the zwitterionic intermediates prior
to elimination of HQD in the product-forming step. The
E-isomer was predominant in all cases, apart from 2d, which
gave a 1:1 ratio of geometric isomers. Separation by flash
chromatography provided pure samples of the less polar
E-isomers; however the minor Z-isomers could generally not
be isolated completely free of the remaining E-isomers. Dif-
ferentiation of the two geometric isomers was initially based
upon NOE experiments with 4a. The doublet at δ 5.91 ppm of
the major isomer collapsed to a singlet upon D2O exchange,
establishing it as the signal from the benzylic proton R to the
sulfonamide moiety. Irradiation of this signal led to an enhance-
ment of 16% for the γ-proton (δ 6.64 ppm) of the dienyl sulfone
moiety, while the reverse experiment gave an enhancement of
14%, indicating the E-geometry. Subsequently, a crystal struc-
ture was obtained for the major isomer of 4a, clearly demon-
strating its E-geometry (see Supporting Information). The E,Z
assignments for the other products in Table 1 were based on
the similarity of their NMR spectra to the respective geometric
isomers of 4a. The E/Z ratios in Table 1 are based on integration
of the signals of the respective isomers in the unseparated
mixtures.
a
with Dienyl Sulfone 3
imine
R
yield of 4 (%)
E:Z ratio of 4
2
2
2
2
2
2
2
2
2
2
2
2
a
b
c
d
e
f
g
h
i
Ph
86
73
63
46
46
31
70
75
61
70:30
70:30
70:30
50:50
60:40
70:30
70:30
70:30
65:35
p-Cl-C6H4
m-Cl-C6H4
o-Cl-C6H4
p-CH3O-C6H4
p-NO2-C6H4
p-CH3O2C-C6H4
p-NC-C6H4
R-naphthyl
3-pyridyl
mesityl
b
c
c
d
d
j
k
l
-
-
-
-
-
-
cyclohexyl
a
All reactions were carried out in DMF containing 0.25 equiv of HQD
b
at room temperature for 4-6 h unless otherwise noted. 0.5 equiv of HQD
was employed. Reaction was carried out in THF for 16-20 h. d The crude
product was used directly in a one-pot preparation of 5j (see Table 2).
c
SCHEME 3
Table 1 reveals that the method is compatible with both
electron-withdrawing and -donating substituents on the aryl
moiety of the imine. However, the nitro- and cyano-substituted
derivatives 2f and 2h reacted very rapidly in DMF to afford
complex mixtures of products, while the use of THF resulted
in slower reactions and improved yields of the corresponding
adducts. Adduct 4j, produced from the reaction of the 3-pyridyl
derivative 2j and dienyl sulfone 3, could not be isolated in a
pure state. The crude product was therefore converted directly
into the cyclized product 5j without isolation (vide infra). The
more hindered mesityl derivative 2k and the aliphatic imine 2l
failed to undergo the aza-Morita-Baylis-Hillman reaction
under all of the conditions attempted. Similarly, the methyl-
to similar reactions and cyclizations of methyl 2,4-pentadienoate
(
6). We also report the first examples of aza-Morita-Baylis-
Hillman reactions of conjugated dienones, in which 7 and 8
were successfully transformed into the corresponding adducts.
Results and Discussion
The required imines 2 were prepared from their corresponding
19
aldehydes by a standard procedure. The dienyl ester 6 is
commercially available (Fluka), while dienyl sulfone 3 was
20
21
22
obtained by a literature method, and dienones 7 and 8 were
prepared from the corresponding known23 R-(phenylseleno)-
ketones by selenoxide elimination, as shown in Scheme 3.
Using N-(benzylidene)benzenesulfonamide (2a) and 1-(p-
toluenesulfonyl)-1,3-butadiene (3) as representative starting
materials for the aza-Morita-Baylis-Hillman reaction, a series
of different catalysts was screened, including triethylamine,
triphenylphosphine, DABCO, DMAP, DBU, and HQD. Catalyst
loadings of 0.1, 0.25, 0.5, 1.0, and 3.0 mol equiv were employed
in a variety of different solvents, including acetonitrile, metha-
nol, THF, dichloromethane, dioxane, and DMF. Optimal results
were generally obtained at room temperature with 25 mol % of
HQD in dry DMF. Reactions also proceeded well in THF, but
at a slower rate. The optimized conditions, with a few excep-
tions, were then applied to a series of aldimines, and the results
are listed in Table 1.
20
20
24
substituted analogs 9, 10, and 11 of dienyl sulfone 3 failed
to react with imine 2a, even at elevated temperatures, presum-
ably because of increased steric effects. No significant amounts
of the regioisomeric products 12 were formed via γ-attack of
the sulfone-stabilized zwitterions upon the imines (Scheme 4).
Cyclizations of the E-isomers of 4 by intramolecular conju-
gate addition of their respective anions to the terminal positions
of the diene substituents were effected at room temperature in
DMF-water (10:1) containing K2CO3 to afford the correspond-
ing functionalized piperidines 5 (Scheme 2, Table 2). As
expected, the Z-isomers failed to cyclize under these conditions
because of their inability to adopt a conformation compatible
with the 6-centered transition state required for the cyclization.
The nitro derivative (E)-4f gave complex mixtures of products
under these conditions.
In some cases, imine 2 was employed in excess over sulfone
3
to compensate for its partial hydrolysis during the reaction.
However, equimolar amounts of 2 and 3 afforded comparable
yields of 4 if rigorously anhydrous conditions were maintained.
(
19) Vishwakarma, L. C.; Stringer, O. D.; Davis, F. A. Org. Synth. 1988,
6, 203-210.
20) Barluenga, J.; Martinez-Gallo, J. M.; N a´ jera, C.; Fa n˜ an a´ s, F. J.; Yus,
M. J. Chem. Soc., Perkin Trans. 1 1987, 2605-2609.
21) Bloch, R.; Abecassis, J.; Hassan, D. Can. J. Chem. 1984, 62, 2019-
024.
6
(
The lack of reactivity of the Z-isomers of 4 prompted us to
investigate the in situ equilibration of the geometrical isomers
(
2
6
(
(
22) Yu, Y.; Lin, R.; Zhang, Y. Tetrahedron Lett. 1993, 34, 4547-4550.
23) Ponthieux, S.; Outurquin, F.; Paulmier, C. Tetrahedron 1997, 53,
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5837.
365-6376.
328 J. Org. Chem., Vol. 72, No. 9, 2007
3

Aza-Morita-Baylis-Hillman Reactions
SCHEME 4
TABLE 2. Cyclizations of the E Isomers of
Aza-Morita-Baylis-Hillman Adducts 4a
adduct
R
yield of 5 (%)
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
g
h
i
Ph
p-Cl-C6H4
m-Cl-C6H4
o-Cl-C6H4
p-CH3O-C6H4
p-NO2-C6H4
p-CH3O2C-C6H4
p-NC-C6H4
R-naphthyl
3-pyridyl
91
95
89
82
79
-
65
80
86
b
j
30
a
Cyclizations were performed in DMF-water (10:1) containing an
b
equimolar amount of K2CO3 for 24 h at room temperature. The yield is
for both steps of a one-pot preparation directly from imine 2j and dienyl
sulfone 3.
SCHEME 5
TABLE 3. Aza-Morita-Baylis-Hillman Reactions and
Cyclizations of Imines 2 with Ester 6a
b
imine
R
yield of 13 (%)
E/Z ratio of 13
yield of 16 (%)
2
2
2
a
b
e
H
Cl
MeO
NO2
CN
85
85
66
61
91
80:20
80:20
75:25
80:20
75:25
77
91
89
49
70
SCHEME 6
2f
2h
a
Aza-Morita-Baylis-Hillman reactions were performed in dry DMF
in the presence of a trace of MeOH and 25 mol % of HQD for 1-3 days
at room temperature. Cyclizations were carried out in DMF containing 1.0
mol equiv of DBU for 1-3 days at room temperature. Yields of 16 are
based on the use of the pure E-isomers of 13.
b
TABLE 4. Aza-Morita-Baylis-Hillman Reactions of Imines 2
with Dienones 7 and 8a
product
R
R’
yield (%)
E:Z ratio
1
1
1
1
1
1
1
1
1
1
4a
5a
4b
5b
4e
5e
4f
5f
4h
5h
H
H
Cl
Me
Ph
Me
Ph
Me
Ph
Me
Ph
80
70
47
67
-
30
55
68
61
88
>95:5
65:35
>95:5
65:35
-
60:40
>95:5
65:35
>95:5
70:30
Cl
MeO
MeO
NO2
NO2
CN
Me
Ph
CN
a
Aza-Morita-Baylis-Hillman reactions were performed in dry DMF
in the presence of a trace of MeOH and 25 mol % of HQD for 6-12 h at
room temperature.
during the cyclization process in order to facilitate the consump-
tion of both isomers from the corrresponding unseparated E,Z
mixtures. We observed in separate control experiments that both
pure (E)-4a and a 40:60 mixture of (E)- and (Z)-4a afforded
identical 70:30 mixtures of the two isomers after irradiation with
UV light at 300 nm (Scheme 5). Thus, photoisomerization is
possible, and the 70:30 ratio represents the system at equilib-
rium. The feasibility of a one-pot isomerization-cyclization
process was demonstrated by subjecting an unseparated 65:35
mixture of (E)- and (Z)-4a to the usual cyclization conditions
reaction in the presence of HQD, or by catalyzing the photoi-
2
5
somerization with diphenyl diselenide, proved less effective
than the above protocol. Similarly, the 3-pyridyl derivative 5j
was prepared via the one-pot procedure because the intermediate
adduct 2j could not be isolated in a pure state.
A similar investigation of dienoate ester 6 and of dienones 7
and 8 revealed their facile reactions with representative imines
2a, 2b, 2e, 2f, and 2h in anhydrous DMF containing a trace of
methanol at room temperature for 1-3 days in the presence of
25 mol % of HQD. The results are shown in Scheme 6 and
Tables 3 and 4. Again, compatibility with both electron-
withdrawing and electron-donating groups on the aryl moiety
of the imine was observed. Products 13 (Table 3) were obtained
as E/Z mixtures, from which the dominant E-isomers were
separated by flash chromatography. The assignment of E/Z
configuration was confirmed unequivocally for the major isomer
(K2CO3-DMF-H2O), while simultaneously irradiating the
mixture with UV light at 300 nm. Piperidine 5a was thus
produced in 84% yield (Scheme 5), only slightly lower than
the 91% yield obtained by cyclization of the pure E-isomer and
ca. 20% higher than the yield expected from the cyclization of
the E-isomer present in a 70:30 unseparated E/Z mixture, without
subjecting it to simultaneous isomerization. Attempts to promote
the E/Z equilibration by addition-elimination through prolonged
(25) Back, T. G.; Krishna, M. V. J. Org. Chem. 1988, 53, 2533-2536.
J. Org. Chem, Vol. 72, No. 9, 2007 3329

Sorbetti et al.
Supporting Information of our preliminary communication.17 Adduct
4j and piperidine derivatives 5c, 5d, 5e, 5g, 5i, and 5j are described
in the accompanying Supporting Information. Methyl 2,4-penta-
dienoate was purchased from a commercial source.
Typical Procedure for the Morita-Baylis-Hillman Reaction
of Aldimines 2 with Methyl 2,4-Pentadienoate (6). Preparation
of 13a. A solution of ester 6 (0.200 mL, 1.72 mmol), imine 2a
of 13a by an NOE experiment, in which irradiation of the
benzylic hydrogen signal at δ 5.76 (d, J ) 10.3 Hz, collapsed
to s with D2O) resulted in an enhancement of 18% to the
multiplet assigned to the vinylic hydrogen atom γ to the ester
at δ 6.82-6.69 ppm, and vice versa. The E/Z assignments of
1
3b, 13e, 13f, and 13h were made by analogy because of the
similarity of their NMR spectra to the respective geometrical
isomers of 13a. The E,Z-configurations of products 14a and
(426 mg, 1.74 mmol), methanol (60 µL, 1.5 mmol), and HQD (56.5
mg, 0.444 mmol) in 7 mL of anhydrous DMF was stirred for 24 h
at room temperature. The reaction mixture was diluted with ether
and washed with water and brine. The organic layer was dried
15a, derived from dienones 7 and 8, respectively, were similarly
established by NOE experiments. Furthermore, the E-configura-
tions of the major isomers of 14f and 15a were confirmed by
X-ray crystallography (see Supporting Information).
(MgSO ), concentrated, and chromatographed (toluene-ethyl ac-
4
etate, 16:1) to afford 526 mg (85%) of 13a as a mixture of
geometrical isomers (E:Z ) 80:20). Further chromatography of the
latter product afforded the less polar pure E-isomer, followed by a
mixture of both geometrical isomers. Ester (E)-13a: viscous
In contrast to the results with phenyl 2,4-pentadienoate
18
reported earlier by Shi and Shi, we observed the smooth
cyclization of the E-isomers of 13a, 13b, 13e, 13f, and 13h in
anhydrous DMF in the presence of DBU to the corresponding
piperidines 16 (Scheme 6 and Table 3). Once again, the
corresponding Z-isomers failed to cyclize.
-1 1
colorless oil; IR (film) 3292, 1716, 1164 cm ; H NMR (300 MHz,
CDCl
3
) δ 7.77 (d, J ) 7.7 Hz, 2 H), 7.53-7.48 (m, 1 H), 7.42-
.37 (m, 2 H), 7.26-7.20 (m, 5 H), 7.14 (d, J ) 11.8 Hz, 1 H),
.82-6.69 (dt, J ) 16.4, 10.8 Hz, 1 H), 6.39 (d, J ) 10.8 Hz, 1 H,
O), 5.76 (d, J ) 10.3 Hz, 1 H), 5.70-5.62 (m,
2 H), 3.57 (s, 3 H); irradiation of the proton at δ 6.82-6.69 showed
7
6
The aza-Morita-Baylis-Hillman reaction of imines 2a, 2b,
e, 2f, and 2h with dienones 7 and 8 proceeded under similarly
exchanged with D
2
2
1
3
an NOE of 18% for the signal at δ 5.76 and vice versa; C NMR
75 MHz, CDCl
mild conditions to afford corresponding products 14 and 15,
respectively (Scheme 6, Table 4). Imine 2e, containing the
electron-donating p-methoxy derivative, gave the poorest results
of the examples studies, affording only 30% of adduct 15e from
the phenyl ketone 8 and no isolable product with the methyl
ketone 7. Interestingly, while 8 afforded E/Z mixtures of 15a,
(
1
%
3
) δ 166.8, 141.6, 141.1, 138.8, 132.6, 130.6, 128.9,
28.7, 128.6, 127.6, 127.1, 126.0, 53.9, 52.1; mass spectrum (m/z,
+
) 341 (M - O, 11), 216 (10), 200 (26), 185 (17), 141 (18), 104
+
(13), 77 (100). HRMS calcd for C19
H19NO
3
S (M - O): 341.1086.
Found: 341.1102.
Products 13b, 13e, 13f, and 13h were prepared similarly in the
yields and E/Z ratios given in Table 3. Their properties are given
in the Supporting Information.
Typical Procedure for the Morita-Baylis-Hillman Reaction
of Aldimines 2 with Dienones 7 and 8. Preparation of Methyl
Ketone 14a. A solution of imine 2a (54.6 mg, 0.223 mmol), HQD
15b, 15e, 15f, and 15h in the ratio of ca. 2:1, ketone 7 produced
the E-isomers of 14a, 14b, 14f, and 14h almost exclusively.
Attempts to effect the cyclization of products 14 and 15 in Table
4
under the same conditions that had been used successfully
for the preparation of 5 (Table 2) and 16 (Table 3) failed. A
variety of other conditions, including the use of potassium
carbonate, DABCO, DMAP, and diisopropylethylamine in a
variety of solvents, also proved unsuccessful, generally resulting
in the gradual polymerization of starting materials 14 and 15.
In conclusion, these results demonstrate that the aza-Morita-
Baylis-Hillman reaction can be carried out between variously
substituted N-(phenylsulfonyl)aldimines and conjugated dienes
activated by sulfone, ester, or ketone moieties to afford highly
functionalized allylic amine derivatives. The E-isomers of the
products from the dienyl sulfone and the dienoate underwent
facile intramolecular conjugate additions to produce the corre-
sponding functionalized piperidine derivatives, whereas adducts
obtained from the dienones failed to cyclize under similar
conditions.
(
9.1 mg, 0.072 mmol), methanol (5 µL, 0.1 mmol), and 7 (18.7
mg, 0.195 mmol) in dry DMF was stirred at room temperature for
h. The solution was poured into water, extracted with ether, and
6
washed with water and brine. The organic fractions were combined,
dried, and concentrated. The crude product was chromatographed
(toluene:ethyl acetate, 16:1), followed by recrystallization (ethyl
acetate-toluene) to afford 53.6 mg (80%) of the product (E)-14a
as a single geometrical isomer: off-white solid; mp 95-99 ˚C (from
ethyl acetate-toluene); IR (film) 3278, 1657, 1332, 1163, 1091
-
1 1
cm ; H NMR (300 MHz, CDCl
7
6
3
) δ 7.74 (d, J ) 7.2 Hz, 2 H),
.53-7.47 (m, 1 H), 7.43-7.36 (m, 2 H), 7.28-7.18 (m, 5 H),
.92-6.77 (m, 2 H), 6.50 (d, J ) 10.3 Hz, 1 H, exchanged with
O), 5.77-5.67 (m, 3 H), 2.03 (s, 3 H); the sample was shaken
with D O, and irradiation of the signal at δ 5.64 ppm resulted in
D
2
2
an NOE of 19% for the signal at δ 6.8, while irradiation of the
signal at δ 6.8 gave an NOE of 18% for the signal at δ 5.64 ppm;
1
3
3
C NMR (75 MHz, CDCl ) δ 200.1, 142.9, 141.2, 139.0, 137.1,
Experimental Section
132.5, 131.1, 129.3, 128.9, 128.5, 127.5, 127.2, 125.9, 54.4, 26.2;
mass spectrum (m/z, %) 341 (M , 0.6), 246 (8), 200 (97), 141 (25),
+
+
Imines 2a-l were prepared according to the general procedure
77 (100). HRMS calcd for C H NO S (M - C H O): 245.0511.
1
3
11
2
6
8
1
9
19
+
of Davis et al. The following imines are known compounds: 2a,
2
Found: 245.0518. Calcd for C H NO (M - C H SO ): 200.1075.
1
3
14
6
5
2
26
26
26
27
28
29
30
b, 2c, 2e, 2f, 2i, 2j, and 2l. Imines 2d, 2g, 2h, and 2k
Found: 200.1063.
were described in the Supporting Information of our preliminary
Products 14b, 14f, 14h, 15a, 15b, 15e, 15f, and 15h were
prepared similarly in the yields and E/Z ratios given in Table 4.
Their properties are given in the Supporting Information. All
reactions were performed at room temperature for durations between
communication.17 Dienyl sulfones 3, 9, 10, and 11 were
obtained by literature methods. The preparations of adducts 4a-i
and cyclized piperidines 5a, 5b, and 5h were also reported in the
20
20
20
24
6
and 12 h. Products 14 were produced as essentially pure
E-isomers, while 15 were obtained as E/Z-mixtures. In all cases
where E/Z-mixtures were produced, except for 15c, the E-isomers
could be isolated in a relatively pure state and are described below,
while the Z-isomers were contaminated with the E-isomers. The
opposite was true for 15c, and the reported properties are those of
the pure minor Z-isomer.
(
26) Jin, T.-S.; Feng, G.-L.; Yang, M.-N.; Li, T.-S. J. Chem. Res. Synop.
003, 591-593.
27) Davis, F. A.; Lal, S. G.; Durst, H. D. J. Org. Chem. 1988, 53, 5004-
007.
2
5
9
1
(
(
28) Stojanovic, M. N.; Kishi, Y. J. Am. Chem. Soc. 1995, 117, 9921-
922.
(29) Batal, D. J.; Madison, S. A. U.S. Patent 5041232, 1991; Chem. Abstr.
Typical Procedure for Cyclization Reactions of Esters 13.
Preparation of Piperidine 16a. A mixture of the E-isomer of
991, 115, 258737.
(30) Chemla, F.; Hebbe, V.; Normant, J.-F. Synthesis 2000, 75-77.
3330 J. Org. Chem., Vol. 72, No. 9, 2007

Aza-Morita-Baylis-Hillman Reactions
adduct 13a (61.1 mg, 0.171 mmol) and DBU (26 µL, 0.17 mmol)
was stirred in 4 mL of dry DMF at room temperature for 3 days.
The reaction mixture was diluted with ether and washed once with
Products 16b, 16e, 16f, and 16h were prepared similarly, using
reaction times of 1-3 days in the yields given in Table 3. Their
properties are given in the Supporting Information.
water and once with brine. The organic phase was dried (MgSO
filtered, and concentrated. The crude product was purified by
chromatography (toluene-ethyl acetate, 16:1) to afford 47.0 mg
4
),
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada (NSERC) for financial
support. J.M.S. acknowledges receipt of Postgraduate Scholar-
ships from NSERC and Alberta Ingenuity. D.A.R. thanks
NSERC for an Undergraduate Summer Research Assistantship.
J.E.W. thanks NSERC, the Alberta Heritage Foundation for
Medical Research, and the Killam Foundation for Postgraduate
Scholarships.
(
77%) of product 16a: off-white solid; mp 114-116 °C (from ethyl
-1 1
acetate-toluene); IR (film) 1714, 1344, 1161, 1102 cm ; H NMR
300 MHz, CDCl ) δ 7.80 (d, J ) 7.2 Hz, 2 H), 7.57-7.51 (m, 1
H), 7.46-7.41 (m, 2 H), 7.30-7.28 (m, 5 H), 7.04 (t, J ) 3.6 Hz,
H), 6.01 (s, 1 H), 3.82-3.70 (m, 1 H), 3.65 (s, 3 H), 3.05-2.95
m, 1 H), 2.21-2.14 (m, 2 H); 13C NMR (75 MHz, CDCl
) δ 165.2,
(
3
1
(
1
Supporting Information Available: Characterization data, H
3
and 13C NMR spectra of new compounds, and X-ray crystal-
lographic data for 4a, 14f, and 15a. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
40.8, 139.0, 138.6, 132.6, 129.7, 128.9, 128.4, 128.2, 128.0, 127.0,
+
55.0, 51.9, 36.7, 24.1; mass spectrum (m/z, %) 357 (M , 2), 280
+
(55), 216 (100), 77 (79). HRMS calcd for C19
H19NO
4
S (M ):
357.1035. Found: 357.1042.
JO062655+
J. Org. Chem, Vol. 72, No. 9, 2007 3331