Hydroxy chalcogenide-promoted Morita-Baylis-Hillman Alkylation reaction: Intermolecular applications with alkyl halides as electrophiles

Article abstract of DOI:10.1002/ejoc.201301743

Hydroxysulfides acted as catalysts to promote the Morita-Baylis-Hillman alkylation reaction of cyclohexenones and dihydropyridinones. The procedure worked efficiently with a variety of halides as electrophiles. Side reactions were in competition with the MBH alkylation, but fine-tuning the reaction conditions minimized their occurence.

Full text of DOI:10.1002/ejoc.201301743

FULL PAPER
DOI: 10.1002/ejoc.201301743
Hydroxy Chalcogenide-Promoted Morita–Baylis–Hillman Alkylation Reaction:
Intermolecular Applications with Alkyl Halides as Electrophiles
Ana Gradillas,[a] Efres Belmonte,[a] Rondes Ferreira da Silva,[a] and Javier Pérez-Castells*[a]
Keywords: Synthetic methods / Alkylation / Enones / Halides / Organocatalysis / Sulfur
Hydroxysulfides acted as catalysts to promote the Morita–
Baylis–Hillman alkylation reaction of cyclohexenones and di-
hydropyridinones. The procedure worked efficiently with a
variety of halides as electrophiles. Side reactions were in
competition with the MBH alkylation, but fine-tuning the re-
action conditions minimized their occurence.
ment of unusual substrates and new organic catalysts. In
particular, we believe that the MBH-type alkylation process
deserves more attention, as it is an attractive way to pro-
duce functionalized molecules that are not attainable by
classical MBH methodology. We recently published the un-
precedented use of hydroxylsulfides as catalysts to perform
the MBH alkylation reaction efficiently under basic condi-
tions.[10] In that work, we used α,β-unsaturated lactams and
lactones as the activated alkenes (see Scheme 1).[11]
Introduction
The Morita–Baylis–Hillman reaction (MBH) is an im-
portant carbon–carbon bond-forming transformation, in
which a reaction occurs between the α-position of an acti-
vated alkene and an electrophile under the influence of a
catalyst to provide a densely functionalized molecule.[1] In
recent years, many groups have expanded the utility of this
process with respect to the three essential components.[2]
With regard to the substrates, these include acyclic and cy-
clic alkenes, alkynes, and allenes that are activated by
ketone, ester, amide, nitrile, nitro, sulfonate, and phosphate
functional groups. Electrophiles are generally aldehydes, ac-
tivated ketones, and imines (aza-MBH).[3] Activated alkenes
can also act as electrophiles to result in dimerization and
cross-coupling reactions (Rauhut–Courrier reaction).[4]
A
few reports account for the use of a limited number of alkyl
halides,[5] and there are two instances of the use of epoxides
as electrophiles.[6] All of these latter reagents imply that
there is an alkylation version of MBH chemistry that is
underdeveloped, especially the intermolecular version, as
most examples reported to date involve cyclizations of halo-
gen-containing MBH substrates. With regard to the cata-
lyst, the vast majority of published reactions use tertiary
amines or phosphines. The chalcogenide-mediated Morita–
Baylis–Hillman reaction is an alternative procedure, which
mainly involves sulfides and selenides in combination with
TiCl4.[7] The use of chiral sulfinylimines in the asymmetric
aza-Morita–Baylis–Hillman reaction has also been re-
ported,[8] and cysteine was shown to catalyze a Rauhut–
Courier reaction.[9]
Scheme 1. MBH reaction of α,β-unsaturated lactams and lactones
with different electrophiles.
However, the need for a noncommercial, chiral catalyst
was superfluous in this reaction because no stereogenic cen-
ters were created. In the present communication, the poten-
tial use of other hydroxysulfides as viable catalysts in this
intriguing reaction is studied, and the method is applied to
cyclohexenones and dihydropyridinones.
Results and Discussion
As starting materials for the present study, we selected
cyclohexenones 1a and 1b and N-protected 2,3-dihydro-4-
pyridinones 2a and 2b, which were prepared by using a re-
ported procedure.[12] We and others have shown the positive
outcome of having hydroxy groups situated at an appropri-
ate distance within the catalyst molecule to accelerate the
MBH reaction.[13] Thus, we selected a group of hydroxysulf-
ides for the purpose of comparing their catalytic behavior
in the MBH process (see Figure 1). In addition to the cam-
In the course of our studies of the MBH reaction, we
were interested in exploring alternatives such as the employ-
[a] Departamento de Química y Bioquímica, Facultad de
Farmacia, Universidad San Pablo-CEU,
Urb. Montepríncipe, 28668 Boadilla del Monte (Madrid), Spain
E-mail: jpercas@ceu.es
www.uspceu.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301743
Eur. J. Org. Chem. 2014, 1935–1941
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1935

A. Gradillas, E. Belmonte, R. F. da Silva, J. Pérez-Castells
FULL PAPER
phor-derived hydroxysulfides 3 and 4, which were used pre- solvent was carried out (see Table 1, Entries 5–8), in which
viously by us[10] and other groups,[14] we employed simple we showed that by using tBuOH, tetrahydrofuran (THF),
commercial compounds such as 5–9.
acetone, or CH3CN, the MBH product yield was below the
one achieved by using the CH3CN/tBuOH (1:1) mixture.
When the reaction was extended to 4,4-dimethyl-2-cyclo-
hexenone (1b), in which the 4-position was blocked from
enolization by the two geminal methyl groups, we were un-
able to detect the desired MBH product, which was proba-
bly because of the steric effects associated with this hin-
dered enone.
Figure 1. Substrates and catalysts selected for this study.
The first step was to perform the MBH alkylation reac-
tion with 2-cyclohexenone (1a) and all of the different
hydroxysulfides. In the first attempt, we used catalyst 7 and
cinnamyl bromide, which revealed a wide array of second-
ary reactions (see Scheme 2). Three processes were in com-
petition with each other, and their products were isolated
and characterized. Thus, the MBH alkylation reaction gave
product 10a (50%) upon displacement of the bromide atom
by A to give intermediate B and then elimination of the
catalyst. In addition, the reaction of intermediate A with a
second molecule of 1a gave Rauhut–Courier product 11
(20%) through intermediate C. The formation of enolate D
allowed for a double alkylation at C-4 of the substrate to
give 13 (15%) through monoalkylated product 12, which
was not detected (see Table 1, Entry 1). As previously de-
Scheme 2. MBH alkylation and side reactions of cyclohexenone 1a
scribed in the literature, 11 could also be formed from enol- with cinnamyl bromide.
ate D through a conjugate addition to 2-cyclohexenone and
shift of the double bond.[15] We checked this possibility by
The conditions that were employed in Entry 4 were then
carrying out the reaction of 1a with Cs2CO3 in the absence used with the other catalysts (see Table 1, Entries 9–14).
of the other reagents, and 11 was produced in 99% yield Phenylthioethanol (7) was the best catalyst among the com-
(see Table 1, Entry 2). The dimerization of unsaturated mercial compounds tested. The performance of compound
ketones is not a trivial process and has recently received 3 was slightly below that of 7, but good results were still
attention.[16] In addition, trace amounts of a different dialk- obtained (see Table 1, Entry 9). This is the first time that a
ylation product were observed in the spectrum of crude simple sulfide catalyzed a MBH reaction without the assist-
products, which could possibly correspond to compound 15 ance of other additives.
as a result of the formation of the less favored enolate E.
Other electrophiles were then employed to expand the
After the first attempt, the main conclusion was that we scope of the process (for reaction conditions, see Table 2,
were able to perform the MBH alkylation reaction by using Entries 1 and 2). Thus, allyl bromide gave 10b in good
hydroxysulfides, but the conditions needed fine-tuning to yields of 75–83% (see Table 2, Entries 3–5,) along with
improve the yields. We then increased the reaction time and small amounts of dimer 11. In addition, 1-bromo-2-butyne
the amount of electrophile to 1.5 equiv. to increase the yield gave a 63% yield of 10c and 15% of α,α-dialkylated deriva-
of 10a to 70% (see Table 1, Entry 4). This attempt also tive 15c along with 10% of 11 (see Table 2, Entry 6). The
showed the result of performing the reaction from the start reaction of 2-cyclohexenone with ethyl 2-(bromomethyl)-
at 80 °C as well as employing a 1:1 mixture of CH3CN/ prop-2-enoate gave product 10d in 60% yield (see Table 2,
tBuOH as the solvent. Under these conditions we reached Entry 7). Finally, the reactions with methyl iodide and
a 70% yield of 10a and obtained only a small amount of benzyl bromide gave 10e and 10f in 65 and 45% yield,
the dimer 11. An evaluation of the effect of changing the respectively (see Table 2, Entries 8 and 9).
1936
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1935–1941

Hydroxy Chalcogenide-Promoted Morita–Baylis–Hillman Alkylation
Table 1. Reaction conditions of 1a with cinnamyl bromide.[a]
Entry
Cat.
RЈ–Br
[equiv.]
Solvent[b]
Temp.
[°C]
Time
[h]
% Yield[c]
11
1a
10a
13a
15a
1
2
3
4
5
6
7
8
7
–
–
7
7
7
7
7
3
4
5
6
8
9
1
–
2.5:1
2.5:1
2.5:1
1:1
tBuOH
THF
acetone
CH3CN
1:1
1:1
1:1
1:1
1:1
r.t.–80
r.t.–80
r.t.–80
80
82
67
57
80
80
80
80
80
80
80
12
12
12
24
24
24
24
24
24
24
24
24
24
24
10
–
50
–
–
15
99
60
11
45
25
30
25
11
15
45
40
12
40
15
–
25
10
–
15
5
5
Ͻ5
Ͻ5
10
10
10
10
Ͻ5
–
Ͻ5
–
–
Ͻ5
–
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
10
Ͻ5
10
25
10
10
10
10
20
25
10
15
70
40
30
55
60
65
60
–
–
9
Ͻ5
Ͻ5
Ͻ5
Ͻ5
Ͻ5
Ͻ5
10
11
12
13
14
–
58
–
1:1
[a] Reagents and conditions for all reactions: Cat. (catalyst, 0.2 equiv.), Cs2CO3 (2 equiv.). [b] Ratios correspond to mixtures of CH3CN/
tBuOH mixtures. [c] Yield of pure product.
Table 2. Reactions of 1a with different halides.[a]
lead to the diallylation of the tosylamide. Thus, we envi-
sioned that changing the protecting group at the nitrogen
would possibly reduce the occurrence of these processes and
allow for the desired MBH-type reaction. In fact, when 2b
was submitted to the reaction under the optimal conditions
(see Table 2, Entry 1) with cinnamyl bromide as the electro-
phile, most of unreacted starting material 3b was recovered,
so the reaction time was extended to 48 hours, thereby in-
creasing the yield of 19a to 45% (see Table 3, Entry 1). For
byproducts of this reaction, we isolated 18 in 20% yield and
[a] Reagents and conditions for all reactions: catalyst (0.2 equiv.),
Cs2CO3 (2 equiv.), CH3CN/tBuOH (1:1), R–X (1.5 equiv.), 80 °C.
[b] Yield of pure product.
The second part of the present study involves the use of
dihydropyridinones as substrates. These interesting hetero-
cycles have the advantage of avoiding the side reactions that
result from enolization. However, our first reaction between
compound 2a and allyl bromide was disappointing, as the
only detected reaction product was 16a (90%), whereas 16b
(89%) was isolated as the only product of the parent reac-
tion with cinnamyl bromide (see Scheme 3). We have not
studied in detail a plausible reaction pathway to explain the
formation of 16, but the instability of 2a under the basic
reaction conditions surely causes the ring opening of the
dihydropyridinone and a subsequent cascade process to 2b.
Scheme 3. MBH alkylation reactions of dihydropyridinones 2a and
Eur. J. Org. Chem. 2014, 1935–1941
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1937

A. Gradillas, E. Belmonte, R. F. da Silva, J. Pérez-Castells
FULL PAPER
2-[(2E)-3-Phenylprop-2-en-1-yl]cyclohex-2-en-1-one (10a): Follow-
ing the general procedure (see Table 1, Entry 4), 1a (100 mg,
1.04 mmol), the catalyst 2-(phenylsulfanyl)ethanol (7, 31 mg,
0.20 mmol), Cs2CO3 (678 mg, 2.08 mmol), and cinnamyl bromide
(307 mg, 1.56 mmol) gave the crude product that was purified by
column chromatography (hexane/ethyl acetate, 9:1) to afford 10a
the open-chain product 17 in 15% yield. The reaction with
allyl bromide (see Table 3, Entry 2) gave MBH adduct 19b
in 65% yield, and the amounts of the side products were
reduced. The reaction with 1-bromo-2-butyne (see Table 3,
Entry 3) afforded 19c in only 40% yield. On the other hand,
ethyl 2-(bromomethyl)prop-2-enoate was not reactive under
the conditions (see Table 3, Entry 4). Finally, methyl iodide
gave the best results with the isolation of 19e in 70% yield
along with a 25% yield of the side product 18e (see Table 3,
1
(155 mg, 70%) as a colorless oil. H NMR (300 MHz, CDCl3): δ
= 1.98–2.02 (m, 2 H, CH2), 2.35–2.37 (m, 2 H, CH2), 2.44–2.48
(m, 2 H, CH2), 3.10 (d, J = 7.0 Hz, 2 H, CH2), 6.16–6.26 (dt, J =
15.8 Hz, J = 7.0 Hz, 1 H, =CH), 6.40 (d, J = 15.8 Hz, 1 H, =CH),
Entry 5). From these results, it is clear that dihydropyrid- 6.78 (t, J = 4.1 Hz, 1 H, =CH), 7.17–7.36 (m, 5 H, ArH) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 23.1 (CH2), 26.1 (CH2), 32.8 (CH2),
38.5 (CH2), 126.1 (CH), 127.1 (CH), 128.5 (CH), 131.6 (CH), 137.5
inones are less reactive toward a 1,4-addition than other
enones such as cyclohexenones, and this has already been
noted by other groups.[17] The carbamate protecting group,
which was revealed as critical for the reaction, has the draw-
back of being unstable under the employed basic condi-
tions, and nucleophilic alkylation products such as 18 are
produced.
(C), 138.4 (C), 146.0 (CH), 199.0 (CO) ppm. IR (NaCl): ν = 3110,
˜
1680 (C=O) cm–1. MS (ESI): m/z = 213 [M + H]+. C15H16O
(212.29): calcd. C 84.87, H 7.60; found C 85.06, H 7.71.
4,4-Bis[(2E)-3-phenylprop-2-en-1-yl]cyclohex-2-en-1-one (13a): Fol-
lowing the general procedure (see Table 1, Entry 4), 1a (100 mg,
1.04 mmol), catalyst 7 (31 mg, 0.20 mmol), Cs2CO3 (678 mg,
2.08 mmol), and cinnamyl bromide (307 mg, 1.56 mmol) gave the
crude product that was purified by column chromatography (hex-
ane/ethyl acetate, 9:1) to afford 13a (34 mg, 10%) as a colorless oil.
1H NMR (300 MHz, CDCl3): δ = 2.29–2.41 (m, 6 H, CH2), 2.64–
2.71 (m, 2 H, CH2), 5.65 (d, J = 10.0 Hz, 1 H, =CH), 6.02–6.10
(m, 3 H, =CH), 6.37 (d, J = 15.8 Hz, 2 H, =CH), 7.17–7.38 (m, 10
H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 24.5 (CH2), 38.8
(CH2), 42.4 (CH2), 53.6 (C), 125.3 (CH), 126.2 (CH), 127.2 (CH),
127.8 (CH), 128.5 (CH), 132.6 (C), 133.2 (C), 137.4 (CH), 213.9
Table 3. MBH alkylation reaction of 2b with different electro-
philes.[a]
Entry
RЈ–X
[equiv.]
% Yield[b]
18
2b
17
19
1
2
3
4
5
a (1.5)[c]
b (1.5)[d]
c (1.5)[e]
d (1.5)[f]
e (1.5)[g]
10
Ͻ5
20
40
Ͻ5
15
10
Ͻ5
Ͻ5
Ͻ5
20
15
25
–
45
65
40
–
25
70
(CO) ppm. IR (NaCl): ν = 3065, 3027, 2900, 1707 (C=O) cm–1.
˜
[a] Reagents and conditions for all reactions: catalyst 7 (0.2 equiv.),
Cs2CO3 (2 equiv.). CH3CN/tBuOH (1:1), 80 °C, 48 h. [b] Yield of
pure product. [c] Cinnamyl bromide. [d] Allyl bromide. [e] 1-
C24H24O (328.45): calcd. C 87.76, H 7.37; found C 87.67, H 7.49.
2-Allyl-cyclohex-2-en-1-one (10b): Following the general procedure
(see Table 2, Entry 5), 1a (100 mg, 1.04 mmol), catalyst 7 (31 mg,
0.20 mmol), Cs2CO3 (678 mg, 2.08 mmol), and allyl bromide
(189 mg, 1.56 mmol) gave the crude product that was purified by
column chromatography (hexane/ethyl acetate, 9:1) to afford 10b
Bromo-2-butyne.
[g] Methyl iodide.
[f] Ethyl
2-(bromomethyl)prop-2-enoate.
1
(106 mg, 75%) as a colorless oil. H NMR (300 MHz, CDCl3): δ
Conclusions
= 1.97–2.02 (m, 2 H, CH2), 2.36–2.37 (m, 2 H, CH2), 2.42–2.47
(m, 2 H, CH2), 2.95 (dd, J = 6.7 Hz, J = 1.4 Hz, 2 H, CH2), 5.05
(dd, J = 14.8 Hz, J = 1.4 Hz, 2 H, CH=CH2), 5.77–5.86 (m, 1 H,
CH=CH2), 6.74 (t, J = 4.2 Hz, 1 H, =CH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 23.1 (CH2), 26.1 (CH2), 33.5 (CH2), 38.5
(CH2), 116.2 (CH2), 135.9 (CH), 138.1 (C), 145.8 (CH), 199.1
In summary, the reactions of a variety of cyclic enones
with different electrophiles and hydroxysulfides under
MBH conditions have been explored for the first time. This
study reveals that hydroxysulfides can be successfully em-
ployed as effective catalysts to promote MBH alkylation re-
actions of cyclic enones. Different side reactions can be avo-
ided by selecting the best reaction conditions for each sub-
strate.
(CO) ppm. IR (NaCl): ν = 2944, 1687 (C=O) cm–1. C H O
˜
9
12
(136.19): calcd. C 79.37, H 8.88; found C 79.54, H 8.74.
2-(But-2-yn-1-yl)cyclohex-2-en-1-one (10c): Following the general
procedure (see Table 2, Entry 6), 1a (100 mg, 1.04 mmol), catalyst
7 (31 mg, 0.20 mmol), Cs2CO3 (678 mg, 2.08 mmol), and 1-bromo-
2-butyne (207 mg, 1.56 mmol) gave the crude product that was
purified by column chromatography (hexane/ethyl acetate, 20:1) to
afford 10c (97 mg, 63%) as a colorless oil. 1H NMR (400 MHz,
CDCl3): δ = 1.84 (t, J = 2.5 Hz, 3 H, CH3), 1.99–2.03 (m, 2 H,
CH2), 2.41–2.46 (m, 4 H, CH2), 3.08–3.10 (m, 2 H, CH2), 7.13–
7.16 (m, 1 H, =CH) ppm. 13C NMR (100 MHz, CDCl3): δ = 3.5
(CH3), 19.3 (CH2), 23.0 (CH2), 26.0 (CH2), 38.3 (CH2), 75.4 (C),
Experimental Section
General Methods: Products 10e,[18] 10f,[19] 11,[20] 16a,[21] 16b,[22]
17a,[23] 17b,[24] and 18e.[25] were characterized by comparison with
the literature data.
General Procedure: To a stirred mixture of the cyclic enone
(1 equiv.) and catalyst 7 (0.2 equiv.) in a mixture of CH3CN/tBuOH
(1:1 v/v, 6 mL) were added Cs2CO3 (2 equiv.) and the correspond-
ing electrophile (1.5 equiv.). The resulting suspension was stirred at
80 °C. Upon completion of the reaction (as monitored by TLC),
the mixture was quenched by filtration through Celite, which was
washed with AcOEt (15 mL). The combined organic layers were
then concentrated under reduced pressure, and the resulting crude
oil was purified by column chromatography on silica gel to afford
the desired product.
79.3 (C), 135.1 (C), 146.0 (CH), 198.5 (CO) ppm. IR (NaCl): ν =
˜
3334, 2920, 2218, 1669 (C=O) cm–1. C10H12O (148.20): calcd. C
81.04, H 8.16; found C 80.44, H 8.06.
6,6-Di(but-2-yn-1-yl)cyclohex-2-en-1-one (15c): Following the gene-
ral procedure (see Table 2, Entry 6), 1a (100 mg, 1.04 mmol), cata-
lyst 7 (31 mg, 0.20 mmol), Cs2CO3 (678 mg, 2.08 mmol), and 1-
bromo-2-butyne (207 mg, 1.56 mmol) gave the crude product that
was purified by column chromatography (hexane/ethyl acetate,
1938
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1935–1941

Hydroxy Chalcogenide-Promoted Morita–Baylis–Hillman Alkylation
20:1) to afford 15c (27 mg, 15%) as a colorless oil. 1H NMR + 2H]2+. C17H19NO3 (285.34): calcd. C 71.56, H 6.71, N 4.91;
(400 MHz, CDCl3): δ = 1.76 (t, J = 2.6 Hz, 6 H, CH3), 2.43 (dd, J found C 71.74, H 6.61, N 5.01.
= 4.5 Hz, J = 2.4 Hz, 4 H, CH2), 2.47–2.50 (m, 2 H, CH2), 2.59–
2,3-Dihydro-1-[(2E)-3-phenylprop-2-en-1-yl]-1H-pyridin-4-one (18a):
2.60 (m, 2 H, CH2), 5.78 (dt, J = 9.9 Hz, J = 1.6 Hz, 1 H, =CH),
Following the general procedure (see Table 3, Entry 1), 2b (90 mg,
6.04 (dt, J = 9.9 Hz, J = 3.9 Hz, 1 H, =CH) ppm. 13C NMR
0.53 mmol), catalyst 7 (17 mg, 0.11 mmol), Cs2CO3 (345 mg,
(100 MHz, CDCl3): δ = 3.5 (CH3), 25.4 (CH2), 27.7 (CH2), 37.9
1.06 mmol), and cinnamyl bromide (158 mg, 0.80 mmol) gave the
(CH2), 51.2 (C), 74.8 (C), 78.6 (C), 128.1 (CH), 131.5 (CH), 212.1
crude product that was purified by column chromatography [gradi-
(CO) ppm. IR (NaCl):
ν = 3028, 2924, 2861, 2236, 1718
˜
ent of hexane/ethyl acetate (9:1) to ethyl acetate] to afford 18a
(23 mg, 20%) as a colorless oil. H NMR (400 MHz, CDCl3): δ =
(C=O) cm–1. C14H16O (200.28): calcd. C 83.96, H 8.05; found C
84.16, H 8.15.
1
2.51 (t, J = 8.0 Hz, 2 H, CH2), 3.49 (t, J = 7.7 Hz, 2 H, CH2), 3.95
(dd, J = 1.3 Hz, J = 11.7 Hz, 2 H, CH2), 5.01 (d, J = 7.4 Hz, 1 H,
=CH), 6.17 (dt, J = 6.5 Hz, J = 15.7 Hz, 1 H, =CH), 6.59 (d, J =
15.8 Hz, 1 H, =CH), 7.1 (d, J = 7.5 Hz, 1 H, =CH), 7.29–7.40 (m,
5 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 35.6 (CH2),
46.9 (CH2), 58.0 (CH2), 98.7 (CH), 123.4 (CH), 126.6 (CH), 128.3
(CH), 128.8 (CH), 134.5 (CH), 135.8 (C), 153.9 (CH), 191.7
Ethyl 2-[(2-Oxocyclohex-3-en-1-yl)methyl]prop-2-enoate (10d): Fol-
lowing the general procedure (see Table 2 Entry 7), 1a (100 mg,
1.04 mmol), catalyst 7 (31 mg, 0.20 mmol), Cs2CO3 (678 mg,
2.08 mmol), and ethyl 2-(bromomethyl)prop-2-enoate (301 mg,
1.56 mmol) gave the crude product that was purified by column
chromatography (hexane/ethyl acetate, 20:1) to afford 10d (130 mg,
1
60%) as a colorless oil. H NMR (400 MHz, CDCl3): δ = 1.28 (t,
(CO) ppm. IR (NaCl): ν = 3029, 2935, 2840, 1637 (C=O), 1588
˜
J = 7.1 Hz, 3 H, CH3), 1.96–2.02 (m, 2 H, CH2), 2.34–2.37 (m, 2
(C=C) cm–1. MS (ESI): m/z = 214 [M + H]+, 215 [M + 2H]2+
.
H, CH2), 2.42–2.46 (m, 2 H, CH2), 3.22 (s, 2 H, CH2), 4.18 (q, J C14H15NO (213.28): calcd. C 78.84, H 7.09, N 6.57; found C 78.78,
= 7.2 Hz, 2 H, CH2), 5.55 (d, J = 1.4 Hz, 1 H, =CH), 6.21 (t, J =
0.6 Hz, 1 H, =CH), 6.76 (t, J = 4.2 Hz, 1 H, =CH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 14.2 (CH3), 23.0 (CH2), 26.1 (CH2), 31.3
(CH2), 38.4 (CH2), 60.6 (CH2), 126.5 (CH2), 137.1 (C), 138.4 (C),
H 7.00, N 6.32.
Ethyl 5-Allyl-3,4-dihydro-4-oxo-2H-pyridine-1-carboxylate (19b):
Following the general procedure (see Table 3, Entry 2), 2b (90 mg,
0.53 mmol), catalyst 7 (17 mg, 0.11 mmol), Cs2CO3 (345 mg,
1.06 mmol), and allyl bromide (97 mg, 0.80 mmol) gave the crude
product that was purified by column chromatography (hexane/ethyl
acetate, 9:1) to afford 19b (72 mg, 65%) as a colorless oil. 1H NMR
(400 MHz, [D6]DMSO): δ = 1.26 (t, J = 7.1 Hz, 3 H, CH3), 2.51
(t, J = 7.2 Hz, 2 H, CH2), 2.85 (dd, J = 6.5 Hz, J = 1.0 Hz, 2 H,
CH2), 3.92 (t, J = 7.2 Hz, 2 H, CH2), 4.22 (q, J = 7.1 Hz, 2 H,
CH2), 4.98–5.06 (m, 2 H, CH2), 5.73–5.84 (m, 1 H, =CH), 7.68 (s,
1 H, =CH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 14.2
(CH3), 30.4 (CH2), 35.3 (CH2), 42.2 (CH2), 62.8 (CH2), 106.0 (C),
115.8 (CH2), 136.3 (CH), 140.5 (CH), 152.4 (COO), 192.2
146.8 (CH), 166.9 (COO), 198.5 (CO) ppm. IR (NaCl): ν = 2924,
˜
1718 (C=O), 1682 (C=O) cm–1. C12H16O3 (208.26): calcd. C 69.21,
H 7.74; found C 69.46, H 7.87.
2-Methylcyclohex-2-en-1-one (10e):[18] Following the general pro-
cedure (see Table 2, Entry 8), 1a (100 mg, 1.04 mmol), catalyst 7
(31 mg, 0.20 mmol), Cs2CO3 (678 mg, 2.08 mmol), and methyl iod-
ide (221 mg, 1.56 mmol) gave the crude product that was purified
by column chromatography (hexane/ethyl acetate, 9:1) to afford 10e
1
(96 mg, 65%) as a colorless oil. H NMR (400 MHz, CDCl3): δ =
1.69 (d, J = 1.8 Hz, 3 H, CH3), 1.91 (q, J = 6.5 Hz, 2 H, CH2),
2.19–2.31 (m, 2 H, CH2), 2.39 (t, J = 6.5 Hz, 2 H, CH2), 6.71–6.73 (CO) ppm. IR (NaCl): ν = 2965, 2929, 2857, 1727 (N-CO-O), 1678
˜
(m, 1 H, =CH) ppm. Compound 10e is a known compound.[18]
(C=O), 1624 (C=C) cm–1. C11H15NO3 (209.24): calcd. C 63.14, H
7.23, N 6.69; found C 63.29, H 7.13, N 6.82.
2-Benzylcyclohex-2-en-1-one (10f):[19] Following the general pro-
cedure (see Table 2, Entry 9), 1a (100 mg, 1.04 mmol), catalyst 7
1-Allyl-2,3-dihydro-1H-pyridin-4-one (18b): Following the general
(31 mg, 0.20 mmol), Cs2CO3 (678 mg, 2.08 mmol), and benzyl procedure (see Table 3, Entry 2), 2b (90 mg, 0.53 mmol), catalyst 7
bromide (267 mg, 1.56 mmol) gave the crude product that was puri-
fied by column chromatography (hexane/ethyl acetate, 9:1) to af-
ford 10f (75 mg, 45%) as a colorless oil. 1H NMR (400 MHz,
(17 mg, 0.11 mmol), Cs2CO3 (345 mg, 1.06 mmol), and allyl brom-
ide (97 mg, 0.80 mmol) gave the crude product that was purified
by column chromatography [gradient of hexane/ethyl acetate (9:1)
1
CDCl3): δ = 1.95–2.01 (m, 2 H, CH2), 2.33–2.40 (m, 2 H, CH2), to ethyl acetate] to afford 18b (11 mg, 15%) as a colorless oil. H
2.47–2.50 (m, 2 H, CH2), 3.51 (br. d, J = 1.3 Hz, 2 H, CH2), 6.55
NMR (400 MHz, CDCl3): δ = 2.50 (t, J = 7.9 Hz, 2 H, CH2), 3.44
(t, J = 4.2 Hz, 1 H, =CH), 7.10–7.22 (m, 3 H, ArH), 7.25–7.35 (m, (t, J = 7.9 Hz, 2 H, CH2), 3.78 (d, J = 5.7 Hz, 2 H, CH2), 4.98 (d,
2 H, ArH) ppm. Compound 10f is a known product.[19]
Ethyl 3,4-Dihydro-4-oxo-5-[(2E)-3-phenylprop-2-en-1-yl]-2H-pyr-
idine-1-carboxylate (19a): Following the general procedure (see
Table 3, Entry 1) 2b (90 mg, 0.53 mmol), catalyst (17 mg,
J = 7.5 Hz, 1 H, =CH), 5.27–5.31 (m, 2 H, =CH2), 5.78–5.86 (m,
1 H, =CH), 7.03 (d, J = 7.5 Hz, 1 H, =CH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 35.6 (CH2), 46.8 (CH2), 58.3 (CH2), 98.5
(CH), 119.1 (CH2), 132.5 (CH), 154.0 (CH), 191.6 (CO) ppm. IR
7
(NaCl): ν = 2966, 2921, 2850, 1646 (C=O), 1597 (C=C) cm–1. MS
˜
0.11 mmol), Cs2CO3 (345 mg, 1.06 mmol), and cinnamyl bromide
(158 mg, 0.80 mmol) gave the crude product that was purified by
column chromatography (hexane/ethyl acetate, 9:1) to afford 19a
(ESI): m/z = 138 [M + H]+. C8H11NO (137.18): calcd. C 70.04, H
8.08, N 10.21; found C 70.15, H 7.99, N 10.05.
1
(68 mg, 45%) as a colorless oil. H NMR (400 MHz, CDCl3): δ =
Ethyl 5-(But-2-ynyl)-3,4-dihydro-4-oxo-2H-pyridine-1-carboxylate
1.34 (t, J = 7.1 Hz, 3 H, CH3), 2.59 (t, J = 7.2 Hz, 2 H, CH2), 3.10 (19c): Following the general procedure (see Table 3, Entry 3), 2b
(d, J = 6.9 Hz, 2 H, CH2), 4.01 (t, J = 7.2 Hz, 2 H, CH2), 4.28 (q,
J = 7.1 Hz, 2 H, CH2), 6.21 (dt, J = 15.8 Hz, J = 7.0 Hz, 1 H,
=CH), 6.43 (d, J = 15.8 Hz, 1 H, =CH), 7.20–7.35 (m, 5 H, ArH),
7.75 (s, 1 H, =CH) ppm. 13C NMR [100 MHz, deuterated dimethyl
(90 mg, 0.53 mmol), catalyst 7 (17 mg, 0.11 mmol), Cs2CO3
(345 mg, 1.06 mmol), and 1-bromo-2-butyne (106 mg, 0.80 mmol)
gave the crude product that was purified by column chromatog-
raphy (hexane/ethyl acetate, 9:1) to afford 19c (47 mg, 40%) as a
sulfoxide ([D6]DMSO)]: δ = 14.2 (CH3), 29.7 (CH2), 35.3 (CH2), colorless oil. 1H NMR (400 MHz, CDCl3): δ = 1.36 (t, J = 7.1 Hz,
42.2 (CH2), 62.8 (CH2), 116.2 (C), 125.9 (CH2), 127.0 (CH), 128.3 3 H, CH3), 1.84 (t, J = 2.6 Hz, 3 H, CH3), 2.58 (t, J = 7.4 Hz, 2
(CH), 128.5 (CH), 130.4 (CH), 137.0 (C), 140.8 (CH), 152.5 (COO),
H, CH2), 3.11 (dd, J = 1.4 Hz, J = 3.8 Hz, 2 H, CH2), 4.01 (t, J =
7.3 Hz, 2 H, CH2), 4.31 (dd, J = 7.1 Hz, J = 21.4 Hz, 2 H, CH2),
8.06 (s, 1 H, =CH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
192.4 (CO) ppm. IR (NaCl): ν = 2965, 2929, 1727 (N-CO-O), 1628
˜
(C=O), 1547 (C=C) cm–1. MS (ESI): m/z = 286 [M + H]+, 287 [M
Eur. J. Org. Chem. 2014, 1935–1941
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1939

A. Gradillas, E. Belmonte, R. F. da Silva, J. Pérez-Castells
FULL PAPER
Ed. 2007, 46, 4614–4628; h) J. Mansilla, J. M. Saa, Molecules
2010, 15, 709–734; i) Y. Wei, M. Shi, Chem. Rev. 2013, 113,
6659–6690; j) Y. Wei, M. Shi, Acc. Chem. Res. 2010, 43, 1005–
1018.
For reviews, see: a) Y.-L. Shi, M. Shi, Eur. J. Org. Chem. 2007,
2905–2916; b) V. Declerck, J. Martinez, F. Lamaty, Chem. Rev.
2009, 109, 1–48.
For a review, see: C. E. Aroyan, A. Dermenci, S. J. Miller, Tet-
rahedron 2009, 65, 4069–4084; and also see: R. Kumar, T. Ku-
mar, S. M. Mobin, I. N. N. Namboothiri, J. Org. Chem. 2013,
78, 5073–5077.
a) J. W. Cran, M. E. Krafft, K. A. Seibert, T. F. N. Haxell, J. A.
Wright, C. Hirosawa, K. A. Abboud, Tetrahedron 2011, 67,
9922–9943; b) M. E. Krafft, T. F. N. Haxell, K. A. Seibert,
K. A. Abboud, J. Am. Chem. Soc. 2006, 128, 4174–4175; c)
M. E. Krafft, T. F. N. Haxell, J. Am. Chem. Soc. 2005, 127,
10168–10169; d) M. E. Krafft, K. A. Seibert, T. F. N. Haxell,
C. Hirosawa, Chem. Commun. 2005, 5772–5774; e) M. E.
Krafft, K. A. Seibert, Synlett 2006, 3334–3336; f) M. E. Krafft,
K. A. Seibert, T. F. N. Haxell, Synlett 2010, 2583–2588; g) D.
Basavaiah, N. Kumaragurubaran, D. S. Sharada, Tetrahedron
Lett. 2001, 42, 85–87.
3.1 (CH3), 14.1 (CH3), 16.3 (CH2), 35.1 (CH2), 42.1 (CH2), 62.9
(CH2), 75.9 (C), 78.6 (C), 113.2 (C), 140.6 (CH), 152.2 (COO),
191.7 (CO) ppm. IR (NaCl): ν = 2965, 2920, 2852 (C), 1732 (N-
˜
CO-O), 1673 (C=O), 1619 (C=C) cm–1. C12H15NO3 (221.26): calcd.
C 65.14, H 6.83, N 6.33; found C 65.20, H 6.93, N 6.55.
[3]
[4]
1-(But-2-yn-1-yl)-2,3-dihydro-1H-pyridin-4-one (18c): Following the
general procedure (see Table 3, Entry 3), 2b (90 mg, 0.53 mmol),
catalyst 7 (17 mg, 0.11 mmol), Cs2CO3 (345 mg, 1.06 mmol), and
1-bromo-2-butyne (106 mg, 0.80 mmol) gave the crude product that
was purified by column chromatography [gradient of hexane/ethyl
acetate (9:1) to ethyl acetate] to afford 18c (20 mg, 25%) as a color-
less oil. 1H NMR (400 MHz, CDCl3): δ = 1.86 (t, J = 2.4 Hz, 3 H,
CH3), 2.52 (t, J = 8.0 Hz, 2 H, CH2), 3.48 (t, J = 8.0 Hz, 2 H,
CH2), 3.89 (dd, J = 2.4 Hz, J = 7.16 Hz, 2 H, CH2), 5.05 (d, J =
7.6 Hz, 1 H, =CH), 7.09 (d, J = 7.6 Hz, 1 H, =CH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 3.5 (CH3), 35.7 (CH2), 45.3 (CH2), 47.1
[5]
(CH ), 100.0 (CH), 153.4 (CH), 191.9 (CO) ppm. IR (NaCl): ν =
˜
2
2971, 2926, 2854, 1660 (C=O), 1597 (C=C) cm–1. C9H11NO
(149.19): calcd. C 72.46, H 7.43, N 9.39; found C 72.78, H 7.05, N
9.11.
[6]
[7]
a) M. E. Krafft, J. A. Wright, Chem. Commun. 2006, 2977–
2979; b) K. Biswas, C. Borner, J. Gimeno, P. J. Goldsmith, D.
Ramazzotti, A. L. K. So, S. Woodward, Tetrahedron 2005, 61,
1433–1442.
Ethyl 3,4-Dihydro-5-methyl-4-oxo-2H-pyridine-1-carboxylate (19e):
Following the general procedure (see Table 3, Entry 5), 2b (90 mg,
0.53 mmol), catalyst 7 (17 mg, 0.11 mmol), Cs2CO3 (345 mg,
1.06 mmol), and methyl iodide (114 mg, 0.80 mmol) gave the crude
product that was purified by column chromatography (hexane/ethyl
acetate, 9:1) to afford 19e (68 mg, 70%) as a colorless oil. 1H NMR
(400 MHz, [D6]DMSO): δ = 1.19 (t, J = 7.1 Hz, 3 H, CH3), 1.58
(d, J = 1.1 Hz, 3 H, CH3), 2.41 (t, J = 7.3 Hz, 2 H, CH2), 3.83 (t,
J = 7.2 Hz, 3 H, CH2), 4.13 (q, J = 7.1 Hz, 2 H, CH2), 7.67 (s, 1
H, =CH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 12.6 (CH3),
14.2 (CH3), 35.3 (CH2), 42.2 (CH2), 62.7 (CH2), 113.6 (C), 140.0
For a review, see: a) T. Kataoka, H. Kinoshita, Eur. J. Org.
Chem. 2005, 45–58, and also see: T. Kataoka, T. Iwama, S.-i.
Tsujiyama, T. Iwamura, S.-i. Watanabe, Tetrahedron 1998, 54,
11813–11824; b) T. Kataoka, T. Iwama, S.-i. Tsujiyama, Chem.
Commun. 1998, 197–198; c) J. S. Rao, J. F. Brière, P. Metzner,
D. Basavaiah, Tetrahedron Lett. 2006, 47, 3553–3556; d) D. Ba-
savaiah, K. Muthukumaran, B. Sreenivasulu, Synlett 1999,
1249–1250; e) L. M. Walsh, C. L. Winn, J. M. Goodman, Tet-
rahedron Lett. 2002, 43, 8219–8222; f) T. Bauer, J. Tarasiuk,
Tetrahedron: Asymmetry 2001, 12, 1741–1745; g) R. Pathak,
A. K. Shaw, A. P. Bhaduri, Tetrahedron 2002, 58, 3535–3541.
a) V. K. Aggarwal, A. M. M. Castro, A. Mereu, H. Adams,
Tetrahedron Lett. 2002, 43, 1577–1581; b) M. Shi, Y.-M. Xu,
Tetrahedron: Asymmetry 2002, 13, 1195–1200.
(CH), 152.4 (COO), 193.2 (CO) ppm. IR (NaCl): ν = 2960, 2924,
˜
1718 (N-CO-O), 1669 (C=O), 1619 (C=C) cm–1. MS (ESI): m/z =
184 [M + H]+. C9H13NO3 (183.21): calcd. C 59.00, H 7.15, N 7.65;
found C 59.11, H 7.05, N 7.55.
[8]
[9]
C. E. Aroyan, S. J. Miller, J. Am. Chem. Soc. 2007, 129, 256–
257.
S. Villar, A. Gradillas, G. Domínguez, J. Pérez-Castells, Org.
Lett. 2010, 12, 2418–2421.
For a recent contribution about using γ-lactams as substrates,
see: J. Zhang, X. Liu, X. Ma, R. Wang, Chem. Commun. 2013,
49, 3300–3302.
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra for MBH products.
[10]
[11]
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra for 10a–d, 13a, 15c, 18a–c, 19a–c
and 19e.
[12]
a) R. Sebesta, M. G. Pizzuti, A. J. Boersma, A. J. Minnaard,
B. L. Feringa, Chem. Commun. 2005, 1711–1713; b) D. L.
Comins, G. Chung, M. A. Foley, Heterocycles 1994, 37, 1121–
1140.
Acknowledgments
[13]
[14]
a) J. S. Hill, N. S. Isaacs, J. Phys. Org. Chem. 1990, 3, 285–293;
b) D. Basavaiah, P. K. Sarma, Synth. Commun. 1990, 20, 1611–
Funding of this project by the Spanish Ministerio de Economía y
Competitividad (MINECO) (project number CTQ2012-31063) is
acknowledged. R. F. da S. thanks Airbus Military for a predoctoral
fellowship.
1615; see ref.[10]
.
a) T. Kataoka, T. Lwama, S. Tsujiyama, K. Kanematsa, T.
Lwamura, S. Watanabe, Chem. Lett. 1999, 257–258; b) T.
Iwama, S. Tsujiyama, H. Kinoshita, K. Kanematsu, Y. Tsuru-
kami, T. Iwamura, S. Watanabe, T. Kataoka, Chem. Pharm.
Bull. 1999, 47, 956–961.
S. Luo, X. Mi, P. G. Wang, J.-P. Cheng, J. Org. Chem. 2004,
69, 8413–8422.
G. Kumaraswamy, D. Rambabu, Tetrahedron Lett. 2012, 53,
1042–1044.
R. Shintani, N. Tokunaga, H. Doi, T. Hayashi, J. Am. Chem.
Soc. 2004, 126, 6240–6241.
[1] The Chemistry of the Morita–Baylis–Hillman Reaction (Eds.:
M. Shi, F.-J. Wang, M. X. Zhao, Y. Wei), The Royal Society of
Chemistry, Cambridge, 2011, Catalyst Series No. 8.
[15]
[16]
[17]
[18]
[2] For reviews, see: a) D. Basavaiah, K. V. Rao, R. J. Reddy,
Chem. Soc. Rev. 2007, 36, 1581–1588; b) D. Basavaiah, G. Veer-
araghavaiah, Chem. Soc. Rev. 2012, 41, 68–78; c) D. Basavaiah,
A. J. Rao, T. Satyanarayana, Chem. Rev. 2003, 103, 811–891;
d) P. Langer, Angew. Chem. 2000, 112, 3177; Angew. Chem. Int.
Ed. 2000, 39, 3049–3052; e) V. Singh, S. Batra, Tetrahedron
2008, 64, 4511–4574; f) G.-N. Ma, J.-J. Jiang, M. Shi, Y. Wei,
Chem. Commun. 2009, 5496–5514; g) G. Masson, C. Housse-
man, J. Zhu, Angew. Chem. 2007, 119, 4698; Angew. Chem. Int.
D. H. Mac, R. Samineni, J. Petrignet, P. Srihari, S. Chandrase-
khar, J. S. Yadav, R. Grée, Chem. Commun. 2009, 31, 4717–
4719.
[19]
K. Hogenauer, J. Mulzer, Org. Lett. 2001, 3, 1495–1497.
1940
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1935–1941

Hydroxy Chalcogenide-Promoted Morita–Baylis–Hillman Alkylation
[20]
[23] J. D. Kim, M. H. Lee, M. J. Lee, Y. H. Jung, Tetrahedron Lett.
2000, 41, 5073–5076.
K. Dudzinski, A. M. Pakulska, P. Kwiatkowski, Org. Lett.
2012, 14, 4222–4225.
[24] A. Inesi, V. Mucciante, L. Rossi, J. Org. Chem. 1998, 63, 1337–
[21] C. R. Larsen, D. B. Grotjahn, J. Am. Chem. Soc. 2012, 134,
1338.
10357–10360.
[25] T. Diao, S. S. Stahl, J. Am. Chem. Soc. 2011, 133, 14566–14569.
Received: November 20, 2013
[22] Y. Ashikari, T. Nokami, J. Yoshida, J. Am. Chem. Soc. 2011,
133, 11840–11843.
Published Online: January 17, 2014
Eur. J. Org. Chem. 2014, 1935–1941
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1941