Morita-Baylis-Hillman reaction of lactams and lactones with alkyl halides and epoxides catalyzed by hydroxysulfides

Article abstract of DOI:10.1021/ol100788g

A new Morita-Baylis-Hillman reaction methodology in which alkyl halides and epoxides act as electrophiles in their reaction with lactones and lactams is shown. Catalysis is efficiently performed by hydroxy sulfides under basic conditions. The procedure works efficiently with many alkyl halides but fails with aldehydes with which a conventional acid-catalyzed procedure is used.

Full text of DOI:10.1021/ol100788g

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2418-2421
Morita-Baylis-Hillman Reaction of
Lactams and Lactones with Alkyl
Halides and Epoxides Catalyzed by
Hydroxysulfides
Irene Suarez del Villar, Ana Gradillas, Gema Dom´ınguez, and
Javier Pe´rez-Castells*
Facultad de Farmacia, Dpto. Qu´ımica, UniVersidad San Pablo CEU, Urb.
Montepr´ıncipe, ctra. Boadilla km 5, 300 Boadilla del Monte, 28668 Madrid, Spain
jpercas@ceu.es
Received April 6, 2010
ABSTRACT
A new Morita-Baylis-Hillman reaction methodology in which alkyl halides and epoxides act as electrophiles in their reaction with lactones
and lactams is shown. Catalysis is efficiently performed by hydroxy sulfides under basic conditions. The procedure works efficiently with
many alkyl halides but fails with aldehydes with which a conventional acid-catalyzed procedure is used.
The Morita-Baylis-Hillman reaction (MBH) can be defined
as a reaction between the R position of an activated alkene and
an electrophile that generally contains an sp2 electron-deficient
carbon atom, catalyzed most times by a tertiary amine. The
generally accepted mechanism consists of a Michael addition
and subsequent elimination of the amine.1
Typical substrates for the MBH reaction are activated
alkenes like alkyl vinyl ketones, alkyl acrylates, acrylonitrile,
vinyl sulfones, acrylamides, allenic esters, vinyl sulfonates,
vinyl phosphonates, and acrolein. As electrophiles, aldehydes
have been exhaustively studied in the MBH reaction. In
addition, R-keto esters, diketones, activated alkenes, and
amidines give MBH adducts. In particular, imines also can
take part in the reaction if they are activated adequately. In
this case, the process is called aza-Morita-Baylis-Hillman.2
DABCO is the most widely used catalyst, but other tertiary
amines such as DBU or quinuclidine and phosphines can
also catalyze the reaction.3 The asymmetric version is carried
out mostly using chiral amines.4
Sulfur-containing catalysts are able to mediate in MBH
reactions, although they have been scarcely used. The first
studies of MBH reactions with sulfur catalysts were realized
in 1998 by Kataoka.5 This group described the reaction of
catalytic sulfides and stoichiometric quantities of Lewis acid
TiCl4 to carry out MBH reactions between a Michael
acceptor and an aldehyde. The asymmetric version of the
MBH reaction catalyzed by sulfur compounds has been used
(1) Reviews: (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem.
ReV. 2003, 103, 811–891. (b) Singh, V.; Batra, S. Tetrahedron 2008, 64,
4511–4574. (c) Basavaiah, D.; Rao, K.; Venkateswara, R.; Raju, J. Chem.
Soc. ReV. 2007, 36, 1581–1588. (d) Basavaiah, D.; Rao, P. D.; Hyma, R. S.
Tetrahedron 1996, 52, 8001–8062.
(2) Reviews on aza-MBH: (a) Declerck, V.; Martinez, J.; Lamaty, F.
Chem. ReV. 2009, 109, 1–48. (b) Shi, Y. S.; Shi, M. Eur. J. Org. Chem.
2007, 2905–2916.
(3) For recent appications of phosphine-catalyzed MBH-type reactions,
see: (a) Webber, P.; Krische, M. J. J. Org. Chem. 2008, 73, 9379–9387.
(b) Koech, P. K.; Krische, M. J. Tetrahedron 2006, 62, 10594–10602. (c)
Koech, P. K.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 5350–5351. (d)
Jellerich, B. G.; Kong, J.-R.; Krische, M. J. J. Am. Chem. Soc. 2003, 125,
7758–7759.
(4) (a) Krishna, P. R.; Sachwani, R.; Reddy, P. Synlett 2008, 289, 7–
2912. (b) Masson, G.; Housseman, C.; Zhu, J. Angew. Chem., Int. Ed. 2007,
46, 4614–4628.
(5) (a) Kataoka, T.; Iwama, T.; Tsujiyama, S.-I. Chem. Commun. 1998,
197–198. (b) Kataoka, T.; Iwama, T.; Tsujiyama, S.-I.; Iwamura, T.;
Watanabe, S.-I. Tetrahedron 1998, 54, 11813–11824.
10.1021/ol100788g  2010 American Chemical Society
Published on Web 04/23/2010

for the synthesis of allylic chiral alcohols.6 Kataoka used
several chiral sulfides and selenides that contained a hydroxy
group or an ether. They achieved low enantiomeric excesses,
and in some cases, the yields were low. The authors attributed
the low yields to the formation of titanium alkoxides that
disabled the MBH.7 Miller recently reported the use of sulfur-
based nucleophiles in asymmetric Rauhut-Currier reactions8
also developed by Krische wherein tethered enones serve as
electrophiles.9
carbonate as the base to study the competition between the
MBH and the cyclopropanation reactions. The reaction with
1a led to the [2,3]-sigmatropic reorganization product 3
together with starting material (Scheme 1).10 On the other
Scheme 1. Reaction of Lactam 2a with Sulfonium Salts
Alkyl halides have only been used as electrophiles in
the MBH reaction in a few works, in which it is said that
they have a poor reactivity. The first example is due to
Basavaiah’s group and consisted of an intermolecular
reaction of an allyl halide, 2-bromomethyl-2-propenoate,
and various Michael acceptors.10 On the other hand, in
the second precedent, Krafft’s group developed the
synthesis of cyclic 5- and 6-membered ketones from
chlorides derived from primary and secondary allylic
alcohols through an intramolecular MBH reaction.11
Therefore, the intermolecular sulfide catalyzed MBH
reaction, using alkyl bromides as electrophiles and lactams
or lactones as substrates, lacks precedent.
In the present study, we describe the behavior of lactams
and lactones in their MBH reactions with alkyl halides and
epoxides using sulfides as catalysts. Several studies have
demonstrated that the formation of a hydrogen bond in the
reaction intermediate can favor the reaction rate. A good
example of this consisted of the introduction of a hydroxy
group at the terminal position of alkyl acrylates in their
reaction with benzaldehyde using DABCO as catalyst.12 We
envisioned the possibility of using sulfides bearing a suitable
situated hydroxy group to promote the MBH reaction using
alkyl halides as electrophiles. We used basic conditions to
aid in the elimination of the sulfide avoiding the presence
of Lewis acids. In principle, the main problem could be the
competence with a cyclopropanation reaction that uses
similar reaction conditions.13
hand, the reaction with 1b provided the MBH adduct with a
moderate yield, recovering 36% of 2a not detecting any
cyclopropanation products (Scheme 1, Table 1, entry 1).
Although this preliminary result was not completely satisfac-
tory, it encouraged us in searching for new conditions, if
possible catalytic, that improved the yields. Thus, we carried
out the reaction of 2a with 0.2 equiv of sulfonium salt 1b and
1.5 equiv of 3-phenylallyl bromide. The temperature was
determinant in this reaction since at 0 °C only 15% of the final
product was formed (Table 1, entry 2), whereas at 80 °C the
yield raised to 56% (entry 3). With substrate 2b, a low yield
was observed at room temperature (entry 4, 38%) that increased
to 65% at 80 °C (entry 5). The next step was verifying the
behavior of sulfide 5 as the catalyst. The reaction of compound
2b with 0.2 equiv of 5 provided the product 4b with good yield
(entry 6, 75%), which became excellent on prolonging the
reaction time to 12 h (entry 7, 89%). Then, we verified the
crucial role of the base. The reaction in the absence of cesium
carbonate scarcely took place though the product was detected
in the crude mixture (entry 8). An essential question in this
development was to justify the need of the presence of the
hydroxyl group on the catalyst. When we used ketone 6 as
catalyst, only starting material was recovered (entries 9 and 10).
In addition, THT proved to be unable to catalyze this reaction
as no conversion was observed even with stoichiometric
quantities of this reagent (entries 11 and 12). Finally, the
conditions of entry 6, applied to compound 2a, gave 4a in high
yield (entry 13, 85%).
The sulfonium salts 1a,b, described by Tang, were selected
as their synthesis was straightforward and their chirality could
be used further to induce asymmetry in the reaction with
aldehydes or imines.10 We performed the reaction of lactam
2a with an excess of these sulfonium salts, using cesium
(6) Langer, P. Angew. Chem., Int. Ed. 2000, 39, 3049–3052.
(7) (a) Kataoka, T.; Kinoshita, H.; Iwama, T.; Tsujiyama, S.-I.; Iwamura,
T.; Watanabe, S.-I.; Muraokab, O.; Tanabe, G. Tetrahedron 2000, 56, 4725–
4731. (b) Iwama, T.; Tsujiyama, S.; Kinoshita, H.; Kanematsu, K.;
Tsurukami, Y.; Iwamura, T.; Watanabe, S.-I.; Kataoka, T. Chem. Pharm.
Bull. 1999, 47, 956–961. (c) Kataoka, T.; Iwama, T.; Tsujiyama, S.;
Kanematsu, K.; Iwamura, T.; Watanabe, S.-I. Chem. Lett. 1999, 257–258.
(8) Aroyan, C. E.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 256–257.
(9) Wang, L.-C.; Luis, A. L.; Agapiou, K.; Jang, H.-Y.; Krische, M. J.
J. Am. Chem. Soc. 2002, 124, 2402–2403.
(10) (a) Basavaiah, D.; Sharada, D. S.; Kumaragurubaran, N.; Reddy,
R. M. J. Org. Chem. 2002, 67, 7135–7137. (b) Basavaiah, D.; Kumaragu-
rubaran, N.; Sharada, D. S. Tetrahedron Lett. 2001, 42, 85–87.
(11) (a) Krafft, M. E.; Haxell, T. F. N. J. Am. Chem. Soc. 2005, 127,
10168–10169. (b) Krafft, M. E.; Seibert, K. A. Synlett 2006, 3334–3336.
(c) Krafft, M. E.; Seibert, K. A.; Haxell, T. F. N.; Hirosawa, C. Chem.
Commun. 2005, 5772–5774. (d) Krafft, M. E.; Haxell, T. F. N.; Seibert,
K. A.; Abboud, K. A. J. Am. Chem. Soc. 2006, 128, 4174–4175.
(12) (a) Hill, J. S.; Isaacs, N. S. J. Phys. Org. Chem. 1990, 285–293.
(b) Basavaiah, D.; Sarma, P. K. Synth. Commun. 1990, 20, 1611–1615.
(13) Ye, S.; Huang, Z. Z.; Xia, C.-A.; Tang, Y.; Dai, L.-X. J. Am. Chem.
Soc. 2002, 124, 2432–2433.
After this initial work, we studied the scope of the
process so that we reacted compound 2b with various alkyl
Org. Lett., Vol. 12, No. 10, 2010
2419

Table 1. Reaction Conditions for the MBH Reaction of
Lactams 2a,b
Table 2. MBH Reaction of Lactones and Lactams with
Different Electrophiles
yield (%)
(°C) 2a,b 4a,b
Cs2CO3 time temp
entry
P
cat. (equiv) (equiv)
(h)
1
2
3
4
5
6
7
8
9
10
11
12
13
Boc 1b (1.2)a
Boc 1b (0.2)
Boc 1b (0.2)
2
2
2
2
2
2
2
96
24
2
36
2
rt
0
80
rt
80
80
80
80
80
80
80
80
80
44
70
10
50
5
36
15
56
38
65
75
89
<5
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
1b (0.2)
1b (0.2)
5 (0.2)
5 (0.2)
5 (0.2)
2
12
96
12
12
12
12
2
90
100
98
100
80
6 (0.2)
6 (0.2)
2
2
2
2
THTb (0.2)
THTb (1.2)
Boc 5 (0.2)
85
a Conditions: 1.5 equiv of 3-phenylallyl bromide (except for entry1, in
which no halide was added), CH3CN/tBuOH (2.5:1) as solvent. b THT )
tetrahydrothiophene.
halides under our best conditions (entry 7, Table 1).14 The
results are summarized in Table 2. The reaction with allyl
bromide, benzyl bromide, and methyl iodide gave products
4c, 4d, and 4e with good yields (entries 1-3). In the case
of cyclopropyl bromide (entry 4), though we tried different
conditions, changing the temperature and the reaction time,
we were not able to obtain any positive results, always
recovering the starting material. Propargyl bromide did
not react, possibly due to interference of the hydrogen of
the triple bond. Moreover, 2-butyne bromide gave the
desired adduct 4f with good yield (entries 5 and 6). On
the other hand, since the epoxides are excellent electro-
philes, we studied the reaction of 2b with propylene oxide,
which provided product 4g with 63% yield (entry 7),
whereas we could not detect any products in the reaction
with styrene oxide (entry 8).15 Finally, we applied the
reaction to lactones, in particular, 5,6-dihydro-2-pyranone
and 2-(5H)-furanone (entries 9 and 10), obtaining the
MBH aducts 4h,i with acceptable yields. In these cases,
no starting product was recovered.
(14) General Procedure for the MBH Reaction with Alkyl Halides.
To a solution of the catalyst 5 (0.2 equiv) and the R,ꢀ-unsaturated lactone
or lactam (1 equiv) in CH3CN/tBuOH (2.5:1) were added Cs2CO3 (2 equiv)
and the electrophile (1.5 equiv). The resulting mixture was heated to 40 °C
and stirred until the reaction was complete (TLC). The solvent was then
eliminated under vacuo, and the resulting crude oil was purified by column
chromatography on silica gel. Synthesis of 1-[(4-methylphenyl)sulfonyl]-
3-[(2E)-3-phenyl-2-propen-1-yl]-5,6-dihydro-(1H)-2-pyridinone, 4b. Fol-
lowing the general procedure (Table 1, entry 7), from compound 2b 50 mg
(0.19 mmol), (E)-3-bromo-1-phenylpropene (56 mg, 0.3 mmol), and 8 mg
of 5 (0.03 mmol), reaction time 12 h at 80 °C, 64 mg (89%) of 4b was
obtained as a colorless oil (hexane/EtOAc, 4:1). 1H NMR (300 MHz,
CDCl3): δ 2.39 (s, 3H, CH3); 2.50 (d, 2H, J ) 4.9 Hz, CH2); 3.06 (d, 2H,
J ) 7.3 Hz, CH2); 4.43 (t, 2H, J ) 6.3 Hz, CH2); 6.06-6.14 (m, 1H, CHd);
6.33 (d, 1H, J ) 16.1 Hz, CHd); 6.53-6.56 (m, 1H, CHd); 7.18-7.31
(m, 7H, ArH); 7.91 (d, 2H, J ) 8.3 Hz, ArH). 13C NMR (75 MHz, CDCl3)
δ 21.6, 25.1, 32.9, 44.1, 126.0, 126.3, 127.2, 128.4, 128.5, 129.4, 132.4,
134.3, 136.0, 137.0, 139.3, 144.6, 163.8. IR (film) 3010, 2920, 1800, 1680,
1590, 1489, 1462, 1440, 1345, 1278, 1160, 1100 cm-1. Anal. Calcd for
C21H21NO3S (367.46): C, 68.64; H, 5.76; N, 3.81. Found: C, 68.56; H, 5.57;
N, 3.65.
Finally we explored the feasibility of our procedure for
the synthesis of MBH adducts using aldehydes as electro-
philes. As aromatic aldehydes bearing electron-withdrawing
groups are those that react better in these reactions, we
selected p-nitrobenzaldehyde which was reacted with 2b
(Scheme 2). Under our experimental conditions the MBH
reaction did not take place, so we used a Lewis acid to
activate the aldehyde instead of the base. Thus, in the
(15) The only precedent in the use of epoxides in MBH reactions is an
intramolecular phosphine-catalyzed reaction: Krafft, M. E.; Wright, J. A.
Chem. Commun. 2006, 2977–2979.
2420
Org. Lett., Vol. 12, No. 10, 2010

In conclusion, a new MBH methodology where alkyl
halides and epoxides act as electrophiles in their reaction
with lactones and lactams is shown. Catalysis is efficiently
performed by hydroxy sulfides. Extension of this proce-
dure to other substrates is underway in our laboratories.
Scheme 2. MBH Reaction of 2b with p-Nitrobenzaldehyde
Acknowledgment. Funding of this project by the Spanish
MEC (No. CTQ2009-007738/BQU) and FUSP-CEU (PC16/
09) is acknowledged. I.S.-V. thanks the Fundacio´n San
Pablo-CEU for a predoctoral fellowship.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and spectra for compounds
4a,c-i and 7. This material is available free of charge via
the Internet at http://pubs.acs.org.
presence of 1.5 equiv of TiCl4 at 40 °C we obtained a 57%
of the MBH adduct 7, observing hardly no induction.16
(16) The ee was 3%, determined by HPLC using a CHIRAL-AGP
column (100 × 4.0 mm); with 9% 2-propanol in 10 mM sodium phosphate
buffer as mobile phase; pH ) 7.0; flow rate ) 0.9 mL/min.
OL100788G
Org. Lett., Vol. 12, No. 10, 2010
2421