Baylis-Hillman reaction of cyclic enones with arenecarbaldehydes and N-arylidene-4-methylbenzenesulfonamides by using NAP-MgO

Article abstract of DOI:10.1055/s-2008-1077959

Baylis-Hillman reaction of cyclic enones with arenecarbaldehydes and N-arylidene-4-methylbenzenesulfonamides under mild conditions by using nanocrystalline MgO (NAP-MgO) afforded the Baylis-Hillman adducts in moderate to good yields with higher selectivit

Full text of DOI:10.1055/s-2008-1077959

1946
LETTER
Baylis–Hillman Reaction of Cyclic Enones with Arenecarbaldehydes and
N-Arylidene-4-methylbenzenesulfonamides by Using NAP-MgO
B
aylis–HillmanReacti
.
onof Cyclic
L
E
nones akshmi Kantam,*a L. Chakrapani,a B. M. Choudaryb
a
Inorganic & Physical Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160921; E-mail: mlakshmi@iict.res.in
b
Ogene Systemes (I) Private Limited, Balanagar, Hyderabad 500037, India
Received 11 January 2008
view of the ease of handling, simple workup and catalyst
recovery and recyclability.
Abstract: Baylis–Hillman reaction of cyclic enones with arene-
carbaldehydes and N-arylidene-4-methylbenzenesulfonamides un-
der mild conditions by using nanocrystalline MgO (NAP-MgO)
afforded the Baylis–Hillman adducts in moderate to good yields
with higher selectivity than the corresponding aldol products.
We herein report the use of nanocrystalline magnesium
oxide (NAP-MgO) for the Baylis–Hillman reaction of cy-
clic enones with arenecarbaldehydes and N-benzylidine-
4-methylbenzenesulfonamides which affords the Baylis–
Hillman adducts in moderate to good yields with high se-
lectivity under mild conditions (Scheme 1). Recently, our
group reported the synthesis of chiral epoxy ketones,
chiral nitro alcohols and Michael adducts, chiral b-hy-
droxy carbonyl compounds, flavanones, and a-diazo-b-
hydroxy esters using NAP-MgO.15
Keywords: Baylis–Hillman reaction, cyclic enones, NAP-MgO,
heterogeneous, solid base
Carbon–carbon bond formation is one of the most funda-
mental reactions in organic synthesis. The Baylis–Hill-
man reaction, which involves the coupling of activated
alkenes with carbon electrophiles in the presence of Lewis
base catalysts is particularly attractive as the resulting ad-
ducts serve as key synthetic intermediates for several bio-
logically active molecules.1 Baylis–Hillman reactions of
arenecarbaldehydes and a,b-unsaturated cyclic ketones
are very sluggish under the traditional reaction condi-
tions.2 Due to their low reactivity, cyclic enones have
been less explored among various classes of activated al-
kenes. Gaied et al. reported the Baylis–Hillman reaction
of cyclic enones with formaldehyde in aqueous media us-
ing DMAP as a catalyst.3 Later, several methods were de-
veloped for the Baylis–Hillman reaction involving cyclic
enones using imidazole,4 LiClO4 with DABCO,5 chalco-
genide–TiCl4,6 tributylphosphine with 1,1¢-bi-2-naph-
thol,7 lithium phenylselenide (PhSeLi),8 piperidine,9
pyrrolizidines10 and DBU.11 Recently, Li et al. reported
the Baylis–Hillman reaction of cyclic enones with various
aliphatic and aromatic aldehydes by using a Lewis acid in
the absence of a Lewis base.12 Shi et al. investigated the
Lewis base effects in the Baylis–Hillman reaction of
arenecarbaldehydes and N-benzylidine-4-methylbenzene-
sulfonamides with a,b-unsaturated cyclic ketones.13 Re-
cently, V. J. Rao et al. reported the synthesis of Baylis–
Hillman adducts using pyridinecarboxaldehyde deriva-
tives and cyclic enones.14
O
XH
O
NAP-MgO
MeOH, r.t.
R
RCH=X
+
n
n
n = 1 or 2
X = O, NTs
Scheme 1 Baylis–Hillman reaction of cyclic enones with arene-
carbaldehydes and N-arylidene-4-methylbenzenesulfonamides using
NAP-MgO
Various magnesium oxide crystals16 [commercial MgO,
CM-MgO (30 m2/g); conventionally prepared MgO,
NAP-MgO (252 m2/g); aero gel prepared NAP-MgO (590
m2/g)] were initially screened in the reaction of 4-ni-
trobenzaldehyde and cyclopent-2-en-1-one at room tem-
perature and NAP-MgO was found to be more active
when compared to the other crystalline forms of MgO
(Table 1). In the process of optimization of the reaction
conditions, we explored the use of various solvents such
as DMF, DMSO, MeOH, THF, MeCN, CH2Cl2 and tolu-
ene. The reaction proceeded well only in MeOH to give
the Baylis–Hillman adducts in good yields. Other protic
Table 1 Screening of Different Crystallites of MgO for the Reac-
tion of 4-Nitrobenzaldehyde and Cyclopent-2-en-1-onea
Although several methods have been developed, there are
many drawbacks of the homogeneous conditions includ-
ing catalyst recovery and waste disposal problems. Indus-
try favors catalytic processes induced by heterogeneous
catalysts over those induced by homogeneous catalysts in
Entry
Catalyst
Solvent
MeOH
MeOH
MeOH
Time (h) Yield (%)b
1
2
3
NAP-MgO
CP-MgO
CM-MgO
6
12
12
84
78
37
a Reaction conditions: 4-nitrobenzaldehyde (0.5 mmol), cyclopent-1-
en-1-one (1.0 mmol), catalyst (25 mg), MeOH (3 mL).
b Isolated yields.
SYNLETT 2008, No. 13, pp 1946–1948
Advanced online publication: 15.07.2008
DOI: 10.1055/s-2008-1077959; Art ID: D00508ST
x
x
.x
x
.2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

LETTER
Baylis–Hillman Reaction of Cyclic Enones
1947
solvents such as ethanol and isopropanol were unable to
promote the reaction under the same reaction conditions.
Table 2 Baylis–Hillman Reaction of Arenecarbaldehydes with Cy-
clic Enones using NAP-MgOa
O
O
O
OH
OH
A variety of aromatic aldehydes, containing electron-
withdrawing or -donating groups, heteroaromatic alde-
hydes and aliphatic aldehydes were subjected to the reac-
tion with cyclopent-2-en-1-one and the results are
summarized in Table 2. As expected the rate of reaction
was high for the aldehydes possessing electron-withdraw-
ing groups compared with the aldehydes bearing electron-
donating groups. That ortho-substituted aromatic alde-
hydes showed very little or no activity might be due to an
ortho steric effect (Table 2, entry 3). The heteroaromatic
aldehydes gave moderate to good yields of Baylis–Hill-
man product and the aliphatic aldehydes afforded poor
yields of the corresponding Baylis–Hillman adducts. In
few cases, the aldol product was obtained as a side prod-
uct in addition to the desired Baylis–Hillman product and
the results are included in Table 2. The effect of substitu-
ents on the cyclopent-2-en-1-one ring system was also
studied. The Baylis–Hillman reaction of 2-methyl- and 3-
methyl-substituted cyclopent-2-en-1-one with 4-nitro-
benzaldehyde under the same reaction conditions afford-
ed only the aldol product (Table 2, entries 15 and 16).
NAP-MgO
MeOH, r.t.
R
R
+
RCHO
+
n
n
n
1b
1a
n = 1 or 2
Entry Cyclic Aldehyde
enoneb (R)
Time
(h)
Yield
(%)c
Ref.
1a
1b
9
1
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
3
4
4
4
4
4
4-NO2Ph
3-NO2Ph
2-NO2Ph
4-CF3Ph
4-ClPh
Ph
6
6
84
4a
4b
13
4a
13
4b
13
4b
4b
4a
14
14
7
77
13
–
3
12
6
10
4
90, 86d
80
4
5
12
16
12
12
16
12
2
10
8
6
80
7
4-OMePh
4-MePh
4-Me2NPh
2-furyl
H1b
23
–
8
36
trace
–
9
trace
84
10
11
12
13
14
15
16
17
18
19
20
21
6
MeO
N
Cl
Ph
O
N
Cl
62
10
6
O
H1
H2
H2b
6
68
O
O
O
Et
18
18
12
12
24
24
24
24
24
12
–
i-Bu
10
–
4b
–
4-NO2Ph
4-NO2Ph
4-NO2Ph
3-NO2Ph
2-NO2Ph
Ph
–
16
20
–
1
2
3
4
–
–
Figure 1
25
4b
4b
4b
4b
4b
Subsequently, we have carried out the Baylis–Hillman re-
action of cyclohex-2-en-1-one with the arenecarbalde-
hydes under the same reaction conditions. The reaction
rates were slower than those of cyclopent-2-en-1-one and
only moderate yields of product were obtained. In these
cases the unreacted aldehydes were recovered by column
chromatography. The yields of the Baylis–Hillman prod-
ucts were improved by conducting the reaction at elevated
temperature (Table 2, entries 20 and 21).
23
–
N.R.
32 (60)e
15 (46)e
–
–
4-ClPh
–
a Reaction conditions: aldehyde (0.5 mmol), cyclic enone (1.0 mmol),
NAP-MgO (25 mg), MeOH (3 mL).
b See Figure 1.
c Isolated yields.
Later, we examined the reaction of N-benzylidine-4-
methylbenzenesulfonamides with cyclopent-2-en-1-one
in methanol at room temperature and Baylis–Hillman ad-
ducts were obtained in moderate to good yields without
any side product (Table 3, entries 1–6). This might be due
to the fact that aldol condensation reaction is difficult for
small cyclic ketones in the presence of Lewis bases.13
d Yield after third cycle.
e The values in parentheses are the isolated yields at 65 °C.
To understand the relationship between structure and re-
activity of the catalyst in detail, we need to know the
structure and nature of the reactive sites of NAP-MgO.16
NAP-MgO has a three-dimensional structure, which, hav-
ing high surface concentrations of edge/corner and vari-
ous exposed crystal planes (such as 002, 001, 111), leads
to an inherently high surface reactivity per unit area. Thus,
NAP-MgO indeed displayed the highest activity com-
pared to NA-MgO and CM-MgO. Moreover, the NAP-
We also examined the reaction of other N-benzylidine-4-
methylbenzenesulfonamides with cyclohex-2-en-1-one
using the same reaction conditions. Similar to aldehydes,
the reaction rates were slow with cyclohex-2-en-1-one
compared to cyclopent-2-en-1-one.
Synlett 2008, No. 13, 1946–1948 © Thieme Stuttgart · New York

1948
M. L. Kantam et al.
LETTER
Table 3 Baylis–Hillman Reaction of N-Arylidene-4-methylben-
References and Notes
zenesulfonamides with Cyclic Enones using NAP-MgOa
(1) (a) Mortia, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn.
1968, 41, 2815. (b) Basavaiah, D.; Rao, P. D.; Hyma, R. S.
Tetrahedron 1996, 52, 8001. (c) Fort, Y.; Berthe, M. C.
Tetrahedron 1992, 48, 6371. (d) Drewes, S. E.; Roos, G. H.
P. Tetrahedron 1988, 44, 4653.
O
O
NHTs
Ar
NAP-MgO
MeOH, r.t.
ArCH=NTs
+
n
n
(2) (a) Ciganek, E. Org. React. (N. Y.) 1997, 51, 201.
(b) Aggarwal, V. K.; Dean, D. K.; Mereu, A.; Williams, R.
J. Org. Chem. 2002, 67, 510.
(3) Gaied, M. M.; Rezgui, F. Tetrahedron Lett. 1998, 39, 5965.
(4) (a) Cheng, J.-P.; Luo, S.; Zhang, B.; Janczuk, A.; He, J.;
Wang, P. G. Tetrahedron Lett. 2002, 43, 7369. (b) Cheng,
J.-P.; Luo, S.; Wang, P. G. J. Org. Chem. 2004, 69, 555.
(5) Kobayashi, S.; Kawamura, M. Tetrahedron Lett. 1999, 40,
1539.
(6) (a) Kataoka, T.; Iwama, T.; Tsujiyama, S. Chem. Commun.
1998, 197. (b) Kataoka, T.; Iwama, T.; Tsujiyama, S.;
Iwamura, T.; Watanabe, S. Tetrahedron 1998, 54, 11813.
(7) Ikegami, S.; Yamada, Y. Tetrahedron Lett. 2000, 41, 2165.
(8) Jaunch, J. J. Org. Chem. 2001, 66, 609.
(9) Black, G. P.; Dinon, F.; Fratucello, S.; Murphy, P. J.;
Nielsen, M.; Williams, H. L. Tetrahedron Lett. 1997, 38,
8561.
Entry
n
1
1
1
2
2
2
R
Time (h)
Yield (%)b
1
2
3
4
5
6
4-O2NC6H4
4-ClC6H4
4-MeOC6H4
4-O2NC6H4
4-ClC6H4
4-MeOC6H4
6
6
82
80
12
18
24
24
58
66
46
20 (45)c
a Reaction conditions: N-arylidene-4-methylbenzenesulfonamide
(0.25 mmol), cyclic enone (1.0 mmol), NAP-MgO (25 mg), MeOH (3
mL).
b Isolated yields.
c The value in parentheses is the isolated yield at 65 °C.
(10) Barret, G. M.; Cook, A. S.; Kamimura, A. Chem. Commun.
1998, 2533.
MgO has Lewis acidic sites, Mg2+, Lewis basic sites O2–
and O–, lattice-bound and isolated Brønsted hydroxyl
groups and anionic and cationic vacancies. Baylis–Hill-
man reactions are known to be driven by both Lewis acids
and Lewis bases and accordingly, the Lewis base (O2–/
O–) of the catalyst activates the cyclic enone and the
Lewis acid moiety (Mg2+/Mg+) activates the carbonyls of
the aldehyde. Thus, Baylis–Hillman reaction proceeds via
dual activation of both substrates (nucleophiles and elec-
trophiles) by nanocrystalline MgO.
(11) Aggarwal, V. K.; Mereu, A. Chem. Commun. 1999, 2311.
(12) Li, G.; Wei, H.; Gao, J. J.; Caputo, T. D. Tetrahedron Lett.
2000, 41, 1.
(13) Shi, M.; Xu, Y.-M.; Zhao, G.-L.; Wu, X.-F. Eur. J. Org.
Chem. 2002, 3666.
(14) Narender, P.; Gangadasu, B.; Ravinder, M.; Srinivas, U.;
Swamy, G. Y. S. K.; Ravikumar, K.; Jayathirtha Rao, V.
Tetrahedron 2006, 62, 954.
(15) (a) Choudary, B. M.; Kantam, M. L.; Ranganath, K. V. S.;
Sreedhar, B. J. Am. Chem. Soc. 2004, 126, 3396.
(b) Choudary, B. M.; Ranganath, K. V. S.; Pal, U.; Sreedhar,
B. J. Am. Chem. Soc. 2005, 127, 13167. (c) Choudary, B.
M.; Chakrapani, L.; Ramani, T.; Vijay Kumar, K.; Kantam,
M. L. Tetrahedron 2006, 62, 9571. (d) Choudary, B. M.;
Ranganath, K. V. S.; Yadav, J.; Kantam, M. L. Tetrahedron
Lett. 2005, 46, 1369. (e) Kantam, M. L.; Chakrapani, L.;
Ramani, T. Tetrahedron Lett. 2007, 48, 6121.
(16) (a) Klabunde, K. J.; Stark, J.; Koper, O.; Mohs, C.; Park, D.
G.; Decker, S.; Jiang, Y.; Lagadic, I.; Zhang, D. J. Phys.
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K. J. Langmuir 2002, 18, 5309.
(17) General Procedure for the Baylis–Hillman Reaction of
Cyclic Enones using NAP-MgO: To a dried 25-mL round-
bottomed flask charged with NAP-MgO (25 mg) were added
MeOH (3 mL), followed by aldehyde (0.5 mmol) and cyclic
enone (1 mmol) at r.t. The reaction was monitored by TLC.
After completion of the reaction, the catalyst was separated
by centrifuging the reaction mixture, and the supernatant
liquid was concentrated to afford the crude product. Column
chromatography of the crude (silica gel, 60–120 mesh,
EtOAc–hexane, varying proportions) gave the
After completion of the reaction (monitored by TLC), the
reaction mixture was centrifuged to separate the catalyst
and washed several times with ethyl acetate and diethyl
ether and air-dried. The recovered catalyst was recycled
three times without loss of activity after activation at 250
°C for one hour under a flow of nitrogen.
In conclusion, we have shown that NAP-MgO is a highly
active, reusable heterogeneous catalyst for the Baylis–
Hillman reaction of cyclic enones with arenecarbalde-
hydes
and
N-benzylidine-4-methylbenzenesulfon-
amides17 to afford the Baylis–Hillman adducts with high
selectivity under mild conditions. Thus, nanocrystalline
MgO with its definite shape, size, and accessible OH
groups, and higher density of Mg+ at the edges/corners
shows high activity for the Baylis–Hillman reaction.
corresponding Baylis–Hillman adduct. All the products are
known compounds, which were identified by IR, 1H NMR
spectroscopy, and mass spectrometry.
Acknowledgment
L.C.P. thanks CSIR for providing a research fellowship.
Synlett 2008, No. 13, 1946–1948 © Thieme Stuttgart · New York