The Acrylamide Moiety as an Activated Alkene Component in the Intramolecular Baylis-Hillman Reaction: Facile Synthesis of Functionalized α-Methylene Lactam and Spirolactam Frameworks

Article abstract of DOI:10.1002/ejoc.201301526

A facile strategy for the intramolecular Baylis-Hillman reaction by utilizing an acrylamide moiety as an activated alkene component was developed, which thus provides a convenient protocol for obtaining five- and six-membered α-methylene lactam and spirolactam derivatives.

Full text of DOI:10.1002/ejoc.201301526

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301526
The Acrylamide Moiety as an Activated Alkene Component in the
Intramolecular Baylis–Hillman Reaction: Facile Synthesis of Functionalized
α-Methylene Lactam and Spirolactam Frameworks
Deevi Basavaiah,*[a] Guddeti Chandrashekar Reddy,[a] and Kishor Chandra Bharadwaj[a]
Keywords: Baylis–Hillman reaction / Lactams / Nitrogen heterocycles / Spiro compounds
A facile strategy for the intramolecular Baylis–Hillman reac-
tion by utilizing an acrylamide moiety as an activated alkene
component was developed, which thus provides a conve-
nient protocol for obtaining five- and six-membered α-meth-
ylene lactam and spirolactam derivatives.
Introduction
The Baylis–Hillman (BH) reaction is an emerging conti-
nent on the globe of organic chemistry, as it provides di-
verse classes of proximal densely functionalized molecules
possessing high synthetic potential.[1,2] It involves atom-
economical construction of carbon–carbon bonds through
coupling of activated alkenes with electrophiles under the
influence of an appropriate catalyst. The intramolecular BH
reaction is a growing branch of BH chemistry that has at-
tracted the attention of synthetic and medicinal chemists,
because it produces various carbocyclic and heterocyclic
compounds of different ring sizes.[1,3] Although there has
been considerable progress in intramolecular BH reactions
with the use of various activated alkene components,[3] the
application of an acrylamide framework as an activated
alkene component has not been well studied.[4] In fact,
application of an acrylamide unit as an activated alkene in
the regular BH reaction itself has not been studied system-
atically, possibly due to the lower reactivity of the acryl-
amide moiety.[5] Therefore, the development of the BH reac-
tion and its intramolecular versions by employing an acryl-
amide framework as an activated alkene component contin-
ues to be a challenging endeavor in BH chemistry.
Figure 1. α-Methylene lactone and lactam frameworks.
lecules show various biological activities[8] [cytotoxicity in
drug-resistant MDA-MB-231 breast cancer cells,[8a] inhibi-
tion activity of homoserine transacetylase (HTA),[8b] and
cytotoxicity against leukemia cells].[8c,8d] Therefore, there is
increased interest in the development of appropriate syn-
thetic strategies for obtaining these frameworks.[9]
In continuation of our long-term ongoing research pro-
gram in this fascinating reaction,[10] we herein report a fac-
ile intramolecular BH reaction by using an acrylamide
framework as an activated alkene and an aldehyde as the
electrophile component. This study provides a useful proto-
col for obtaining functionalized α-methylene (γ- and δ-)-
lactam derivatives and also spiropyrrolidin-2-ones in high
yields.
Results and Discussion
Although α-methylene (γ- and δ-)lactone skeletons A[6]
are abundantly available structural organizations in a
number of natural products, the presence of α-methylene
(γ- and δ-)lactam frameworks B are less common among
natural products (Figure 1).[7]
We planned the intramolecular BH reaction for ob-
taining functionalized 3-methylenepiperidin-2-ones 1 and 3-
methylenepyrrolidin-2-ones 2 according to the retrosyn-
thetic strategy shown in Scheme 1.
However, in recent years α-methylene (γ- and δ-)lactam
derivatives have gained increasing importance, as these mo-
[a] School of Chemistry, University of Hyderabad,
Hyderabad 500046, India
E-mail: dbsc@uohyd.ernet.in
basavaiahdchem@uohyd.ac.in
http://www.uohyd.ernet.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301526.
Scheme 1. Retrosynthetic strategy for α-methylene (γ- and δ-)-
lactam derivatives.
Eur. J. Org. Chem. 2014, 1157–1162
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1157

D. Basavaiah, G. C. Reddy, K. C. Bharadwaj
SHORT COMMUNICATION
Accordingly, we first selected arylamide–aldehyde (AA)
3a (n = 1, Ar = phenyl) as a substrate for the intramolecular
BH reaction. Required aldehyde 3a was obtained according
to the synthetic sequence shown in Scheme 2 starting from
amino alcohol 5a.[11a] During the initial studies, encourag-
ing yields were obtained if 1,4-diazabicyclo[2.2.2]octane
(DABCO, 1.0 equiv.) was used as a promoter and aceto-
nitrile as a solvent at room temperature; these conditions
provided desired cyclic allylic alcohol 1a in 60% yield
(Table 1, Entry 1).
To optimize the reaction, we performed it under various
conditions [by using different promoters and solvents, by
varying the loading of DABCO and selected additives
(Table 1)]. The best result was obtained upon treating 3a
(1.0 mm) with DABCO (1.0 mm) in tBuOH (6 mL) as the
solvent under reflux conditions, which provided desired
product 1a in 75% yield (Table 1, Entry 22). Notably, the
formation of substantial amounts of N-phenylacrylamide
(11) was observed (Table 1, Entries 7–15, 19–21, 26–29) un-
Scheme 2. Synthesis of acrylamide–aldehydes 3a–e and 4a–g. TBS
= tert-butyldimethylsilyl.
der most reaction conditions upon performing the reaction Entries 30 and 31). The formation of acrylamide 11 may be
at high temperatures and also in the case of Bu3P (Table 1, attributed to the abstraction of the proton α to the aldehyde
Table 1. Optimization of the reaction conditions.[a]
Entry
Solvent
Amount of solvent
[mL/mmol of 3a]
Catalyst
(mmol)
Conditions
Additive
(5 mol-%)
Time
[h]
Yield[b] [%]
1a[c]
11[c]
1
2
3
4
5
6
7
8
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
1
1
1
1
3
6
2
2
2
2
2
2
2
2
2
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
DABCO (1.0)
DABCO (0.5)
DABCO (0.25)
DABCO (2.5)
DABCO (1.0)
DABCO (1.0)
DABCO (1.0)
DABCO (1.0)
DABCO (1.0)
DABCO (1.0)
DABCO (1.0)
DABCO (1.0)
DABCO (1.0)
DABCO (1.0)
DABCO (1.0)
DABCO (1.0)
DABCO (1.0)
DABCO (1.0)
DABCO (1.0)
DABCO (1.0)
DABCO (1.0)
DABCO (1.0)
DABCO (1.0)
DABCO (1.0)
DABCO (1.0)
DABCO (1.0)
DMAP (1.0)
DMAP (1.0)
DMAP (1.0)
P(Bu)3 (1.0)
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
–
–
–
–
–
–
–
24
60
96
12
60
132
6
6
6
0.5
0.5
0.5
6
6
6
36
36
36
1
60
61
58
59
64
71
63
62
65
36
34
33
66
64
63
67
66
68
31
35
30
75
72
74
–
–
–
–
–
–
–
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
65 °C
reflux
reflux
reflux
r.t.
15
13
19
47
46
48
16
14
13
–
–
–
54
51
55
–
–
–
–
15
34
75
27
30
28
MeSO3H
TFA
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
–
DMF
DMF
MeSO3H
TFA
tBuOH
tBuOH
tBuOH
CH3CN
CH3CN
CH3CN
DMF
DMF
DMF
tBuOH
tBuOH
tBuOH
DCE
–
MeSO3H
TFA
–
MeSO3H
TFA
–
MeSO3H
TFA
1
1
–
13
13
13
12
1.5
72
1
72
0.25
0.25
MeSO3H
TFA
–
–
–
–
–
–
–
THF/H2O (1:1)
CH3CN
DMF
47
30
–
26
–
tBuOH
CH3CN
tBuOH
P(Bu)3 (1.0)
r.t.
–
[a] All reactions were performed on a 1.0 mmol scale of aldehyde 3a. DCE =1,2-dichloroethane, DMAP = 4-(dimethylamino)pyridine,
TFA = trifluoroacetic acid. [b] Yield of isolated, pure product based on the aldehyde. [c] Fully characterized.
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1157–1162

Synthesis of Functionalized α-Methylene Lactams and Spirolactams
carbonyl group by the base followed by a retro-Michael- Table 3. Synthesis of α-methylene γ-lactam derivatives 2a–g.[a]
type reaction. With the view to understand the generality
of this protocol, we prepared representative acrylamide–
aldehydes 3b–e by applying the reaction sequence shown
in Scheme 2 and subjected them to the intramolecular BH
reaction under conditions similar to those used in the case
of 3a. The resulting cyclic allylic alcohols (functionalized 3-
methylenepiperidin-2-ones 1b–e) were obtained in 73–78%
yield (Table 2).
Entry
AA
Ar
Product[b] Time
[h]
Yield[c]
[%]
1
2
3
4
5
4a
4b
4c
4d
4e
4f
4g
4a
4a
C6H5
3,5-Me2C6H3
2-MeOC6H4
4-ClC6H4
4-BrC6H4
4-Br-2-MeC6H3
1-naphthyl
C6H5
2a
2b
0.5
1.5
2.5
0.16
0.16
1
73
67
70
71
69
72
70
Table 2. Synthesis of α-methylene δ-lactam derivatives 1a–e.[a]
2c
2d[d]
2e
6
2f
7
2g
1.5
30
8[e]
9[g]
2a
65 (10)[f]
63 (5)[f]
C6H5
2a
30
[a] All reactions were performed on a 1.0 mmol scale of the alde-
hyde by using DABCO (1.0 equiv.) in tBuOH (6.0 mL) at reflux
temperature. AA = acrylamide–aldehyde. [b] All products were ob-
tained as (colorless/white/yellow/brown) solids and fully charac-
terized (see the Supporting Information). [c] Yield of the pure, iso-
lated product based on the aldehyde. [d] Structure of this com-
pound was also confirmed by single-crystal X-ray diffraction analy-
sis.[12] [e] This reaction was performed on a 1.0 mmol scale of the
aldehyde by using quinine (1.0 equiv.). [f] Enantiomeric excess was
determined by HPLC analysis by using a chiral column, Chiralcel-
OJ-H. [g] This reaction was performed on a 1.0 mmol scale of the
aldehyde by using quinidine (1.0 equiv.).
Entry
AA
Ar
Product[b]
Time
[h]
Yield[c]
[%]
1
2
3
4
5
3a
3b
3c
3d
3e
C6H5
1a
1b
1c
1d
1e
13
24
84
6
75
77
73
74
78
3,5-Me2C6H3
2-MeOC6H4
4-ClC6H4
4-BrC6H4
6
[a] All reactions were performed on a 1.0 mmol scale of the alde-
hyde by using DABCO (1.0 equiv.) in tBuOH (6.0 mL) at reflux
temperature. AA = acrylamide–aldehyde. [b] All products were ob-
tained as white solids and fully characterized (see the Supporting
Information). [c] Yield of pure, isolated product based on the alde-
hyde.
Encouraged by these results, we next focused our atten-
tion on the synthesis of five-membered lactam derivatives.
Accordingly, we prepared required substrates 4a–g by ap-
plying the synthetic sequence described in Scheme 2 start-
ing from amino alcohols 6a–g and subjected them to the
BH cyclization reaction (Table 3). We were delighted to see
that these reactions were clean and provided corresponding
3-methylenepyrrolidin-2-ones 2a–g in 67–73% yield. The
structure of 2d was further confirmed by single-crystal X-
ray diffraction analysis (Figure 2).[12] It is clear from the
above results that the BH cyclization of N-aromatic sub-
strates containing electron-donating groups is slower than
the cyclization of substrates containing electron-with-
drawing groups. This is probably due to the increasing/
decreasing electron-donating ability of the nitrogen atom
towards the amide carbonyl group. We were pleased to see
that the reaction rates for the formation of five-membered
lactams 2a–g were faster than those for the formation of
six-membered lactams 1a–e.
Figure 2. ORTEP diagram (50% probability) of 2d.
We also performed the intramolecular BH reaction of N-
(2-oxoethyl)-N-phenylcinnamamide (phenyl group at the β-
We also examined a possible asymmetric version of this position of the acrylamide). This reaction was not success-
strategy by using the easily available cinchona alkaloids ful even after heating under reflux conditions for 24 h, and
(amines) quinine and quinidine as reaction promoters in the most of the starting amide–aldehyde remained intact.
case of 4a (Table 3, Entries 8 and 9). These reactions re-
The spiro-γ-lactam framework containing a nitrogen
quired 30 h for completion, and desired adduct 2a was ob- atom α to the spiro center is another important structural
tained in 65 (using quinine) and 63% (using quinidine) yield skeleton that is an integral part of some interesting natural
with low enantioselectivities (10 and 5% ee). Though the products[13] and bioactive compounds.[14] Therefore, the de-
enantioselectivities were not high, these reactions are en- velopment of a facile strategy to obtain such spiro-γ-lactam
couraging in the sense that there is a possibility to achieve derivatives has attracted the attention of medicinal and syn-
higher enantioselectivities by using appropriate catalysts.
thetic chemists in recent years.[15]
Eur. J. Org. Chem. 2014, 1157–1162
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1159

D. Basavaiah, G. C. Reddy, K. C. Bharadwaj
SHORT COMMUNICATION
We therefore directed our focus towards the development
of an intramolecular BH protocol for the synthesis of these
spiro-γ-lactam derivatives containing a nitrogen atom α to
the spiro center. Required acrylamide–aldehyde substrates
18a,b and 19a,b were conveniently prepared from amino
alcohols 12a,b and 13a,b[11b] according to Scheme 3. Sub-
strates 18a,b and 19a,b were then subjected to the intramo-
lecular BH reaction under conditions similar to those used
for 3 and 4 to provide resulting spiro-γ-lactams 20a,b and
21a,b in 68–75% yield (Table 4). The structure of 20a was
further confirmed by single-crystal X-ray diffraction analy-
sis (Figure 3).[12]
Scheme 3. Synthesis of acrylamide–aldehydes 18a,b and 19a,b.
DMP = Dess–Martin periodinane.
Conclusions
We developed a facile intramolecular BH reaction of
substrates containing an acrylamide as an activated alkene
(less-explored activated alkene unit) component and an al-
dehyde as the electrophile component. This protocol pro-
vides a convenient strategy for construction of five- and six-
membered α-methylene lactam and spirolactam derivatives.
This methodology clearly demonstrates the importance of
the acrylamide unit as a suitable activated alkene compo-
nent for intramolecular BH reactions. This strategy also
gives opportunities to design new classes of such substrates,
which would lead to the construction of various lactam
moieties with different ring sizes. Some of our work is in
progress in this direction.
Table 4. Synthesis of spiro-γ-lactam derivatives 20a,b and 21a,b.[a]
Entry
AA
Ar
n
Product[b] Time Yield[c]
[h]
[%]
1
2
3
4
18a
18b
19a
19b
C6H5
4-BrC6H4
C6H5
1
1
0
0
20a[d]
20b
10
2.5
2
75
72
68
70
21a
4-BrC6H4
21b
0.5
[a] All reactions were performed on a 1.0 mmol scale of the alde-
hyde by using DABCO (1.0 equiv.) in tBuOH (6.0 mL) at reflux
temperature. AA = acrylamide–aldehyde. [b] All products were ob-
tained as colorless or white solids and were fully characterized (see
the Supporting Information). [c] Yield of the pure, isolated product
based on the aldehyde. [d] The structure of this compound was also
confirmed by single-crystal X-ray diffraction analysis.[12]
Experimental Section
Synthesis of 4-Hydroxy-3-methylene-1-phenylpiperidin-2-one (1a) as
a Representative Procedure for the Intramolecular Baylis–Hillman
Reaction: A solution of N-(3-oxopropyl)-N-phenylacrylamide (3a;
0.203 g, 1 mmol) and DABCO (0.112 g, 1 mmol) in tBuOH (6 mL)
was heated under reflux for 13 h (until the disappearance of the
aldehyde, as monitored by TLC). The solvent was then removed
under reduced pressure, and the crude product thus obtained was
purified by column chromatography (silica gel, EtOAc/hexane, 3:1)
to furnish title compound 1a in 75% yield (0.152 g) as a white solid.
Supporting Information (see footnote on the first page of this arti-
cle): General information; experimental procedures; data and cop-
ies of the 1H and 13C NMR spectra of compounds 1a–e, 2a–g, 20a,
20b, 21a, and 21b; ORTEP diagrams of 2d and 20a; HPLC traces
of racemic 2a (obtained by using DABCO) and 2a (with low enan-
tiomeric purity obtained by using quinine and quinidine).
Acknowledgments
We thank the Department of Science and Technology (DST), New
Delhi, for funding this project. G. C. R. thanks the Council of Sci-
entific and Industrial Research (CSIR), New Delhi, for his research
fellowship. K. C. B. is thankful to the University Grants Commis-
sion (UGC) for a Dr. D. S. Kothari fellowship. We thank the UGC
(New Delhi) for support and for providing some instrumental facil-
Figure 3. ORTEP diagram (50% probability) of 20a.
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Eur. J. Org. Chem. 2014, 1157–1162

Synthesis of Functionalized α-Methylene Lactams and Spirolactams
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Received: October 8, 2013
Published Online: January 23, 2014
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