Highly diastereoselective synthesis of tertiary alcohols via intramolecular Baylis-Hillman reaction using less reactive acrylamides as activated alkenes and ketones as electrophiles

Article abstract of DOI:10.1016/j.tet.2016.12.069

A simple and convenient protocol for highly diastereoselective intramolecular Baylis-Hillman (IBH) reaction of substrates containing less reactive acrylamides as activated alkene and ketones with α-chiral center (racemic) as electrophile components, thus

Full text of DOI:10.1016/j.tet.2016.12.069

Accepted Manuscript
Highly diastereoselective synthesis of tertiary alcohols via intramolecular Baylis-
Hillman reaction using less reactive acrylamides as activated alkenes and ketones as
electrophiles
Deevi Basavaiah, Guddeti Chandrashekar Reddy, Balthu Lingaiah, Ram Tilak
Naganaboina
PII:
S0040-4020(16)31366-7
10.1016/j.tet.2016.12.069
TET 28361
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 August 2016
Revised Date: 21 December 2016
Accepted Date: 26 December 2016
Please cite this article as: Basavaiah D, Reddy GC, Lingaiah B, Naganaboina RT, Highly
diastereoselective synthesis of tertiary alcohols via intramolecular Baylis-Hillman reaction using less
reactive acrylamides as activated alkenes and ketones as electrophiles, Tetrahedron (2017), doi:
10.1016/j.tet.2016.12.069.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Highly diastereoselective synthesis of tertiary alcohols Leave this area blank for abstract info.
via intramolecular Baylis-Hillman reaction using
less reactive acrylamides as activated alkenes and
ketones as electrophiles
Deevi Basavaiah*, Guddeti Chandrashekar Reddy, Balthu Lingaiah, Ram Tilak Naganaboina
School of chemistry, University of Hyderabad, Hyderabad-500 046, India

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Highly diastereoselective synthesis of tertiary alcohols via intramolecular
Baylis-Hillman reaction using less reactive acrylamides as activated alkenes
and ketones as electrophiles
Deevi Basavaiah*, Guddeti Chandrashekar Reddy, Balthu Lingaiah, Ram Tilak Naganaboina
School of Chemistry, University of Hyderabad, Central University (PO), Gachibowli, Hyderabad 500 046, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and convenient protocol for highly diastereoselective intramolecular
Baylis-Hillman (IBH) reaction of substrates containing less reactive acrylamides as
activated alkene and ketones with α-chiral center (racemic) as electrophile
components, thus producing α-methylene-γ-lactam frameworks having β-tertiary
alcoholic functional group, has been developed.
Available online
.
.
Keywords:
Diastereoselective synthesis
Intramolecular Baylis-Hillman reaction
α-Methylene-γ-lactam framework
tertiary Alcohols
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
OH
OH
Development of strategies1 for diastereoselective synthesis of
tertiary alcohols having α-chiral center has been and continues
to be one of the challenging and attractive endeavors in synthetic
chemistry because of the presence of such frameworks in
number of natural products 2a-c and bioactive compounds2a,d-g (for
selected examples see Fig.1). 4-Hydroxy-3,4,5-trisubstituted-
O
O
H
H
OH
O
OH
O
H
O
(-)-Jiadifenolide
neurotrophic activity
(ref.2a)
(+)-Omphadiol (ref.2b)
pyrrolidin-2-one skeleton3
is one such unique structural
organization (few examples are presented in Figure 2) that has
attracted the attention of organic and medicinal chemists in recent
years.1d-f,3a,b
OH
OH
HO
OMe
OH
It has been well documented in the literature that substituent on
the chiral carbon α to the keto group plays an important role in
directing the attack of nucleophile on keto carbonyl, thus
controlling the stereochemistry (diastereo-selectivity of the
reaction) at the newly formed chiral center.1 In continuation of
our interest4 on the Baylis-Hillman (also known as Morita-
Baylis-Hillman) reaction5,6 we herein report a facile and
convenient strategy for highly diastereoselective synthesis of
tertiary alcohols via the intramolecular Baylis-Hillman (IBH)
reaction of substrates containing less reactive acrylamides as
activated alkene and ketones with α-chiral center (racemic) as
electrophile components.
N
δ Opioid agonist (ref.2d)
(-)-Isoamijiol (ref.2c)
Fig. 1. Representative
natural products and
compounds containing tertiary alcoholic moiety α- to the chiral
bioactive
center.
The growth of IBH reaction in principle depends on the design
and synthesis of substrates containing both activated alkene and
electrophile components in a suitable position so that the
coupling takes place to yield cyclic compounds. 5f,j,7,8 From the
literature it is quite clear that there are few reports on
diastereoselective intramolecular Baylis-Hillman reactions
producing secondary alcohols8e,h,i,k and tertiary alcohols.8f,g,i,j
Intramolecular Baylis-Hillman (IBH) reaction represents unique
branch of BH reaction as it produces useful carbocylic and
heterocyclic compounds having several functional groups. 5f,j,7,8

2
Tetrahedron
ACCEPTED MANUSCRIPT
Our previous work:
O
OH
R2
R1
O
R2
DABCO
(1.0 equiv.)
R1
N
OH
O
O
N
OH
N
Eq. 1
N
N
O
O
dioxane:water (1:1)
H
HO
65 0C, 1-44 h, 52-88 %
OH
O
O
Neooxazolomycin (ref.3i)
an antitumor antibiotic
R1 = aryl; R2 = aryl, Me
Accordingly we have first selected N-(1-oxo-1-phenylpropan-2-
yl)-N-phenylacrylamide (2a R1= R2 = phenyl, R3 = methyl) as a
suitable substrate for diastereoselective intramolecular Baylis-
Hillman reaction. This compound was conveniently prepared
from easily accessible amino-ketone (4a, R1= R2 = phenyl)9
following the reaction sequence as shown in Table 1. This
reaction sequence involves two steps: i) amino-ketone (4a) was
H
H
O
O
O
O
HO
O
HO
HN
S
OR
OH
N
HN
OH
OH
R
O
H
H
10
methylated (according to the known procedure) with methyl
iodide in presence of NaH to provide amino-α-methyl ketone
(3a), ii) the crude ketone 3a was used as such (without
purification) for treatment with acryloyl chloride in presence of
triethylamine to provide N-(1-oxo-1-phenylpropan-2-yl)-N-
phenylacrylamide (2a) in 70 % isolated yield over two steps.
R = H Cinnabaramide F
R = CH3 Cinnabaramide G
R = OH Cinnabaramide D
R = H Cinnabaramide E
potent and selective inhibitors of human 20S proteasome (ref.3f)
Fig. 2. Representative natural products containing pyrrolidin-2-
one framework with tertiary alcoholic moiety α- to the chiral
center.
R3
R3
OH
R1
O
R2
R1
N
R2
N
2. Results and discussion
IBH
Eq.2
O
Recently we have reported8c,d an interesting intramolecular
Baylis-Hillman (IBH) reaction of acrylamide-ketone substrates
(less reactive components) under the influence of DABCO, using
reaction
O
1
2
diastereoselectivity ?
o
Subsequently we have subjected acrylamide-ketone (2a) to the
IBH reaction. Based on our previous work as shown in Eq.1, we
have treated acrylamide-ketone (2a) with DABCO (1.0 eq.) in
dioxane-water (1:1) solvent system, at 65 °C. We were pleased to
notice that the reaction went on very well and is highly
diastereoselective thus producing syn adduct (syn-1a) as the
major product and anti adduct (anti-1a) as a minor product.
(syn-1a : anti-1a is 93:7) in 86% combined isolated yield after
purification through column chromatography (Table 2, entry1)
(also see experimental section). Diastereoselectivity was
dioxane:water solvent system at 65 C to obtain the resulting
IBH-adducts containing tertiary alcoholic functional group
(Eq.1). Based on this report and also on our long experience in
development of the BH reaction, we envisioned that it is possible
to achieve high diastereoselectivity in IBH reaction of
acrylamide-ketone (AK) substrates 2 containing chiral (racemic)
center α to the keto group to produce α-methylene-γ-lactam
frameworks 1 according to equation 2.
Table 1: Synthesis of acrylamide-ketones (AK) (2a-j)a
R3
i) NaH, DMF
R3
R1
O
R2
0 0C, 0.5 h
R1
R2
acryloyl chloride
N
R1
R2
N
H
N
O
Et3N, DCM
0 oC-r.t., 1 h
ii) R3-X, 0 0C, 3 h
O
H
O
2a-j
4a-e
3a-j
Productb
α
-Alkylated
Amino
ketone (4)
Yieldc
(%)
Entry
R1
R2
R3-X
acrylamide-ketone
(2)
amino ketone
(3)
1
2
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-ClC6H4
2-naphthyl
C6H5
4a
4b
4c
4a
MeI
MeI
3a
3b
3c
3d
3e
3f
2a
2b
2c
2d
2e
2f
70
65
67
62
60
50
54
55
57
48
3
MeI
4
EtI
5
4-ClC6H4
C6H5
4b
4a
EtI
6
allyl bromide
allyl bromide
iBuI
7
3, 5-Me2C6H3
C6H5
C6H5
4d
3g
3h
3i
2g
2h
2i
8
C6H5
4a
4e
9
C6H5
4-MeC6H4
C6H5
iBuI
10
C6H5
4a
iPrI
3j
2j
a All the reactions were carried out on a 5.0 mmol scale of amino ketone (4a-e) with alkyl halide (6.5 mmol) in the presence of NaH (5.25 mmol) in DMF. The
crude product (3a-j) thus obtained was treated with acryloyl chloride (6.0 mmol) in the presence of Et3N (7.0 mmol) in DCM.
b These compounds are fully characterized (see experimental section)
c Overall two step yield of pure and isolated products

3
Table 2. Synthesis of 4-hydroxy-3,4,5-trisubstituted-pyrrolidin-2-ones (1a-l).a,b
ACCEPTED MANUSCRIPT
R3
R3
R3
DABCO
(1.0 equiv.)
OH
R2
Hb
OH
R2
Hb
R1
O
R2
R1
R1
N
N
N
+
O
dioxane:water (1:1)
0
O
O
65 C
Ha
1a-l
Ha
1a-l
2a-l
syn-
Major
anti-
Minor
drd
Yielde (%)
Entry
AK
R1
R2
R3
Productsc
t
(h)
1
2
2a
2b
2c
2d
2e
2fh
2g
2h
2i
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-ClC6H4
2-naphthyl
C6H5
Me
Me
Me
Et
syn-1af + anti-1a
syn-1bf + anti-1b
syn-1c + anti-1c
syn-1d + anti-1d
syn-1e + anti-1e
syn-1f + anti-1f i
syn-1g + anti-1g
syn-1h + anti-1h
syn-1i + anti-1i
syn-1j + anti-1j
syn-1k + anti-1k
syn-1l + anti-1l
6
93:7
93:7
94:6
95:5
94:6
96:4
96:4
96:4
96:4
˃99:˂1
86 ( 60)g
79 (58)g
88 (64) g
84 (62) g
80 (63) g
81(78+3)g ,i
77 (56) g
82 (59) g
81(56)g
83j
5
3
14
13
11
13
60
60
96
84
5
4
5
4-ClC6H4
C6H5
Et
6
allyl
allyl
iBu
iBu
iPr
7
3, 5-Me2C6H3
C6H5
C6H5
8
C6H5
9
C6H5
4-MeC6H4
C6H5
10
11
12
2j
C6H5
2k
2l
CH2C6H5
n-butyl
C6H5
Me
Me
83:17 (97:3)k
83 (59)k
C6H5
7
83:17
86
AK = acrylamide-ketone, t = time, dr = diastereomeric ratio
a Unless otherwise mentioned, all the reactions were carried out on a 0.5 mmol scale of acrylamide-ketone using DABCO (1.0 equiv.) in dioxane:water (1:1) (1.0
mL) at 65 0C temperature.
b All products were obtained as mixture of syn (major) and anti (minor) isomers after purification through column chromatography (see experimental section) .
Pure syn diastereomers were obtained by crystallization [ethyl acetate : hexanes (1:2)] and fully characterized (see experimental section and also SI).
c We have assigned syn- and anti configurations for 4-hydroxy-3,4,5-trisubstituted-pyrrolidin-2-one derivatives (1a-l).as in chemical equation shown above
(Table 2) [ in syn diastereomers ‘R3’ and ‘OH’ groups are on the same side and in anti isomer ‘R3’ and ‘OH’ groups are on opposite side].
d Diastereomeric ratio was determined by integration of the separated olefinic proton (Ha and Hb) signals of syn (major) and anti (minor) isomers in the 1H
NMR spectra of the crude mixtures (also see the text).
e Isolated yields of mixture of syn and anti diastereomers after purification through column chromatography based on acrylamide-ketones (2a-l).
f Syn stereochemistry of these pure diastereomers was assigned on the basis of single crystal X-ray data analysis.11 We have assigned the syn stereochemistry to
all the major isomers of 1c-1l in analogy with 1a and 1b.
g yields in parenthesis are isolated yields of pure syn- diastereomers (1a-i) (obtained after crystallization as mentioned in footnote b) based on acrylamide-
ketones 2a-j.
h The reaction was carried out on a 4.0 mmol scale of acrylamide-ketone using DABCO (1.0 equiv.) in dioxane:water (1:1)(8.0 mL) at 65 0C temperature.
i In this case we have separated major and minor diastereomers by column chromatography.
j In the case of 1j pure syn isomer ( ˃99:˂1) was obtained after purification through column chromatography.
kDiastereomeric ratio after crystallization [ethyl acetate : hexanes (1:1)] and yield in parenthesis is the corresponding yield.
determined by the integration of the separated olefinic proton
O
O
H
(Ha and Hb) signals of syn (major) and anti (minor) isomers
in the 1H NMR spectra of the crude mixture [as well as that of the
compound (syn and anti-mixture) after purification by column
chromatography]. The major product (syn-1a) was obtained in
N
CH3CN
R1
NaHCO3, rt, 2 h
R1 NH2
Br
diastereomerically pure form in 60
%
yield by careful
Et3N, DCM
0 oC-r.t., 30 min
acryloyl chloride
crystallization. We have assigned the syn stereochemistry to the
major product (syn-1a) on the basis of its single crystal X-ray
data analysis.11 Encouraged by this interesting result, we have
prepared representative acrylamide-α-substituted ketones (2b-j)
and subjected them to IBH reaction under similar conditions. The
resulting adducts (1b-j) were obtained in 93:7-˃99:˂1(syn:anti)
diastereomeric ratios and 77-88 % isolated yields (Table 2,
entries 2-10). In all the cases (except in the case of 1f) we were
able to obtain pure syn diastereomers through careful
crystallization as in the case of syn-1a. Interestingly major and
minor diastereomers in the case of 1f were separated during
column chromatography itself.
O
O
N
2k, R1 = benzyl, 49%
R1
, R1 = n-butyl, 61%
2l
Scheme 1. Synthesis of acrylamide-ketones 2k and 2l
bromopropiophenone13 in a two step process as described in
Scheme1. The strategy involves the treatment of
α-
bromopropiophenone with benzylamine (or butyl amine)14
followed by the reaction of the in situ prepared secondary amine
with acryloyl chloride to provide the required acrylamide-
ketones (2k and 2l) (Scheme 1). Subsequent intramolecular BH
reaction of 2k and 2l using DABCO (1.0 equiv.) in dioxane
In all the above examples (1a-j) the substitution on nitrogen is an
aryl group (R1= aryl). With a view to understand the effect of
substitution on nitrogen we have also prepared two acrylamide-
ketones, 2k ( R1= benzyl) and 2l (R1=n-butyl), starting from α-
o
water (1:1) at 65 C provided the desired BH adducts, 1-benzyl-
4-hydroxy-5-methyl-3-methylene-4-phenylpyrrolidin-2-one (1k),

4
Tetrahedron
and
1-butyl-4-hydroxy-5-methyl-3-methylene-4-phenyl-
favored because of absence of such unfavorable gauche
ACCEPTED MANUSCRIPT
pyrrolidin-2-one (1l) respectively (Table 2 entries 11 and 12) in
83:17 (syn:anti) diastereomeric ratio. In the case of 1k,
crystallization [ethyl acetate : hexanes (1:1)] provided the
resulting syn adduct in 94% diastereomeric excess (syn:anti is
97:3).
interactions.
3. Conclusion
In conclusion, we have developed a simple methodology for high
diastereoselective synthesis of tertiary alcohols via DABCO
mediated intramolecular Baylis-Hillman cyclization
of
We have determined the diastereoselectivity of the IBH reaction
acrylamide-ketones, containing a chiral (racemic) centre α to
ketone functionalty. Our study also demonstrates the high
potential of less reactive acrylamides as activated alkene and
ketones as electrophile components in IBH reactions.
and assigned the stereochemistry of the major (syn) and minor
1
(anti) products in the case of 1c-1l by examining the HNMR
spectra of the crude reaction mixtures in analogy with that of 1a
and 1b. In the 1H NMR spectra, isomeric olefinic protons
O
Me
O
Me
Ph
N
Ph
Ph
N
H
N
Ph
O
HO
Me
N
N
O
N
O
N
O
H
O
H
Ph
Me
Ph
Ph
N
N
N
Ph
(±) syn-1a
conformer A
more favored
N
Transition model-I
more favored
major
O
Ph
major
N
- DABCO
+
+
+
(DABCO)
Me
N
O
Ph
Ph
Ph
Me
Ph
HO
Me
Ph
H
Ph
O
Ph
N
(±) 2a
N
N
Me
N
O
N
O
O
Ph
O
H
O
Me
N
H
O
Ph
N
N
N
-1a
(±) anti
N
conformer B
less favored
minor
minor
Transition model-II
less favored
Scheme 2. Plausible mechanism for diastereoselective IBH reaction
Ha and Hb) signals of syn (major) and anti (minor) isomers
separate nicely in all the compounds 1a-l. Ha and Hb protons in
anti isomers are deshielded in comparison to that of syn
isomers. Ha protons of syn isomer appear at ≈ δ 6.21- 6.42
while that of anti isomer appear at ≈ δ 6.32- 6.54. Hb Protons
in syn isomers appear at ≈ δ 5.37-5.60 while that of anti isomer
appear at ≈ δ 5.49-5.76. Diastereomeric ratios were determined
by the integration ratios of diastereomeric olefinic protons (Ha
4. Experimental section
4.1 General remarks
Melting Points were recorded on a MR-Vis+ visual melting point
range apparatus of LABINDIA instruments private limited and
were uncorrected. Infrared spectra were recorded on a Thermo
Scientific Nicolet 380 FT-IR spectrophotometer. All the spectra
were calibrated against polystyrene absorption at 1601 cm-1.
Solid samples were recorded as KBr wafers. Proton magnetic
resonance spectra were recorded on a Bruker-AVANCE-500 and
carbon-13 magnetic resonance spectra on a Bruker-AVANCE-
400 spectrometer. 1H NMR (500 MHz) spectra for all the
samples were measured in chloroform-d, with TMS (δ 0 ppm) as
an internal standard. 13C NMR (100 MHz) spectra for all the
samples were measured in chloroform-d with middle peak of the
triplet (δ 77.10 ppm) of chloroform-d as an internal standard.
HRMS spectra were recorded on Bruker maXis ESI-TOF
spectrometer. The X-ray diffraction measurement for compound
(syn-1a) was carried out at 298 K on Oxford Diffraction Xcalibur
Eos Gemini diffractometer with graphite-monochromated Cu- Kα
radiation with wavelength of 1.54184 Å and while for compound
(syn-1b) was carried out at 298 K on Bruker SMART APEX
1
as well as Hb) of major and minor products in the H NMR
spectra of the crude mixtures.
Though it is not highly remarkable, we have noticed that, the
diastereoselectivity has increased from 86 to 92 % with
increasing steric bulk of the substituent at the α-position of keto
group in acrylamide-ketones (2a-i). It is important to note that
the substrate (2j), containing iso-propyl group at α- to keto
group, produced the resulting IBH-adduct (1j) in excellent
diastereoselectivity ( ˃ 99 %) in 83 % isolated yield. From these
results it is clear that steric bulk of substituent on carbon α- to
keto group plays a key role in directing the stereochemical
course of the reaction. From the comparatively low
diastereoselectivities obtained in the cases of 1k and 1l, it is quite
clear that the substrates having aryl groups on nitrogen (R3 is
aryl) offer better diastereoselectivities than substrates having
alkyl groups on nitrogen (R3 is alkyl).
CCD area detector system equipped with
monochromator and a Mo-Kα fine-focus sealed tube (λ =
a
graphite
0.71073 Å).
A
plausible mechanism for high diastereoselectivities is
presented in the Scheme 2 (on basis of well known Felkin-Anh
model)12 by taking the reaction of N-(1-oxo-1-phenylpropan-2-
yl)-N-phenylacrylamide (2a) with DABCO, as a model case.
Diastereoselectivities are explained on the basis of conformers A,
B and transition states I and II. The conformer B and transition
state II are disfavored due to the presence of Ph-Me - gauche
interactions while the conformer A and transition state I are
4.2. Representative procedure for Acrylamide-ketones (2a-j)
4.2.1. N-(1-Oxo-1-phenylpropan-2-yl)-N-phenylacrylamide (2a):
This was prepared in two steps:
Step 1:Preparation of 1-phenyl-2-phenylaminopropanone
(methylation of 1-phenyl-2-phenylaminoethanone was performed
following the known procedure) 10

5
To a stirring suspension of NaH (0.210 g, 5.25 mmol, 60% w/w
in mineral oil) in dry DMF (37 mL) at 0 ºC was added 1-phenyl-
2-(phenylamino)ethanone (1.055 g, 5.0 mmol). After stirring 30
min at 0 ºC, MeI (0.923 g, 6.5 mmol) was added slowly. Stirring
was continued at 0 ºC for 3 h. Then the reaction was carefully
poured into ice-cold water and stirred for 10 minutes. Reaction
mixture was extracted with EtOAc (2 x 60 mL). Combined
organic layer was washed with water (2 x 30 mL) and dried over
anhydrous Na2SO4. Solvent was removed under reduced pressure
and the crude product (1-phenyl-2-phenylaminopropanone) thus
obtained, was used as such without purification for the next step.
MHz, CDCl3): δ 0.97 (t, J = 7.5 Hz, 3H), 1.62-1.72 (m, 1H),
ACCEPTED MANUSCRIPT
1.85-1.95 (m, 1H), 5.50 (dd, J = 10.5 and 2.0 Hz, 1H), 5.84 (dd, J
= 16.5 and 10.5 Hz, 1H), 6.27 (t, J = 7.5 Hz, 1H), 6.39 (dd, J =
16.5 and 2.0 Hz, 1H), 6.99 (bs, 2H), 7.28-7.38 (m, 3H), 7.47-7.52
(m, 2H), 7.57-7.62 (m, 1H); 8.07-8.11 (m, 2H); 13C NMR (100
MHz, CDCl3): δ 11.03, 22.49, 60.25, 128.42, 128.60, 128.72,
128.91, 129.31, 130.02, 133.43, 136.40, 138.06, 165.90, 198.19;
HRMS (ESI): calculated for C19H19NO2Na: 316.1313 (M+Na)+,
found: 316.1313 (M+Na)+.
4.2.5. N-[1-(4-Chlorophenyl)-1-oxobutan-2-yl]-N-phenylacryl-
amide (2e). Yield: 60 %; Rf (20% EtOAc in hexanes): 0.40;
Yellow viscous liquid; IR (neat): ν 1687, 1649, 1616, 1589 cm-1;
1H NMR (500 MHz, CDCl3): δ 0.97 (t, J = 7.5 Hz, 3H), 1.62-
1.72 (m, 1H), 1.82-1.92 (m, 1H), 5.52 (dd, J = 10.5 and 2.0 Hz,
1H), 5.83 (dd, J = 17.0 and 10.5 Hz, 1H), 6.20 (t, J = 7.5 Hz,
1H), 6.39 (dd, J = 16.5 and 2.0 Hz, 1H), 6.97 (bs, 2H), 7.29-7.38
(m, 3H), 7.45-7.49 (m, 2H), 8.03-8.07 (m, 2H); 13C NMR (100
MHz, CDCl3): δ 10.96, 22.48, 60.12, 128.26, 128.69, 128.85,
129.25, 129.40, 129.95, 130.05, 134.75, 137.89, 139.90, 165.93,
197.10; HRMS (ESI): calculated for C19H18ClNO2Na: 350.0924
(M+Na)+, found: 350.0929 (M+Na)+.
Step 2: Acrylamide formation
Above obtained crude product 1-phenyl-2-phenylamino-
propanone (3a) was dissolved in dichloromethane (DCM) (15
mL). To this stirring solution at 0 ºC, Et3N (0.707 g, 7.0 mmol)
was added, followed by a dropwise addition of acryloyl chloride
(0.543 g, 6.0 mmol). After stirring for 1h at the same temperature
(at 0 ºC), the reaction mixture was diluted with water (30 mL)
and extracted with DCM (2 x 30 mL). Combined organic layer
was dried over anhydrous Na2SO4 and concentrated. The crude
product, thus obtained, was purified by column chromatography
[silica gel, 20 % ethyl acetate in hexanes] to provide the required
4.2.6.
N-(1-Oxo-1-phenylpent-4-en-2-yl)-N-phenylacrylamide
product,
N-(1-oxo-1-phenylpropan-2-yl)-N-phenylacrylamide
(2f). Yield: 50 %; Rf (20% EtOAc in hexanes): 0.38; Yellow
1
(2a), in 70 % (0.976 g) yield (over two steps), as a reddish
viscous liquid. Rf (20% EtOAc in hexanes): 0.30; IR (neat): ν
viscous liquid; IR (neat): ν 1687, 1654, 1610, 1594 cm-1; H
NMR (500 MHz, CDCl3): δ 2.39-2.48 (m, 1H), 2.60-2.68 (m,
1H), 5.06-5.11 (m, 1H), 5.12-5.17 (m, 1H), 5.50 (dd, J = 10.0 and
2.0 Hz, 1H), 5.76-5.86 (m, 2H), 6.39 (dd, J = 17.0 and 2.0 Hz,
1H), 6.48 (dd, J = 8.5 and 6.5 Hz, 1H), 6.99 (bs, 2H), 7.28-7.37
(m, 3H), 7.47-7.52 (m, 2H), 7.57-7.62 (m, 1H), 8.06-8.10 (m, 2
H); 13C NMR (100 MHz, CDCl3): δ 33.39, 58.31, 118.15, 128.33,
128.57, 128.64, 128.84, 128.94, 129.33, 130.12, 133.54, 134.04,
136.04, 137.90, 165.84, 197.47; HRMS (ESI): calculated for
C20H19NO2Na: 328.1313 (M+Na)+, found: 328.1312 (M+Na)+.
1687, 1654, 1616, 1594 cm-1; H NMR (500 MHz, CDCl3): δ
1
1.26 (d, J = 6.0 Hz, 3H), 5.50 (dd, J = 10.5 and 2.0 Hz, 1H), 5.87
(dd, J = 17.0 and 10.5 Hz, 1H), 6.27 (q, J = 7.0 Hz, 1H), 6.37
(dd, J = 17.0 and 2.0 Hz, 1H), 7.12-7.18 (m, 2H), 7.34-7.40 (m,
3H), 7.47-7.52 (m, 2H), 7.57-7.61 (m, 1H) 8.05-8.08 (m, 2H);
13C NMR (100 MHz, CDCl3): δ 15.31, 55.38, 128.31, 128.41,
128.53, 128.69, 128.84, 129.33, 130.39, 133.30, 135.81, 138.24,
165.65, 198.93; HRMS (ESI): calculated for C18H17NO2Na:
302.1157 (M+Na)+, found: 302.1162 (M+Na)+.
4.2.7. N-(3,5-Dimethylphenyl)-N-(1-oxo-1-phenylpent-4-en-2-yl)-
acrylamide (2g). Yield: 54 %; Rf (20% EtOAc in hexanes): 0.46;
Yellow viscous liquid; IR (neat): ν 1687, 1649, 1616, 1594 cm-1;
1H NMR (500 MHz, CDCl3): δ 2.22 (bs, 6 H), 2.40-2.49 (m,
1H), 2.61-2.69 (m, 1H), 5.06-5.11 (m, 1H), 5.12-5.18 (m, 1H),
5.49 (dd, J = 10.0 and 2.0 Hz, 1H), 5.77-5.89 (m, 2H),* 6.34-6.65
(m, 4H), # 7.46-7.52 (m, 2H), 7.56-7.61 (m, 2H), 8.03-8.08 (m, 2
H). *It contains a dd (J = 16.5 and 10.0 Hz). # It contains a dd (J =
16.5 and 2.0 Hz) and it also contains another dd (J = 8.0 and 7.0
Hz); 13C NMR (100 MHz, CDCl3): δ 21.16, 33.49, 58.36, 118.03,
127.66, 128.26, 128.45, 128.59, 128.88, 130.44, 133.41, 134.28,
136.31, 137.59, 138.99, 165.77, 197.60; HRMS (ESI): calculated
for C22H23NO2Na: 356.1626 (M+Na)+, found: 356.1624
(M+Na)+.
4.2.2. N-[1-(4-Chlorophenyl)-1-oxopropan-2-yl]-N-phenylacryl-
amide (2b). Yield: 65 %; Rf (20% EtOAc in hexanes): 0.36;
0
Yellow solid; mp: 113-116 C; IR (KBr): ν 1687, 1649, 1610,
1
1583 cm-1; H NMR (500 MHz, CDCl3): δ 1.25 (d, J = 7.5 Hz,
3H), 5.51 (dd, J = 10.5 and 2.0 Hz, 1H), 5.86 (dd, J = 17.0 and
10.5 Hz, 1H), 6.20 (q, J = 7.5 Hz, 1H), 6.37 (dd, J = 17.0 and 2.0
Hz, 1H), 7.10-7.15 (m, 2H), 7.35-7.40 (m, 3H), 7.45-7.49 (m,
2H), 8.00-8.03 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 15.20,
55.27, 128.24, 128.54, 128.79, 129.16, 129.40, 129.95, 130.28,
134.15, 138.05, 139.70, 165.65, 197.76; HRMS (ESI): calculated
for C18H16ClNO2Na: 336.0767 (M+Na)+, found: 336.0769
(M+Na)+.
4.2.3. N-[1-(Naphthalen-2-yl)-1-oxopropan-2-yl]-N-phenylacryl-
amide (2c). Yield: 67 %; Rf (20% EtOAc in hexanes): 0.32;
Yellow viscous liquid; IR (neat): ν 1687, 1654, 1618, 1594 cm-1;
1H NMR (500 MHz, CDCl3): δ 1.32 (d, J = 7.0 Hz, 3H), 5.49 (dd,
J = 10.5 and 2.0 Hz, 1H), 5.87 (dd, J = 17.0 and 10.5 Hz, 1H),
6.38 (dd, J = 17.0 and 2.0 Hz, 1H), 6.43 (q, J = 7.0 Hz, 1H),
7.13-7.20 (m, 2H), 7.33-7.40 (m, 3H), 7.48-7.58 (m, 1H), 7.59-
7.63 (m, 1H), 7.89 (d, J = 7.0 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H),
8.00 (d, J = 8.0 Hz, 1H), 8.06 (dd, J = 8.5 and 1.5 Hz, 1H), 8.67
(s, 1H); 13C NMR (100 MHz, CDCl3): δ 15.44, 55.51, 124.38,
126.80, 127.82, 128.31, 128.51, 128.58, 128.72, 129.37, 129.89,
130.19, 130.45 132.74, 133.15, 135.80, 138.35, 165.73, 198.91;
HRMS (ESI): calculated for C22H19NO2Na: 352.1313 (M+Na)+,
found: 352.1317 (M+Na)+.
4.2.8. N-(4-Methyl-1-oxo-1-phenylpentan-2-yl)-N-phenylacryl-
amide (2h). Yield: 55 %; Rf (20% EtOAc in hexanes): 0.46;
Yellow viscous liquid; IR (neat): ν 1693, 1660, 1610, 1594 cm-1;
1H NMR (500 MHz, CDCl3): δ 0.89 (d, J= 6.5 Hz, 3 H), 1.01 (d,
J= 6.5 Hz, 3 H), 1.49-1.56 (m, 1H), 1.57-1.66 (m, 1H),* 1.67-
1.73 (m, 1H), 5.50 (dd, J=10.0 and 2.0 Hz, 1H), 5.83 (dd, J =
17.0 and 10.0 Hz, 1H), 6.39 (dd, J = 17.0 and 2.0 Hz, 1H), 6.46
(dd, J = 8.0 and 6.0 Hz, 1H), 6.98 (bs, 2H), 7.28-7.38 (m, 3 H),
*
7.48-7.53 (m, 2H), 7.57-7.62 (m, 1H), 8.09-8.13 (m, 2 H). It
contains moisture peak; 13C NMR (100 MHz, CDCl3): δ 22.58,
22.78, 24.83, 37.82, 56.92, 128.23, 128.38, 128.51, 128.58,
128.80, 129.17, 129.99, 133.31, 136.15, 137.93, 165.66, 198.10;
HRMS (ESI): calculated for C21H23NO2Na: 344.1626 (M+Na)+,
found: 344.1632 (M+Na)+.
4.2.4.
N-(1-Oxo-1-phenylbutan-2-yl)-N-phenylacrylamide(2d).
Yield: 62 %; Rf (20% EtOAc in hexanes): 0.38; Yellow viscous
4.2.9.
N-(4-Methyl-1-oxo-1-(4-methylphenyl)pentan-2-yl)-N-
1
liquid; IR (neat): ν 1693, 1654, 1616, 1594 cm-1; H NMR (500
phenylacrylamide (2i). Yield: 57 %; Rf (20% EtOAc in hexanes):

6
Tetrahedron
0
0.48; Yellow solid; mp: 109-112 C; IR (KBr): ν 1676, 1654,
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK (for compound syn-1a: CCDC #
1491071).
ACCEPTED MANUSCRIPT
1611, 1605 cm-1; H NMR (500 MHz, CDCl3): δ 0.90 (d, J=6.5
Hz, 3 H), 1.01 (d, J= 6.5 Hz, 3 H), 1.48-1.55 (m, 1H), 1.56-1.65
(m, 1H),* 1.66-1.73 (m, 1H), 2.43 (s, 3H), 5.49 (dd, J = 10.0 and
2.0 Hz, 1H), 5.82 (dd, J = 16.5 and 10.0 Hz, 1H), 6.39 (dd, J =
16.5 and 2.0 Hz, 1H), 6.45 (dd, J = 8.0 and 6.0 Hz, 1H), 6.97
1
*
(bs, 2H), 7.27-7.36 (m, 5H), 8.00 (d, J = 8.0 Hz, 2H). It
contains moisture peak; 13C NMR (100 MHz, CDCl3): δ 21.73,
22.70, 22.87, 24.91, 37.93, 56.79, 128.22, 128.53, 128.63,
128.74, 129.22, 129.59, 130.10, 133.73, 138.04, 144.24, 165.71,
197.70; HRMS (ESI): calculated for C22H25NO2Na: 358.1783
(M+Na)+, found: 358.1784 (M+Na)+.
4.2.10. N-(3-Methyl-1-oxo-1-phenylbutan-2-yl)-N-phenylacryl-
amide (2j). Yield: 48 %; Rf (20% EtOAc in hexanes): 0.46;
0
Yellow solid; mp: 140-142 C; IR (KBr): ν 1692, 1644, 1611,
1590 cm-1; 1H NMR (500 MHz, CDCl3): δ 0.94 (d, J = 6.5 Hz, 3
H), 1.19 (d, J = 6.5 Hz, 3 H), 2.30-2.45 (m, 1H), 5.51 (dd, J =
10.0 and 2.0 Hz, 1H), 5.83 (dd, J = 16.5 and 10.0 Hz, 1H), 6.23
(d, J = 10.5 Hz, 1 H), 6.41 (dd, J = 16.5 and 2.0 Hz, 1H), 6.60-
7.38 (m, 5H),* 7.45-7.54 (m, 2H), 7.56-7.65 (m, 1H), 8.06-8.12
(m, 2H). * It contains CHCl3 peak; 13C NMR (100 MHz, CDCl3):
δ 19.25, 19.82, 27.32, 63.06, 128.26, 128.45, 128.48, 128.56,
128.79, 129.12, 133.42, 136.47, 137.97, 165.80, 196.47; HRMS
(ESI): calculated for C20H21NO2H: 308.1651 (M+H)+, found:
308.1650 (M+H)+ and calculated for C20H21NO2Na: 330.1470
(M+Na)+, found: 330.1473 (M+Na)+
Fig. 1. ORTEP diagram of compound syn-1a.
4.3.2. (4S,5S)/(4R,5R)-4-(4-Chlorophenyl)-4-hydroxy-5-methyl-
3-methylene-1-phenylpyrrolidin-2-one (syn-1b). Reaction time: 5
h; Yield of diastereomeric mixture (syn-1b+anti-1b) (after
column purification): 79 %; diastereomeric ratio: 93:7; Yield of
syn-1b (after crystallization): 58 %; colorless solid; mp: 188-190
0C; Rf (30% EtOAc in hexanes): 0.36, IR (KBr): ν 3326, 1676,
1649, 1589 cm-1; 1H NMR (500 MHz, CDCl3): δ 1.21 (d, J = 6.5
Hz, 3H), 2.45 (s, 1H), 4.28 (q, J = 6.5 Hz, 1H), 5.53 (s, 1H), 6.38
(s, 1H), 7.23-7.28 (m, 1H)*, 7.35-7.43 (m, 6H), 7.48 (d, 2H,
4.3. Representative procedure
*
J=8.0 Hz), It contains CHCl3 peak; 13C NMR (100 MHz,
4.3.1.
(4S,5S)/(4R,5R)15-4-Hydroxy-5-methyl-3-methylene-1,4-
CDCl3): δ 12.38, 65.85, 76.36, 121.18, 124.38, 126.53, 127.74,
128.54, 129.05, 133.79, 136.79, 141.57, 147.84, 165.64; HRMS
(ESI): calculated for C18H16ClNO2Na: 336.0767 (M+Na)+, found:
336.0770 (M+Na)+.
diphenylpyrrolidin-2-one (syn-1a). DABCO (0.056 g, 0.5 mmol)
was added to a solution of N-(1-oxo-1-phenylpropan-2-yl)-N-
phenylacrylamide (0.139 g, 0.5 mmol) (2a) in dioxane : H2O
(1:1) (0.5 mL :0.5 mL) solvent system. Resulting reaction
mixture was heated at 65 °C, for 6 h (reaction monitored by
TLC) with stirring. The reaction mixture was diluted with water
(2 mL) and extracted with DCM (2 x 15 mL). Combined organic
layer was washed with water (10 mL) and dried over anhydrous
Na2SO4. Solvent was removed under reduced pressure. The
crude product thus obtained (in 93:7 diastereomeric ratio) was
subjected to column chromatography [silica gel, EtOAc:Hexanes
(30:70);] to provide the required Baylis-Hillman adduct 1a as
93:7 diastereomeric mixture (syn-1a: anti-1a) in 86 % (0.120 g)
isolated yield.
The major diastereomer (syn-1a) was obtained by crystallization
[ethyl acetate : hexanes (1:2)] of diastereomeric mixture (syn-
1a+anti-1a) (obtained through silicagel column chromatography)
in 60 % (0.083 g) yield as a colorless solid. Rf (30% EtOAc in
Fig. 2. ORTEP diagram of compound syn-1b.
0
4.3.2.1. Crystal data for syn-1b. empirical formula:
C18H16ClNO2; formula weight: 313.77; crystal color: colorless;
block; crystal dimensions: 0.36 X 0.24 X 0.12 mm3; crystal
system: tetragonal; unit cell parameters: a = 19.9759(18) Å, b =
19.9759(18) Å, c = 16.065(3) Å, α = 90.00, β = 90.00, γ = 90.00;
V = 6410.6(14) Å3; space group: I 41/a; Z = 16; D calcd = 1.300
g / cm3; F000 = 2624; λ(Mo-Kα) = 0.71073 Å; R (I ≥ 2σ1) =
0.0569; wR2 = 0.1411. Detailed X-ray crystallographic data is
available from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK (for compound syn-1b:
CCDC # 1491072).
hexanes): 0.36.; mp: 184-186 C; IR (KBr): ν 3227, 1687, 1650,
1
1594 cm-1; H NMR (500 MHz, CDCl3): δ 1.24 (d, J = 6.5 Hz,
3H), 2.32 (s, 1H), 4.34 (q, J = 6.5 Hz, 1H), 5.55 (s, 1H), 6.38 (s,
1H), 7.22-7.27 (m, 1H), 7.32-7.37 (m, 1H), 7.38-7.43 (m, 6H),
7.52-7.55 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 12.56, 65.78,
76.71, 120.90, 124.23, 126.14, 126.29, 127.86, 128.42, 129.00,
137.04, 143.12, 148.17, 165.68; HRMS (ESI): calculated for
C18H17NO2H: 280.1338 (M+H)+, found: 280.1332 (M+H)+ and
calculated for C18H17NO2Na:
302.1157 (M+Na)+, found:
302.1152 (M+Na)+.
4.3.1.1. Crystal data for syn-1a. empirical formula: C18H17NO2;
formula weight: 279.32; crystal color: colorless; block; crystal
dimensions: 0.36 X 0.24 X 0.12mm3; crystal system: tetragonal;
unit cell parameters: a = 20.2021(5) Å, b = 20.2021(5) Å, c =
14.6232(6) Å, α = 90.00, β = 90.00, γ = 90.00; V = 5968.1(3) Å3;
4.3.3.
(4S,5S)/(4R,5R)-4-Hydroxy-5-methyl-3-methylene-4-
(naphth-2-yl)-1-phenylpyrrolidin-2-one (syn-1c). Reaction time:
14 h; Yield of syn-1c+anti-1c (after column purification): 88 %;;
diastereomeric ratio: 94:6; Yield of syn-1c (after crystallization):
64 %; white solid; mp: 195-197 0C; Rf (30% EtOAc in hexanes):
space group: I 41/a; Z = 16; D calcd = 1.243 g / cm3; F000
=
0.38; IR (KBr): ν 3265, 1682, 1650, 1594 cm-1; H NMR (500
1
2368; λ(Cu-Kα) = 1.54184 Å; R (I ≥ 2σ1) = 0.0520; wR2 =
MHz, CDCl3): δ 1.26 (d, J = 6.5 Hz, 3H), 2.64 (s, 1H), 4.45 (q, J
0.1417. Detailed X-ray crystallographic data is available from the

7
= 6.5 Hz, 1H), 5.55 (s, 1H), 6.42 (s, 1H), 7.22-7.27 (m, 1H)*,
7.37-7.43 (m, 4H), 7.49-7.55 (m, 3H), 7.84-7.89 (m, 3H), 8.09 (d,
J = 1.5 Hz, 1H), * It contains CHCl3 peak; 13C NMR (100 MHz,
CDCl3): δ 12.56, 65.56, 76.89, 121.20, 124.15, 124.33, 125.35,
126.37, 126.46, 126.54, 127.63, 128.33, 128.39, 129.02, 132.84,
132.96, 137.00, 140.19, 148.15, 165.75; HRMS (ESI): calculated
for C22H19NO2Na: 352.1313 (M+Na)+, found: 352.1310
(M+Na)+.
60 h; Yield of syn-1g+anti-1g (after column purification): 77
ACCEPTED MANUSCRIPT
%; diastereomeric ratio: 96:4; Yield of syn-1g (after
crystallization): 56 %; white solid; mp: 170-172 C; Rf (30%
0
EtOAc in hexanes): 0.46; IR (KBr): ν 3260, 1676, 1649, 1600
cm-1; H NMR (500 MHz, CDCl3): δ 2.31 (s, 6H), 2.53-2.63 (m,
1
2H), 2.66 (s, 1H), 4.39 (dd, J = 7.0 and 3.5 Hz, 1H), 5.00-5.05
(m, 1H), 5.06-5.12 (m, 1H), 5.55 (s, 1H), 5.71-5.81 (m, 1H), 6.34
(s, 1H), 6.85-6.89 (m, 1H), 7.07 (s, 2H), 7.29-7.34 (m, 1H), 7.35-
7.40 (m, 2H), 7.47-7.50 (m, 2H) 13C NMR (100 MHz, CDCl3): δ
21.43, 33.29, 69.35, 77.00, 118.40, 120.27, 121.72, 125.35,
127.80, 128.24, 128.57, 134.27, 137.07, 138.82, 145.20, 148.67,
165.34; HRMS (ESI): calculated for C22H23NO2H: 334.1807
(M+H)+, found: 334.1810 (M+H)+.
4.3.4.
(4S,5S)/(4R,5R)-5-Ethyl-4-hydroxy-3-methylene-1,4-
diphenylpyrrolidin-2-one (syn-1d). Reaction time: 13 h; Yield of
syn-1d+anti-1d (after column purification): 84 %; diastereomeric
ratio: 95:5; Yield of syn-1d (after crystallization): 62 %; white
0
solid; mp: 124-126 C; Rf (30% EtOAc in hexanes): 0.40; IR
1
(KBr): ν 3210, 1682, 1660, 1594 cm-1; H NMR (500 MHz,
4.3.9. (4S,5S)/(4R,5R)-4-Hydroxy-5-iso-butyl-3-methylene-1,4-
diphenylpyrrolidin-2-one (syn-1h). Reaction time: 60 h; Yield of
syn-1h+anti-1h (after column purification): 82 %; diastereomeric
ratio: 96:4; Yield of syn-1h (after crystallization): 59 %; white
CDCl3): δ 0.81 (t, J = 7.5 Hz, 3H), 1.73-1.91 (m, 2H), 2.54 (s,
1H), 4.29 (dd, J = 8.5 and 3.5 Hz, 1H), 5.50 (s, 1H), 6.34 (s, 1H),
7.21-7.25 (m, 1H), 7.29-7.34 (m, 1H), 7.35-7.45 (m, 6H), 7.49-
7.54 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 10.49, 21.87,
70.88, 76.74*, 120.34, 124.07, 125.70, 126.32, 127.77, 128.50,
129.08, 137.51, 145.02, 149.07, 165.50, * It almost merges with
one of CDCl3 peak; HRMS (ESI): calculated for C19H19NO2H:
294.1494 (M+H)+, found: 294.1495 (M+H)+.
0
solid; mp: 160-162 C; Rf (30% EtOAc in hexanes): 0.32; IR
(KBr): ν 3232, 1682, 1650, 1594 cm-1; H NMR (500 MHz,
1
CDCl3): δ 0.61 (d, J = 6.5 Hz, 3H), 0.73 (d, J = 6.5 Hz, 3H),
1.32-1.40 (m, 1H), 1.55-1.66 (m, 1H)*, 1.78-1.85 (m, 1H), 2.39
(s, 1H), 4.39 (dd, J = 9.5 and 4.0 Hz, 1H), 5.47 (s, 1H), 6.34 (s,
1H), 7.23-7.27 (m, 1H)@, 7.30-7.35 (m, 1H), 7.36-7.43 (m, 6H),
4.3.5. (4S,5S)/(4R,5R)-4-(4-Chlorophenyl)-5-ethyl-4-hydroxy-3-
methylene-1-phenylpyrrolidin-2-one (syn-1e). Reaction time: 11
h; Yield of syn-1e+anti-1e (after column purification): 80 %;
diastereomeric ratio: 94:6; Yield of syn-1e (after crystallization):
63 %; white solid; mp: 148-152 0C; Rf (30% EtOAc in hexanes):
*
@
7.49-7.54 (m, 2H), It contains moisture peak,
It contains
CHCl3 peak; 13C NMR (100 MHz, CDCl3): δ 21.44, 23.56,
24.67, 37.83, 67.88, 76.84&, 120.79, 124.73, 125.93, 126.50,
&
127.68, 128.39, 129.02, 137.29, 144.38, 149.18, 165.57, It
almost merges with one of CDCl3 peak; HRMS (ESI): calculated
1
0.37; IR (KBr): ν 3205, 1682, 1654, 1594 cm-1; H NMR (500
for C21H23NO2H: 322.1807 (M+H)+, found: 322.1805 (M+H)+.
MHz, CDCl3): δ 0.78 (t, J = 7.5 Hz, 3H), 1.70-1.89 (m, 2H), 2.66
(s, 1H), 4.21 (dd, J = 8.5 and 3.5 Hz, 1H), 5.47 (s, 1H), 6.33 (s,
1H), 7.23-7.27 (m, 1H)*, 7.31-7.35 (m, 2H), 7.40 (d, J = 4.0 Hz,
4H), 7.44-7.48 (m, 2H), * It contains CHCl3 peak; 13C NMR (100
MHz, CDCl3): δ 10.51, 21.77, 70.96, 76.35, 120.68, 124.27,
126.56, 127.31, 128.60, 129.14, 133.65, 137.30, 143.50, 148.87,
165.37; HRMS (ESI): calculated for C19H18ClNO2Na: 350.0924
(M+ Na)+, found: 350.0928 (M+ Na)+.
4.3.10.
(4S,5S)/(4R,5R)-4-Hydroxy-5-iso-butyl-3-methylene-1-
phenyl-4-(4-methylphenyl)pyrrolidin-2-one (syn-1i). Reaction
time: 96 h; Yield of syn-1i+anti-1i (after column purification):
81 %; diastereomeric ratio: 96:4; Yield of syn-1i (after
0
crystallization): 56 %; white solid; mp: 190-192 C; Rf (30%
EtOAc in hexanes): 0.36; IR (KBr): ν 3265, 1682, 1650, 1589
cm-1; H NMR (500 MHz, CDCl3): δ 0.63 (d, J = 6.5 Hz, 3H),
1
0.73 (d, J = 6.5 Hz, 3H), 1.31-1.38 (m, 1H), 1.57-1.67 (m, 1H)*,
1.77-1.84 (m, 1H), 2.36 (s, 3H), 2.45 (s, 1H), 4.37 (dd, J = 9.5
and 4.0 Hz, 1H), 5.47 (s, 1H), 6.32 (s, 1H), 7.18 (d, J = 8.0 Hz,
2H), 7.22-7.27 (m, 1H)@, 7.36-7.41 (m, 6H); *It contains
moisture peak, @ It contains CHCl3 peak; 13C NMR (100 MHz,
CDCl3): δ 21.10, 21.55, 23.54, 24.70, 37.95, 67.80, 76.84,
120.54, 124.60, 125.79, 126.39, 128.98, 129.08, 137.37, 141.49,
149.19, 165.56; HRMS (ESI): calculated for C22H25NO2Na:
358.1783 (M+Na)+, found: 358.1783 (M+Na)+.
4.3.6.
(4S,5S)/(4R,5R)-5-Allyl-4-hydroxy-3-methylene-1,4-
diphenylpyrrolidin-2-one (syn-1f). Reaction time: 13h;
diastereomeric ratio: 96:4; Yield of syn-1f: 78 %; white solid;
0
mp: 130-133 C; Rf (30% EtOAc in hexanes): 0.45; IR (KBr): ν
3227, 1687, 1654, 1594 cm-1; H NMR (500 MHz, CDCl3): δ
1
2.40-2.80 (m, 3H), 4.45 (dd, J = 7.0 and 3.5 Hz, 1H), 5.02 (d, J=
10.0Hz, 1H,), 5.04-5.10 (m, 1H), 5.58 (s, 1H), 5.71-5.81 (m, 1H),
6.36 (s, 1H), 7.21-7.25 (m, 1H), 7.30-7.34 (m, 1H), 7.35-7.42 (m,
4H), 7.46-7.51 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 33.22,
69.31, 76.84, 118.32, 120.55, 123.86, 125.41, 126.29, 127.77,
128.50, 129.06, 134.04, 137.24, 145.08, 148.34, 165.48; HRMS
(ESI): calculated for C20H19NO2H: 306.1494 (M+ H)+, found:
306.1496 (M+ H)+.
4.3.11. (4S,5S)/(4R,5R)-4-Hydroxy-5-isopropyl-3-methylene-1,4-
diphenylpyrrolidin-2-one (syn-1j). Reaction time: 84 h; Yield of
syn-1j+anti-1j (after column purification): 83 %; diastereomeric
ratio: ˃99:˂1; colorless solid; mp: 160-162 0C; Rf (30% EtOAc in
1
hexanes): 0.42; IR (KBr): ν 3292, 1676, 1649, 1595 cm-1; H
4.3.7. (4R,5S)/(4S,5R)-5-Allyl-4-hydroxy-3-methylene-1,4-diphe-
nylpyrrolidin-2-one (anti-1f). Yield of anti-1f: 3 %; white solid;
NMR (500 MHz, CDCl3): δ 0.83 (d, J = 7.5 Hz, 3H), 1.04 (d, J =
7.0 Hz, 3H), 2.30-2.55 (m, 2H), 4.32 (d, J = 2.5 Hz, 1H), 5.60 (s,
1H), 6.37 (s, 1H), 7.17-7.22 (m, 1H), 7.30-7.40 (m, 7H), 7.46-
7.51 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 17.73, 19.98,
30.12, 74.60, 77.78, 118.65, 124.10, 124.99, 126.19, 127.88,
128.70, 128.87, 138.34, 146.77, 148.56, 165.58; HRMS (ESI):
calculated for C20H21NO2H: 308.1651 (M+H)+, found: 308.1647
(M+H)+.
0
mp: 147-150 C; Rf (30% EtOAc in hexanes): 0.36; IR (KBr): ν
3353, 1676, 1649, 1594 cm-1; H NMR (500 MHz, CDCl3): δ
1
1.89-1.96 (m, 1H), 1.98-2.06 (m, 1H), 2.90 (s, 1H), 4.34 (dd, J =
8.5 and 4.0 Hz, 1H), 4.49-4.56 (m, 1H), 4.61-4.66 (m, 1H), 4.91-
5.01 (m, 1H), 5.63 (s, 1H), 6.45 (s, 1H), 7.20-7.25 (m, 1H), 7.33-
7.42 (m, 5H), 7.53-7.61 (m, 4H); 13C NMR (100 MHz, CDCl3): δ
35.45, 70.61, 78.17, 117.67, 121.67, 123.74, 126.16, 127.81,
128.14, 128.33, 129.12, 132.51, 137.66, 139.43, 147.28, 165.43;
HRMS (ESI): calculated for C20H19NO2Na: 328.1313 (M+ Na)+,
found: 328.1317 (M+ Na)+.
4.3.12. N-Benzyl-N-(1-oxo-1-phenylpropan-2-yl)acrylamide (2k):
To a stirring mixture of 2-bromo-1-phenylpropan-1-one (2.13 g,
10.0 mmol) and benzylamine (2.14 g, 20.0 mmol) in acetonitrile
(10 mL), NaHCO3 (1.26 g, 15 mmol) was added. After stirring at
rt for 2 h (reaction monitored by TLC), the solvent was
evaporated and the reaction mixture was diluted with DCM (15
4.3.8. (4S,5S)/(4R,5R)-5-Allyl-1-(3,5-dimethylphenyl)-4-hydroxy-
3-methylene-4-phenylpyrrolidin-2-one (syn-1g). Reaction time:

8
Tetrahedron
ACCEPTED MANUSCRIPT
mL). The resulting organic layer was washed with water
J = 6.5 Hz, 3H), 0.91 & 0.95 (2t, J = 7.5 Hz, 3H), 1.26-1.55 (m,
(2x15 mL), and dried over anhydrous sodium sulphate and
concentrated under reduced pressure. The crude thus obtained
was used as such for the next step without any purification.
4H), 2.54 (bs, 1H), 2.95-3.09 (m, 1H), 3.70-3.87 (m, 2H), 5.37
& 5.49 (2s, 1H), 6.21 & 6.32 (2s, 1H), 7.29-7.34 (m, 1H), 7.34-
7.39 (m, 2H), 7.41-7.48 (m, 2H); 13C NMR (100 MHz, CDCl3): δ
11.76, 13.82, 13.86, 16.75, 20.17, 20.20, 29.43, 29.46, 40.15,
40.40, 64.04, 64.45, 76.65, 78.83, 119.69, 119.88, 126.21,
127.22, 127.59, 127.83, 127.99, 128.21, 140.77, 143.20, 147.73,
148.37, 166.34, 166.48; HRMS (ESI): calculated for
C16H21NO2H: 260.1651 (M+H)+, found: 260.1649(M+H)+. The
underlined chemical shift values with low intensity arise due to
the minor isomer. The ratio is determined by the integration of
isomeric olefinic proton signals at δ 6.32 & 6.21.
The crude, thus obtained, was dissolved in DCM (15 mL) and
the resulting solution was cooled at 0 ºC. To this stirring solution,
Et3N (1.11g, 11.0 mmol) was added followed by the dropwise
addition of acryloyl chloride (0.99 g, 11.0 mmol) at 0 ºC. After
stirring for 30 min at same temperature, the reaction mixture
was diluted with water (30 mL) and extracted with DCM (2 x 30
mL). Combined organic layer was dried over anhydrous Na2SO4
and concentrated. The residue thus obtained was purified by
column chromatography [silica gel, 20 % ethyl acetate in
hexanes] to afford the desired product 2k in 49% (1.44 g) yield
(over two steps), as a yellow viscous liquid. Rf (30% EtOAc in
hexanes): 0.48; IR (neat): ν 1686, 1644, 1613 cm-1; 1H NMR (400
MHz, CDCl3): δ 1.36 (d, J = 7.2 Hz, 3H), 4.60 & 4.72 (AB q, J =
18.0 Hz, 2H), 5.65 (dd, J = 10.0 and 2.4 Hz, 1H), 6.29 (q, J = 7.2
Hz, 1H), 6.35 (dd, J = 16.4 and 10.0 Hz, 1H), 6.45 (dd, J = 16.4
and 2.4 Hz, 1H), 7.09 (d, J = 6.8 Hz, 2H), 7.18-7.29 (m, 3H)*,
7.43 (t, J = 7.6 Hz, 2H), 7.55 (t, J = 7.6 Hz, 1H), 7.91-8.02 (m,
Acknowledgement: We thank Department of Science and
Technology (New Delhi) for funding this project. GCR and BL
thank Council of Scientific and Industrial Research (New Delhi)
and DST (New Delhi) for research fellowships, RTN is thankful
to University Grants Commission (UGC) (New Delhi) for
Kothari Post-doctoral research fellowship. We thank the UGC for
support and for providing instrumental facilities. We are grateful
to the National Single-Crystal X-ray facility funded by DST. We
also thank Professor S. Pal, School of Chemistry, University of
Hyderabad for helpful discussions regarding single crystal X-ray
data analysis.
2H), It contains CHCl3 peak; 13C NMR (125 MHz, CDCl3): δ
*
14.60, 47.91, 53.72, 126.08, 127.33, 127.76, 128.51, 128.69,
128.74, 129.68, 133.37, 135.51, 137.77, 167.27, 199.49; HRMS
(ESI): calculated for C19H19NO2H: 294.1494 (M+H)+, found:
294.1487(M+H)+.
References and notes
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4.3.13. N-Butyl-N-(1-oxo-1-phenylpropan-2-yl)acrylamide (2l):
Yield: 61 %; Rf (30% EtOAc in hexanes): 0.46;Yellow viscous
1
liquid; IR (neat): ν 1686, 1644, 1608 cm-1; H NMR (500 MHz,
CDCl3): δ 0.86 (t, J = 7.5 Hz, 3H), 1.18-1.48 (m, 7H), 3.10-3.30
(m, 2H), 5.73 (dd, J = 9.0 and 3.5 Hz, 1H), 6.19 (q, J = 7.0 Hz,
1H), 6.40-6.53 (m, 2H)*, 7.40-7.48 (m, 2H), 7.52-7.58 (m, 1H),
7.96-8.03 (m, 2H) * it contains one dd at δ 6.43 (J = 16.5 and 3.5
Hz) and one dd at δ 6.49 (J = 16.5 and 9.0 Hz), one of the peaks
of dd at δ 6.43 with high chemical shift value merges with one of
the peaks of dd at δ 6.49 with lower chemical shift value; 13C
NMR (125 MHz, CDCl3): δ 13.53, 14.40, 20.15, 33.44, 44.29,
53.26, 127.40, 128.38, 128.68, 128.97, 133.32, 135.40, 165.92,
199.22; HRMS (ESI): calculated for C16H21NO2H: 260.1651
(M+H)+, found: 260.1652(M+H)+.
4.3.14.
1-Benzyl-4-hydroxy-5-methyl-3-methylene-4-phenyl-
pyrrolidin-2-one (1k): Reaction time: 5 h; Yield of syn+anti
(after column purification): 83 %; syn:anti diastereomeric ratio:
83:17; white solid; Crystallization [from ethyl acetate : hexanes
(1:1)] of this mixture provided the BH adduct in 59 % yield :
in diastereomeric ratio: 97:3( syn:anti); white solid; mp: 160-161
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1
0C; IR (KBr): ν 3297, 1680, 1644 cm-1; H NMR (500 MHz,
CDCl3): δ 0.66 & 1.19 (2d, J = 6.5 Hz, 3H), 3.00 (bs, 1H), 3.58
& 3.63 (2q, J = 6.5 Hz, 1H), 4.07 (d, J = 15.0 Hz, 1H), 5.17 (d, J
= 15.0 Hz, 1H), 5.43 & 5.56 (2s, 1H), 6.28 & 6.39 (2s, 1H), 7.18-
7.40 (m, 10H), * It contains CHCl3 peak; 13C NMR (125 MHz,
CDCl3): δ 11.58, 44.32, 63.54, 76.62, 120.38, 126.21, 127.51,
127.64, 128.00, 128.11, 128.73, 136.05, 142.90, 148.13, 166.85
ppm. HRMS (ESI): calculated for C19H19NO2H: 294.1494
(M+H)+, found: 294.1496 (M+H)+. The underlined chemical shift
values with low intensity arise due to the minor isomer. The ratio
is determined by the integration of isomeric olefinic proton
signals at δ 6.39 & 6.28.
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4.3.15. 1-Butyl-4-hydroxy-5-methyl-3-methylene-4-phenylpyrro-
lidin-2-one (1l):. Reaction time: 7 h; Yield of syn+anti (after
purification by column chromatography): 86 %; syn:anti
diastereomeric ratio: 83:17; white solid; mp (mixture): 101-102
oC, Rf (30% EtOAc in hexanes): 0.22; IR (KBr): ν 3282,
1682,1644 cm-1; 1H NMR (500 MHz, CDCl3): δ 0.71 & 1.24 (2d,

9
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11) Detailed X-ray crystallographic data is available from the CCDC, 12
ACCEPTED MANUSCRIPT
Union Road, Cambridge CB2 1EZ, UK for compounds syn-1a (CCDC
# 1491071), syn-1b (CCDC # 1491072)
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)
with α-
bromopropiophenone was carried out following the literature procedure
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are mixture of syn and anti diastereomers.
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For reviews on Baylis-Hillman reaction, see: a) Santos, M. S.; Coelho,
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