Enantioselective tandem conjugate addition elimination reactions 2

Chapter 2
11










Chapter 2

Tandem Conjugate Addition-Elimination Reaction of Cyclic
Activated Allylic Bromides



Chapter 2
12
2.1 Reaction between 2-(bromomethyl)cyclopent-2-enone and dimethyl
malonate

2.1.1 Preliminary studies
As a starting point, a MBH allylic bromide 3 was prepared by an imidazole promoted
Baylis-Hillman reaction
1
between 2-cyclopentenone and formaldehyde followed by
bromination
2

using PBr
3
(Scheme 2.1). We subsequently chose this allylic bromide as the
target of initial studies, which focused on standardizing reaction conditions. To the best of
our knowledge, this MBH allylic bromide 3 has never been investigated as an
electrophile for any nucleophilic substitution or conjugate addition reaction before.
O
+HCHO
N
H
N
(1.0 eq)
THF-H
2
O(1:1,v/v),rt
O
OH
PBr
3
ether, 0
o
C
O
Br
32
1

Scheme 2.1 Synthesis of cyclic MBH allylic bromide 3.
We found that with 2 equivalents of triethylamine, the reaction between
2-(bromomethyl)cyclopent-2-enone (3) and dimethyl malonate completed in 24 hrs at

room temperature in CH
2
Cl
2
. Stoichiometric base was needed for this reaction as HBr
could be generated during the nucleophilic reaction process. It is worth noting that S
N
2’
product was obtained in an isolated yield of 85% while S
N
2 type product was not
observed (Scheme 2.2). Other dialkyl malonates such as diethyl malonate and
di-isopropyl malonate were also subjected to the reaction condition. However, the S
N
2′
type products were obtained only in moderate yields. Thus we focused on the reaction
between 3 and dimethyl malonate, which could be used as a model reaction for

1
S. Luo, B. Zhang, J. He, A. Janczuk, P. G. Wang and J-P. Cheng, Tetrahedron Lett., 2002, 43, 7369-7371.
2
H K. Yim, Y. Liao and H. N. C. Wong, Te trahedron, 2003, 59, 1877-1884.
Chapter 2
13
asymmetric studies.
O
Br
3
+
CO

2
Me
CO
2
Me
CH
2
Cl
2
,rt
O
MeO
2
C
CO
2
Me
4 S
N
2' type product
24hrs, 85% yield
O
CO
2
Me
CO
2
Me
S
N

2typeproduct
2eq.Et
3
N

Scheme 2.2 Reaction between 3 and dimethyl malonate.
To better understand how the S
N
2′ type product was formed, we particularly looked
at the mechanistic aspects of this reaction. Based on the results obtained and Lee’s
proposed mechanism
3
, we postulated that the reaction may proceed through a tandem
conjugate addition-elimination (C-AE) process (Scheme 2.3).
Model reaction:
O
Br
Et
3
N
O
NEt
3
Br
O
CO
2
Me
MeO
2

C
O
NEt
3
CO
2
Me
MeO
2
C
-Et
3
N
3
4
S
N
2' product
5
CO
2
Me
CO
2
Me
H
Et
3
N

Asymmetric version:
O
Br
ch iralamine
O
NR
3
Br
Nu
O
Nu
NR
3
*
*
*
3
6

Scheme 2.3 Proposed mechanism of tandem CA-E process.

In Scheme 2.3, an initial nucleophilic substitution by triethylamine on the bromide of
3 resulted in the formation of an ionic intermediate. Deprotonation of dimethyl malonate

3
H Y. Chen, L. N. Patkar, S H. Ueng, C C. Lin, A. S Y. Lee, Synlett, 2005, 13, 2035-2038.
Chapter 2
14
by triethylamine generated the carbon nucleophile. Subsequently, nucleophilic attack of
dimethyl malonate anion onto the β-carbon of the α,β-unsaturated double bond led to the

formation of the enolate 5. Finally, the elimination of the promoter would give rise to the
S
N
2′ type product 4. In contrast, the formation of the S
N
2 type product would be via the
direct nucleophilic substitution on the carbon adjacent to the leaving group.
Based on the results obtained from the model reaction between 3 and dimethyl
malonate, we are keen to develop an asymmetric tandem conjugate addition-elimination
(CA-E) reaction using chiral leaving group strategy (Scheme 2.3). Using a chiral tertiary
amine as the promoter, enantioselectivity could be achieved through a tandem CA-E
fashion.
2.1.2 Cinchona alkaloids promoted tandem CA-E reactions
Nowadays, Cinchona alkaloid and its derivatives have attracted lots of chemists’
attention and have been widely used as organocatalysts for various kinds of reactions
such as Michael reaction
4
, Henry reaction
5
, Mannich reaction
6
, Friedel-Crafts
7
reaction,
Diels-Alder reaction
8
and so forth.
With various kinds of commercially available Cinchona alkaloids (Figure 2.1), we
embarked on the study of asymmetric tandem CA-E reaction between 3 and dimethyl
malonate (Table 2.1). When 2 equivalents alkaloids such as quinidine and quinine were

employed, the reaction could reach 100% conversion according to TLC
9
after several

4
Selected examples of Michael reactions catalyzed by cinchona alkaloids: a) H. Li, Y. Wang, L. Tang, F. Wu, X. Liu, C.
Guo, B. M. Foxman and L. Deng, Angew. Chem. Int. Ed., 2005, 44, 105-108. b) M. Bella and K. A. Jørgenson, J. Am.
Chem. Soc., 2004, 126, 5672-5673. c) B. Vakulya, S. Varga, A. Csámpai and T. Soós, Org. Lett., 2005, 7, 1967-1969.
5
H. Li, B. Wang and L. Deng, J. Am. Chem. Soc., 2006, 128, 732-733.
6
a) J. Song, Y. Wang and L. Deng, J. Am. Chem. Soc., 2006, 128, 6048-6049. b) A. Ting, S. Lou and S. E. Schaus, Org.
Lett., 2006, 8, 2003-2006.
7
Y Q. Wang, J. Song, R. Hong, H. Li and L. Deng, J. Am. Chem. Soc., 2006, 128, 8156-8157.
8
Y. Wang, H. Li, Y Q. Wang, Y. Liu, B. M. Foxman and L. Deng, J. Am. Chem. Soc., 2007, 129, 6364-6365.
9
When the substrate spot on TLC disappeared on TLC, it was considered as 100% conversion. However, a big spot
was observed on the baseline (not corresponds to alkaloid), which was suspected to be the salt intermediate 6.
Chapter 2
15
hours at room temperature (entries 1 and 2). However, reaction yields were very poor
along with moderate enantioselectivities. It was deduced that the majority of substrate
remained as an ionic intermediate (Scheme 2.3, intermediate 6) after the initial
nucleophilic substitution of chiral promoter to the substrate. In addition, it was observed
that cinchonidine and cinchonine only promoted the reaction at very slow reaction rates.
Table 2.1 Cinchona alkaloid and its derivatives promoted tandem CA-E reactions.
O
Br

3
+
CO
2
Me
CO
2
Me
CH
2
Cl
2
,rt
O
MeO
2
C
CO
2
Me
2 eq. promoter
4
*

Entry Promoter Time(hr) Yield/%
a
ee/%
b

1

q
uinidine 1.5 52 25
2 quinine 3 34 36
3 hydroquinine 4 41 25
4
A
29 99 39
5
B
29 77 10
6
C
29 66 38
7
D
29 61 2
8
E
29 55 23
9
F
29 92 8
10
G
- No reaction -
a
Isolated yield.
b
Determined by chiral HPLC analysis.

Subsequently, the effects of several other commercially available alkaloids
hydroquinine and A-F (entries 3-9) were explored. As expected, these alkaloids did not
provide decent enantioselectivities although there was an improvement on the yield of the
reaction. The best results (99% yield and 39% ee) were obtained with a quinidine
derivative A as the promoter. It is interesting to note that when promoter G was employed,
Chapter 2
16
no product was observed.
N
H
N
HO
MeO
quinidin e
N
H
N
HO
MeO
quinine
NN
O O
N
N
MeO
R
N
OMe
N
R=CH

2
CH
3
A (DHQD)
2
Pyr
R
NN
O O
N
MeO
N
OMe
B (DHQ)
2
Pyr
N
CH
3
N
H
3
C
OO
N
Me O
N
OMe
N
CH

3
N
H
3
C
NN
C (DHQ)
2
PHAL
N
H
H
3
C
N
H
MeO
O
O
Cl
D
N
H
H
3
C
N
H
MeO
O

O
Cl
E
N
H
H
3
C
N
H
MeO
O
F
N
CH
3
N
H
N
HO
MeO
hydroquinine
N
H
NH
OMe
SHN
F
3
C CF

3
G

Figure 2.1 Cinchona alkaloid and its derivatives.
Furthermore, we surveyed the reaction between substrate 3 and dimethyl malonate
under a phase-transfer condition (Scheme 2.4). With 10 mol% N-benzylcinchonidinium
chloride as the phase-transfer catalyst (PTC) and 1M NaHCO
3
aqueous solution as the
Chapter 2
17
stoichiometric base, 3 reacted smoothly with dimethyl malonate in a very good yield but
with almost no enantioselectivity.
O
Br
3
+
CO
2
Me
CO
2
Me
CH
2
Cl
2
1M NaHCO
3
,rt

10mol% PTC
O
MeO
2
C
CO
2
Me
4
*
14 hrs, 99% yield
6% ee
N
H
N
HO
Ph
Cl
P
T
C

Scheme 2.4 Tandem CA-E reaction under PTC condition.
2.1.3 Other chiral tertiary amines as promoters
In order to find a suitable promoter for this tandem CA-E reaction, we also attempted
other chiral tertiary amines (Table 2.2), which are either commercially available or
synthesized molecules. However, chiral imidazoline (entry 1)
10
and a (-)-pseudoepherin
derivative (entry 2)

11
were proved to be ineffective promoters. Other two chiral tertiary
amines (entries 3, 4) could only promote this reaction at very slow reaction rate with very
poor enantioselectivies.
Table 2.2 Several chiral tertiary amines promoted tandem CA-E reaction.
O
Br
3
+
CO
2
Me
CO
2
Me
CH
2
Cl
2
,rt
O
MeO
2
C
CO
2
Me
2 eq. promoter
4
*

10
J. Xu, Y. Guan, S. Yang, Y. Ng, G. Peh, C H. Tan, Chemistry: An Asian Journal 2006, 1, 724-729.
11
Compound was prepared by the following procedures:
Ph
N
H
OH
+
Ph
O
Cl
CH
2
Cl
2
,Et
3
N
0
o
C-r t
Ph
N
OH
O
Ph
95% yield

LiAlH
4
THF, reflux
Ph
N
OH
Ph
79% yie ld

Chapter 2
18
Entry Promoter Time(hr) Yield/%
a
ee/%
b

1
N
N
P
h
-
Poor
conversion
-
2
Ph
N
OH
Ph

- No reaction
3
N
N
(
S
)
-
(
-
)
-Nicotine
24 33 3
4
Ph N

24 41 6
a
Isolated yield.
b
Determined by chiral HPLC analysis.

2.2 Chiral pyrrolidinyl sulfonamide (CPS).
2.2.1 Introduction
From the above results, we concluded that an efficient and highly selective promoter
was desirable for this tandem CA-E reaction. Therefore, we designed a class of
bi-functional promoters, chiral pyrrolindinyl sulfonamide (CPS) (Figure 2.2). This
promoter contains a tertiary amine which can undergo nucleophilic substitution with
MBH allylic bromide to form the salt intermediate 6. In addition, the acidic -NH group

might activate the carbonyl group of the substrate via hydrogen-bonding.
N
R
1
NH
nS
R
2
O
O
Nucleophilic amine
Hydrogen-bonding donor

Figure 2.2 Chiral pyrrolidinyl sulfonamide (CPS).
Chapter 2
19
As organocatalysts, simple and versatile chiral sulfonamides available for various
catalytic asymmetric reactions have been developed recently. Wang and co-workers
reported that a chiral sulfonamide 7 (Figure 2.3), which resembles L-proline, could be
utilized as an organocatalyst for enantioselective Michael addition reaction of aldehydes
and ketones towards nitroolefins
12
. 7 also serves as an effective organocatalyst for
promoting direct, highly enantioselective Aldol reactions of α,α-dialkylaldehydes with
aromatic aldehydes
13
. In addition, 7 can catalyze α-selenenylation and α-sulfenylation
reactions in which L-proline shows poor catalytic activity
14
. The enhanced catalytic

activity and enantioselectivity for these reactions promoted by 7 are due to the acidic and
sterically bulky properties of the trifluoro-methanesulfonamide group
11b
.
Another bifunctional chiral sulfonamide 8 (Figure 2.3) was firstly reported by Nagao
to achieve a highly enantioselective thiolysis of prochiral cyclic dicarboxylic anhydride
15
.
Impressively, only 5 mol% catalyst 8 was required for the reaction between cyclic
anhydride and 1.2 equivalents benzyl mercapten (BnSH).
N
H
NHTf
7
Ph
Ph
H
N
N
S
O
2
CF
3
F
3
C
8
O
2

S
i
Pr
i
Pr
i
Pr
NH
O
Si
t
Bu
Ph Ph
N
N
NH
NHTf
9
10

Figure 2.3 Various sulfonamides as organocatalysts.
Ishihara also disclosed that an L-histidine derived chiral sulphonamide 9 acted as an

12
a) W. Wang, J. Wang and H. Li, Angew. Chem. Int. Ed., 2005, 44, 1369-1371. b) J. Wang, H. Li, B. Lou, L. Zu, H.
Guo and W. Wang, Chem. Eur. J., 2006, 12, 4321-4332.
13
W. Wang, H. Li and J. Wang, Tetrahedron Lett., 2005, 46, 5077-5079.
14
J. Wang, H. Li, Y. Mei, B. Lou, D. Xu, D. Xie, H. Guo and W.Wang, J. Org. Chem., 2005, 70, 5678-5687.

15
T. Honjo, S. Sano, M. Shiro and Y. Nagao, Angew. Chem. Int. Ed., 2005, 44, 5838-5841.
Chapter 2
20
artificial acylase for the kinetic resolution of racemic alcohols
16
. Polymer-bound catalyst
was also prepared and reused more than 6 cycles without loss of activity. This could be a
practical method to prepare chiral diols or chiral amino alcohols.
An attractive direct Mannich reaction catalyzed by an axially chiral amino
sulfonamide 10 was recently reported by Maruoka for the synthesis of anti-β-amino
aldehyde
17
. Excellent enantioselectivities (>99%) with high anti-selectivies could be
achieved by employing only 2 mol% chiral catalyst. Sulfonamide 10 has also been found
to catalyze the syn-selective direct asymmetric cross-aldol reactions between aldehydes.
Similarly, with the use of 5 mol% of catalyst 5, excellent levels of enantioselectivities (92
to 99%) and syn/anti ratios (up to >20/1) were obtained for the rare example of a
syn-selective direct cross-aldol reaction via an enamine intermediate
18
. The use of
catalyst loadings as low as 5 mol% or lower makes organocatalysts almost as competent
as the traditional organometallic catalysts, which are well known for their low catalysts
loading.
Inspired by these chiral sulfonamides catalyzed highly enantioselective reactions; we
were keen to utilize our designed chiral pyrrolidinyl sulphonamide (CPS) on the tandem
CA-E reaction.
2.2.2 Synthesis of chiral pyrrolidinyl sulfonamide (CPS)
The CPS promoters could be prepared via two different routes as presented in
Scheme 2.5 and 2.6. In Scheme 2.5, N-sulfonyl aziridines were readily prepared from

their corresponding commercially available chiral amino alcohols
19
. The regioselective

16
K. Ishihara, Y. Kosugi and M. Akakura, J. Am. Chem. Soc., 2004, 126, 12212-12213.
17
T. Kano, Y. Yamaguchi, O. Tokuda and K. Maruoka, J. Am. Chem. Soc., 2005, 127, 16408-16409.
18
T. Kano, Y. Yamaguchi, Y. Tanaka and K. Maruoka, Angew. Chem. Int. Ed., 2007, 46, 1738-1740.
19
a) W. Ye, D. Leow, S. L. M. Goh, C T. Tan, C H. Chian and C H. Tan, Tetrahedron Lett., 2006, 47, 1007-1010. b)
B. M. Kim, S. M. So, H. J. Choi, Org. Lett., 2002, 4, 949-952.
Chapter 2
21
ring opening reaction using pyrrolidine or piperidine afforded the desired CPS promoters.
In 3 steps, the CPSs can be obtained in multigram quantities and high yields. In Scheme 2.6,
the amino group of L-tert-leucinol was protected using Boc anhydride and 2M NaOH
solution. Boc-L-tert-leucinol 12 was then coupled with pyrrolidine or piperidine using
HOBt and DCC. The intermediate 13 was then subjected to deprotection condition
followed by reduction to afford the chiral diamine 15. The final step involved a protection
step using p-TsCl or other kinds of sulfonyl chlorides.
OH
NH
2
R
1
i
N
NHR

2
R
1
N
R
1
R
2
ii
n
11a-k

Scheme 2.5 Synthesis of CPS promoters from chiral amino alcohols. Reagents and
conditions: (i) R
1
= Bn: p-TsCl or other sulfonyl chlorides, Et
3
N, CH
3
CN; R
1
=
t
Bu:
p-TsCl or other sulfonyl chlorides, Et
3
N, CH
3
CN, MS(4A), 0
o

C then MsCl, DMAP, Et
3
N,
CH
2
Cl
2
, rt; (ii) pyrrolidine or piperidine, CH
3
CN, reflux.

OH
NHBoc
R
1i
O
NH
R
1
O
N
Boc
ii
NH
2
R
1
O
N
OH

NH
2
R
1
O
iii
NH
2
R
1
N
iv v
N
NHR
2
R
1
n
n
n
n
11a-e,11k R
1
=Bn
11f-j,R
1
=
t
Bu
12

13 14
15

Scheme 2.6 Synthesis of CPS promoters from chiral amino acids. Reagents and
conditions: (i) (Boc)
2
O, 2M NaOH, 0
o
C to rt; (ii) pyrrolidine or piperidine, HOBt, DCC,
THF, 0
o
C to rt; (iii) 3M HCl in EtOAc; (iv) LiAlH
4
, THF, rt to reflux; (v) p-TsCl or other
sulfonyl chlorides, DMAP, Et
3
N, CH
2
Cl
2
, 0
o
C to rt.

Comparing two synthetic pathways, the first one makes use of chiral amino alcohols
whereas the second involves chiral amino acids. As the number of steps in Scheme 2.6 is
more than twice than that of Scheme 2.5, the synthetic route employing chiral amino
Chapter 2
22
acids would be more time-consuming with a lower overall yield. However, this may

provide an easy way to install various sulfonyl groups onto the amino group to afford the
CPS promoters containing same R
1
group. Considering the efficiency, the first route
(Scheme 2.5) was the preferred synthetic pathway and it was used for the synthesis of
most of the promoters used in the following research.

2.3 Chiral Pyrrolidinyl sulphonamide (CPS) promoted tandem CA-E
reactions

2.3.1 Reaction between 2-(bromomethyl)cyclopent-2-enone and 1,3-dicarbonyl
compounds

It was found that with 2 equivalents CPS 11a, the tandem CA-E product 4 was
obtained in 41% isolated yield and 78% ee (Scheme 2.7). However, the reaction was too
slow to be useful. We have recently found that S,S'-dialkyl dithiomalonates are effective
donors for chiral bicyclic guanidine catalysed Michael reactions
20
due to the high
α-proton acidity. Thus, we envisaged that S,S'-dialkyl dithiomalonate could be an enol
equivalent with high reactivity.
O
Br
+
CO
2
Me
CO
2
Me

CH
2
Cl
2
,rt
O
MeO
2
C
CO
2
Me
*
3
N
Bn
NHTs
11a
2eq
4
4days, 41%yield,78%ee

Scheme 2.7 CPS 11a promoted reaction between 3 and dimethyl malonate.
Firstly, we examined the reaction between 3 and S,S'-di-n-propyl dithiomalonate 16a
by employing a variety of promoters listed in Figure 2.4. As a reliable starting point,
these reactions were conducted in dichloromethane at room temperature (Table 2.3).

20
W. Ye, Z. Jiang, Y. Zhao, S. L. M. Goh, D. Leow, Y T. Soh and C H. Tan, Adv. Synth. Catal., 2007, 349, 2454-2458.
Chapter 2

23
N
Bn
NHTs
N
NHTs
N
NHTs
11a
11f
11g
11h
NH
MesO
2
S
N
N
Bn
NH
BnO
2
S
11b
N
Bn
NHNs
Ns = p-nitrobenzenesulfonyl
11c
NH

MesO
2
S
N
Bn
Mes = 2,4,6-trimethylphenyl
11d
NH
MesO
2
S
N
Bn
11e
NH
N
Bn
S
HN CF
3
CF
3
11k
NH
RO
2
S
N
R = 2,4,6-triisopropylphenyl
11i

NH
MesO
2
S
N
OMe
11j

Figure 2.4 Various CPSs.

As expected, reaction with S,S'-di-n-propyl dithiomalonate 16a as the donor could
complete within 1 day and provided satisfactory results (Table 2.3, entry 1). There was no
improvement of enantioselectivity when the Ts group of CPS 11a was replaced by BnSO
2

(entry 2) or Nosyl group (entry 3). When we installed a bulky 2,4,6-trimethylphenyl
group onto the promoter, the enantioselectivity increased by 10% along with very good
yield (entry 4). CPS 11e with a pipridine ring was proven to be ineffective (less than 20%
conversion after 24 hours) so 11g was not investigated in this part. Moreover, the results
obtained with promoter 11f revealed that a bulkier tert-butyl group would be essential to
the enantioselectivity of the reaction. Finally, we observed the best results with CPS 11h
(entry 7) and it was used in the subsequent studies. It is interesting to note that CPS 11i,
which contains a bulkier protecting group, produced almost the same ee value as that of
11h. When we installed an extra chiral center on the CPS 11i, the enantioselectivity
slightly decreased (entry 9). We also attempted combining chiral pyrrolidine with
Chapter 2
24
thiourea
21
, which was known as an activator of carbonyl group by double hydrogen

bonding interactions. Although 66% yield was obtained after 22 hours (entry 10), the
selectivity dropped by 11% comparing with that of 11a.
Table 2.3 CPS promoted reaction between 3 and S,S'-di-n-propyl dithiomalonate 16a
a
.
O
Br
+
COS
n
Pr
COS
n
Pr
316a
CH
2
Cl
2
,rt
2eqpromoter
O
n
PrSOC
COS
n
Pr
17a

Entry Promoter Time(hr) Yield/%

b
ee/%
c

1
11a
22 57 68
2
11b
22 58 62
3
11c
15 99 67
4
11d
15 95 78
5
d

11e
18 - -
6
11f
4 77 71
7
11h
16 96 79
8
11i
21 63 78

9
11j
28 51 61
10
11k
e

22 66 47
a
Two equivalents of the 16a were used to react with one equivalent of 3.
b
Isolated yield.
c
Determined by chiral HPLC analysis. The absolute configuration was determined by
single crystal X-ray analysis, see Experimental chapter.
d
Slow reaction.
e
11k was
prepared by mixing chiral diamine 15 with corresponding isothiocyanate.

When 2 equivalents CPS 11h were employed, various S,S'-dialkyl dithiomalonates
were observed to participate in the reaction with 3, giving the tandem CA-E products
17b-g in moderate to good yields (Table 2.4). Most of dithiomalonates gave similar levels
of yield and ee except S,S'-dibenzyl dithiomalonate, which is a very unreactive donor for

21
P. M. Pihko, Angew. Chem. Int. Ed. 2004, 43, 2062-2064.
Chapter 2
25

this reaction. Since S,S'-di-tert-butyl dithiomalonate (16f) produced the best results, it
was used for the optimization of the reaction conditions. It is noteworthy that a less
hindered donor, S,S'-diethyl dithiomalonate, afforded the tandem CA-E product with 84%
ee (entry 1). However, lowering the temperature to 0
o
C and -20
o
C slowed the reaction
rate considerably without any improvement in enantioselectivity.
Table 2.4 CPS 11h promoted reaction between 3 and various S,S'-dialkyl
dithiomalonates.
O
Br
+
COSR
COSR
3
CH
2
Cl
2
,rt
2eq11h
O
RSOC
COSR
16b-g 17b-g

Entry R Product Time(hr) Yield/%
a

ee/%
b

1 Et
17b
5 59 84
2
n
Hex
17c
22 80 83
3
c
Bn
17d
- - -
4 Cy
d

17e
24 89 85
5


t
Bu
17f
19 90 90
6 CPh
3

17g
40 62 85
a
Isolated yield.
b
Determined by chiral HPLC analysis.
c
Very slow reaction.
d
Cyclohexyl.
Solvent effect was studied by screening various solvents at room temperature using 2
equivalents CPS 11a (Table 2.5, entries 1-6). It was found that non-polar solvents such as
toluene resulted in a low yield of 15% even after 48 hours of reaction time (entry 1). The
low yield could be attributed to the low solvating power of toluene, as it could not fully
dissolve all the starting materials as well as promoter 11a. Reactions in chlorinated
solvents such as CH
2
Cl
2
(entry 2) and CHCl
3
(entry 3) were much faster with 54% and
46% ee respectively. When THF (entry 4) was used, there was a slight decrease of ee.
Chapter 2
26
The best results were obtained with a polar solvent, CH
3
CN (88% isolated yield, 59% ee).
Thus, we believed that polar solvents would be preferred in the chiral tandem CA-E

reaction by solvating the starting materials and promoters well enough, and increasing the
nucleophilicity of the promoters to achieve reasonably high yields. Nonetheless, when the
reaction was conducted in another polar solvent, DMSO (entry 6), the ee decreased to
28%.
Table 2.5 Optimization of tandem CA-E reaction between 3 and S,S'-di-tert-butyl
dithiomalonate 16f.
O
Br
+
COS
t
Bu
COS
t
Bu
3
solvents, rt
2eqpromoter
O
t
BuSOC
COS
t
Bu
16f 17f


Entry Solvent CPS(equiv.) Time(hr) Yield/%
a
ee/%

b

1
c
toluene 48 15 44
2 CH
2
Cl
2
18 74 54
3 CHCl
3
24 88 46
4 THF 21 74 42
5 DMSO 2.5 85 28
6 CH
3
CN
11a(2.0)
16 88 59
7 11f(2.0) 14 97 73
8 11g(2.0) 20 74 70
9
CH
3
CN
11h(2.0) 12 97 90
10 11h(1.5) 12 97 90
11
CH

3
CN
11h(2.5) 10 91 90
a
Isolated yield.
b
Determined by chiral HPLC analysis.
c
Very slow reaction.

Other CPSs (11f-h) were also investigated with CH
3
CN as the solvent (entries 7-9).
Optimization based on making structural changes to CPS revealed that the tert-butyl group
increases the enantioselectivity of the reaction (entry 7). When the pyrrolidine ring was
Chapter 2
27
replaced by a piperidine, there was a slight decrease of both yield and ee (entry 8). As
expected, the most hindered CPS 11h promoted the reaction smoothly with the best yield
and ee value (entry 9). The loading of CPS promoter could be reduced to 1.5 equivalents
while the yield and enantioselectivity were maintained at a satisfactory level (entry 10). We
also examine the reaction with only 1.1 equivalents CPS 11h, but the reaction did not go to
completion even after 28 hours.
Table 2.6 1.5 equivalents 11h promoted tandem CA-E reaction between 3 and 16f under
other conditions.

Entr
y
Solvent Conditions Time
(

hr
)
Yield/%
a
ee/%
b

1 CH
3
CN reflux 1 99 86
2 CH
3
CN Microwave,100
o
C 15min 99 77
3 H
2
O rt 7 99 0
a
Isolated yield.
b
Determined by chiral HPLC analysis.

It is known that in many cases of asymmetric catalysis, lowering temperature could
be beneficial to the selectivity. However, the tandem CA-E reactions were generally slow
at low temperatures. Therefore, we attempted several other conditions to reduce the
reaction time and while maintaining the enantioselectivity. To our surprise, the tandem
CA-E reaction could proceed even at reflux condition but the ee only dropped 4% (Table
2.6, entry 1). Under microwave condition, 77% ee could be obtained in only 15 minutes.
However, the results in H

2
O were quite disappointing as no enantioselectivity was
obtained though the reaction was fast (entry 3). A possible explanation for the low ee
could be that H
2
O might have acted as a H-bond acceptor to form H-bonding with the NH
group of the promoter, thereby weakening any H-bonds formed between the CPS and 3.
As a consequence, the ionic intermediate formed between the CPS and 3 would not be
locked in a particular conformation to favor the attack of the nucleophile from a
Chapter 2
28
particular face.
Table 2.7 11h promoted reaction between 3 and various diketones or ketoesters.
O
Br
+
COR
2
COR
1
3
CH
3
CN, rt
1.5 eq 11h
O
R
2
OC
COR

1
18a-h 19a-h

Entry 18[R
1
, R
2
] Product Time(hr) Yield/%
a
ee/%
b

1 18a[Me, Me]
19a
24 42 88
2 18b[Ph, Ph]
19b
42 16 94
3
c

18b 19b
38 39 94
4 18c[Ph, OEt]
19c
27 47 91,94
5
d

18c 19c

44 72 91,94
6 18d[p-NO
2
Ph, OEt]
19d
30 33 95,93
7
d
18e[p-CF
3
Ph, OEt]
19e
84 85 96,93
8 18f[p-ClPh, OEt]
19f
27 69 95,89
9 18g[o-MeOPh, OEt]
19g
30 63 96,93
10 18h[p-MePh, OEt]
19h
27 55 95,93
a
Isolated yield.
b
Determined by chiral HPLC analysis.
c
Reaction at 40
o
C with 2 equiv.

CPS 11h.
d
Reaction with 2 equiv. CPS 11h.

In the mean time, we were delighted to find that other kinds of 1,3-dicarbonyl
compounds 18a-h could be suitable donors for the reaction (Table 2.7). In entries 2,3,5
and 7, two equivalents CPS 11h were required as these reactions were generally slow. In
Table 2.7, tandem CA-E products 19a-h were obtained in moderate to good yields,
though the ee values were higher than that of S,S'-dialkyl dithiomalonates Those
reactions employing ketoesters (entries 4-10) afforded the products with diastereomeric
ratios of approximately 1:1. In order to improve the yield of these reactions, we also
Chapter 2
29
examined conditions at 40
o
C with 2 equivalents 11h (entry 3). Nevertheless, the reaction
still could not go to completion though the enantioselectivity was maintained. Other
1,3-dicarbonyl compounds listed in Figure 2.5 were proved to be ineffective donors.
Therefore, we focused on searching for other reactive donors such as bulky S,S'-dialkyl
dithiomalonates and keto-thioesters.
O
O
Ph
CF
3
CN
CN
O
O
CN

CO
2
Et
NO
2
CO
2
Et
NO
2

Figure 2.5 Other unreactive donors for tandem CA-E reaction with 3.
With the optimized conditions, a series of 1,3-dicarbonyl compounds were explored
as nucleophiles towards 3 (Table 2.8). Since S,S'-di-tert-butyl dithiomalonate could
provide very good enantioselectivity, we tested other bulkier S,S'-dialkyl dithiomalonates
such as 20a (entry 1) and 20b (entry 4). Both two donors reacted smoothly with high
yield and ee values. However, the reaction of S,S'-di-adamantyl dithiomalonate 20b was
carried out in CH
2
Cl
2
as the starting material was not soluble in CH
3
CN.
We were concerned about the high amounts of CPS required for this reaction.
Fortunately, the CPS promoter 11h could be recovered with 90% yield, using a simple
acid-base workup. It can also be reused without further purification, for two further
cycles without loss of yield and enantioselectivity of the product 21a (entries 2,3). This
could be a milestone as less amounts of CPS are needed for developing a number of
tandem CA-E reactions.

Table 2.8 11h promoted tandem CA-E reaction between 3 and 1,3-dicarbonyl compounds
under optimized conditions.
Chapter 2
30
O
Br
+
COR
2
COR
1
3
CH
3
CN, rt
1.5 eq 11h
O
R
2
OC
COR
1
20a-e 21a-e


Entry 20[R
1
, R
2
] Product Time(hr) Yield/%

a
ee/%
b

1
20a[R
1
= R
2
=
S
]
21a
16 83 94
2
c

20a 21a
21 74 94
3
d

20a 21a
21 87 95
4
e

20b[R
1
= R

2
=
S
]
21b
44 77 97
5

20c[Ph, S
t
Bu]
21c
26 91 94,94
6 20d[4-MeOPh, S
t
Bu]
21d
23 89 98,95
7 20e[Me, S
t
Bu]
21e
43 76 94,94
8
20f
O
O

21f
29 60 98,95

a
Isolated yield.
b
Determined by chiral HPLC analysis.
c
Recovered 11h, 2
nd
cycle.
d
Recovered 11h, 3
rd
cycle.
e
Reaction in CH
2
Cl
2
.

Other 1,3-dicarbonyl compounds such as keto-thioesters were proved to be effective
donors for this reaction (entries 5-7). As discussed in Table 2.5, while the
enantioselectivities obtained from ketoesters were generally high, the reactions always
suffered from slow reaction rates and low yields. We replaced ketoester with ketothioester,
which revealed the same concept using S,S'-dialkyl dithiomalonates. The ketothioesters
were prepared by heating 1,3-dioxin-4-ones with tert-butyl thiol
22
. When S-tert-butyl
ketothioesters such as 20c-e were employed, tandem CA-E reactions were significantly
faster and products 21c-e were obtained in high yields and ees, with diastereomeric ratios

22
J i. Sakaki, S. Kobayashi, M. Sato and C. Kaneko, Chem. Pham. Bull., 1990, 38, 2262-2264.
Chapter 2
31
of approximately 1:1. Interestingly, when 2-acetylcyclopentanone 20f was subjected to
this reaction, high enantioselectivity was also observed (entry 8).
2.3.2 Reaction between other cyclic allylic bromides/chlorides and 1,3-dicarbonyl
compounds
+HCHO
N
H
N
(1.0 eq)
THF-H
2
O (1:1, v/v), rt
AcCl
MeOH , 0
o
C
O
O OH
O Cl
22a
Ac
2
O
Ch
2
Cl

2
,Et
3
N
O OAc

Scheme 2.8 Synthesis of 22a.

In order to determine the scope of this reaction, we prepared several allylic bromides
or chlorides of different ring sizes (22a-c). As presented in Scheme 2.8, allylic chloride
22a was synthesized through a Baylis-Hillman reaction followed by protection and
chlorination. This substrate was much easier to handle than its corresponding allylic
bromide, which was unstable under the reaction conditions and led to many side
products.
Under the optimized conditions, we investigated the tandem CA-E reaction between
22a-c and S,S'-di-tert-butyl dithiomalonate (Table 2.9). The reactions between 22a-c and
16f were promoted by 11h and gave slightly lower levels of enantioselectivities than 3.
These reactions were much slower and yields were much lower when they were conducted
at room temperature. Increasing reaction temperature improved the reaction rate without
affecting the enantioselectivity. Under reflux condition and with 2 equivalents of 11h, we
were able to improve the yield to a moderate level. Reaction of cycloheptenone 22c was
still carried out at room temperature as product 23c was found to be unstable at elevated
Chapter 2
32
temperature. Double addition products, derived from the addition of a second 1,3-dicarbonyl
donor onto 23a-c, were found to be major side products in these reactions.
Table 2.9 11h promoted tandem CA-E reaction between cyclic MBH allylic bromides
and S,S'-di-tert-butyl dithiomalonate.

O

R R
X
n
+
22a
n=1, R=H, X=Cl
22b n=1, R=Me, X=Br
22c
n=2,
R
=H,
X
=Br
16f
11h
(2 equiv. )
CH
3
CN, reflux
O
R R
n
O
S
t
BuO
S
t
Bu
23a-c

COS
t
Bu
COS
t
Bu


Entry Substrate Product Time(hr) Yield/%
a
ee/%
b

1
22a 23a
11 40 74
2
22b 23b
20 37 88
3
c

22c 23c
29 46 94
a
Isolated yield.
b
Determined by chiral HPLC analysis.
c
Reaction at room temperature.

In order to expand the substrate scope of the methodology, we have also attempted
other kinds of cyclic allylic bromides which structurally resemble 3. Therefore, we
synthesized substrates 24-26 (Scheme 2.9), hoping that similar level of
enantioselectivities could be obtained.
Substrates 24 and 25, which are lactone analogs of 3, were prepared by a
Baylis-Hillman reaction involving paraformaldehyde followed by bromination using PBr
3
.
When 24 and 25 were subjected to the tandem CA-E reaction condition, no S
N
2′ type
products were observed. Instead, the reaction between these two substrates and
S,S'-di-tert-butyl dithiomalonate gave pure S
N
2 type product.
Chapter 2
33
X
O
+ (HCHO)
n
THF, rt
1eqDABCO
X
O
24,X=O
25
,
X

=S
OH
ether, 0
o
C
PBr
3
X
O
Br

N
O
O
Ph
1. Ph
3
P, Ac OH
2. (HCHO)
n
, reflux, 1h
N
O
O
Ph
Br
2
,CH
2
Cl

2
0
o
C-rt
N
O
O
Ph
Br
Br
CH
2
Cl
2
,rt
Et
3
N
N
O
O
Ph
Br
26

Scheme 2.9 Synthesis of other cyclic allylic bromides 24-26.
Table 2.10 Reaction between 26 and S,S'-diethyl dithiomalonate (16b), S,S'-di-tert-octyl
dithiomalonate (20a) or ethyl benzoylacetate (18c).

N

O
O
Ph
Br
26
+
COR
1
COR
2
CH
2
Cl
2
,rt
promoters
N
O
O
Ph
R
1
OC
COR
2
27

Entry Donor
Promoter
(equiv.)

Time(hr) Yield/%
a

1
16b
DABCO(2.0) 2 min 16
b

2
16b
Et
3
N(2.0) 0.5 31
3
c

16b
Et
3
N(1.5) 2 20
4
d

16b
11h (1.5) - -
5
20a
Et
3
N(1.5) 1 43

6
18c
Et
3
N(1.5) 3 57
a
Isolated yield.
b
100% conversion after 2min, white precipitate formed during the
reaction.
c
Reaction at -20
o
C.
d
Very slow reaction.

Similarly, the reaction between substrate 26 and 1,3-dicarbonyl compounds always
Chapter 2
34
produced undesired product 27, which could be an isomerization product under basic
condition (Table 2.10 and Scheme 2.10). The possible reason could be that product 27,
which contains an endo-conjugate system, was thermodynamically preferred comparing
with the exo-conjugated tandem CA-E product.
N
O
O
Ph
Br
26

+
COR
1
COR
2
N
O
O
Ph
R
1
OC
R
2
OC
N
O
O
Ph
R
1
OC
COR
2
27
H
:B
N
O
O

Ph
R
1
OC
COR
2
tandem CA-E
+BH
B
H

Scheme 2.10 Formation of side product in the reaction between 26 and 1,3-dicarbonyl
compounds.

In the mean time, we have attempted to prepare several other cyclic allylic bromides
(Figure 2.6). However, we were not successful in synthesizing these substrates, most of
which have not been reported so far. Therefore, we decided to investigate the other
reaction partner, the nucleophiles.
O
O
O
Br
O
O
Br
O
O
Br
O
Br

N
O
Br
Ph
O
O
Br

Figure 2.6 Other cyclic allylic bromides.
2.3.3 Reaction between 2-(bromomethyl)cyclopent-2-enone and N-nucleophiles.

The feasibility of using N-containing compounds as nucleophiles for the tandem
conjugate CA-E reaction with 3 was first explored. The achiral environment was
achieved with 2 equivalents triethylamine and using CH
2
Cl
2
as the solvent (Table 2.11).
Chapter 2
35
Experimental results showed that while some cyclic amides (entries 1-4) afforded S
N
2′
type products with reasonable yields, nucleophiles in entries 6-9 gave S
N
2 type products.
Another amide which contains two trifluoroacetyl groups (entry 5) was proved to be an
ineffective donor for this reaction. In addition, only primary sulfonamide nucleophile
could react with 3 in a tandem CA-E fashion and yield S
N

2′ type product. Pure S
N
2 type
products were obtained when secondary sulfonamides such as
N-phenyltoluenesulfonamide (entry 11) and N-phenylmethanesulfonamide (entry 12)
were employed. According to the proposed mechanism discussed in Scheme 2.3, we
deduced that steric hindrance could be a factor influencing the type of products obtained.
Less hindered nucleophiles such as succinamide and maleimide could undergo tandem
CA-E reaction after the initial attack of triethylamine to the substrate 3. Nonetheless,
those bulky N-containing compounds preferred direct nucleophilic attack towards the
carbon next to the leaving group Br. However, the actual reason behind this observation
is not known and further studies would be required to better understand the selectivity of
different nucleophiles forming different products.
Table 2.11 Reaction between 3 and N-containing compounds in an achiral environment.
a

O
Br
3
+Nu
CH
2
Cl
2
,rt
2eq E t
3
N
O
Nu

O
Nu
S
N
2' type S
N
2type

Entry Nucleophile Time(hr) Yield%
b
Product
1
H
N
O
O

4 64
S
N
2′ type
2
H
N
O
O

2 90
S
N

2′ type