A dimethylsulfonium methylide mediated highly regioselective olefination of conjugated polyolefin 1,1-dioates to conjugated polyene-2-yl-malonates and their applications in Diels-Alder reactions

Article abstract of DOI:10.1016/j.tet.2010.02.013

The reactions between dimethylsulfonium methylide and 1,3-diene- or 1,3,5-triene-1,1-dioates under specific conditions enable the highly regioselective tandem ylide addition-eliminative olefination to provide 1,3-butadien-2-yl- or 1,3,5-hexatriene-2-yl-malonates. Alkylation at malonate methine carbon of 1,3-butadien-2-ylmalonates with a suitable alkyl halide having in-built functionalities for a dienophile generation led to quick assembly of precursors for type 2 intramolecular Diels-Alder reaction. Syntheses of functionalized bicyclo[n.3.1] alkenes (n=5 or 6) with the double bond at the bridgehead position have been achieved via the IMDA. An asymmetric version of this reaction has been developed using a MacMillan's imidazolidinone catalyst, which provided a bicyclo[5.3.1] alkene with very high enantioselectivity. In situ methylation at malonate methine carbon of 1,3,5-hexatriene-2-yl-malonates followed by intermolecular Diels-Alder reaction with N-methylmaleimide provided the cycloadduct with complete regiocontrol and high diastereoselectivity.

Full text of DOI:10.1016/j.tet.2010.02.013

Tetrahedron 66 (2010) 2284–2292
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A dimethylsulfonium methylide mediated highly regioselective olefination
of conjugated polyolefin 1,1-dioates to conjugated polyene-2-yl-malonates
and their applications in Diels–Alder reactions
*
Rekha Singh, Sunil K. Ghosh
Bio-Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 January 2010
Received in revised form 1 February 2010
Accepted 1 February 2010
Available online 4 February 2010
The reactions between dimethylsulfonium methylide and 1,3-diene- or 1,3,5-triene-1,1-dioates under
specific conditions enable the highly regioselective tandem ylide addition–eliminative olefination to
provide 1,3-butadien-2-yl- or 1,3,5-hexatriene-2-yl-malonates. Alkylation at malonate methine carbon of
1,3-butadien-2-ylmalonates with a suitable alkyl halide having in-built functionalities for a dienophile
generation led to quick assembly of precursors for type 2 intramolecular Diels–Alder reaction. Syntheses
of functionalized bicyclo[n.3.1] alkenes (n¼5 or 6) with the double bond at the bridgehead position have
been achieved via the IMDA. An asymmetric version of this reaction has been developed using a Mac-
Millan’s imidazolidinone catalyst, which provided a bicyclo[5.3.1] alkene with very high enantiose-
lectivity. In situ methylation at malonate methine carbon of 1,3,5-hexatriene-2-yl-malonates followed by
intermolecular Diels–Alder reaction with N-methylmaleimide provided the cycloadduct with complete
regiocontrol and high diastereoselectivity.
Keywords:
Dimethylsulfonium methylide
Regioselective
olefination
Diels–Alder reactions
Organocatalysis
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
reaction of the ylide 1 with the Michael acceptor 2 gives a betaine
intermediate 3, which in principle can undergo various reactions
Carbon–carbon double bond forming reactions play important
role in organic synthesis and a large number of methods have been
developed over the past century. Amongst these, ylide mediated
olefin synthesis from carbonyl compounds especially with phos-
phorus stabilized carbanions such as Wittig1 and related reactions2
are frequently used. In comparison, dimethylsulfonium methylide
(popularly known as Corey–Chaykovsky reagent),3 generated from
a trimethylsulphonium salt and a base behaves differently. It is
known to react with an aldehyde or a ketone to give an epoxide by
an overall methylene insertion. Some interesting transformations
are reported when excess reagent was used leading to the forma-
tion of allylic alcohol by further addition of the ylide on the epox-
ide.4 In line with the carbonyl compounds, imines give aziridines
and then further get transformed to allylic amines with excess of 1.5
The ylide also acts as a nucleophile and can be used for the
conversion of halides and mesylates to one-carbon homologated
terminal alkenes.6 Although phosphorus ylides sometimes add in
1,4-fashion to suitably functionalized Michael acceptors,7 dime-
thylsulfonium methylide has been widely used to add on Michael
acceptors in 1,4-fashion to provide cyclopropanes.3 Thus, the
(Scheme 1), the driving force in all cases being the elimination of
Me2S. The most well known amongst these is the formation of
cyclopropane 4 (path ‘a’ Scheme 1). The other possible mode
of reaction which could be envisioned from the intermediate 3 is
the loss of a proton and Me2S in the presence of excess base
resulting in the formation of an olefin 5 (path ‘b’). While the
formation of cyclopropane 4 following path ‘a’ has been well
studied, olefination by path ‘b’ is not. We have recently reported8 an
interesting observation that 1 in combination with a base, like so-
dium dimsylate, undergoes a tandem ylide addition–eliminative
olefination on various activated olefins thus favoring path ‘b’. Thus,
the combination also acted as an equivalent of carbene anion.9 This
strategy has been used in sequential tandem olefination–alkylation
for the preparation of 1-substituted vinyl silanes, styrenes and
products derived from them.10 The methodology has been
R
Me
Me
H
H
E1
E2
S
E1
E2
R
H
'a'
1
4
+
E1
E2
'b'
base
R1X
Me
R
S
R
E1
E2
R1
Me
3
5
2
* Corresponding author.
Scheme 1. Two modes of reactions of dimethylsulfonium methylide with Michael
E-mail address: ghsunil@barc.gov.in (S.K. Ghosh).
acceptors.
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.013

R. Singh, S.K. Ghosh / Tetrahedron 66 (2010) 2284–2292
2285
extended for sequential tandem double olefination of vinyl phos-
phonates and aldehydes to provide di and tri substituted 1,3-dienes
with very high regio- and stereoselectivity.11
suffer from poor regioselectivity or low yield and, in some cases,
require starting materials that are not readily accessible. More re-
cently, attractive alternative methods such as Barbier-type cou-
pling25,28c and ethylene–alkyne cross-metathesis28b,d have been
reported for their preparation. However, although efficient, few
methods are applicable to the synthesis of 2-substituted 1,3-buta-
dienes where a quick assembly of a dienophile fragment can be made
to perform T2IMDA. We have found out conditions for a regiose-
lective nucleophilic addition (1,4-addition) of dimethylsulfonium
methylide in combination with a base or excess of itself (a carbene
anion equivalent9) to 1,3-diene 1,1-dioates 6 (Scheme 2) providing
1,3-diene-2-yl-malonates.
When 4-phenyl dienedioate 6a was added to ylide 1, generated
using 1.2 equiv of Me3SI and 2.5 equiv sodium dimsylate in DMSO/
THF (3:7) under the reported conditions,8 we obtained a mixture of
diene 8a, vinylcyclopropane 13a, and the thiomethyl product 14a
(8a/13a/14a¼50:20:30) (Scheme 4; Table 1, entry 1). The diene 8a
and the vinylcyclopropane 13a were also inseparable. Although, the
formation of the cyclopropane 13a could be curbed (Table 1) by
increasing the quantities of the base (3–4 equiv) and the salt (1.5–
2.5 equiv) (Table 1, entries 2 and 3), the formation of the thiomethyl
product 14a29 could not be minimized. Besides, sodium dimsylate is
known for its explosive nature. Therefore, we modified10b the
procedure for the generation of the ylide 1 by using n-BuLi in THF
instead of sodium dimsylate. As n-BuLi is reactive, it cannot be used
in excess. Instead, excess ylide was generated using 3 equiv each of
n-BuLi and trimethylsulfonium iodide in THF at ꢀ10 ꢁC. When
4-phenyl dienedioate 6a was added to excess ylide (3 equiv),
generated by the modified procedure, the dienic product 8a was
formed in very good yield (96%) (Scheme 5). The reaction was
highly regioselective and the dienic product 9 could not be detected
as 1,6-addition of ylide 1 did not take place. Moreover, if the
reaction was quenched with MeI (5 equiv) before work up, meth-
ylated product 15a was obtained in 87% yield.
We were curious to know whether this novel olefination is ap-
plicable to extended conjugated system like 1,3-diendioates 6 or
1,3,5-triendioates 7 and if so formation of which regioisomer
(Scheme 2) will dominate? Although, the conjugate addition12 of
carbon or heteroatomic nucleophilic reagents to activated olefins is
a highly useful reaction in organic synthesis, the regioselectivity issue
viz. 1,4-addition versus 1,6-addition13–16 sometimes becomes chal-
lenging to extended conjugate systems. This report is the full version
of our preliminary communication17 relating to the first example of
tandem 1,4-addition–elimination of ylide 1 to 4-aryl/alkyl sub-
stituted 1,3-diendioates 6 to give 1,3-butadien-2-yl-malonates 8,
a novel class of dienes with a functionality at 2-position amenable for
further maneuvering and/or quick lodging of a dienophile fragment.
We also report that this technique can be extended for regioselective
olefination of 1,3,5-trienedioates 7 under specific conditions to pro-
vide 1,3,5-hexatriene-2-yl-malonates 10. Intramolecular type 2 DA
(T2IMDA) reaction with former class of products and intermolecular
DA with latter class of products also provided interesting bridged
bicyclo[n.3.1] and fused ring systems, respectively.
CO2Et
CO2Et
1,4-addition
R
8
CH
path "a"
path "b"
b
R
a
CO2Et
CO2Et
6
CO2Et
CO2Et
R
1,6-addition
9
C
Et
O2
1,4-addition
R
R
10
C
O Et
2
path "a"
CH
a
c
b
CO2Et
11 CO2Et
1,6-addition
path "b"
CO2Et
CO2Et
R
e
M 3SI
CO2Et
CO2Et
Ph
Ph
Na-dimsylate
Me2S=CH2
7
8a
path "c"
+
CO2Et
12 CO2Et
1
CO2Et
CO2Et
1,8-addition
CO2Et
CO2Et
R
Ph
13a
6a
SMe
CO2Et
CO2Et
+
Scheme 2. Probable olefination pathways of 1,3-diendioates or 1,3,5-triendioates with
ylide 1.
Ph
14a
2. Results and discussion
Scheme 4. Reaction of diendioate 6a with ylide
1
generated from Me3SI and
Na-dimsylate.
Bicyclo[n.3.1] alkenes with multiple functionalities and
a bridgehead double bond are found in a number of biologically
important natural products including paclitaxel (taxol),18 phomoi-
drides (CP molecules),19 esperamicin,20 and other classes of natural
products.21 Amongst the few available direct methods,22 the
T2IMDA reaction23 (Scheme 3) is the most efficient one to assemble
a bridged bicyclic framework, incorporating a bridgehead double
bond24 (anti-Bredt olefin). The syntheses of these ring systems via
T2IMDA proceed with predictable regio- and stereoselectivity.
For T2IMDA, the dienophile component is attached to 2-position
of the 1,3-diene with an appropriate tether. For this, 1,3-butadienes
substituted with suitable functionality at 2-position is a prerequisite,
which would enable the attachment of the dienophile fragment. A
number of methods have been developed for their preparation.25–28
Many of these methodologies involve organometallic species such as
1,3-butadienyl-2-metal26 or 2,3-butadienyl-1-metal,27 which often
Table 1
Tandem addition–eliminative olefination on 6a mediated by Me3SI and
Na-dimsylate
Entry
Na-dimsylate (equiv)
Me3SI (equiv)
8a/13a/14aa
1
2
3
4
2.5
3
4
1.2
1.5
2.5
3
50:20:30
74:db:26
78:db:22
45:30:25
3
a
Determined from crude product by 1H NMR.
b
Peaks for 13a could not be seen in the 1H NMR spectrum of the crude reaction
mixture.
C
Et
O2
1.
Ph
CO2Et
R
6a
Me SI + n-Bu
Li
CO2Et
CO2Et
96%
3
Ph
3 equiv
2. H3O+ or MeI
type 2 IMDA
8a; R = H
15a; R = Me 87%
Scheme 3. Schematic representation of T2IMDA.
Scheme 5. Reaction of diendioate 6a with ylide 1 generated from Me3SI and n-BuLi.

2286
R. Singh, S.K. Ghosh / Tetrahedron 66 (2010) 2284–2292
To find the generality of the olefination–alkylation process,
By quenching the reaction with a suitable alkyl halide, which
has desired tether length and an in-built dienophile, or has the
capability to provide one, the system would be ideally suited for
T2IMDA. The cycloadduct from T2IMDA reaction would be the
bicyclo[n.3.1] alkene with a bridgehead double bond and the size of
the bridge would depend upon the tether length. As a model study,
the olefination product 8a was deprotonated using sodium hydride
and reacted with the substituted benzyl bromide 16,30 which pro-
vided the alkylated diene 15j in excellent yield (Scheme 6). The
benzyl bromide in turn was prepared from o-cresol as shown in
Scheme 7. For this, sodium phenolate of o-cresol was alkylated with
bromoacetaldehyde diethyl acetal in the presence of catalytic
amount of tetrabutylammonium iodide to give the acetal 17, which
in turn underwent benzylic bromination to bromide 16 by N-bro-
mosuccinimide initiated by dibenzoyl peroxide in CCl4. The acetal
group in 15j was hydrolyzed (Scheme 6) and the resulting aldehyde
18 was subjected to Knoevenagel condensation with malononitrile
catalyzed by triphenylphosphine31 under solvent-free condition at
80 ꢁC. Interestingly, a domino32 Knoevenagel–T2IMDA sequence
a few diendioates 6b–e (Table 2) were prepared from the com-
mercially available substituted cinnamaldehydes by Knoevenagel
condensation with diethyl malonate. When these substrates were
reacted with dimethylsulfonium methylide 1, generated using
n-BuLi and trimethylsulfonium iodide, the desired products 15b–e
were isolated in good yields after methylation (Table 2). Methoxy
substituent in the aryl ring and methyl substituent at position-3 of
the diendioates did not retard the reaction (Table 2, entries 2–5).
The substituent at position-4 of the diene 6 may not necessarily to
be an aryl group, e.g., Me in diene 6f (Table 2, entry 6), and Me and
an alkyl group in 6g (Table 2, entry 7) also gave the desired
methylated products 15f and 15g, respectively. The stereochemistry
of the double bond at g,d position remained unaffected during the
process. The (E)-stereochemistry of this double bond in products
15a–d was assigned from the 1H coupling constants (Jz16 Hz). The
starting dienes 6e and 6g were contaminated with 18% and 35% of
(Z)-isomer, respectively. Thus the products 15e and 15g were also
contaminated with the isomeric product in the same proportions.
When the reaction between 6a and ylide 1 was quenched with
3 equiv of allyl and benzyl bromides, the corresponding alkylated
products 15h (74%) and 15i (53%) were isolated. The lower yields
are probably due to protonation of the malonate carbanion by the
byproducts formed due to decomposition of the excess ylide used
in the reaction. The yields were therefore improved (Table 2; en-
tries 8 and 9) by adding anhydrous K2CO3 into the reaction mixture
prior to addition of bromides.
OEt
O
1. NaH, THF
Br
EtO
Ph
Et
CO2Et
CO2Et
Ph
C
O2 CO2Et
15j
8a
OEt
OEt
O
16
95%
s
T HO
2
CH (
)
C
N
2
PPh3, 802oC
O
O
Me C ,
H
2O
O
reflux
H
Table 2
67%
Ph
97%
Sequential tandem sulfonium ylide addition–eliminative olefination–alkylation of
diendioates 6
Et C
O2
CO2Et
18
Entry
1
Substrate
Product
CO2Et
CO2Et
Yielda (%)
87
H
nOe
H
Ph
H
O
NC
O
C
NC
N
C
CO2Et
CO2Et
Ph
Ph
EtO2C
Ph
Me
15a
Et
O2
NC
6a
EtO C
CO2Et
2
CO2Et
CO2Et
CO2Et
19
o-MeOC6H4
15b
o-MeOC6H4
m-MeOC6H4
p-MeOC6H4
2
3
4
CO2Et
81
88
85
Me
Scheme 6. Synthesis of a bicyclo[6.3.1] alkene by T2IMDA.
6b
CO2Et
CO2Et
CO2Et
1. NaH, THF
m-MeOC6H4
15c
CO2Et
Me
2. BrCH2CH(OEt)2
Bu4NI, DMF, 80 °C
1. NBS, Bz2O2
6c
Me
O
Me
OH
CCl4, hν, reflux
Br
OEt
OEt
OEt
OEt
CO2Et
CO2Et
CO2Et
O
84%
85%
p-MeOC6H4
15d
CO2Et
Me
17
16
6d
Scheme 7. Synthesis of substituted benzyl bromide 16.
Me CO2Et
e
M
CO2Et
CO2Et
Ph
Ph
CO2Et
5
6
78
68
Me
15e
6e
CO2Et
CO2Et
CO2Et
CO2Et
Me
Me
Me
15f
6f
CO2Et
CO2Et
CO2Et
CO2Et
7
8
65
83b
81c
Me
Me
15g
Me
6g
C
Et
O2
CO2Et
CO2Et
Ph
Ph
Ph
Ph
CO2Et
6a
15h
CO2Et
CO2Et
Ph
CO2Et
CO2Et
9
6a
15i
a
Isolated yield.
3 equiv each of K2CO3 and allyl bromide used.
3 equiv each of K2CO3 and benzyl bromide used.
b
c
Figure 1. ORTEP plot of two molecules of 19þCDCl3.

R. Singh, S.K. Ghosh / Tetrahedron 66 (2010) 2284–2292
2287
provided the bridged bicyclic product 19 with a bicyclo[6.3.1] al-
kene in good yield. The stereochemical feature of 19 was de-
termined by COSY and ROESY analysis and was further confirmed
by X-ray crystallography33 as shown in Figure 1.
therefore, converted aldehyde 22 to
a
,
b
-unsaturated aldehyde 24
by reacting with formylmethylenetriphenylphosphorane37 and
then subjected under T2IMDA in the presence of 20 mol % of
MacMillan’s imidazolidinone catalyst 25 (Scheme 9). We were de-
lighted to find that a facile cycloaddition took place to provide the
corresponding bicyclo[5.3.1] aldehyde 26 in good yield and as
a single diastereoisomer with excellent enantioselectivity. The en-
antiomeric purity (92% ee) of the product 26 was ascertained
by chiral HPLC analysis of the corresponding benzoate 28, obtained
by borohydride reduction of the aldehyde to alcohol 27 followed by
benzoylation with benzoyl chloride. The stereochemical feature of
28 was also determined by ROESY analysis and 1H coupling con-
stant values (Scheme 9). The absolute stereochemistry of the
product 26 was not determined but tentatively assigned to be 6R,7S
following MacMillan’s T2IMDA outcome.35
Inspired by this, we next aimed to make the lower homologue,
bicyclo[5.3.1] alkene system. For this, diene-2-yl malonate 8a was
reacted with sodium hydride in DMF and the resulting anion was
alkylated with 5-tert-butyldimethylsilyloxypentyl iodide 20,34
which provided the desired alkylated product 15k in excellent
yield (96%) (Scheme 8). Silyl deprotection with p-toluenesulfonic
acid in aqueous ethanol gave the alcohol 21, which on Swern oxi-
dation provided the corresponding aldehyde 22 in very good yield.
Following the domino32 Knoevenagel–T2IMDA procedure de-
veloped for aldehyde 18 to bridged bicyclic product 19, when al-
dehyde 22 was treated with malononitrile in the presence of
catalytic amount of triphenylphosphine31 under solvent-free con-
ditions at 80 ꢁC, the bridged bicyclo[5.3.1] alkene 23 was produced
in moderate yield.
Subsequent to our studies on the olefination of dienedioates,
similar reactions between the trienedioates 7a,b and dimethylsulfo-
nium methylide 1 were attempted. The trienedioates were pre-
pared by Knoevenagel condensation of diethyl malonate with
dienic aldehydes 29a,b (Scheme 10), which in turn were prepared
by Wittig reaction of formylmethylenetriphenylphosphorane37
with cinnamaldehyde and 3-(2-methoxyphenyl)-propenal, re-
spectively. When trienedioate 7a was added to dimethylsulfonium
methylide, generated using 4 equiv each of Me3SI and n-BuLi in THF
under the established conditions for dien-1,1-dioates 6, we were
gratified to obtain only one regioisomeric olefin product 30a
formed by exclusive addition of the ylide in 1,4-fashion followed by
eliminative olefination and methylation, as the reaction was
quenched by adding methyl iodide (Scheme 11). Similarly, the
trien-1,1-dioate 7b also provided the olfination product 30b in good
yield after methylation. Formation of 1,6 and 1,8 addition products
viz. 11 and 12, respectively, could not be detected in both the cases.
These trienic products 30a,b were not very stable and decompose
on storing even at lower temperature. So for their characterization,
these trienes were individually reacted with N-methylmalemide to
give the Diels–Alder adducts 31a,b in excellent regioselectivity and
yield. The stereochemistry of the major diastereoisomer 31a was
assigned to be all cis on the basis of ROESY interactions between Ha
and Hc protons (Scheme 11). These adducts were contaminated
CO2Et
CO2Et
1. NaH, DMF
CO2Et
CO2Et
Ph
Ph
TBDMSO
2.
I
3
8a
3
20
96%
TBDMSO
15K
TsOH
1. DMSO, (COCl)2,
CH2Cl2, -60 °C
CO2Et
EtOH, H2O
reflux
Ph
CO2Et
2. Et3N
67%
3
87%
HO
°C
-60
to r.t.
21
CO2Et
CO2Et
H
H
Ph
H
CH2(CN)2,
CO2Et
Ph
2
OHC
22
NC
°C
PPh3, 80
61%
CN
23
CO2Et
Scheme 8. Synthesis of a bicyclo[5.3.1] alkene by T2IMDA.
Bicyclo[5.3.1] alkenes are the key structural feature in many
natural and biologically important molecules. They also possess
a number of chiral centers depending upon the substituents. At this
stage it was therefore imperative to induce asymmetry during the
build up of the bicyclo skeleton. MacMillan and co-workers35 have
shown that their imidazolidine derived catalysts can activate a,b-
Ph3P=CHCHO
Bz, reflux
CHO
Ar
CHO
unsaturated carbonyl compounds as dienophiles as well as impart
enantioselectivity in type 1 and 2 IMDA reactions. Shea and co-
workers36 have also used similar strategy to introduce asymmetry
while building bicyclo[n.3.1] alkenes by T2IMDA reactions. We,
Ar
Ar = Ph
Ar = Ph; 29a
68-70%
Ar = 2-MeO-C6H4-; 29b
Ar = 2-MeO-C6H4-
CH2(CO2Et)2
CO2Et
CO2Et
Ar
CO2Et
CO2Et
Piperidinium
benzoate
Bz, reflux
CO2Et
CO2Et
Ph
Ph3PCH=CHO
Ph
Ar = Ph; 7a
Ar = 2-MeO-C6H4-; 7b
OHC
2
Bz, reflux
65%
2
OHC
22
56-60%
24
Scheme 10. Synthesis of triene-1,1-dioates.
O
Me
Ph
N
N
CO2Et
1. Ar
H
Bu-t
25 20 mol%
Ph
EtO2C CO2Et
CO2Et
Me3SI
+
7
Ph
O
CO2Et
Ar
Me
N
N
C Et
O2
n-BuLi
(4 equiv)
TsOH, CHCl
3
2. MeI 80-87%
Ar = Ph; 30a
Me
t-Bu
61%
Ar = 2-MeO-C6H4-; 30b
nOe
Ph
H
O
Me
O
Hc
H
H
EtO2C
N
H
H
Et
O2
C
e
N M
O
NaBH4
Hb
Ph
CHO
J = 9 Hz
CO2Et
CO2Et
O
EtO2C
Ar
CH2OR
R = H; 27
EtOH
80%
EtO2C
Ha
Me
Ar = Ph; 31a
Ar = 2-MeO-C6H4-; 31b
Scheme 11. Reaction of trien-1,1-dioates with ylide 1.
Bz, reflux
74-80%
Bz
Cl
26
Py
86%
R = Bz; 28
Scheme 9. Chiral synthesis of a bicyclo[5.3.1] alkene by T2IMDA.

2288
R. Singh, S.K. Ghosh / Tetrahedron 66 (2010) 2284–2292
with small amounts (w25%) of the 1,2-trans diastereoisomer since
the trienedioates were contaminated with the 3,4-cis isomer in the
same proportion.
F2 using SHELX-9738 software. Non-hydrogen atoms were refined
with anisotropic thermal parameters. All hydrogen atoms were
geometrically fixed and allowed to refine using a riding model.
3. Conclusions
4.2. General procedures
The reactivities of alkylidene malonates with extended conju-
gation for dimethylsulfonium methylide mediated olefination have
been thoroughly investigated. The studies have shown that in all
cases the sulfonium ylide adds to the alkylidene malonates exclu-
sively in 1,4-fashion leading to 1,3-butadien-2-yl- or 1,3,5-hexa-
triene-2-yl-malonates. No other regioisomer formation was
observed. This study led to the synthetically valuable intermediates
suitable for quick assembly of dienophiles thus ready for a T2IMDA.
The ability of this methodology has been demonstrated by syn-
thesizing a bicyclo[6.3.1] dodecene and bicyclo[5.3.1] undecene
skeletons efficiently in a domino Knoevenagel–T2IMDA sequence
with excellent stereocontrol. An asymmetric version of the T2IMDA
using a chiral organocatalyst has been achieved with very high
enantio- and diastereocontrol. 1,3,5-Hexatriene-2-yl-malonates
also underwent DA cycloaddition with N-methylmalimide with
very high regio- and stereoselectivity.
4.2.1. General procedure I. Preparation of dienals 29a,b. A mixture of
a,b-unsaturated aldehyde (10 mmol, 2 equiv) and formylmethyl-
enetriphenylphosphorane37 (1.52 g, 5 mmol, 1 equiv) in benzene
(15 mL) was heated at 80 ꢁC argon atmosphere. After 17 h, the re-
action mixture was concentrated under reduced pressure and the
residue was purified by column chromatography on silica-gel using
hexane/ethyl acetate as eluent to give dienals 29a,b39 (68–70%).
4.2.2. General procedure II. Preparation of dienoates 6a–g. A mix-
ture of a,b-unsaturated aldehyde (7 mmol, 1 equiv), diethyl malo-
nate (1.06 mL, 7 mmol, 1 equiv), piperidine (0.14 mL, 1.4 mmol,
0.2 equiv), and benzoic acid (171 mg, 1.4 mmol, 0.2 equiv) in ben-
zene (16 ml) was refluxed for 3 h under a Dean-Strake apparatus.
The reaction mixture was brought to room temperature, washed
with water, and evaporated under vacuum. The residue was puri-
fied by column chromatography on silica-gel using hexane/ethyl
acetate as eluent to give the dienoates 6a–g (60–90%).
4. Experimental
4.2.3. General procedure III. Preparation of trienoates 7a,b. A solu-
tion of the appropriate dienal 29 (2.08 mmol, 1 equiv), diethyl
4.1. General details
malonate (0.32 mL, 2.08 mmol, 1 equiv), piperidine (42 mL,
n-BuLi (1.6 M in hexane) solution was purchased from Aldrich.
All reactions were carried out in flame-dried glasswares under
an atmosphere of high purity nitrogen/argon. THF was dried over
Na/benzophenone ketyl. Trimethylsulfonium iodide was purchased
from Spectrochem, India. Solvent removal was carried out using
a rotary evaporator connected to a dry ice condenser. TLC (0.5 mm)
was carried out using home made silica plates with fluorescence
indicator. Column chromatography was performed on silca gel
(230–400 mesh).
0.42 mmol, 0.2 equiv), benzoic acid (51 mg, 0.42 mmol, 0.2 equiv)
in benzene (10 mL) was refluxed in a Dean-Starke apparatus for 3 h.
The reaction mixture was concentrated on rotary evaporator and
the residue was purified by chromatography on silica-gel using
hexane/ethyl acetate as eluent to give trienoates 7a,b40 (56–60%).
4.2.4. General procedure IV. Preparation of 1,3-dienes 15a–i. To
a ꢀ10 ꢁC suspension of Me3SI (612 mg, 3 mmol) in THF (3 ml) was
added n-BuLi (3 mmol, 1.9 mL of 1.6 M hexane solution). After
15 min, appropriate diendioate 6 (1.0 mmol) in THF (3 mL) was
introduced and the reaction mixture was slowly allowed to warm
to room temperature. After 1 h, the reaction mixture was cooled on
an ice-water bath and methyl iodide (0.32 mL, 5 mmol) or allyl
bromide/benzyl bromide (3 mmol) was added and stirred at am-
bient temperature for 15 h. The reaction mixture was diluted with
water and extracted with diethyl ether. The combined extracts
were washed with brine, dried over magnesium sulfate, filtered,
and concentrated under vacuum. The residues were purified by
column chromatography on silica-gel using hexane/ethyl acetate as
eluent to give the dienes 15a–i.
1H and 13C NMR spectra were recorded in either a 200 MHz (1H:
200 MHz, 13C: 50 MHz) or 500 MHz (1H: 500 MHz, 13C: 125 MHz)
Bruker spectrometers. 1H and 13C shifts are given in parts per mil-
lion,
d scale and are measured relative to internal CHCl3 and CDCl3
as standards, respectively. High resolution mass spectra were
recorded at 60–70 eV on a Waters Micromass Q-TOF spectrometer
(ESI, Ar) or on a Bruker Daltonics Micro TOF-Q spectrometer (ESI,
N2). Optical rotations were recorded on a JASCO DIP-370 Polarim-
eter. Enantiomeric excess (ee) determinations were carried out by
HPLC using a JASCO (JASCO PU-2080) instrument fitted with
a Daicel chiralpak AD-H column and UV-2075 detector with l fixed
at 254 nm. Elemental analyses were performed at the Hydromet-
allurgy Division, Bhabha Atomic Research Centre, Mumbai. The IR
spectra were recorded with a JASCO FT IR spectrophotometer in
NaCl cells or in KBr discs. Peaks are reported in cmꢀ1. Melting points
(mp) were determined on a Fischer John’s melting point apparatus
and were uncorrected. Imidazolidinone catalyst 2535 and for-
mylmethylenetriphenylphosphorane37 were prepared following
the literature procedures.
4.2.5. General procedure V. Preparation of 1,3,5-trienes 30a,b. To
a ꢀ10 ꢁC suspension of Me3SI (470 mg, 2.3 mmol) in THF (5 mL) was
added n-BuLi (2.3 mmol, 1.43 mL of 1.6 M hexane solution). After
15 min, a solution of the appropriate trienoate 7 (0.57 mmol) in THF
(2 mL) was added to the reaction mixture at ꢀ10 ꢁC and was
allowed slowly to rise to room temperature in a period of 1.5 h. The
reaction mixture was cooled to 0 ꢁC and methyl iodide (180
mL,
Suitable X-ray quality crystals of 19 were grown in CDCl3 and
X-ray diffraction studies were undertaken. Relevant crystallographic
data has been submitted to the Cambridge Crystallographic Data
Centre (CCDC 671605). X-ray crystallographic data were collected at
the Department of Chemistry, IIT, Mumbai from single crystal
samples of volume 0.42ꢂ0.38ꢂ0.33 mm3 at 150(2) K mounted on
a OXFORD DIFFRACTION XCALIBUR-S CCD system equipped with
2.85 mmol) was added into the reaction mixture and stirred over-
night. The reaction mixture was diluted with water and extracted
with ethyl acetate. The organic extract was washed with water,
dried over anhydrous MgSO4, and evaporated under reduced
pressure. The residue was purified by column chromatography on
silica-gel using hexane/ethyl acetate as eluent to give the methyl-
ated trienes 30a,b (80–87%).
graphite monochromated Mo Ka radiation (0.71073 Å). The data
were collected by –2 scan mode, and absorption correction was
applied by using multi-Scan. The structure was solved by direct
methods SHELX-97 and refined by full-matrix least squares against
u
q
4.2.6. General procedure VI. Reaction of 6a with Me3SI and sodium
dimsylate. 4.2.6.1. (I) Protonation. A solution of sodium dimsylate
(2.5–4 mmol) in DMSO (2.5 mL) was prepared. The solution was

R. Singh, S.K. Ghosh / Tetrahedron 66 (2010) 2284–2292
2289
diluted with THF (3 mL) and cooled on an ice-salt bath (ꢀ8 ꢁC).
Solid trimethylsulfonium iodide (1.2–3 mmol) was introduced into
the flask and the reaction mixture was stirred under same condi-
tions for 15 min. A solution of 6a (274 mg, 1 mmol) in dry THF
(3 mL) was rapidly added to the reaction mixture. It was slowly
brought to room temperature (about 1 h) and stirred for 1 h. The
reaction mixture was diluted with water and extracted with ether.
The organic extract was washed with brine, dried (MgSO4), and
evaporated. The residue was purified by column chromatography
on silica-gel using hexane/EtOAc (95:5) as eluent to give 8a (37–
60 mg, 13–21%) and an inseparable mixture of 13a and 14a.
alkylated malonate 15k (2.9 g, 96%). Rf (95% hexane/EtOAc) 0.29;
nmax (liquid film) 3026, 2954, 2931, 2857, 1732, 1495, 1463, 1448,
1247, 1177, 1096, 1038, 963, 836, 775, 754 and 693 cmꢀ1
; dH
(200 MHz, CDCl3) 7.40–7.22 (5H, m, Ph), 6.77 (1H, d, J¼16.2 Hz,
PhCH]CH), 6.66 (1H, d, J¼16.2 Hz, PhCH]CH), 5.60 (1H, s,
C]CHaHb), 5.25 (1H, s, C]CHaHb), 4.22 (4H, q, J¼7.2 Hz,
2ꢂCO2CH2CH3), 3.57 (2H, t, J¼6.4 Hz, SiOCH2), 2.09 (2H,br t,
J¼7.2 Hz, CH2CCO2Et), 1.51 (2H, t, J¼6.4 Hz, CH2), 1.40–1.30 (4H, m,
2ꢂCH2), 1.25 (6H, t, J¼7.2 Hz, 2ꢂCO2CH2CH3), 0.03 (6H, s, SiMe2),
0.88 (9H, s, SiBu-t); dC (50 MHz, CDCl3) 169.8 (2C), 142.9, 136.8,
129.9, 128.3 (2C), 127.8, 127.4, 126.3 (2C), 114.5, 62.6, 62.2, 61.0 (2C),
34.1, 32.3, 25.9, 25.7 (3C), 24.2, 18.0, 13.8 (2C), ꢀ5.6 (2C).
4.2.6.2. (II) Methylation. A solution of sodium dimsylate
(3 mmol) in DMSO (2.5 mL) was prepared. The solution was diluted
with THF (3 mL) and cooled on an ice-salt bath (ꢀ8 ꢁC). Solid tri-
methylsulfonium iodide (1.5 mmol) was introduced into the flask
and the reaction mixture was stirred under same conditions for
15 min. A solution of 6a (274 mg, 1 mmol) in dry THF (3 mL) was
rapidly added to the reaction mixture. After 1 h, the reaction mix-
ture was cooled on an ice-water bath and methyl iodide (0.32 mL,
5 mmol) was added and stirred at ambient temperature for 15 h.
The reaction mixture was diluted with water and extracted with
diethyl ether. The combined extracts were washed with brine, dried
over magnesium sulfate, filtered, and concentrated under vacuum.
The residues were purified by column chromatography on silica-gel
using hexane/ethyl acetate as eluent to give the diene methylated
product 15a (205 mg, 68%) and the methylated product of thio-
methyl derivative 14a (53 mg, 15%).
4.2.9. (4E)-Ethyl 2-ethoxycarbonyl-2-[2-(20-ethanaloxy)phenyl]methyl-
3-methylene-5-phenyl-4-pentenoate (18). A solution of acetal 15j
(510 mg, 1 mmol), p-toluene sulfonic acid (48 mg, 0.25 mmol) in 2%
aqueous acetone (50 mL) was heated under reflux for 15 h in argon
atmosphere. The reaction mixture was neutralized with solid so-
dium bicarbonate and the solvent was evaporated. The residue was
purified by silica-gel column chromatography using hexane/ethyl
acetate as eluent to give the aldehyde 18 (421 mg, 97%). Rf (80%
hexane/EtOAc) 0.24; nmax (liquid film) 3090, 3070, 3035, 2980,
2936, 1733, 1601, 1494, 1479, 1454, 1367, 1247, 1118, 1036 and
754 cmꢀ1
; dH (200 MHz, CDCl3) 9.80 (1H, s, CHO), 7.28–7.14 (7H, m,
Ph, Ar), 6.94 (1H, t, J¼7.4 Hz, Ar), 6.72 (1H, d, J¼16 Hz, PhCH]CH),
6.60 (1H, d, J¼7.6 Hz, Ar), 6.54 (1H, d, J¼15.8 Hz, PhCH]CH), 5.58
(1H, s, PhCH]CHC]CHaHb), 5.24 (1H, s, PhCH]CHC]CHaHb), 4.41
(2H, d, J¼0.8 Hz, ArOCH2CHO), 4.27–4.13 (4H, m, 2ꢂCO2CH2CH3),
3.70 (2H, s, ArCH2), 1.22 (6H, t, J¼7.2 Hz, 2ꢂCO2CH2CH3); dC
(50 MHz, CDCl3) 199.6, 169.7 (2C), 156.2, 142.6, 136.9, 131.7, 129.4,
128.5 (2C), 128.2 (2C), 127.5, 126.4 (2C), 125.6, 121.3, 114.8, 110.9,
72.6, 63.4, 61.4 (2C), 33.6, 13.8 (2C).
4.2.7. (4E)-Ethyl 2-[2-(20,20-diethoxyethyloxy)phenyl]methyl-2-ethoxy-
carbonyl-3-methylene-5-phenyl-4-pentenoate (15j). A solution of 8a
(251 mg, 0.87 mmol) in THF (5 mL) was added to an oil-free sus-
pension of sodium hydride (42 mg, 0.96 mmol, w55% in oil) in THF
(1 mL) at 0 ꢁC. The reaction mixture was stirred at room tempera-
ture for 15 min, cooled on an ice-bath, and a solution of bromide 16
(300 mg, 1 mmol) in THF (2 mL) was added. The reaction mixture
was brought to room temperature and stirred for 15 h. The reaction
mixture was diluted with water and extracted with ether. The
combined extract was washed with brine and concentrated under
vacuum. The residue was purified by silica-gel chromatography
using hexane/ethyl acetate as eluent to provide 15j (410 mg, 95%).
Rf (90% hexane/EtOAc) 0.59; nmax (liquid film) 3020, 2983, 1722 and
4.2.10. (1RS,14SR)-15,15-Dicyano-14-phenyl-3-oxa-tricy-
clo[10.3.1.0
*
4,9 ]hexadeca-4(9),5,7,12-tetraene-11,11-dicarboxylic acid
*
diethyl ester (19). A mixture of aldehyde 18 (180 mg, 0.41 mmol),
triphenylphosphine (22 mg, 0.08 mmol), and malononitrile
(0.15 mL, 2.4 mmol) was heated (75 ꢁC, bath) under argon for 4 h.
The reaction mixture was brought to room temperature, excess
malononitrile was removed under high vacuum and the residue
was purified by silica-gel column chromatography using hexane/
ethyl acetate as eluent to give 19 (132 mg, 67%) as a colorless solid.
Mp 175–176 ꢁC. Rf (80% hexane/EtOAc) 0.35; nmax (CHCl3) 3063,
3024, 2982, 2959, 2248, 1731, 1637, 1601, 1585, 1494, 1453, 1392,
963 cmꢀ1
; dH (200 MHz, CDCl3) 7.31–7.15 (7H, m, Ph, Ar), 6.86 (1H, t,
J¼7.4 Hz, Ar), 6.78–6.70 (2H, m, PhCH]CH, Ar), 6.60 (1H, d,
J¼16 Hz, PhCH]CH), 5.58 (1H, s, PhCH]CHC]CHaHb), 5.19 (1H, s,
PhCH]CHC]CHaHb), 4.75 (1H, t, J¼5.2 Hz, CHO(CH2CH3)2), 4.23–
4.11 (4H, m, 2ꢂCO2CH2CH3), 3.89 (2H, d, J¼5.2 Hz, ArOCH2), 3.75–
3.53 (6H, m, CHO(CH2CH3)2, ArCH2), 1.22 (6H, t, J¼7 Hz,
2ꢂCO2CH2CH3), 1.19 (6H, t, J¼7 Hz, 2ꢂOCH2CH3); dC (50 MHz,
CDCl3) 169.8 (2C), 157.0, 142.9, 137.1, 130.9, 129.3, 128.3 (2C), 128.2,
127.8, 127.3, 126.4 (2C), 125.4, 120.3, 114.5, 111.0, 100.7, 69.0, 63.5,
62.7 (2C), 61.2 (2C), 33.2, 15.2 (2C),13.7 (2C); m/z (ESI) 533 (MþþNa,
10%), 397 (100), 221 (14), 120 (7); HRMS (ESI): MNaþ, found
533.2504. C30H38O7Na requires 533.2515.
1368, 1276, 1222, 1183, 1122, 1061, 1036, 860 and 756 cmꢀ1
; dH
(200 MHz, CDCl3) 7.45–7.42 (5H, m, Ph), 7.28 (1H, dt, J¼8, 1.5 Hz,
Ar), 7.24 (1H, dd, J¼7.5, 1.5 Hz, Ar), 6.98 (1H, t, J¼7.5 Hz, Ar), 6.92
(1H, d, J¼8 Hz, Ar), 5.96 (1H, t, J¼3 Hz, C]CH), 4.73 (1H, d,
J¼12.5 Hz, OCHaHb), 4.46 (1H, dd, J¼13, 6 Hz, OCHaHb), 4.32 (1H, m,
CO2CHaHbCH3), 4.29–4.22 (1H, m, CO2CHaHbCH3), 4.20–4.14 (2H, m,
CO2CH2CH3), 3.73 (1H, d, J¼13.5 Hz, ArCHaHb), 3.72 (1H, d, J¼3 Hz,
PhCH), 3.50 (1H, d, J¼13.5 Hz, ArCHaHb), 3.12 (1H, dd, J¼7.5, 6 Hz,
CNCCH), 2.69 (1H, ddt, J¼16, 8, 2 Hz, C]C–CHaHb), 2.61 (1H, d,
J¼16 Hz, C]C–CHaHb), 1.32 (3H, t, J¼7 Hz, CO2CH2CH3), 1.26 (3H, t,
J¼7.5 Hz, CO2CH2CH3); dC (50 MHz, CDCl3) 169.7, 168.8, 161.6, 142.7,
136.2, 133.1, 129.4, 129.3 (2C), 129.1, 129.0 (2C), 127.3, 125.0, 122.5,
117.9, 116.4, 114.1, 73.4, 64.2, 62.0, 61.6, 48.1, 46.2, 44.3, 38.1, 27.4,
14.0, 13.9; m/z (ESI) 486 (3%), 485 (MþþH, 100), 439 (3). HRMS
(ESI): MHþ, found 485.2059. C29H29N2O5 requires 485.2076.
4.2.8. (8E)-1-tert-Butyldimethylsilyoxy-6,6-diethoxycarbonyl-7-
methylene-9-phenyl-8-nonene (15k). A solution of the dien-2-yl-
malonate 8a (1.8 g, 6.25 mmol) in DMF (10 mL) was added to
a stirred oil-free suspension of NaH (300 mg, 55% in oil, 6.9 mmol)
in DMF (10 mL). After 0.5 h at room temperature, a solution of
5-tert-butyldimethylsilyloxy-1-iodopentane (3 g, 9.4 mmol) in
DMF (5 mL) was added to the reaction mixture and stirred for 18 h.
The reaction mixture was diluted with water and extracted with
benzene. The organic extract was washed with water, dried over
anhydrous MgSO4, and evaporated under reduced pressure. The
residue was purified by column chromatography to give the
4.2.11. (8E)-6,6-Diethoxycarbonyl-7-methylene-9-phenyl-nona-8-
ene-1-ol (21). p-Toluenesulfonic acid (17 mg, 0.09 mmol) was
added to a stirred solution of silyl ether 15k (440 mg, 0.9 mmol) in
EtOH/THF/water (80:15:5) (10 mL). After 2 h at room temperature,
the reaction mixture was concentrated on rotary evaporator. The
residue was diluted with water and extracted with ethyl acetate.

2290
R. Singh, S.K. Ghosh / Tetrahedron 66 (2010) 2284–2292
The organic extract was washed with water, dried over anhydrous
MgSO4, and evaporated under reduced pressure. The residue was
purified by column chromatography using hexane/ethyl acetate as
eluent to give the alcohol 21 (292 mg, 87%). Rf (70% hexane/EtOAc)
0.3; nmax (liquid film) 3435 (br), 2979, 2934, 2869, 1733, 1637, 1600,
at 80 ꢁC for 3 days. The reaction mixture was concentrated on rotary
evaporator and the residue was purified by column chromatography
using hexane/ethyl acetate as eluent to provide the a,b unsaturated
aldehyde 24 (155 mg, 65%). This product is contaminated with
w10% of 2Z,10E-isomer. Rf (90% hexane/EtOAc) 0.19; nmax (liquid
film) 3023, 2981, 2934, 2858, 1730, 1687, 1638, 1448, 1243, 1097,
1464,1448,1369,1242,1094,1037, 961, 912, 862, 752 and 695 cmꢀ1
;
dH (200 MHz, CDCl3) 7.41–7.18 (5H, m, Ph), 6.77 (1H, d, J¼16 Hz,
PhCH), 6.65 (1H, d, J¼16 Hz, PhCH]CH), 5.60 (1H, s, C]CHaHb),
5.23 (1H, s, C]CHaHb), 4.22 (4H, q, J¼7.2 Hz, 2ꢂCO2CH2CH3), 3.61
(2H, t, J¼6.6 Hz, CH2OH), 2.14–2.05 (2H, m, CH2CCO2Et), 1.63–1.50
(3H, m, OH and CH2), 1.42–1.31 (4H, m, 2ꢂCH2), 1.25 (6H, t, J¼7.2 Hz,
2ꢂCO2CH2CH3); dC (50 MHz, CDCl3) 170.0 (2C), 142.7, 136.8, 129.9,
128.3 (2C), 127.7, 127.4, 126.2 (2C), 114.6, 62.2, 62.1, 61.1 (2C), 34.0,
32.0, 25.8, 24.2, 13.7 (2C); m/z (ESI) 397 (MþþNa, 31%), 375 (MþþH,
52), 329 (40), 283 (23), 201 (8), 155 (13); HRMS (ESI): MHþ, found
375.2172. C22H31O5 requires 375.2171.
1029, 971, 910, 756, 734 and 694 cmꢀ1
; dH (200 MHz, CDCl3) 9.40
(1H, d, J¼8 Hz, CHO from 2Z-isomer), 9.36 (1H, d, J¼8 Hz, CHO),
7.31–7.10 (5H, m, Ph), 6.78–6.62 (1H, m, CH]CHCHO), 6.67 (1H, d,
J¼16 Hz, PhCH]CH), 6.54 (1H, d, J¼16 Hz, PhCH]CH), 5.99 (1H, ddt,
J¼15.6, 8, 1.2 Hz, CH]CHCHO), 5.50 (1H, s, C]CHaHb), 5.11 (1H, s,
C]CHaHb), 4.13 (4H, q, J¼7.2 Hz, 2ꢂCO2CH2CH3), 2.30–2.18 (2H, m,
CH2CH]CHCHO), 2.04–1.96 (2H, m, CH2CCO2Et), 1.50–1.25 (4H, m,
2ꢂCH2), 1.15 (6H, t, J¼7.2 Hz, 2ꢂCO2CH2CH3); dC (50 MHz, CDCl3)
193.7, 170.4 (minor), 169.8 (2C), 158.2, 152.5 (minor), 146.5 (minor),
142.6, 136.7, 134.0 (minor), 132.7, 130.1, 128.3 (2C), 127.5 (2C), 126.3
(2C), 114.7, 62.2, 61.2 (2C), 33.7, 32.0, 27.8, 24.0, 13.8 (2C).
4.2.12. (8E)-6,6-Diethoxycarbonyl-7-methylene-9-phenyl-nona-8-
eneal (22). Oxalylchloride(80
a solution of DMSO (130
m
L, 0.91 mmol,1.1 equiv)wasadded to
4.2.15. (8R,9S)-2,2-Diethoxycarbonyl-9-phenylbicyclo[5.3.1]undec-1-
(10)-ene-8-carbaldehyde (26). Water (33 mL) was added to a stirred
m
L,1.83 mmol, 2.2 equiv) in CH2Cl2 (2 mL) at
ꢀ60 ꢁC. After stirring for 5 min, a solution of alcohol 21 (310 mg,
solution of unsaturated aldehyde 24 (125 mg, 0.31 mmol), imida-
zolidinone catalyst 25 (15 mg, 0.062 mmol, 20 mol %), and p-tol-
uenesulfonic acid (12 mg, 0.062 mmol, 20 mol %) in chloroform
(1.6 mL). After 4 days at room temperature, the reaction mixture
was diluted with water and extracted with ethyl acetate. The or-
ganic extract was washed with water, dried over anhydrous MgSO4,
and evaporated under reduced pressure. The residue was purified
by column chromatography using hexane/ethyl acetate as eluent to
0.83 mmol, 1 equiv) in CH2Cl2 (3 mL) was added and the reaction
mixture was stirred at ꢀ60 ꢁC for 15 min. Triethylamine (578
mL,
4.15 mmol, 5 equiv) was added and the reaction mixture was stirred
for 5 min at ꢀ60 ꢁC. The reaction mixture was allowed to attain room
temperature and was diluted with water. The reaction mixture was
extracted with CH2Cl2 and the organic extract was washed with wa-
ter, dried over anhydrous MgSO4, and evaporated under reduced
pressure. The residue was purified by column chromatography using
hexane/ethyl acetate as eluent to give the aldehyde 22 (208 mg, 67%).
The material was unstable and used directly in the next step. Rf (90%
hexane/EtOAc) 0.19; nmax (liquid film) 3082, 3025, 2980, 2938, 2872,
2722, 2255,1728,1636,1600,1494,1448,1389,1366,1246,1096,1034,
give the bicyclic product 26 (56 mg, 61%) and recovered aldehyde
26
26 (32 mg). Rf (90% hexane/EtOAc) 0.29; [
a
]
þ86.7 (c 1.2, CHCl3);
D
nmax (liquid film) 3062, 3028, 2981, 2934, 2925, 2854, 1725, 1464,
1367, 1038, 910, 731 and 635 cmꢀ1
;
dH (200 MHz, CDCl3) 9.57 (1H, s,
CHO), 7.26–7.08 (5H, m, Ph), 5.68 (1H, br s, PhCHCH]C), 4.23–3.90
(4H, m, 2ꢂCO2CH2CH3), 3.74 (1H, dt, J¼3.3, 2 Hz, PhCH), 2.45–1.85
(6H, m), 1.80–1.30 (6H, m), 1.15 (3H, t, J¼7 Hz, CO2CH2CH3), 1.10 (3H,
t, J¼7.2 Hz, CO2CH2CH3); dC (50 MHz, CDCl3) 201.8, 171.0, 170.4,
145.1, 135.3, 128.8 (3C), 128.1 (2C), 126.4, 62.9, 61.4 (2C), 61.3, 39.2,
35.9, 34.7, 31.7, 28.5, 25.5, 24.9, 14.0 (2C).
963,912,858,754, 731and695 cmꢀ1
;dH (200 MHz,CDCl3)(200 MHz,
CDCl3) 9.73 (1H, br s, CHO), 7.46–7.19 (5H, m, Ph), 6.76 (1H, d, J¼16 Hz,
PhCH]CH), 6.64 (1H, d, J¼16 Hz, PhCH]CH), 5.59 (1H, s, C]CHaHb),
5.21 (1H, s, C]CHaHb), 4.22(4H, q, J¼7.2 Hz, 2ꢂCO2CH2CH3), 2.42(2H,
t, J¼7.2 Hz, CH2CHO), 2.14–2.05 (2H, m, CH2CCO2Et),1.73–1.52 (2H, m,
CH2), 1.50–1.31 (2H, m, CH2), 1.25 (6H, t, J¼7.2 Hz, 2ꢂCO2CH2CH3); dC
(50 MHz, CDCl3) 202.1,169.9 (2C),142.9,136.9,130.3,128.5 (2C),127.8,
127.6,126.4 (2C),114.8, 62.4, 61.3 (2C), 43.3, 33.9, 24.2, 22.2,13.9 (2C).
4.2.16. (8R,9S)-2,2-Diethoxycarbonyl-8-hydroxymethyl-9-phenyl-
bicyclo[5.3.1]undec-1-(10)-ene (27). Sodium borohydride (5 mg,
0.13 mmol) was added to a stirred solution of the bicyclic aldehyde
26 (20 mg, 0.05 mmol) in ethanol (0.5 mL) at 0 ꢁC and stirred for 1 h.
The reaction mixture was concentrated on rotary evaporator, diluted
with water, and extracted with ethyl acetate. The organic extract was
washed with water, dried over anhydrous MgSO4, and evaporated
under reduced pressure. The residue was purified by column chro-
4.2.13. (9RS)-2,2-Diethoxycarbonyl-8,8-dicyano-9-phenyl-
bicyclo[5.3.1]undec-1-(10)-ene (23). A mixture of aldehyde 22
(46 mg, 0.12 mmol), triphenylphosphine (32 mg, 0.12 mmol), and
malononitrile (8 m
L, 0.12 mmol) was heated (75 ꢁC, bath) under
argon for 4 h. The reaction mixture was brought to room temper-
ature and the residue was purified by silica-gel column chroma-
tography using hexane/ethyl acetate as eluent to give 23 (31 mg,
61%) as colorless solid. Mp 113–115 ꢁC. Rf (80% hexane/EtOAc) 0.47;
nmax (CHCl3) 3031, 2935, 2835, 2244, 1728, 1663, 1602, 1410, 1440,
matography using hexane/ethyl acetate as eluent to give the alcohol
25
27 (16 mg, 80%). Rf (80% hexane/EtOAc) 0.22; [
a
]
þ81.5 (c 1.08,
D
CHCl3); nmax (liquid film) 3607–3400 (br), 3026, 2979, 2922, 2854,
1729, 1451, 1366, 1300, 1239, 1157, 1040 and 703 cmꢀ1
;
dH (200 MHz,
1367, 1297, 1236, 1120, 1099, 1033, 826, 733 and 703 cmꢀ1
;
dH
CDCl3) 7.23–7.09 (5H, m, Ph), 5.63 (1H, s, C]CH), 4.18–3.91 (4H, m,
2ꢂCO2CH2CH3), 3.52 (1H, dd, J¼10.6, 4.6 Hz, CHaHbOH), 3.38 (1H, dd,
J¼10.6, 7.4 Hz, CHaHbOH), 2.84 (1H, dd, J¼8.2, 1.8 Hz, PhCH), 2.16–
2.14 (4H, m, C]CCH2 and CH2CCO2Et), 2.11–2.00 (1H, m, HOCH2CH),
1.80–1.30 (8H, m, 3ꢂCH2, OH and C]CCH2CH), 1.16 (3H, t, J¼8 Hz,
CO2CH2CH3), 1.08 (3H, t, J¼8 Hz, CO2CH2CH3); dC (50 MHz, CDCl3)
171.2,170.4,146.0,136.1,130.1,128.5 (2C),128.4 (2C),126.2, 64.4, 63.0,
61.3, 61.2, 51.0, 43.8, 36.0, 35.2, 34.4, 29.3, 25.4, 24.7, 14.0, 13.9.
(200 MHz, CDCl3) 7.51–7.36 (5H, m, Ph), 5.97 (1H, br s, C]CH),
4.15–4.13 (4H, m, 2ꢂCO2CH2CH3), 3.96 (1H, br s, PhCH), 2.80–2.56
(2H, m, CH2), 2.55–2.35 (2H, m, CH2), 2.33–2.20 (1H, m, CH), 2.05–
1.67 (4H, m, 2ꢂCH2), 1.62–1.40 (2H, m, CH2), 1.27 (3H, t, J¼7.2 Hz,
CO2CH2CH3), 1.23 (3H, t, J¼7.2 Hz, CO2CH2CH3); dC (50 MHz, CDCl3)
170.2, 169.7, 139.4, 137.5, 129.4 (2C), 129.2 (2C), 128.9, 125.1, 117.8,
113.3, 62.8, 61.8, 61.7, 48.8, 43.2, 40.6, 35.4, 30.7, 27.8, 25.1, 24.5, 14.0
(2C); m/z (ESI) 421 (MþþH, 39%), 348 (8), 347 (100); HRMS (ESI):
MHþ, found 421.2124. C25H29N2O4 requires 421.2127.
4.2.17. (8R,9S)-8-Benzyloxymethyl-2,2-diethoxycarbonyl-9-phenyl-
bicyclo[5.3.1]undec-1-(10)-ene (28). Benzoyl chloride (15 mL,
4.2.14. (2E,10E)-8,8-Diethoxycarbonyl-9-methylene-11-phenyl-un-
dec-2,10-dieneal (24). A mixture of aldehyde 22 (225 mg, 0.6 mmol)
and formylmethylenetriphenylphosphorane36 (365 mg, 1.2 mmol,
2 equiv) in dry benzene (5 mL) was heated under argon atmosphere
0.1 mmol) was added to a stirred solution of the alcohol 27 (12 mg,
0.03 mmol) and 4-dimethylaminopyridine (3.5 mg, 0.03 mmol) in
CH2Cl2 (0.5 mL) at 0 ꢁC. The reaction mixture was stirred overnight
at room temperature, diluted with water, and extracted with

R. Singh, S.K. Ghosh / Tetrahedron 66 (2010) 2284–2292
2291
chloroform. The organic extract was washed with water, dried over
anhydrous MgSO4, and evaporated under reduced pressure. The
residue was purified by column chromatography using hexane/
(3H, t, J¼7 Hz, CO2CH2CH3); dC (50 MHz, CDCl3) 179.3, 178.8, 170.5,
170.4, 138.1, 136.7, 130.5, 128.5 (2C), 127.9, 127.5, 126.2 (2C), 125.8,
61.7, 61.6, 59.7, 44.6, 39.5, 38.5, 26.5, 25.0, 20.0, 13.9 (2C); m/z (ESI)
462 (MþþNa,100%), 440 (55), 438 (44), 436 (25); HRMS (ESI): MHþ,
found 440.2042. C25H30NO6 requires 440.2068.
ethyl acetate as eluent to give the benzoate 28 (13 mg, 86%). Rf (85%
25
hexane/EtOAc) 0.26; [
a
]
þ26.08 (c 0.23, CHCl3); nmax (liquid film)
D
3026, 2979, 2925, 2853, 1722, 1451, 1385, 1274, 1245, 1217, 1112,
1069 and 1025 cmꢀ1
dH (500 MHz, CDCl3) 7.95 (2H, d, J¼7 Hz, Ph),
;
4.2.20.2. Data for the (1RS,2RS,6SR) diastereoisomer (minor). Rf
7.55 (1H, t, J¼7 Hz, Ph), 7.41 (2H, t, J¼8 Hz, Ph), 7.34–7.28 (2H, m,
Ph), 7.25–7.20 (3H, m, Ph), 5.80 (1H, d, J¼2.5 Hz, C]CH), 4.26–4.16
(4H, m, CO2CH2CH3, CO2CHaHbCH3, PhCO2CH2), 4.13–4.04 (1H, m,
CO2CHaHbCH3), 3.16 (1H, dd, J¼9, 2.5 Hz, PhCH), 2.40–2.30 (3H, m),
2.23–2.16 (1H, m), 1.96–1.83 (1H, m), 1.82–1.49 (6H, m), 1.48–1.38
(1H, m), 1.28 (3H, t, J¼7 Hz, CO2CH2CH3), 1.19 (3H, t, J¼7 Hz,
CO2CH2CH3); dC (125 MHz, CDCl3) 171.1, 170.4, 166.6, 146.3, 136.6,
132.87, 130.1 (2C), 129.5 (2C), 128.6 (2C), 128.4 (2C), 128.3 (2C),
126.4, 66.6, 63.1, 61.4, 61.3, 47.6, 44.1, 35.9, 35.2 (2C), 29.9, 29.3, 24.4,
14.0, 13.9; m/z (ESI) 527 (MþþNa, 33), 522 (18), 383 (67), 337 (15),
279 (100); HPLC (5% isopropanol in hexane; 1 mL/min) tR (8R,9S)-
28 16.7 min (95.8%), tR (8S,9R)-28 38.6 min (4.2%); HRMS (ESI):
MNaþ, found 527.2384. C31H36O6Na requires 527.2404.
(80% hexane/EtOAc) 0.36; nmax (liquid film) 3023, 2983, 1775, 1729,
1699, 1438, 1384, 1285, 1261, 1109, 1021, 994, 967 and 751 cmꢀ1
; dH
(200 MHz, CDCl3) 7.46–7.26 (5H, m, Ph), 6.72 (1H, dd, J¼15.8, 7.9 Hz,
PhCH]CH), 6.54 (1H, d, J¼15.9 Hz, PhCH), 5.85 (1H, br s,
CH3CC]CH), 4.25 (4H, q, J¼7 Hz, 2ꢂCO2CH2CH3), 3.35–3.10 (3H, m,
3ꢂCH), 2.96 (3H, s, NMe), 2.79 (1H, d, J¼15.6 Hz, CHaHb), 2.54 (1H,
dd, J¼14.8, 5.6 Hz, CHaHb), 1.57 (3H, s, MeC), 1.30 (6H, t, J¼7 Hz,
2ꢂCO2CH2CH3); dC (125 MHz, CDCl3) 179.1, 177.6, 170.5, 170.4, 137.5,
136.9, 131.9, 128.5 (2C), 128.3, 128.0, 127.5, 126.4 (2C), 61.8, 61.7,
59.4, 45.2, 40.2, 40.0, 27.3, 24.7, 20.1, 14.0 (2C); m/z (ESI) 462
(MþþNa, 21%), 440 (25), 439 (19), 438 (64).
4.2.21. (1RS,2SR,6SR)-8-Azamethyl-7,9-dicarbonyl-4-(1,1-diethoxyx-
arbonyl-1-ethyl)-2-[2(2-methoxyphenyl)ethenyl]-bicyclo[4.3.0]nona-
3-ene (31b). A solution of triene 30b (53 mg, 0.15 mmol),
N-methylmalimide (17 mg, 0.15 mmol) in benzene (2 mL) was
heated under reflux for 3 h. The reaction mixture was concentrated
and the residue was purified by column chromatography to give
bicyclic product 31b (56 mg, 80%). This product is contaminated
with w25% of another diastereoisomer. The diastereomeric prod-
ucts were separated by preparative TLC.
4.2.18. (4E,6E)-Ethyl 2-ethoxycarbonyl-2-methyl-3-methylene-7-phe-
nyl-4,6-heptadienoate (30a). Yield: 149 mg, 80%. The product de-
composes on standing. Rf (95% hexane/EtOAc) 0.5; nmax (liquid film)
3058, 3024, 2983, 2938, 2872, 1731, 1631, 1600, 1464, 1448, 1376,
1260, 1107, 1020, 990, 911, 861, 750, 732 and 693 cmꢀ1
; dH
(200 MHz, CDCl3) 7.46–7.25 (5H, m, Ph), 6.92–6.43 (3H, m), 6.31
(1H, d, J¼15.5 Hz, PhCH), 5.53 (1H, s, C]CHaHb), 5.11 (1H, s,
C]CHaHb), 4.28 (4H, q, J¼7 Hz, 2ꢂCO2CH2CH3), 1.72 (3H, s, CCH3),
1.31 (6H, t, J¼7 Hz, 2ꢂCO2CH2CH3); dC (125 MHz, CDCl3) 170.8 (2C),
144.1, 137.0, 132.9, 131.6, 130.8, 128.8, 128.4 (2C), 127.4, 126.2 (2C),
113.6, 61.5 (2C), 58.8, 21.1, 13.8 (2C).
4.2.21.1. Data for the (1RS,2SR,6SR) diastereoisomer (major). Rf
(80% hexane/EtOAc) 0.24; nmax (liquid film) 2982, 2932, 1776, 1729,
1699,1597,1489,1438,1383,1286,1244,1107,1024 and 754 cmꢀ1
; dH
(200 MHz, CDCl3) 7.39 (1H, d, J¼7.6 Hz, Ar), 7.20 (1H, d, J¼7.8 Hz, Ar),
6.95–6.84 (2H, m, Ar), 6.80 (1H, d, J¼16 Hz, ArCH), 6.20 (1H, dd, J¼16,
6.3 Hz, ArCH]CH), 5.85 (1H, dd, J¼7.9, 1.4 Hz), 3.83 (3H, s, OCH3),
3.75–3.60 (1H, m), 3.18 (1H, m), 3.11 (1H, dd, J¼9.2, 2.4 Hz), 2.98 (3H,
s, OCH3), 2.65 (1H, dd, J¼17, 7.2 Hz), 2.51 (1H, dd, J¼15.6, 3 Hz), 1.56
(3H, s, CCH3),1.25 (6H, t, J¼7 Hz, 2ꢂCO2CH2CH3); dC (125 MHz, CDCl3)
179.4, 179.0, 170.5 (2C), 156.5, 137.8, 128.6, 128.4, 126.8, 126.0, 125.8,
125.4, 120.6, 110.8, 61.7, 61.5, 59.8, 55.4, 44.6, 39.6, 38.9, 26.5, 25.0,
20.0, 14.0 (2C); m/z (ESI) 492 (MþþNa, 100%), 470 (15), 466 (24);
HRMS (ESI): MHþ, found 470.2151. C26H32NO7 requires 470.2173.
4.2.19. (4E,6E)-Ethyl 2-ethoxycarbonyl-2-methyl-3-methylene-7-(2-
methoxyphenyl)-4,6-heptadienoate (30b). Yield: 87%. Rf (95% hex-
ane/EtOAc) 0.41; nmax (liquid film) 2982, 2939, 2837, 1731, 1629,
1593, 1488, 1464, 1375, 1295, 1246, 1106, 1025, 993, 902, 861 and
752 cmꢀ1
;
dH (200 MHz, CDCl3) 7.47 (1H, d, J¼7.3 Hz), 7.21 (1H, t,
J¼7.5 Hz), 7.05–6.73 (4H, m), 6.60 (1H, dd, J¼15, 8.8 Hz, ArCH]CH),
6.24 (1H, d, J¼15 Hz, ArCH), 5.54 (1H, s, CH3CCH]CHaHb, minor),
5.47 (1H, s, CH3CCH]CHaHb), 5.04 (1H, s, CH3CCH]CHaHb), 4.23
(4H, q, J¼7.1 Hz, 2ꢂCO2CH2CH3), 3.86 (3H, s, OCH3 major), 3.83 (3H,
s, OCH3 minor), 1.68 (3H, s, CCH3), 0.92 (6H, t, J¼7.2 Hz,
2ꢂCO2CH2CH3); dC (125 MHz, CDCl3) 171.0 (2C), 156.7, 144.4, 131.8,
131.0, 129.5, 128.6, 127.8, 126.3, 126.1, 120.6, 113.4, 110.8, 61.6 (2C),
59.0, 55.4, 21.3, 13.9 (2C).
4.2.21.2. Data for the (1RS,2RS,6SR) diastereoisomer (minor). Rf
(80% hexane/EtOAc) 0.24; nmax (liquid film) 2923, 2851, 1727, 1699,
1599, 1489, 1439, 1381, 1285, 1244, 1108, 1024 and 753 cmꢀ1
; dH
(200 MHz, CDCl3) 7.50 (1H, d, J¼6.7 Hz, Ar), 7.20 (1H, d, J¼7.4 Hz, Ar),
6.96–6.81 (3H, m), 6.64 (1H, dd, J¼16, 8.3 Hz, ArCH]CH), 5.83 (1H, br
s), 4.20 (4H, q, J¼7 Hz), 3.84 (3H, s, OCH3), 3.37–3.10 (3H, m), 2.92 (3H,
s, OCH3), 2.75 (1H, d, J¼14.9 Hz), 2.61–2.40 (1H, m),1.53 (3H, s, CCH3),
1.26 (6H, t, J¼6.9 Hz, 2ꢂCO2CH2CH3); dC (125 MHz, CDCl3) 179.2,
177.7, 170.5, 170.4, 156.5, 137.2, 128.8,128.6, 128.4, 127.0, 126.6, 126.0,
120.7, 110.7, 61.8, 61.6, 59.4, 55.4, 45.4, 40.4, 40.2, 27.2, 24.7, 20.1, 14.0
(2C); m/z (ESI) 492 (MþþNa, 40%), 470 (12), 469 (15), 468 (100).
4.2.20. (1RS,2SR,6SR)-8-Azamethyl-7,9-dicarbonyl-4-(1,1-diethoxyx-
arbonyl-1-ethyl)-2-(2-phenylethenyl)-bicyclo[4.3.0]nona-3-ene
(31a). A solution of triene 30a (69 mg, 0.21 mmol), N-methyl-
malimide (23 mg, 0.21 mmol) in benzene (2 mL) was heated under
reflux for 3 h. The reaction mixture was concentrated and the
residue was purified by column chromatography to give bicyclic
product 31a (68 mg, 74%). This product is contaminated with w25%
of another diastereoisomer. The diastereomeric products were
separated by preparative TLC.
Supplementary data
4.2.20.1. Data for the (1RS,2SR,6SR) diastereoisomer (major). Rf
(80% hexane/EtOAc) 0.36; nmax (liquid film) 3024, 2984, 1776, 1727,
1699, 1440, 1384, 1285, 1261, 1217, 1108, 1018, 910, 759 and
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.02.013.
735 cmꢀ1
; dH (500 MHz, CDCl3) 7.39–7.26 (5H, m, Ph), 6.51 (1H, d,
J¼16 Hz, PhCH), 6.23 (1H, dd, J¼16, 5 Hz, PhCH]CH), 5.91 (1H, d,
J¼6.5 Hz, CH3CC]CH), 4.28–4.20 (4H, m, 2ꢂCO2CH2CH3), 3.72 (1H,
br t, J¼7 Hz, C]CHCH), 3.20 (1H, dt, J¼8.5, 3 Hz), 3.11 (1H, dd, J¼9,
2.5 Hz), 3.01 (3H, s, NCH3), 2.65 (1H, dd, J¼16, 8 Hz), 2.56 (1H, dd,
J¼16, 3 Hz), 1.60 (3H, s, CH3C), 1.29 (3H, t, J¼7 Hz, CO2CH2CH3), 1.28
References and notes
1. For selected reviews, see: (a) Gosney, I.; Rowley, A. G. In Organophosphorus
Reagents in Organic Synthesis; Cadogan, J. I. G., Ed.; Academic: New York, NY,
1979, Chapter 2; (b) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863; (c)
Walker, B. J. In Organophosphorus Reagents in Organic Synthesis; Cadogan, J. I. G.,

2292
R. Singh, S.K. Ghosh / Tetrahedron 66 (2010) 2284–2292
Ed.; Academic: New York, NY, 1979, Chapter 3; (d) Wadsworth, W. S. Org. React.
1977, 25, 73.
Ed. 2000, 39, 1415; (d) Spiegel, D. A.; Njardarson, J. T.; McDonald, I. M.; Wood, J.
L. Chem. Rev. 2003, 103, 2691.
2. For details on these processes and lead references, see:Modern Carbonyl Olefi-
nation; Takeda, T., Ed.; Wiley-VCH: Weinheim, Germany, 2004.
3. (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353; (b) Aube´, J. In
Comprehensive Organic Synthesis: Selectivity, Strategy, and Efficiency in Modern
Synthetic Chemistry; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 1;
Chapter 3.2, pp 822–825; (c) Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997,
9, 2341; (d) Yao, H. Synlett 2009, 2201.
20. Golik, J.; Dubay, G.; Groenewold, G.; Kawaguchi, H.; Konishi, M.; Krishnan, B.;
Ohkuma, H.; Saitoh, K.; Doyle, T. W. J. Am. Chem. Soc. 1987, 109, 3462.
21. Selected references: (a) Zhu, L.; Lauchli, R.; Loo, M.; Shea, K. J. Org. Lett. 2007, 9,
2269; (b) Lauchli, R.; Shea, K. J. Org. Lett. 2006, 8, 5287; (c) Sparks, S. M.; Chow,
C. P.; Zhu, L.; Shea, K. J. J. Org. Chem. 2004, 69, 3025; (d) Whitney, J. M.; Parnes, J.
S.; Shea, K. J. J. Org. Chem. 1997, 62, 8962; (e) Dzierba, C. D.; Zandi, K. S.; Mollers,
T.; Shea, K. J. J. Am. Chem. Soc. 1996, 118, 4711.
4. (a) Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Le Gall, T.; Shin, D.-S.;
Falck, J. R. Tetrahedron Lett. 1994, 35, 5449; (b) Alcaraz, L.; Cridland, A.; Kinchin,
E. Org. Lett. 2001, 3, 4051; (c) Baylon, C.; Heck, M.-P.; Mioskowski, C. J. Org.
Chem. 1999, 64, 3354; (d) Davoille, R. J.; Rutherford, D. T.; Christie, S. D. R.
Tetrahedron Lett. 2000, 41, 1255; (e) Raj, I. V. P.; Sudalai, A. Tetrahedron Lett.
2008, 49, 2646.
5. Alcaraz, L.; Cox, K.; Cridland, A. P.; Kinchin, E.; Morris, J.; Thompson, S. P. Org.
Lett. 2005, 7, 1399.
6. Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Le Gall, T.; Shin, D.-S.;
Falck, J. R. Tetrahedron Lett. 1994, 35, 5453.
7. For recent studies, see: (a) Kimber, M. C.; Taylor, D. K. J. Org. Chem. 2002, 67,
3142 and references cited therein; (b) Bunuel, E.; Bull, S. D.; Davies, S. G.;
Garner, C. A.; Savory, E. D.; Smith, A. D.; Vickers, R. J.; Watkin, D. J. Org. Biomol.
Chem. 2003, 1, 2531; (c) Redon, S.; Leleu, S.; Pannecoucke, X.; Franck, X.; Out-
urquin, F. Tetrahedron 2008, 64, 9293.
8. Ghosh, S. K.; Singh, R.; Date, S. M. Chem. Commun. 2003, 636.
9. For the use of this terminology, see: Cohen, T.; Yu, L. C. J. Org. Chem. 1984,
49, 605.
22. Selected examples of recent approaches to the bridgehead alkene, see: (a)
Mehta, G.; Kumaran, R. S. Chem. Commun. 2002, 1456; (b) Sgarbi, P. W. M.; Clive,
D. L. J. Chem. Commun. 1997, 2157; (c) Sheehan, S. M.; Lalic, G.; Chen, J. S.; Shair,
M. D. Angew. Chem., Int. Ed. 2000, 39, 2714; (d) Cossy, J.; BouzBouz, S.; Laghgar,
M.; Tabyaoui, B. Tetrahedron Lett. 2002, 43, 823; (e) Yoshimitsu, T.; Yanagiya, M.;
Nagaoka, H. Tetrahedron Lett. 1999, 40, 5215; (f) Yoshimitsu, T.; Yanagisawa, S.;
Nagaoka, H. Org. Lett. 2000, 2, 3751; (g) Njardarson, J. T.; Wood, J. L. Org. Lett.
2001, 3, 2431; (h) Kaliappan, K. P.; Ravikumar, V.; Pujari, S. A. Tetrahedron Lett.
2006, 47, 981; (i) Clark, D. A.; Clark, J. R.; Diver, S. T. Org. Lett. 2008, 10, 2055.
23. Recent reviews: (a) Takao, K.-i.; Munakata, R.; Tadano, K.-i. Chem. Rev. 2005,
105, 4779; (b) Bear, B. R.; Sparks, S. M.; Shea, K. J. Angew. Chem., Int. Ed. 2001, 40,
820; (c) Rappoport, Z. The Chemistry of Dienes and Polyenes; John Wiley and
Sons: New York, NY, 2001; Vol. 2; and references cited therein.
24. Reviews on anti-Bredt alkenes and their reactivities: (a) Shea, K. J. Tetrahedron
1980, 36, 1683; (b) Warner, P. M. Chem. Rev. 1989, 89, 1067; (c) Marshall, J. A.;
Faubl, H. J. Am. Chem. Soc. 1967, 89, 5965; (d) Wiseman, J. R. J. Am. Chem. Soc.
1967, 89, 5966; (e) Wiseman, J. R.; Chong, J. A. J. Am. Chem. Soc. 1969, 91, 7775.
25. (a) Alcaide, B.; Almendros, P.; Rodrı
´guez-Acebes, R. J. Org. Chem. 2002, 67, 1925;
10. (a) Date, S. M.; Singh, R.; Ghosh, S. K. Org. Biomol. Chem. 2005, 3, 3369; (b)
Singh, R.; Singh, G. C.; Ghosh, S. K. Tetrahedron Lett. 2005, 46, 4719; (c) Singh, R.;
Singh, G. C.; Ghosh, S. K. Eur. J. Org. Chem. 2007, 5376; (d) Ghosh, S. K.; Singh, R.;
Singh, G. C. Eur. J. Org. Chem. 2004, 4141.
11. (a) Date, S. M.; Ghosh, S. K. Angew. Chem., Int. Ed. 2007, 46, 386; (b) Date, S. M.;
Ghosh, S. K. Bull. Chem. Soc. Jpn. 2004, 77, 2099; (c) Chowdhury, R.; Ghosh, S. K.
Eur. J. Org. Chem. 2008, 3868.
12. Reviews: (a) Lipshutz, B. H.; Sengupta, S. In Organic Reactions; Paquette, L. A.,
Ed.; John Wiley & Sons: New York, NY, 1992; Vol. 41, pp 135; (b) Perlmutter, P.
Conjugate Addition Reactions in Organic Synthesis; Pergamon: Oxford, 1992.
13. Selected examples of Cu catalyzed addition: (a) Yamamoto, Y.; Yamamoto, S.;
Yatagai, H.; Ishihara, Y.; Maruyama, K. J. Org. Chem. 1982, 47, 119; (b) Barbot, F.;
Kadib-Elban, A.; Miginiac, P. Tetrahedron Lett. 1983, 24, 5089; (c) Corey, E. J.;
Boaz, N. W. Tetrahedron Lett. 1985, 26, 6019; (d) Barbot, F.; Kadib-Elban, A.;
Miginiac, P. J. Organomet. Chem. 1983, 255, 1; (e) Uerdingen, M.; Krause, N.
Tetrahedron 2000, 56, 2799; (f) Liu, H.; Gayo, L. M.; Sullivan, R. W.; Choi, A. Y. H.;
Moore, H. W. J. Org. Chem. 1994, 59, 3284; (g) Modi, S. P.; Gardner, J. O.; Mi-
lowsky, A.; Wierzba, M.; Forgione, L.; Mazur, P.; Solo, A. J.; Duax, W. L.; Galdecki,
Z.; Grochulski, P.; Wawrzak, Z. J. Org. Chem. 1989, 54, 2317; (h) Krause, N.;
Gerold, A. Angew. Chem., Int. Ed. 1997, 36, 186.
(b) Bloch, R.; Chaptal-Gradoz, N. J. Org. Chem. 1994, 59, 4162; (c) Patel, R. M.;
Argade, N. P. J. Org. Chem. 2007, 72, 4900; (d) Deagostino, A.; Prandi, C.; Za-
vattaro, C.; Venturello, P. Eur. J. Org. Chem. 2006, 2463; (e) Schreiber, S. L.;
Kiessling, L. L. J. Am. Chem. Soc. 1988, 110, 631; (f) Molander, G. A.; Yokoyama, Y.
J. Org. Chem. 2006, 71, 2493 and references cited therein.
26. (a) Luo, M.; Iwabuchi, Y.; Hatakeyama, S. Synlett 1999, 1109; (b) Nativi, C.;
Taddei, M. Tetrahedron 1989, 45, 1131; (c) Brown, P. A.; Jenkins, P. R. J. Chem. Soc.,
Perkin Trans. 11986, 1129; (d) Wada, E.; Kanemasa, S.; Fujiwara, I.; Tsuge, O. Bull.
Chem. Soc. Jpn. 1985, 58, 1942; (e) Nunomoto, S.; Yamashita, Y. J. Org. Chem.
1979, 44, 4788.
27. (a) Yu, C.-M.; Lee, S.-J.; Jeon, M. J. Chem. Soc., Perkin Trans. 1 1999, 3557; (b) Luo,
M.; Iwabuchi, Y.; Hatakeyama, S. Chem. Commun. 1999, 267; (c) Soundararajan,
R.; Li, G.; Brown, H. C. J. Org. Chem. 1996, 61, 100.
28. (a) Phukan, P.; Bauer, M.; Maier, M. E. Synthesis 2003,1324; (b) Smulik, J. A.; Diver,
S. T. J. Org. Chem. 2000, 65, 1788; (c) Lu, W.; Ma, J.; Yang, Y.; Chan, T. H. Org. Lett.
2000, 2, 3469; (d) Smulik, J. A.; Diver, S. T. Org. Lett. 2000, 2, 2271; (e) Katritzky, A.
R.; Serdyuk, L.; Toader, D.; Wang, X. J. Org. Chem. 1999, 64, 1888; (f) Yu, C.-M.;
Yoon, S.-K.; Lee, S.-J.; Lee, J.-Y.; Yoon, S.-K.; Kim, S. S. Chem. Commun. 1998, 2749.
29. Peng, Y.; Yang, J.-H.; Li, W.-D. Z. Tetrahedron 2006, 62, 1209.
30. Yoshimura, H.; Kikuchi, K.; Hibi, S.; Tagami, K.; Satoh, T.; Yamauchi, T.; Ishibahi,
A.; Tai, K.; Hida, T.; Tokuhara, N.; Nagai, M. J. Med. Chem. 2000, 43, 2929.
31. Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Visali, B.; Narsaiah, A. V.; Nagaiah, K. Eur.
J. Org. Chem. 2004, 546.
14. Iron-catalyzed addition: (a) Fukuhara, K.; Urabe, H. Tetrahedron Lett. 2005, 46,
603; (b) Furstner, A.; Martin, R. Chem. Lett. 2005, 34, 624.
15. RhI-catalyzed addition: (a) Hayahi, T.; Yamamoto, S.; Tokugana, N. Angew. Chem.
, Int. Ed. 2005, 44, 4224; (b) de la Herran, G.; Murcia, C.; Csaky, A. G. Org. Lett.
2005, 7, 5629.
32. Tietze, L. F. Chem. Rev. 1996, 96, 115.
33. Crystallographic data (excluding structure factors) for the structure 19 have
been deposited with the Cambridge Crystallographic Data Centre as supple-
mentary publication CCDC671605.
16. Silicon and tin reagents: Krief, A.; Dumont, W.; Provins, L. Synlett 1995, 121.
17. Singh, R.; Ghosh, S. K. Org. Lett. 2007, 9, 5071.
18. (a) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A. T. J. Am. Chem.
Soc. 1971, 93, 2325; (b) Schiff, P. B.; Fant, J.; Horwitz, S. B. Nature 1979, 277, 665;
(c) Kingston, D. G. I. Chem. Commun. 2001, 867; (d) Nicolaou, K. C.; Dai, W.-.M.;
Guy, R. K. Angew. Chem., Int. Ed. Engl. 1994, 33, 15; (f) Mehta, G.; Singh, V. Chem.
Rev. 1999, 99, 881.
34. Mash, E. A.; Hemperly, S. B.; Nelson, K. A.; Heidt, P. C.; Deusen, S. V. J. Org. Chem.
1990, 55, 2045.
35. Wilson, R. M.; Jen, W. S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 11616.
36. Brailsford, J. A.; Zhu, L.; Loo, M.; Shea, K. J. J. Org. Chem. 2007, 72, 9402.
37. Trippett, S.; Walker, D. M. J. Chem. Soc. 1961, 1266.
19. (a) Dabrah, T. T.; Kaneko, T.; Massefski, W., Jr.; Whipple, E. B. J. Am. Chem. Soc.
1997, 119, 1594; (b) Dabrah, T. T.; Harwood, H. J., Jr.; Huang, L. H.; Jankovich, N.
D.; Kaneko, T.; Li, J.-C.; Lindsey, S.; Moshier, P. M.; Subashi, T. A.; Therrien, M.;
Watts, P. C. J. Antibiot. 1997, 50, 1; (c) Starr, J. T.; Carriera, E. M. Angew. Chem., Int.
38. Sheldrick, G. M. SHELX-97-A Program For Crystal Structure Solution and Re-
finement; University of Goettingen: Germany, 1997; Release 97-2.
39. Spangler, C. W.; McCoy, R. K. Synth. Commun. 1988, 18, 51.
40. Kasatkin, A. N.; Biktimirov, R. K.; Tolstikov, G. A. Zh. Org. Khim. 1991, 27, 727.