The influence of reaction conditions on the Diels-Alder cycloadditions of 2-thio-3-chloroacrylamides; Investigation of thermal, catalytic and microwave conditions

Article abstract of DOI:10.1039/c0ob00368a

The Diels-Alder cycloadditions of cyclopentadiene and 2,3-dimethyl-1,3- butadiene to a range of 2-thio-3-chloroacrylamides under thermal, catalytic and microwave conditions is described. The influence of reaction conditions on the outcome of the cycloaddi

Full text of DOI:10.1039/c0ob00368a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
The influence of reaction conditions on the Diels–Alder cycloadditions of
2-thio-3-chloroacrylamides; investigation of thermal, catalytic and microwave
conditions†
Marie Kissane,a Denis Lynch,a Jay Chopra,a Simon E. Lawrencea and Anita R. Maguire*b
Received 1st July 2010, Accepted 31st August 2010
DOI: 10.1039/c0ob00368a
The Diels–Alder cycloadditions of cyclopentadiene and 2,3-dimethyl-1,3-butadiene to a range of
2-thio-3-chloroacrylamides under thermal, catalytic and microwave conditions is described. The
influence of reaction conditions on the outcome of the cycloadditions, in particular the stereoselectivity
and reaction efficiency, is discussed. While the cycloadditions have been attempted at the sulfide,
sulfoxide and sulfone levels of oxidation, use of the sulfoxide derivatives is clearly beneficial for
stereoselective construction of Diels–Alder cycloadducts.
by Garcia Ruano, excellent asymmetric induction is envisaged in
Introduction
cycloadditions due to the chiral sulfoxide moiety.8,12,13
The Diels–Alder cycloaddition is one of the most frequently used
carbon–carbon bond forming reactions in organic synthesis.1–8
The intramolecular Diels–Alder cycloaddition of the b-
chloroacrylamide derivative 1 was reported by Jung and Street
in 1984.20 To the best of our knowledge, this is the only example
of the employment of a b-chloroacrylamide as a dienophile in the
Diels–Alder reaction. A high degree of diastereoselectivity was
achieved (>95 : 5 endo:exo) when 1 was heated in toluene at reflux
for 1 h (Scheme 1).
The use of highly functionalized adducts in the preparation of
natural products and biologically active compounds is continuing
to grow,5,6 especially with the advent of enantioselective catalysts
for the reaction.9–11 The popularity of the Diels–Alder reaction as
a synthetic tool is partly due to the high degree of stereo- and
regioselectivity which accompanies the reaction.1,2 The presence
of directing groups leads to further control of the reaction with
the result that a desired adduct diastereomer can be formed almost
exclusively. The use of directing groups has been widely exploited
by Garcia Ruano and co-workers in their use of enantiopure
sulfoxides to control the formation of stereogenic centres in the
Diels–Alder reaction.8,12,13
We have recently reported the highly efficient and stereose-
lective transformation of a-thioamides to the corresponding a-
thio-b-chloroacrylamide derivatives on treatment with NCS.14
The chemoselective and stereoselective oxidation of the b-
chloroacrylamides to the sulfoxide and sulfone levels of oxidation
has extended the scope of this methodology.15 The employment of
b-chloroacrylamides as dipolarophiles in 1,3-dipolar cycloaddi-
tions has also been reported recently.16,17 The b-chloroacrylamides
are a highly functionalized group of unsaturated compounds, and
the range of substituents which can be incorporated on the basic
acrylamide framework is substantial.14,18 These derivatives are
potential dienophiles leading to novel cycloadducts in reactions
with dienes. We have described asymmetric and diastereoselective
sulfur oxidation in these series, leading to enantioenriched sulfinyl
derivatives of the b-chloroacrylamides.15,19 Based on earlier work
Scheme 1
Herein, we report the Diels–Alder cycloadditions of a range
of b-chloroacrylamides to cyclopentadiene and 2,3-dimethyl-1,3-
butadiene under thermal, catalytic and microwave conditions.
Results and discussion
Cyclopentadiene
Initial investigations focused on the highly reactive cyclopenta-
diene, which is fixed in the s-cis geometry required for Diels–
Alder cycloaddition. Preliminary experiments involved heating a
solution of the sulfide 5a in dichloromethane with an excess of
cyclopentadiene at reflux for 16 h; these simple thermal processes
proved unsuccessful, with no reaction observed. Elevating the
temperature by conducting the reaction in toluene also failed
to provide the cycloadduct, with the sulfide 5a again recovered
unchanged (Scheme 2).
At this stage it was decided to activate the b-chloroacrylamides
towards Diels–Alder cycloaddition by oxidising the sulfide to the
more electron withdrawing sulfoxide.15 Indeed, reaction of the
sulfoxide 3a in dichloromethane with an excess of cyclopentadi-
ene at reflux for 16 h successfully afforded two diastereomeric
aDepartment of Chemistry, Analytical and Biological Chemistry Research
Facility, University College Cork, Ireland
bDepartment of Chemistry and School of Pharmacy, Analytical and Bi-
ological Chemistry Research Facility, University College Cork, Ireland.
E-mail: a.maguire@ucc.ie
† Electronic supplementary information (ESI) available: Experimental
details. CCDC reference numbers 784305 and 784306. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c0ob00368a
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Table 1 Reaction of the a-sulfinyl-b-chloroacrylamides with cyclopentadiene
Methoda (endo : exo,b % yieldc)
Entry
b-Cl
R1
R2
A
B
C
D
Ed
F
Adduct
1
2
3
4
5
6
7
8
3a
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Tol
Et
Bn
iPr
nBu
Allyl
H
4-F-C6H4
Tol
Bn
Et
Tol
Tol
Bn
4-F-C6H4
4-F-C6H4
4-F-C6H4
Bn
4-F-C6H4
(R)-(+)-CH(CH3)Ph
4-F-C6H4
4-F-C6H4
1.3 : 1e (93)
1.2 : 1 (74)
1.3 : 1f (84)
1.2 : 1 (89)
1.2 : 1 (76)
1.3 : 1 (79)
1.6 : 1 (74)
1.7 : 1 (96)
1.3 : 1 (98)g
1.1 : 1 (89)g
1.2 : 1 (74)
1.3 : 1h (79)
1 : 1 (87)
1 : 1.1 (84)
1.1 : 1 (95)
1.1 : 1 (79)
1.1 : 1 (75)
1 : 1.4 (88)
1 : 1.2 (90)
1 : 1.3 (94)
1 : 1 (93)
1.7 : 1
1.4 : 1i
1.3 : 1j
1.4 : 1k
1.4 : 1l
1.5 : 1m
2.3 : 1
—
—
—
—
—
—
—
—
—
—
—
—
—
1.8 : 1
2.1 : 1
—
2.0 : 1
—
—
2.4 : 1
—
—
—
—
—
—
—
—
—
—
—
—
—
8.8 : 1
5.5 : 1
—
5.4 : 1
—
—
2.4 : 1
—
—
—
—
—
—
—
—
—
—
—
—
—
4.2 : 1
5.2 : 1
6.2 : 1
5.3 : 1
4.8 : 1
4.5 : 1
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
4a
4b
4c
4d
4e
4f
4g
4h
4i
3b
3c
3d
3e
3f
3g
3h
—
9
3i
3j
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
4-NO2-C6H4
nBu
nBu
nBu
nBu
nBu
Bn
Bn
Bn
Me
iPr
3.5 : 1
5.7 : 1
5.2 : 1
—
—
—
—
—
—
—
—
—
1 : 1
—
10
11
12
13
14
15
16
17
18
19
20
21
22
4j
4k
4l
3k
3l
3m
3n
4m
4n
4o
4o
4o
4p
4q
4r
4s
4t
( )3o
(-)-3on
(+)-3oo
3p
3q
1.1 : 1 (69)
—
1 : 1 (97)
—
3r
3s
1 : 1
—
1 : 1
—
1 : 1
—
3t
1.4 : 1 (87)
a Method A: 10 equivalents cyclopentadiene, CH2Cl2, reflux, 16 h; Method B: 10 equivalents cyclopentadiene, 1% CuCl2, CH2Cl2, rt, 10 h to 2 d; Method
C: 7 equivalents cyclopentadiene, 1% CuCl2, CH2Cl2, reflux, 16 h; Method D: 7 equivalents cyclopentadiene, 1% Cu(OTf)2, CH2Cl2, rt, 16 h; Method E: 10
equivalents cyclopentadiene, 1% Cu(OTf)2, CH2Cl2, reflux, 1–2 h; Method F: 10 equivalents cyclopentadiene, CH2Cl2, MW, 100 ◦C, 5 min. b Determined
by integration of the 1H NMR spectra of the crude products for Method A, and purified products for Methods B–F. c Unless otherwise stated, isolated
yield following chromatographic purification. d For the Cu(OTf)2 catalysed reactions at reflux, a blue-black substance formed after heating for ~30 min,
believed to be a polymer of cyclopentadiene. Garcia Ruano and Honeychuck have reported a similar phenomenon.12,21 e Ratio after chromatography was
1.40 : 1. f Ratio after chromatography was 3 : 1. g Yield of crude product; no further purification was conducted. h Purified by trituration in ether/hexane.
i Reaction time 2 days. j Reaction conversion was 50%. k Reaction conversion was 50% after 16 h. Reaction conversion was 100% after 2 days. l Reaction
conversion was 63%. m Reaction conversion was 55%. n % ee of Sulfoxide (+)-3o 53%. o % ee of Sulfoxide (-)-3o 53%.
TLC analysis, and all subsequent cycloadditions were thus heated
at reflux in dichloromethane for 16–18 h.
The scope of the Diels–Alder cycloaddition was investigated
by varying the amide group and the sulfoxide substituent (entries
2–22, Table 1, Method A). In all instances, complete conversion
Scheme 2
was observed and a mixture of endo and exo cycloadducts were
isolated. The endo adduct was the major adduct obtained in most
cycloadducts 4a-endo and 4a-exo, isolated as an inseparable
mixture in a 1.3 : 1 crude ratio, and a 1.4 : 1 ratio following chro-
matographic purification (entry 1, Table 1), confirming that the
sulfoxide group was sufficiently activating to enable cycloaddition
under relatively mild conditions. The major diastereomer was
subsequently shown to have the amide endo, while the minor
diastereomer had the amide exo. Conducting the reaction in
toluene did not lead to a significant increase in the reaction rate,
and thus all further thermal cycloadditions with cyclopentadiene
were routinely carried out in dichloromethane. The optimum
reaction time was determined by monitoring the progress of the
cycloaddition of 3a with cyclopentadiene over a period of 16 h;
after heating at reflux for 10 h, substantial amounts of 3a remained
by TLC analysis. When heating was continued for a further 6 h,
complete conversion of 3a to the cycloadduct 4a was evident by
instances, however the degree of endo/exo selectivity was low,
with the highest diastereomeric ratio (1.7 : 1) achieved for the
N-4-fluorophenyl sulfoxide 3h (entry 8, Table 1). Cycloaddition
of the enantioenriched sulfoxides (+)-3o and (-)-3o afforded
similar diastereomeric ratios as those obtained using racemic 3o
as expected (entries 15–17, Table 1, Method A).
In an attempt to increase the reaction selectivity and the
rate of the cycloaddition, the reaction of the sulfoxides with
cyclopentadiene was next conducted in the presence of two copper
catalysts, CuCl2 and Cu(OTf)2, at both room temperature and at
reflux in dichloromethane (entries 1–7, entries 9–11 and entry 21,
Table 1, Methods B–E).
Employment of 1% CuCl2 by weight at room temperature led to
modest increases in the endo/exo selectivity, with diastereomeric
ratios of up to 2.3 : 1 achieved with b-chloroacrylamide 3g cf. 1.6 : 1
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Scheme 3
with this substrate under thermal conditions, and a highest d.r. of
1.7 : 1 under thermal conditions. Significantly, the cycloaddition
proceeds at room temperature in the presence of CuCl2, albeit
more slowly than the thermal reactions at reflux in the absence
of catalyst. Increasing the temperature of the CuCl2 catalysed
reaction led to similar rates to the non-catalysed process, with
complete conversion in all instances after heating at reflux for 16 h.
A slight increase in the diastereoselectivity of the cycloaddition
was observed, with diastereomeric ratios of up to 2.4 : 1 achieved
(entry 7, Table 1, Method C).
Moving from CuCl2 to Cu(OTf)2 resulted in a significant
increase in the reaction efficiency and diastereoselectivity. The
use of 1% Cu(OTf)2 by weight led to an enhancement of
diastereoselection, with the endo isomer formed in synthetically
useful ratios (d.r. of up to 8.8 : 1). There was also a significant
increase in the reaction rate observed when the cycloaddition
was performed under reflux conditions, with the starting material
completely consumed after 1–2 h, although the diastereoselectivity
was optimum when the cycloadditions were conducted at room
temperature.
Fig. 1
1.4 equivalents of mCPBA; a 1.3 : 1 mixture of diastereomers was
obtained. The presence of two sulfone adduct diastereomers in
the same ratio following oxidation confirmed that the adducts
were diastereomeric at carbon, and did not just differ in relative
configuration at sulfur (Scheme 4).
Finally, the microwave assisted Diels–Alder cycloadditions of
the sulfoxides 3q and 3s with cyclopentadiene were attempted
(entries 19 and 21, Table 1, Method F). Although the endo : exo
selectivities were similar to those achieved under thermal condi-
tions in the absence of Lewis acid catalysis, a large decrease in the
reaction time from 16 h to just 5 min was observed.
Scheme 4
In general, the N-aryl substituted b-chloroacrylamides led to
the greatest diastereoselectivity, with the N-tolyl substituted b-
chloroacrylamide 3a resulting in the greatest diastereomeric ratios
(up to 8.8 : 1) for the copper catalysed processes (entry 1, Table 1),
while the N-4-fluorophenyl derived b-chloroacrylamide 3h gave
the greatest diastereoselectivity (1.7 : 1) under thermal conditions
(entry 8, Table 1). Interestingly, cycloaddition of the S-methyl
sulfoxide 3s with cyclopentadiene led to an equimolar mixture
of diastereomers under thermal, copper catalysed and microwave
conditions (entry 21, Table 1).
To determine if the cycloaddition was under kinetic or ther-
modynamic control, the adduct 4d (d.r. 5.4 : 1) was re-exposed
to the thermal cycloaddition conditions. After heating at reflux
for 18 h, the diastereomeric ratio was unchanged suggesting that
the formation of the adducts is irreversible, and therefore the
diastereomeric ratio is under kinetic control (Scheme 3).
While the cycloadditions produced a mixture of just two
diastereomeric cycloadducts, it was necessary to determine which
two of the potential four cycloadducts were formed. Thus, endo
and exo isomers with opposite stereochemistry at the sulfoxide
could potentially form in the cycloaddition process as illustrated
in Fig. 1.
Though the majority of the adducts (4a, 4c–4t) were isolated as
a chromatographically inseparable mixture of diastereomers, the
two adduct diastereomers of the N-ethyl adduct 4b were separable
by chromatography on silica gel. The relative stereochemistry in
the adducts 4b-endo and 4b-exo was unequivocally determined by
X-ray crystallographic and NOE studies.
Analysis of the crystal structures revealed that the major adduct
diastereomer had the amide moiety endo (Fig. 2), while in the
minor adduct the amide moiety was exo (Fig. 3). In both cases,
the cis relationship of the sulfoxide and the chlorine was retained
as expected. The crystal structures provided firm evidence of the
relative stereochemistry at the sulfoxide in each case.
The stereochemical assignment was confirmed by NOE studies;
for the major adduct 4b-endo, irradiating at H-3 showed the
expected enhancement of H-4 and H-5, as the proton on C-3
is spatially close to that at C-4. The enhancement observed at H-
5 was less than that at H-4. The minor adduct 4b-exo was also
irradiated at H-3, with enhancement of H-4 and H-7a observed.
The enhancement at H-7a is very significant as it is not present in
the experiment employing 4b-endo (Fig. 4).
The assignment of the stereochemistry of each of the other
cycloadducts was by analogy, and in particular the coupling
To determine if the adducts were diastereotopic at sulfur, the
adduct 4a (as a 1.3 : 1 mixture of diastereomers) was oxidized with
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Fig. 6
Fig. 2 Crystal structure of 4b-endo.
the b-chloroacrylamide from the lower face, cyclopentadiene can
add from two directions as depicted in Fig. 6, leading to the
diastereomers with the amide in the endo and exo positions.
Employment of the enantiopure (R)-(+)-a-methylbenzylamine
derived b-chloroacrylamide (R,Ss)-3r yielded a diastereomeric
ratio of 1 : 1.3 (endo:exo) of the inseparable cycloadducts, both
of which are enantiopure, in 94% yield (entry 20, Table 1, Method
A) as illustrated in Fig. 7. The cycloadducts are not readily
separated at this stage, but can be separated through further
functionalisation. The relative stereochemistry of the precursor
sulfoxide was determined by X-ray crystallographic analysis of
the diastereomeric (R,Rs)-3r.19 Thus, asymmetric induction from
the sulfoxide chiral auxiliary is very effective in the cycloaddition
process, with complete diastereofacial control, albeit yielding endo
and exo isomers.
Fig. 3 Crystal structure of 4b-exo.
Fig. 4
constants J3,4 are very characteristic; 4 Hz for the exo adducts
and 2 Hz for the endo adducts (see for example Fig. 5).22
Fig. 7
Similarly, reaction of each of the enantioenriched sulfoxides (-)-
3o and (+)-3o with cyclopentadiene led to the enantioenriched
adducts (-)-4o and (+)-4o, which were isolated in 79% and
75% yield respectively, again as a mixture of endo and exo
diastereomers, but with excellent transfer of chirality from sulfur
to carbon in the cycloaddition process (entries 16 and 17, Table 1,
Method A).
Employment of the Lewis acid catalysts CuCl2 and Cu(OTf)2
led to an increase in the diastereoselectivity of the cycloaddition,
with approach of the diene favouring the formation of the endo
diastereomer. Clearly, the change in the diastereomeric ratio is due
to coordination of the metal to the sulfoxide.
Fig. 5
The a-sulfinyl-b-chloroacrylamides are conformationally con-
strained due to an intramolecular hydrogen bond between the
amide proton and the sulfoxide, adopting the s-cis conformation.14
In each of the cycloadditions, just two diastereomers of each of
the cycloadducts are obtained. Complete diastereofacial control
by the sulfoxide is observed, with the preferred approach of
cyclopentadiene to the b-chloroacrylamides avoiding steric in-
teractions with the R1 group which blocks the approach of the
diene from above (as illustrated in Fig. 6). When approaching
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Table 2 Reaction of sulfide derivatives with cyclopentadiene
Entry
Sulfide
R1
R2
Methoda
% conv.b
Adduct
endo : exob
% yieldc
1
2
3
4
5
6
7
8
5a
5a
5b
5c
5d
5e
5f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Tol
Tol
Et
Bn
A
G
G
G
G
G
G
G
G
G
H
0
—
6a
6b
6c
6d
6e
6f
—
—
65
17+9
39
17+8
25
31
54
33
46
77
27
43
22
34
46
4.0 : 1
1.3 : 1
1.7 : 1
1.5 : 1
1.9 : 1
2.0 : 1
2.7 : 1
4.0 : 1f
2.7 : 1f
3.1 : 1g
iPr
nBu
allyl
Tol
d
5g
5h
5i
4-NO2-C6H4
—
6g
6h
6i
e
9
10
11
nBu
nBu
Bn
Tol
Bn
4-F-C6H4
—
e
—
5j
95
6j
88
a Method A: 10 equivalents cyclopentadiene, CH2Cl2, reflux; Method G: 1. 1.2 equivalents CuCl2, CH2Cl2, rt, 10 days, 2. morpholine, 3. chromatography;
Method H: MW, 300 W, 150 ◦C, 10 min. b Unless otherwise stated, as determined by 1H NMR spectroscopy of the crude product mixture after removal of
the copper catalyst by chromatography on silica gel. c Isolated yield following chromatographic purification. d The % conversion could not be accurately
estimated due to the adduct aromatic proton signals obscuring the b-chloroacrylamide b-proton signal on the 1H NMR spectrum of the crude product
mixture. e The % conversion could not be accurately estimated due to broadening of the signals in the 1H NMR spectra. f Ratio after reaction of the crude
product with morpholine followed by purification by chromatography. g Ratio after purification by chromatography.
Following the success of the copper catalysed and microwave
enhanced cycloadditions of the sulfoxides, the dienophilic be-
haviour of the less reactive sulfide derivatives with cyclopentadiene
was re-examined. The Diels–Alder cycloaddition of the sulfide
5a with cyclopentadiene was attempted in the presence of a
range of Lewis acid catalysts, with CuCl2 proving to be the
most expedient catalyst. However, stoichiometric amounts of the
catalyst (1.2 equivalents) and long reaction times (typically 10
days) were required, and it was necessary to add fresh portions
of cyclopentadiene to the reaction mixture every 48 h. The
cycloaddition was then conducted for a range of sulfides (entries
2–10, Table 2). Even with prolonged reaction times, the highest
conversion of sulfide to cycloadduct observed was 77% (entry
Scheme 5
2, Table 2). Attempts to separate the cycloadduct from the
the relative stereochemistry was the same in the sulfide adducts as
unreacted starting material in each instance by chromatography
in the sulfoxide adducts (Scheme 6), with the same diastereomer
were unsuccessful. It was previously shown that the sulfides
(amide endo) predominating. Interestingly, oxidation of the sulfide
undergo nucleophilic substitutions readily with morpholine to
cycloadducts produced the same sulfoxides as had been isolated
yield very polar substances.15 As the cycloadducts cannot readily
from the cycloaddition with the a-sulfinyl-b-chloroacrylamides.
undergo reaction with morpholine, the substitution of the sulfides
Noevidenceforformationofdiastereomersatsulfurwasobserved.
with morpholine was exploited in separating the unreacted sulfides
from the cycloadducts. Thus, following removal of the copper
catalyst, the product mixture containing the unreacted sulfide and
cycloadduct was dissolved in dichloromethane and, based on the
estimated amount of unreacted starting material as determined
by 1H NMR spectroscopy of the crude reaction mixture, 2.5
equivalents of morpholine was added (Scheme 5). Purification
by chromatography then provided the sulfide cycloadducts free of
starting material.
As with the sulfoxide adducts, only two sets of signals were seen
on both the 1H and 13C NMR spectra; therefore it was envisaged
that the sulfide adducts directly analogous to the sulfoxide adducts
isolated earlier were formed with the amide moiety endo and
exo. Oxidation of the sulfide adduct 6a with mCPBA to the
corresponding sulfoxide adduct 4a and comparison of the shifts
and the coupling constants in the 1H NMR spectra confirmed that
Scheme 6
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Scheme 7
The relative stereochemistry of the sulfide adducts was also
confirmed by examination of the coupling constants of H-3 in the
major and the minor adducts, which were identical in the sulfide
adducts to those of the sulfoxide adducts. Most of the cycloadducts
were isolated as an inseparable mixture of diastereomers following
chromatographic purification, however, it was possible to separate
the N-ethyl adducts 6b-endo and 6b-exo (entry 3, Table 2) and the
N-isopropyl adducts 6d-endo and 6d-exo (entry 5, Table 2).
In general the cycloadditions were most efficient with N-aryl
amides, and equally, diastereoselectivities tended to be highest
with these derivatives (entries 2 and 9, Table 2), as seen in
cycloadditions with the analogous sulfoxides. Interestingly, similar
diastereoselectivities were observed with the n-butylthio and
phenylthio derivatives (entries 2 and 4, Table 2 cf. entries 9 and 10,
Table 2).
After work-up, this material was used without further purification
in the Diels–Alder cycloaddition with cyclopentadiene at reflux
in dichloromethane to give the cycloadduct 7a, with an endo : exo
ratio of 5.0 : 1 (Scheme 8). The increase in diastereoselectivity of
the cycloaddition on oxidizing the sulfoxide (endo:exo 1.3: 1) to the
sulfone (endo : exo 5.0 : 1) may be due to the electronic impact of
the sulfonyl group, or may reflect catalysis of the cycloaddition by
residual 3-chlorobenzoic acid. Further work is required to clarify
this.
The microwave assisted Diels–Alder cycloaddition of the b-
chloroacrylamides with cyclopentadiene was also attempted at the
sulfide level (entry 11, Table 2). Following heating of the sulfide
5j in an excess of cyclopentadiene at 150 ◦C for 10 min under
solvent-free conditions, there was 95% conversion to the resulting
cycloadduct 6j, the highest conversion achieved to date for the
cycloadditions with the sulfides. Significantly, this was also the first
time that the sulfide cycloadducts were formed in the absence of
a Lewis acid catalyst. Following purification by chromatography,
the cycloadduct 6j was isolated in 88% yield in an endo:exo ratio
of 3.1 : 1.
Preliminary investigation into the use of chiral Lewis acid
catalysts was also undertaken as illustrated in Scheme 7. The
Cu(II) bisoxazoline catalyst developed by the Evans group was
employed,23 and initial attempts to effect the cycloaddition of
the N-tolyl sulfide 5a using 10 mol% of the chiral catalyst
in dichloromethane at room temperature resulted in very low
conversion (30% in 6 days). A range of solvents were screened,
including water, methanol, ethanol, hexane and ether, with most
efficient cycloadditions observed using ether as solvent. The enan-
tioselectivities achieved were low, with the highest enantiopurity
(33% ee) achieved for 6a-endo.
Scheme 8
Oxidation of adducts
In order to compare the adducts at the sulfide, sulfoxide and
sulfone levels of oxidation, a series of oxidation experiments
were undertaken where the separated diastereomers of the N-
ethyl adduct 6b-endo and 6b-exo and the N-tolyl adduct 6a were
converted from the sulfide adducts to the sulfoxide adducts and
then on to the sulfone adducts to correlate the diastereomers at
each level of sulfur oxidation (Scheme 9).
The oxidations were conducted by sequential addition of
1
mCPBA with monitoring by H NMR spectroscopy. With the
separated N-ethyl cycloadducts 6b-exo and 6b-endo, it was possible
to observe the oxidation sequence from sulfide to sulfoxide to
sulfone, therefore correlating the cycloadduct diastereomers at
each level of sulfide oxidation. Oxidation of the exo diastere-
omer appeared to proceed more rapidly than oxidation of the
corresponding endo diastereomer, and indeed, further oxidation
of the exo diastereomer to the epoxide 8b-exo was observed in the
presence of excess mCPBA, while the corresponding process was
not seen with the diastereomeric endo sulfone.
Similarly, a mixture of the N-tolyl cycloadducts 6a-endo and
6a-exo was oxidised through the sequence sulfide to sulfoxide
to sulfone, again enabling correlation of the diastereomeric
cycloadducts. In this instance, both diastereomers appeared to
oxidise at approximately the same rate, however, there was some
evidence for over oxidation of 7a-exo to the epoxide 8a-exo on
addition of a third portion of mCPBA.
The Diels–Alder cycloadducts have also been synthesised at
the sulfone level of oxidation. However, due to the difficulty
in forming the sulfone derivatives of the b-chloroacrylamides,15
the majority of the sulfone adducts synthesised were formed by
oxidation of the corresponding sulfoxide adducts using mCPBA in
dichloromethane (see later). The sulfone derivative of the N-tolyl
b-chloroacrylamide 9a was prepared, however, by refluxing the sul-
foxide with a large excess of mCPBA in dichloromethane for 18 h.
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Scheme 9
A mixture of the N-isopropyl sulfoxide adducts 4d-endo and
4d-exo was also exposed to the mCPBA oxidation conditions
(Scheme 9), and again the reaction was monitored by H NMR
spectroscopy. While both the endo and exo diastereomers were
oxidized effectively to the sulfones, partial over-oxidation of 7d-
exo to the corresponding epoxide 8d-exo (up to 30%) was observed,
similar to results with the N-tolyl and N-ethyl adducts.
required for Diels–Alder cycloadditions, rotation around the C(2)–
C(3) bond is possible in 2,3-dimethyl-1,3-butadiene, leading to
both the s-cis and s-trans conformers. The barrier to this rotation
has been calculated experimentally as 4.3 kcal mol-1,24 and as a
result of this rotation the reactivity of 2,3-dimethyl-1,3-butadiene
in cycloadditions with b-chloroacrylamides is expected to be much
lower than cyclopentadiene.25,26
1
Preliminary investigations were conducted using the sulfox-
ide 3a as dienophile. The cycloaddition with 2,3-dimethyl-1,3-
butadiene was attempted in dichloromethane at reflux in the
absence and presence of Cu(OTf)2; the unreacted precursor 3a was
isolated in both instances. The use of elevated pressure, achieved
by heating the solution in a sealed tube, to promote this Diels–
Alder cycloaddition was then investigated. On heating a solution
of the diene with the b-chloroacrylamide 3a in toluene in a sealed
tube for 18 h, the trisubstituted aromatic product 12a was isolated
in 87% yield (Scheme 11).
Cycloadditions of b-chloroacrylates 10a and 10b with cyclopen-
tadiene. We have demonstrated that the synthesis of the b-
chloroacrylamides can be effectively extended to the correspond-
ing acrylates.18 The effect of replacing the amide moiety of the b-
chloroacrylamides with the ester functionality on the Diels–Alder
cycloadditions with cyclopentadiene was therefore investigated.
The cycloaddition of the b-chloroacrylate 10a at the sulfide level
of oxidation with cyclopentadiene was initially attempted using
Method A (10 eq. of cyclopentadiene, dichloromethane, reflux, 16
h); approximately 15% conversion to the adduct 11a was evident
by 1H NMR spectroscopy. This was the first time that an adduct
of a b-chloro compound at the sulfide level of oxidation had
formed without the use of Lewis acid catalysis, high pressure or
microwaves. In order to drive the reaction to completion, the b-
chloroacrylate 10a was reacted with a large excess of cyclopentadi-
ene (approximately 20 equivalents) under solvent-free conditions
at 50 ◦C for 16 h. Following purification by chromatography,
the cycloadducts 11a-endo and 11a-exo were obtained free of
starting material in an 86% yield and a diastereomeric ratio of
4.1 : 1 respectively (Scheme 10). The stereochemistry of the two
diastereomers was assigned by comparison of the NMR spectra
of 11a with those of the amide derivatives. The Diels–Alder
cycloaddition of the bromo derivative 10b with cyclopentadiene
was also conducted using the solvent-free conditions described
above; the cycloadduct 11b was obtained in an 85% yield and a
diastereomeric ratio of 4.3 : 1 (endo:exo) (Scheme 10).
Scheme 11
The use of microwave technology to promote the Diels–
Alder cycloaddition between the acyclic diene 2,3-dimethyl-1,3-
butadiene and the b-chloroacrylamides was next explored to avoid
the use of sealed tubes. The microwave assisted cycloadditions of
the sulfoxides with 2,3-dimethyl-1,3-butadiene proved to be very
successful, with complete conversion to the trisubstituted aromatic
◦
adducts following microwave heating for 30 min at 150 C using
10 equivalents of 2,3-dimethyl-1,3-butadiene under solvent-free
conditions (Table 3).
The Diels–Alder cycloaddition proceeds via the cyclohexene
adduct, but this easily eliminates both the sulfoxide and chloride
groups, either spontaneously or on silica gel, to yield the trisubsti-
tuted aromatic as the final product (Scheme 12).
Scheme 10
Thus, an increase in reactivity and selectivity is observed on
substituting the b-chloroacrylamides with the b-chloroacrylates
in Diels–Alder cycloadditions with cyclopentadiene.
Scheme 12
The cyclohexene intermediate was evident in the 1H NMR
spectra of the crude products from each of the benzylsulfinyl
cycloadditions (entries 3–7, Table 3), although the substituted aro-
matic products account for the major sets of signals present. These
cyclohexene adducts do not survive the purification conditions of
2,3-Dimethyl-1,3-butadiene
The reactivity of the b-chloroacrylamides in cycloadditions with
the acyclic diene 2,3-dimethyl-1,3-butadiene was next explored.
Unlike cyclopentadiene, which is fixed in the s-cis geometry
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Table 3 Microwave assisted cycloaddition of sulfoxides with 2,3-
dimethyl-1,3-butadiene
based on the level of sulfide oxidation is potentially synthetically
useful.
Conclusion
Diels–Alder cycloadditions of cyclopentadiene to a-sulfinyl-b-
chloroacrylamides can be effected under thermal, copper catalysed
and microwave conditions to afford a range of novel cycloadducts.
In all instances, excellent diastereofacial control from the sul-
foxides is observed, although leading to a mixture of endo and
exo diastereomers. An increase in the reactivity and selectivity is
observed on employment of copper catalysts, while a significant
increase in the reaction rate is observed under microwave irradia-
tion. While the Diels–Alder cycloadditions of cyclopentadiene to
a-thio-b-chloroacrylamides could not be achieved under thermal
conditions, successful cycloaddition was observed either through
use of copper catalysis or microwave irradiation.
Entry
Sulfoxide
R1
R2
Product
% yielda
1
2
3
4
5
6
7
3a
3n
3p
3q
3u
3v
3w
Ph
Tol
Bn
Bn
4-F-C6H4
Tol
Me
Ph
12a
12b
12b
12c
12a
12d
12e
59
39
53
83
95
42
53
n-Bu
Bn
Bn
Bn
Bn
Bn
a Isolated yield after chromatography on silica gel.
Cycloaddition of the b-chloroacrylamides at both the sulfide
and sulfoxide levels of oxidation with the acyclic diene 2,3-
dimethyl-1,3-butadiene can be effected thermally using microwave
heating. This is particularly significant, as copper catalysed
cycloaddition with the acyclic diene was unsuccessful. In the case
of the sulfoxides, only the aromatised products are isolated after
purification, while with the more robust sulfides, the cyclohexenes
are readily isolated and characterised.
Table 4 Microwave assisted cycloaddition of sulfides and 2,3-dimethyl-
1,3-butadiene
Sulfide
R1
R2
Product
% yielda
5a
5j
5k
5l
Ph
Bn
Bn
Bn
Tol
4-F-C6H4
Bn
13a
13b
13c
13d
91
98
98
58
Experimental
Me
Solvents were distilled prior to use as follows: dichloromethane
was distilled from phosphorus pentoxide and ethyl acetate was
distilled from potassium carbonate. Hexane was distilled prior
to use. Organic phases were dried using anhydrous magne-
sium sulfate. Cyclopentadiene was freshly prepared by cracking
cyclopentadiene dimer at 180 ◦C and distilling the monomer
into an ice-cooled flask and then stored at -18 ◦C. While this
material was typically used within 2 h of preparation, samples of
cyclopentadiene stored at -18 ◦C were found to dimerise so slowly
that the reagent did not need to be redistilled for up to 5 days.
Infrared spectra were recorded as thin films on sodium chloride
plates for oils or as potassium bromide (KBr) discs for solids on a
Perkin Elmer Paragon 1000 FT-IR spectrometer.
a Isolated yield after chromatography on silica gel.
chromatography on silica gel, and elimination of the sulfoxide and
chloride substituents affords the substituted aromatic products,
with no evidence of the cyclohexene adducts in the H NMR
1
spectra of the purified products. In contrast, the cyclohexene
1
adducts were not evident in the H NMR spectra of the crude
products from the cycloaddition of the benzenesulfinyl derivative
3a (entry 1, Table 3) and the n-butylsulfinyl derivative 3n (entry
2, Table 3) with the 2,3-dimethyl-1,3-butadiene, indicating that
the benzenesulfinyl and n-butylsulfinyl groups are more easily
eliminated than the benzylsulfinyl group. A similar effect was
seen in earlier studies on 1,3-dipolar cycloadditions with the b-
chloroacrylamides.16 Interestingly, the isolated yields of 12a and
12b were lower from the cycloaddition of 3a and 3n than from
the cycloaddition of the corresponding benzylsulfinyl derivatives
3u and 3p (entries 1 and 2, Table 3 vs. entries 3 and 5, Table 3),
presumably associated with the more facile elimination during the
cycloaddition.
The microwave assisted Diels–Alder cycloaddition of 2,3-
dimethyl-1,3-butadiene with the sulfide derivatives, which are
inherently weaker dienophiles, was also investigated. Following
heating of the sulfides with 2,3-dimethyl-1,3-butadiene at 180 ◦C
for 2 h, the cyclohexene adducts were isolated (Table 4).
1H (300 MHz) and 13C (75.5 MHz) NMR spectra were recorded
on a Bruker Avance 300 MHz NMR spectrometer. 1H (400 MHz)
NMR spectra were recorded on a Bruker Avance 400 MHz NMR
1
spectrometer. H (270 MHz) and 13C (67.8 MHz) NMR spectra
were recorded on a JEOL PMX-60SI sp◦ectrometer. All spectra
were recorded at room temperature (~20 C) in deuterated chlo-
roform (CDCl3) unless otherwise stated using tetramethylsilane
(TMS) as an internal standard. Chemical shifts (dH and dC) are
reported in parts per million (ppm) relative to TMS and coupling
constants are expressed in hertz (Hz).
Low resolution mass spectra were recorded on a Waters Quattro
Micro triple quadrupole spectrometer in electrospray ionization
(ESI) mode using 50% water–acetonitrile containing 0.1% formic
acid as eluent; samples were made up in acetonitrile. High
resolution mass spectra (HRMS) were recorded on a Waters LCT
Premier Time of Flight spectrometer in electrospray ionization
(ESI) mode using 50% water–acetonitrile containing 0.1% formic
acid as eluent; samples were made up in acetonitrile.
The 1H NMR spectra of the crude products were very clean and
on purification by chromatography on silica gel, the cyclohexene
adducts 13a–13d were isolated, with no evidence of sulfide or
chloride elimination. The potential to isolate the cyclohexene
adducts or the aromatic products from the cycloaddition processes
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Elemental analyses were performed by the Microanalysis Labo-
ratory, National University of Ireland, Cork, using Perkin–Elmer
240 and Exeter Analytical CE440 elemental analysers. Melting
points were carried out on a uni-melt Thomas Hoover Capillary
melting point apparatus and are uncorrected.
Flash chromatography was performed using Kieselgel silica gel
60, 0.040–0.063 mm (Merck). Thin layer chromatography (TLC)
was carried out on precoated silica gel plates (Merck 60 PF254).
Visualisation was achieved by UV (254 nm) light detection, iodine
staining, vanillin staining and ceric sulfate staining.
Microwave assisted synthesis was achieved using the CEM
Discover Labmate Synthesiser in conjunction with ChemDriver
software (Version 3.5.0) and the CEM Discover S-Class Synthe-
siser in conjunction with Synergy software.
The synthesis of 3a–3w, 5a–5l and 10a and 10b has already been
described.14,15,18 Selected experimental data, including representa-
tives of each of the synthetic methods, are given below–full ex-
perimental procedures and spectroscopic data for all compounds
described in the paper are given in the supporting information.
for all 1800 unique reflections. Data in the q range 2.31–27.46◦
were collected on a Nonius MACH3 diffractometer using Mo-Ka
graphite monochromated radiation, l = 0.71069 A, and corrected
for Lorentz and polarisation effects. The structure was solved by
direct methods and refined by full-matrix least-squares using all
F2 data. The hydrogen atoms were placed in calculated positions
and allowed to ride on the parent atom.
The more polar major adduct diastereomer 4b-endo was isolated
(510 mg, 42%) as a colourless solid; mp 161–163 ◦C (with
decomposition); Found C, 59.82; H, 5.80; N, 4.41; Cl, 11.10; S,
9.90. C16H18NClO2S requires C, 59.34; H, 5.60; N, 4.33; Cl, 10.95;
S, 9.90; nmax/cm-1 (KBr) 1667, 1533, 1076, 1041, 755; dH (270 MHz,
CDCl3) 0.80 (3H, t, J 7, –CH3), 1.88–1.92 (1H, HA of ABq, J 10,
H-7¢), 2.62–2.66 (1H, HB of ABq, J 10, H-7), 2.69–2.99 (2H, m,
NCH2), 3.29 (1H, s, H-4), 3.74 (1H, s, H-1), 4.88 (1H, d, J 2,
H-3), 6.08–6.13 (1H, m, H-5), 6.34–6.40 (1H, m, H-6), 6.48 (1H,
br s, NH), 7.40–7.51 (3H, m, ArH), 7.82–7.91 (2H, m, ArH); dC
(67.8 MHz, CDCl3) 14.2 (–CH3), 34.3 (NCH2), 45.6 (C-7), 50.2
(C-4), 53.9 (C-1), 59.6 (C-3), 76.3 (C-2), 126.7 (aromatic CH),
129.1 (aromatic CH), 130.9 (aromatic CH), 135.5 (C-5), 138.5 (C-
6), 141.4 (aromatic C), 166.0 (CO). MS m/z M+ not seen, 272
(50%, M+–Cl–O), 231 (35), 135 (63), 117 (85), 43 (100). NOE
studies on this compound, 270 and 300 MHz, irradiating at H-3
showed enhancement of H-4 and H-5.
˚
Preparation of sulfoxide adducts
2-exo-Benzenesulfinyl-3-exo-chlorobicyclo[2.2.1]hept-5-ene-2-
endo-carboxylic acid ethylamide 4b-endo and 2-endo-benzenesul-
finyl-3-endo-chlorobicyclo[2.2.1]hept-5-ene-2-exo-carboxylic acid
ethylamide 4b-exo. Freshly distilled cyclopentadiene (1.3 g,
1.6 mL, 19.4 mmol) was added to a solution of 3b (1.0 g, 3.9 mmol)
in dichloromethane (20 mL). The reaction solution was then
heated at reflux for 18 h. The solvent and most of the excess diene
were evaporated at reduced pressure to give the crude adduct 4b as
The relative stereochemistry was determined by single crystal
X-ray diffraction on a crystalline sample of 4b-endo recrystallised
from ethyl acetate–hexane. Crystals of 4b-endo are triclinic, space
¯
˚
group P1, formula C16H18ClNO2S, M = 232.82, a = 8.221(4) ◦A, b =
◦
˚
˚
9.997(3)◦A, c = 10.709(6) A, a = 114.90(4) , b = 92.12(5) , g =
3
-1
˚
99.43(3) , U = 782.0(6) A , F(000) = 340, m(Mo-Ka) 0.381 mm ,
R(Fo) = 0.067, for 1828 observed reflections with I > 2s(I),
wR2(F2) = 0.155 for all 2668 unique reflections. Data in the q range
2.11–25.33◦ were collected on a Nonius MACH3 diffractometer
1
a mixture of separable diastereomers. A H NMR spectrum was
recorded of the crude reaction product (crude ratio of 4b-endo : 4b-
exo 1.2 : 1) before separation by chromatography on silica gel using
ethyl acetate–hexane (gradient elution 10–25% ethyl acetate) as
eluent to give the less polar minor adduct diastereomer 4b-exo
(390 mg, 32%) as a colourless solid; mp 159–162 ◦C; Found C,
59.83; H, 5.70; N, 4.56; Cl, 11.10; S, 9.40. C16H18NClO2S requires
C, 59.34; H, 5.60; N, 4.33; Cl, 10.95; S, 9.90; nmax/cm-1 (KBr) 1669,
1522, 1032, 746; dH (270 MHz, CDCl3) 0.80 (3H, t, J 4, -CH3),
1.58–1.62 (1H, HA of ABq, J 10, H-7¢), 1.77–1.81 (1H, HB of
ABq, J 10, H-7), 2.73–3.02 (2H, m, NCH2), 3.41 (1H, s, H-4), 3.48
(1H, s, H-1), 5.63 (1H, d, J 4, H-3), 6.58–6.64 (1H, m, H-5), 6.77–
6.82 (1H, m, H-6), 6.91 (1H, br s, NH), 7.40–7.52 (3H, m, ArH),
7.78–7.90 (2H, m, ArH); dC (67.8 MHz, CDCl3) 14.1 (-CH3), 34.7
(NCH2), 45.4 (C-7), 50.6 (C-4), 55.0 (C-1), 59.7 (C-3), 78.7 (C-2),
126.3 (aromatic CH), 129.0 (aromatic CH), 130.8 (aromatic CH),
135.3 (C-6), 139.7 (C-5), 141.5 (aromatic C), 167.2 (CO). MS m/z
323 (M+, 7%), 198 (100, M+-SOPh), 162 (46, M+-SOPh-HCl), 91
(93); isotopic Cl pattern observed; 323, 325 (3 : 1 35Cl: 37Cl); Found
(HRMS, EI) m/z 323.0811. C16H18N35ClO2S requires 323.0747.
NOE studies on this compound, 270 and 300 MHz, irradiating at
H-3 showed enhancement of H-4 and H-7¢.
˚
using Mo-Ka graphite monochromated radiation, l = 0.71069 A,
and corrected for Lorentz and polarisation effects. The structure
was solved by direct methods and refined by full-matrix least-
squares using all F2 data. The hydrogen atoms were placed in
calculated positions and allowed to ride on the parent atom.
Cu(II) Catalysed cycloadditions
CuCl2 Catalysed cycloaddition of 3d with cyclopentadiene.
Method i. Freshly distilled cyclopentadiene (0.1 mL, 1.3 mmol)
was added to a solution of the sulfoxide 3d (50 mg, 0.2 mmol)
in dichloromethane (1 mL). A catalytic amount of CuCl2 (1%
by weight cf. the sulfoxide) was added and the resulting brown
suspension was stirred for 16 h when the reaction mixture was
applied directly to the top of a column of silica gel. The product
was eluted using ethyl acetate–hexane (gradient elution: 0–30%
ethyl acetate) as eluent to give a mixture of unreacted sulfoxide 3d
(50% conversion by NMR) and the two adduct diastereomers 4d
in a ratio of 4d-endo : 4d-exo of 1.2 : 1. See supporting information
for spectroscopic details.†
The relative stereochemistry was determined by single crystal
X-ray diffraction on a crystalline sample of 4b-exo recrystallised
from ethyl acetate–hexane. Crystals of 4b-exo are monoclinic,
space group P21/n, formula C16H18ClNO2S, M = 323.82, a =
Method ii. Freshly distilled cyclopentadiene (0.1 mL, 1.3 mmol)
was added to a solution of the sulfoxide 3d (50 mg, 0.2 mmol)
in dichloromethane (1 mL). A catalytic amount of CuCl2 (1%
by weight cf . the sulfoxide) was added and the resulting brown
suspension was stirred for 16 h when a further addition of
cyclopentadiene (0.1 mL, 1.3 mmol) was made. After stirring for
◦
˚
˚
˚
9.9680(10) A, b = 13.712(2) A, c = 11.671(2) A, b = 99.670(10) ,
3
-1
˚
U = 1572.5(4) A , F(000) = 680, m(Mo-Ka) 0.379 mm , R(Fo) =
0.044, for 1009 observed reflections with I > 2s(I), wR2(F2) =
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an additional 26 h, the reaction mixture was applied directly to the
top of a column of silica gel. The product was eluted using ethyl
acetate–hexane (gradient elution: 0–30% ethyl acetate) as eluent
to give two adduct diastereomers (no detectable starting material)
4d-exo in a ratio of 4d-endo : -exo of 1.4 : 1.
until the reaction suspension had been stirred for a total of 10 days.
A short column of silica gel was prepared using ethyl acetate–
hexane as eluent (5 : 95) and the reaction mixture applied directly.
A 1H NMR spectrum of the crude product mixture was recorded
which showed 77% conversion and a crude ratio of 6a-endo : 6a-
exo of 4.0 : 1. The crude product was dissolved in dichloromethane
(15 mL) and morpholine (124 mg, 1.4 mmol) was added. After
stirring for 30 min, the reaction solution was washed with water
(2 ¥ 20 mL) and brine (20 mL), dried and concentrated at reduced
pressure. Chromatography on silica gel using ethyl acetate–hexane
(20 : 80) as eluent gave the adduct 6a (590 mg, 65%) as a mixture
of inseparable diastereomers (ratio of 6a-endo : 6a-exo of 3.0 : 1)
as a sticky brown solid; Found C, 67.90; H, 5.67; N, 3.54; Cl,
9.96; S, 8.21. C21H20NClOS requires C, 68.19; H, 5.45; N, 3.79; Cl,
9.58; S, 8.67. The NMR signals for each diastereomer could be
distinguished:
Major diastereomer 6a-endo: dH (270 MHz, CDCl3) 1.79–1.83
(1H, HA of ABq, dd, J 2, 9, H-7¢), 2.29 (3H, s, Ar–CH3), 2.59–2.63
(1H, HB of ABq, J 9, H-7), 3.08 (1H, br s, H-4), 3.11 (1H, br s,
H-1), 4.62 (1H, d, J 2, H-3), 6.11–6.25 (2H, symmetrical m, H-5,
H-6), 7.01–7.47 (9H, m, ArH), 7.60 (1H, br s, NH); dC (67.8 MHz,
CDCl3) 21.2 (Ar CH3), 46.6 (C-7), 52.3 (C-1 or C-4), 54.0 (C-1 or
C-4), 65.3 (C-3), 67.4 (C-2), 120.4 (aromatic CH), 129.2 (aromatic
C), 129.5 (aromatic CH), 129.9 (aromatic CH), 132.7 (aromatic
CH), 134.5 (aromatic C), 134.8 (aromatic CH), 135.4 (aromatic
C), 136.0 (C-5), 138.3 (C-6), 169.9 (CO).
CuCl2 Catalysed cycloadditions at reflux.
CuCl2 Catalysed cycloaddition of 3a with cyclopentadiene.
Freshly distilled cyclopentadiene (0.1 mL, 1.1 mmol) was added
to a solution of the sulfoxide 3a (50 mg, 0.2 mmol) in the
presence of a catalytic amount of CuCl (1% by weight cf.
the sulfoxide) in dichloromethane (1 mL). The resulting brown
suspension was heated to reflux. After refluxing for 18 h, the
reaction mixture was applied directly to the top of a column of
silica gel. The product was recovered using ethyl acetate–hexane
(gradient elution: 0–30%) as eluent to give a mixture consisting of
both adduct diastereomers (no detectable starting material) in a
ratio of 4a-endo : 4a-exo of 1.8 : 1. See supporting information for
spectroscopic details.†
Cu(OTf)2 Catalysed cycloadditions at room temperature.
Cu(OTf)2 Catalysed cycloaddition of 3a with cyclopentadi-
ene. Freshly distilled cyclopentadiene (0.1 mL, 1.1 mmol) was
added to a solution of the sulfoxide 3a (50 mg, 0.2 mmol) in
dichloromethane (1 mL). A catalytic amount of Cu(OTf)2 (1% by
weight cf. the sulfoxide) was added and the resulting suspension
was stirred for 16 h at room temperature when the reaction mixture
was applied directly to the top of a column of silica gel. After
stirring for 1 h the reaction mixture was blue in colour. The
product was eluted using ethyl acetate–hexane (gradient elution:
0–30% ethyl acetate) as eluent to give two adduct diastereomers in
a ratio of 4a-endo : 4a-exo of 8.8 : 1. See supporting information
for spectroscopic details.†
Minor diastereomer 6a-exo: dH (270 MHz, CDCl3) 1.76–1.80
(1H, HA of ABq, J 9, one of CH2-7), 2.29 (4H, s, one of CH2-7, Ar
CH3), 3.29 (1H, br s, H-1 or H-4), 3.36 (1H, br s, H-1 or H-4), 5.19
(1H, d, J 4, H-3), 6.40–6.46 (1H, m, H-5 or H-6), 6.53–6.59 (1H,
m, H-5 or H-6), 7.01–7.47 (9H, m, ArH), 8.35 (1H, br s, NH); dC
(67.8 MHz, CDCl3) 21.2 (Ar CH3), 46.4 (C-7), 50.6 (C-1 or C-4),
54.0 (C-1 or C-4), 66.0 (C-3), 68.1 (C-2), 120.7 (aromatic CH),
128.5 (aromatic C), 129.5 (aromatic CH), 129.9 (aromatic CH),
132.7 (aromatic CH), 134.5 (aromatic C), 134.8 (aromatic CH),
135.4 (aromatic C), 136.6 (C-5 or C-6), 137.5 (C-5 or C-6), 170.8
(CO).
Cu(OTf)2 Catalysed cycloadditions at reflux.
Cu(OTf)2 Catalysed cycloaddition of 3c with cyclopentadiene.
Freshly distilled cyclopentadiene (0.2 mL, 2.6 mmol) was added to
a solution of the sulfoxide 3c (50 mg, 0.2 mmol) in the presence of
a catalytic amount of Cu(OTf)2 (1% by weight cf. the sulfoxide) in
dichloromethane (1.5 mL). The reaction solution was then heated
to reflux. After about 30 min at reflux, the reaction solution
was deep blue in colour. After refluxing for 2 h, the reaction
mixture was applied directly to the top of a column of silica gel.
The product was recovered using ethyl acetate–hexane (20 : 80) as
eluent to give a mixture consisting of both adduct diastereomers
(no detectable starting material) in a ratio of 4c-endo : 4c-exo of
6.2 : 1. See supporting information for spectroscopic details.†
MS m/z 369 (M+, 1%), 334 (4, M+–Cl), 260 (1, M+–SPh), 196
(13), 149 (40), 109 (20, [SPh]+), 91 (55), 66 (100), 39 (97).
Preparation of sulfone adducts
Method I: Diels–Alder cycloaddition of sulfone 9a.
2-exo-Benzenesulfonyl-3-exo-chlorobicyclo[2.2.1]hept-5-ene-2-
endo-carboxylic acid p-tolylamide 7a-endo and 2-endo-benzenesul-
fonyl-3-endo-chlorobicyclo[2.2.1]hept-5-ene-2-exo-carboxylic acid
p-tolylamide 7a-exo. A solution of mCPBA (116 mg of 70%
pure material, 0.5 mmol) in dichloromethane (10 mL) was added
to a solution of 3a (300 mg, 0.9 mmol) in dichloromethane
(10 ml) at 0 ◦C. The reaction solution was allowed to warm
to room temperature and after stirring for 1.5 h, a further
addition of mCPBA (116 mg of 70% pure material, 0.5 mmol)
in dichloromethane (10 mL) was made. The reaction solution
was stirred for a further 1.5 h when a final addition of mCPBA
(116 mg of 70% pure material, 0.5 mmol) in dichloromethane
(10 mL) was made. After stirring for a further 2 h, the reaction
solvent was evaporated at reduced pressure. The resulting white
solid was slurried in dichloromethane (8 mL) and freshly distilled
cyclopentadiene (320 mg, 0.4 ml, 4.7 mmol) was added. The
Preparation of sulfide adducts
2-exo-Phenylthio-3-exo-chlorobicyclo[2.2.1]hept-5-ene-2-endo-
carboxylic acid p-tolylamide 6a-endo and 2-endo-phenylthio-
3-endo-chlorobicyclo[2.2.1]hept-5-ene-2-exo-carboxylic acid p-
tolylamide 6a-exo. CuCl2 (500 mg, 3.7 mmol) was added to a
solution of the 5a (750 mg, 2.5 mmol) in dichloromethane (15
mL) to give a brown suspension. Freshly distilled cyclopentadiene
(2 mL) was added and the reaction suspension stirred for
48 h. More freshly distilled cyclopentadiene (1 mL) was added
and the reaction mixture was again stirred for 48 h before a
further cyclopentadiene addition was made. This process of fresh
cyclopentadiene additions (1 mL aliquots) was repeated every 48 h
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reaction suspension was heated to reflux and total dissolution of
the reaction mixture occurred. After 2 h at reflux, the reaction
solution was dark green in colour. The solution was refluxed
for a total of 18 h, then water (20 mL) was added and the
phases separated. The organic fraction was washed with water
(20 mL) and brine (20 mL) and concentrated at reduced pressure
to give a brown solid. NMR analysis of this compound indicated
formation of the sulfone adduct 7a with a ratio of 7a-endo : 7a-
exo of approximately 5.0 : 1. The crude reaction product was
chromatographed on silica gel using ethyl acetate–hexane (40 : 60)
as eluent to give 7a (295 mg, 78%) with a ratio of 7a-endo : 7a-exo
of 6.0 : 1 and spectroscopic details as reported below.
aromatic CH), 134.9 (C, aromatic C), 135.0 (C, aromatic C), 135.7
(CH, C-5 or C-6), 136.0 (CH, C-5 or C-6), 164.7 (C, CO).
The aromatic protons for both diastereomers were observed at
d
H (270 MHz, CDCl3) 7.11–7.20 (2H, m, ArH), 7.29–7.48 (4H, m,
ArH), 7.52–7.64 (1H, m, ArH), 7.79–7.90 (2H, m, ArH).
MS m/z 401 (M+, 9%), 366 (39, M+–Cl), 260, 262 (100, M+–
SO2Ph), 224 (37), 121 (50), 77 (87); isotopic Cl pattern observed;
401, 403 (3 : 1 ratio 35Cl: 37Cl); Found (HRMS, EI) m/z 401.0826.
C21H20N35ClO3S requires 401.0852.
Characteristic signals for the epoxide 8a were observed at dH
(270 MHz, CDCl3) 3.81–3.84 (m, H-2 or H-4), 4.18–4.21 (m, H-2
or H-4), 5.33 (d, J 4, H-7), 8.68 (br s, NH) and dC (67.8 MHz,
CDCl3) 24.0 (C-8), 44.9, 48.6, 49.0 (3 signals for 4 CH’s, C-1, C-2,
C-4, C-5), 163.5 (CO).
Method II: Oxidation of 4a.
Oxidation of adducts
2-exo-Benzenesulfonyl-3-exo-chlorobicyclo[2.2.1]hept-5-ene-2-
endo-carboxylic acid p-tolylamide 7a-endo, 2-endo-benzenesul-
fonyl-3-endo-chlorobicyclo[2.2.1]hept-5-ene-2-exo-carboxylic acid
p-tolylamide 7a-exo and 6-endo-benzenesulfonyl-7-endo-chloro-3-
oxatricyclo[3.2.1.0]octane-6-exo-carboxylic acid p-tolylamide 8a.
The sulfoxide adduct 4a (200 mg, 0.5 mmol) was dissolved in
dichloromethane (4 mL) and a sample of 0.4 mL (approximately
20 mg) removed for NMR spectroscopic analysis. The ratio of
4a-endo : 4a-exo in the reaction starting material was determined
2-exo-Benzenesulfonyl-3-exo-chlorobicyclo[2.2.1]hept-5-ene-2-
endo-carboxylic acid p-tolylamide 7a-endo and 2-endo-benzene-
sulfonyl-3-endo-chlorobicyclo[2.2.1]hept-5-ene-2-exo-carboxylic
acid p-tolylamide 7a-exo. A solution of mCPBA (37 mg of 70%
pure material, 0.2 mmol) in dichloromethane (2 mL) was added
to a solution of 6a (50 mg, 0.1 mmol) in dichloromethane (5
mL). Before addition of the mCPBA solution, the ratio of 6a-
1
endo : 6a-exo was estimated at 3.1 : 1 by H NMR spectroscopy
1
to be 1.3 : 1 by H NMR spectroscopy. A solution of mCPBA
of a representative sample. After stirring for 18 h, 0.5 mL of
the reaction solution was removed and the solvent evaporated
at reduced pressure. NMR analysis (1H NMR spectroscopy) of
this sample showed 80% conversion of the sulfide adduct 6a to the
corresponding sulfoxide adduct 4a with a ratio of 4a-endo : 4a-exo
of 3.1 : 1. A solution of mCPBA (40 mg of 70% pure material,
0.2 mmol) in dichloromethane (1 mL) was added to the reaction
solution before stirring for a further 18 h when a sample (1 mL) was
(176 mg of 70% pure material, 0.7 mmol) in dichloromethane
(4 mL) was added slowly to the adduct 4a solution (180 mg,
0.5 mmol) and the reaction mixture stirred for 18 h. NaHSO3
(10 mL of 10% solution) was added and the phases separated. The
organic layer was washed with saturated NaHCO3 (2 ¥ 15 mL),
water (2 ¥ 15 mL) and brine (15 mL), dried and concentrated at
reduced pressure to give the crude sulfone adduct 7a with a ratio
of 7a-endo : 7a-exo of 1.3 : 1. The crude product was purified by
chromatography on silica gel using ethyl acetate–hexane (30 : 70)
as eluent to give 7a (168 mg, 89%), with the same ratio, as a
colourless solid. Some over-oxidation (approximately 24% of the
minor adduct diastereomer) to the epoxide 8a was also evident.
7a: Found C, 62.29; H, 4.96; N, 3.99; Cl, 9.20; S, 8.20.
C21H20NClO3S requires C, 62.75; H, 5.02; N, 3.49; Cl, 8.82; S, 7.98;
The NMR signals for each diastereomer could be distinguished:
Major diastereomer 7a-endo: dH (270 MHz, CDCl3) 1.82–1.91
(1H, HA of ABq, J 9, H-7¢), 2.34 (3H, s, Ar–CH3), 2.95–3.02 (1H,
HB of ABq, J 9, H-7), 3.14 (1H, br s, H-4), 3.91 (1H, br s, H-1), 4.78
(1H, d, J 2, H-3), 6.21–6.33 (2H, symmetrical m, H-5, H-6), 8.50
(1H, br s, NH); dC (67.8 MHz, CDCl3) 20.8 (CH3, Ar–CH3), 47.6
(CH2, C-7), 50.8 (CH, C-1 or C-4), 53.4 (CH, C-1 or C-4), 59.6
(CH, C-3), 83.2 (C, C-2), 120.1 (CH, aromatic CH), 128.9 (CH,
aromatic CH), 129.6 (CH, aromatic CH), 130.2 (CH, aromatic
CH), 134.2 (CH, aromatic CH), 134.9 (C, aromatic C), 135.0 (C,
aromatic C), 137.5 (CH, C-5 or C-6), 139.0 (CH, C-5 or C-6),
164.0 (C, CO).
1
removed and analysed by H NMR spectroscopy which showed
68% sulfone adduct 7a, 32% sulfoxide adduct 4a-endo and an
adduct ratio of 7a-endo : 7a-exo of 3.0 : 1. No evidence of the
sulfoxide adduct of the minor diastereomer 4a-exo was seen. A
final addition of mCPBA (20 mg of 70% pure material, 0.1 mmol)
in dichloromethane (1 mL) was made to the reaction solution and,
after stirring for 18 h, the reaction was worked up as described for
7a to give a white solid. NMR analysis of this material showed
the major diastereomer to be approximately 90% converted to 7a-
endo while some over-oxidation of the minor diastereomer 7a-exo
to the epoxide 8a-exo was also observed.
3, 4-Dimethyl-N-4-methylphenyl-benzamide 12a.
Method a: Sealed tube. A solution of the sulfoxide 3a (100 mg,
0.3 mmol), 2, 3-dimethylbutadiene (1.0 mL, 8.1 mmol) in toluene
(2.0 mL) was charged to a tube which was then sealed. The tube
was heated in an oil bath at 100 ◦C for 18 h before cooling to room
temperature. The crude reaction solution was applied directly to a
column of silica gel. The reaction product was eluted using ethyl
acetate–hexane (gradient elution, 0–20% ethyl acetate) as eluent to
give the crude product (110 mg). Purification by chromatography
on silica gel using ethyl acetate–hexane (gradient elution, 10–20%
ethyl acetate) as eluent gave 12a (65 mg, 87%) as a colourless
solid; mp 123–125 ◦C; Found C, 79.65; H, 7.12; N, 5.83. C16H17NO
requires C, 80.30; H, 7.16; N, 5.85; nmax/cm-1 (KBr) 1652 (CO),
1521, 1319, 807; dH (270 MHz, CDCl3) 2.30 (6H, s, 2 ¥ ArCH3),
2.32 (3H, s, ArCH3), 7.09–7.22 (3H, m, ArH), 7.49–7.67 (4H, m,
Minor diastereomer 7a-exo: dH (270 MHz, CDCl3) 1.50–1.76
(2H, ABq, J 9, CH2-7), 2.34 (3H, s, Ar-CH3), 3.29 (1H, br s, H-4),
3.60 (1H, br s, H-1), 5.33 (1H, d, J 4, H-3), 6.46–6.53 (1H, m,
H-5), 6.66–6.72 (1H, m, H-6), 8.78 (1H, br s, NH); dC (67.8 MHz,
CDCl3) 20.8 (CH3, Ar–CH3), 47.1 (CH2, C-7), 50.8 (CH, C-1 or C-
4), 51.7 (CH, C-1 or C-4), 62.3 (CH, C-3), C-2 obscured by CDCl3
at 76.5–77.5, 120.1 (CH, aromatic CH), 129.0 (CH, aromatic CH),
129.6 (CH, aromatic CH), 130.2 (CH, aromatic CH), 134.2 (CH,
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ArH), 7.86 (1H, br s, NH); dC (67.8 MHz, CDCl3) 19.7 (CH3, 2 ¥
ArCH3 overlapping), 20.9 (CH3, ArCH3), 120.4 (CH, 2 ¥ aromatic
CH), 124.4 (CH, aromatic CH), 128.4 (CH, aromatic CH), 129.6
(CH, 2 ¥ aromatic CH), 130.0 (CH, aromatic CH), 132.8 (C,
aromatic C), 134.0 (C, aromatic C), 135.8 (C, aromatic C), 137.2
(C, aromatic C), 140.8 (C, aromatic C), 165.8 (C, CO). MS m/z
239 (M+, 20%), 133 (100), 105 (40), 77 (72).
(CH, aromatic CH), 129.3 (C, aromatic C), 129.59, 129.62 (2 ¥
CH, 2 ¥ aromatic CH), 134.5, 135.0 (2 ¥ C, 2 ¥ aromatic C),
136.5 (CH, aromatic CH), 169.6 (C, CO); HRMS (ES+): Exact
mass calculated for C22H25NOS35Cl [M+H]+ 386.1345. Found
386.1338; m/z (ES+) 388.0 {[(C22H24NOS37Cl)+H+], 40%}, 386.0
{[(C22H24NOS35Cl)+H+], 100%}.
Method b: Microwave conditions. 2,3-Dimethyl-1,3-butadiene
(1.5 mL, 6.3 mmol) and 3a (0.2 g, 0.6 mmol) were placed in a
sealed microwave reaction vessel with stirring and subsequently
heated for 30 min at 300 W at 100 ◦C. The excess diene was
then evaporated at reduced pressure to give the crude product as
an orange oil. Following purification by column chromatography
using hexane–ethyl acetate as eluent (gradient elution 5–20% ethyl
acetate), 12a was obtained as a white solid (0.08 g, 59%); (Found
C, 80.16; H, 7.21; N, 5.59. C16H17NO requires C, 80.30; H, 7.16; N,
5.85%); nmax/cm-1 (KBr) 3337 (NH), 2916 (CH), 1652 (CO), 1611,
1596, 1521; dH (400 MHz, CDCl3) 2.33 (3H, s, one of ArCH3),
2.34 (6H, s, 2 ¥ ArCH3), 7.17 (2H, d, J 8.4, ArH), 7.24 [1H, d,
J 7.6, aromatic C(5)H], 7.52 (2H, d, J 8.4, ArH), 7.58 [1H, dd,
J 7.6, 1.6, aromatic C(6)H], 7.65 [1H, d, J 1.6, aromatic C(2)H],
7.72 (1H, br s, NH); dC (75.5 MHz, CDCl3) 19.78, 19.82, 20.9
(3 ¥ CH3, 3 ¥ ArCH3), 120.2, 124.3, 128.3, 129.5, 129.9 (5 ¥
CH, 5 ¥ aromatic CH), 132.6, 134.0, 135.6, 137.2, 140.9 (5 ¥
C, 5 ¥ aromatic C), 165.7 (C, CO); HRMS (ES+): Exact mass
calculated for C16H18NO [M+H]+ 240.1388. Found 240.1391; m/z
(ES+) 240.0 {[(C16H17NO)+H+], 100%}.
Acknowledgements
IRCSET, Forbairt and University College Cork are gratefully
acknowledged for funding this work. The authors wish to thank
final year project students D. Foley and P. Ward for their input
into some aspects of this work.
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Org. Biomol. Chem., 2010, 8, 5602–5613 | 5613
©