Rapid entry to functionally rich bicyclo[4.1.0]heptenone systems

Article abstract of DOI:10.1039/c3ra42282h

A facile process for the synthesis of highly substituted bicyclo[4.1.0]heptenones via Corey-Chaykovsky reaction of quinone monoketals is presented. The obtained products were employed to functionalize 3-position of indoles providing compounds which might have potential use in medicinal chemistry.

Full text of DOI:10.1039/c3ra42282h

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Rapid entry to functionally rich
bicyclo[4.1.0]heptenone systems3
Cite this: RSC Advances, 2013, 3, 13663
Santhosh Kumar Chittimalla* and Chennakesavulu Bandi
Received 9th May 2013,
Accepted 11th June 2013
DOI: 10.1039/c3ra42282h
www.rsc.org/advances
A facile process for the synthesis of highly substituted bicy-
clo[4.1.0]heptenones via Corey–Chaykovsky reaction of quinone
monoketals is presented. The obtained products were employed
to functionalize 3-position of indoles providing compounds which
might have potential use in medicinal chemistry.
partners in other than Diels–Alder reactions.6c To this end, we
were convinced that these benzoquinone monoketals as the
substrates would enable us to achieve our goal in obtaining
functionally rich bicyclo[4.1.0]heptenone derivatives. To the best of
our knowledge up until now there are no reports on reaction of
stabilized sulfonium ylides (S-ylides) with benzoquinone mono-
ketals.6d Herein, we present the results of our preliminary
investigation on these reactions.
At the outset, readily available MOB 17 (prepared by oxidation
of 2,3-dimethoxyphenol with diacetoxyiodobenzene in methanol)
on treating with 1.2 equiv. of dimethylphenacylsulfonium bromide
(a)8{ in the presence of 2.5 equiv. of K2CO3 in acetonitrile at room
temperature provided the required bicyclo[4.1.0]heptenone system
in 91% isolated yield (Table 1, entry 1). The structure of compound
1a was confirmed based on 1H, 13C NMR, DEPT and HRMS
analyses. The stereochemistry of the substituents was assigned
Bicyclo[4.1.0]heptane systems were found to have distinctive
biological functions.1a,b Recently, it was demonstrated that
polyhydroxylated bicyclo[4.1.0]heptane products possess a-galacto-
sidase inhibitory activity.1c On the other hand, bicyclo[4.1.0]hep-
tane-7-carboxylic amide derivatives were used as food flavor
substances.2a Moreover, suitably substituted bicyclo[4.1.0]heptan-
4-one derivatives were synthesised as novel odorant substances.2b
In addition, owing to their unique steric and electronic properties,
the cyclopropyl ring is present in a large number of pharmaceu-
ticals and also employed as a replacement of the alkene moiety to
avoid metabolic liability.3 Besides, synthesis of medium sized
rings via the ring opening of the cyclopropane (due to its latent
reactivity) of the fused bicyclic systems was successfully applied in
the synthesis of natural products.4 Therefore, based on our
interest and inspired by the literature reports on the usefulness of
these products, we decided to pursue a general and facile route for
the synthesis of functionally rich bicyclo[4.1.0]heptenone systems
and envisaged these products as precursors to a variety of
compounds with potential applications. Among the reported
methodologies for the synthesis of cyclopropane derivatives, sulfur
ylide mediated cyclopropanation of conjugated double bond has
gained prominent position.5 During the course of studies
involving masked o-benzoquinones (MOBs), we have earlier
developed a simple and efficient synthesis of highly substituted
isoindolines6b and in subsequent studies, we further demon-
strated that nitrile oxide cycloaddition products of MOB can be
transformed to highly substituted benzisoxazoles or rearranged to
novel isoxazoline derivatives.6a These results cast insight into the
new aspects of MOB chemistry in utilizing them as excellent
Table 1 Synthesis of bicyclo[4.1.0]heptenone 1a via cyclopropanation of MOB 1
with S-ylide a or N-ylide a9
Entrya
Ylide source
Condition
Time/Yield (%)
1
2
3
a
a9
a9
K2CO3, CH3CN, rt
K2CO3, CH3CN, rt
K2CO3, CH3CN, 80 uC
12 h/91%
24 h/—b
12 h/89%
Medicinal Chemistry Department, AMRI Singapore Research Centre, 61 Science Park
Road, #05-01, The Galen, Science Park III, Singapore 117525, Singapore.
E-mail: santhosh.chittimalla@amriglobal.com; Fax: (+65)-63985511
a
Reaction was conducted on 0.75 mmol of MOB 1, 0.9 mmol of S-/
b
N-ylide and 1.9 mmol of K2CO3 in 3 mL of acetonitrile. No
reaction.
Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra42282h
3
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based on the coupling constants of protons on the cyclopropane
ring and is in accord with the literature precedents.9 Of late,
nitrogen ylides (N-ylides) are being effectively utilized for the
cyclopropanation reaction.10 Consequently, we were interested to
test the feasibility of exploiting the N-ylides as cyclopropanating
agents in our study. Thus, in situ generated N-ylide from a9
required reflux temperature to provide the identical product 1a on
reaction with MOB 1 (Table 1, entry 3). Due to this marked
difference in the reactivity of S-ylide vs. N-ylide with MOB 1, all our
subsequent reactions were carried-out with S-ylides.
Encouraged by the above successful result, various stabilized
S-ylide precursors ‘b–k’ were reacted with MOB 1 in the presence
of K2CO3 in acetonitrile. To our delight, the reaction is compatible
with all the stabilized S-ylides (having electron-withdrawing and
electron-donating groups on the phenyl residues of the S-ylides,
heteroaromatic and aliphatic S-ylides) employed providing the
desired bicyclo[4.1.0]heptenone derivatives in high to excellent
isolated yields (Scheme 1). Despite the fact that most of the
reactions took place at room temperature, S-ylide generated from
its precursor ‘i’ needed 60 uC to afford the desired bicyclo[4.1.0]-
heptenone 1i, indicating that the electronic factors strongly
influence the reactivity of sulfonium ylides. Interestingly, com-
pound 1e was found to be unstable leading to intractable mixture
of products on long standing at room temperature, nevertheless
could be stored at 0 uC for days without appreciable decomposi-
tion.
To extend the scope of this methodology, MOBs 2–4 were
chosen to react with selected set of stabilized S-ylides generated
from precursors ‘a, b, j and k’. As demonstrated in Scheme 2,
cyclopropanation of MOBs having substituents at 5-position
proved to be general approach for the synthesis of these bicyclic
derivatives. Subsequently we were interested to probe the reaction
of S-ylides with 4-subsituted MOB 5. Reaction of in situ generated
S-ylide from ‘b’ with MOB 5 did not yield any desired product 5b,
instead furnished cyclopropane 611–13 in high yield at 60 uC
(Scheme 3) along with dimer 7 (Scheme 4) and unreacted MOB 5.
Initially, we presumed the poor reactivity of MOB 5 to the steric
hindrance by the ketal functionality near to the reactive centre.
However, after closer analysis, we found that complete consump-
tion of S-ylide leading to the formation of cyclopropane 612 was the
actual reason for the failure of above reaction. We believe that the
presence of residual methanol (from the MOB preparation step) in
the reaction mixture of MOB 5 and sulfonium bromide ‘b’ led to
the formation of cyclopropane 6 (Scheme 3). Nevertheless, when
methanol free fractions of MOB 5 were treated with the in situ
generated sulfur ylides obtained from ‘b’, desired product was
formed albeit with moderate yield (71%) along with dimer 7 (13%,
Scheme 4). To circumvent the MOB dimerization problem and to
improve the yields of the corresponding bicyclic compounds,
excess (2.5 equiv.) of sulfur ylides were utilized in the reaction. As
expected, the corresponding products 5a, 5b, 5j and 5k were
obtained in high yields (Scheme 2).
Scheme 1 Synthesis of bicyclo[4.1.0]heptenone derivatives 1a–1k.
In a separate experiment, sulfonium bromide ‘b’ when heated
at 60 uC in 10% CH3OH in CH3CN as reaction medium in the
presence of K2CO3 for 8 h furnished triaroylcyclopropane 6 in 90%
yield. However, no such product formation occurred when the
same reaction was repeated in acetonitrile as the only solvent,
further indicating that presence of protic solvent is necessary for
such a reaction to take place.12
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Scheme 3 A plausible mechanism for the formation of triaroylcyclopropane
derivative 6 from sulfonium bromide b.
In an effort to widen the scope of the Corey–Chaykovsky
reaction, the cyclopropanation of p-benzoquinone monoketal
(masked p-benzoquinone, MPB) 8 was performed. MPB 8 under-
went facile cyclopropanation with S-ylide generated from ‘a’
providing two isomers, and major isomer 8a is obtained by the
reaction of S-ylide with the less substituted double bond
(Scheme 5); on the other hand, S-ylide generated from ‘k’ gave
exclusively bicyclo[4.1.0]heptenone 8k (Scheme 5). As of now it is
unclear why S-ylide generated from ‘a’ provided mixture of
isomers. Nevertheless, MPBs can also be conveniently utilized
for the synthesis of differently substituted bicyclo[4.1.0]heptenone
systems.
Our next objective was to develop procedures to further
functionalize the obtained bicyclo[4.1.0]heptenone adducts.
Indoles are drug-like scaffolds and numerous synthetic indoles
have been submitted to pharmacological investigation.14 Further,
quite a few indole derivatives have come to have significant
clinical use.15 Consequently, indole, indubitably can be referred to
as ‘privileged scaffold’ in medicinal chemistry.16 Intrigued by the
significance of bicyclo[4.1.0]heptenone systems and the estab-
lished literature precedents on the importance of indoles, we
Scheme 2 Synthesis of bicyclo[4.1.0]heptenone derivatives 2a,b,j,k–5a,b,j,k.
Scheme 4 Diels–Alder dimerization of MOB 5.
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catalytic amount of HClO4–SiO217 (3 mol%) in acetonitrile at 70 uC
for 30 min provided the indolyl bicyclo[4.1.0]heptenone derivative
10a in 85% yield (Scheme 6). Subsequently, indoles 9b–9e were
utilized in this reaction to furnish corresponding indolyl
bicyclo[4.1.0]heptenone systems 10b–10e in high yields.18
Interestingly, N-ethyl indole (9f) also underwent a smooth addition
to compound 1a to give N-ethylindolyl bicyclo[4.1.0]heptenone 10f
in 91% yield indicating that free NH is not necessary for the
success of the reaction.
Conclusions
In conclusion, we have shown that the Corey–Chaykovsky reaction
applied to benzoquinone monoketals is general, convenient and a
rapid procedure for the synthesis of bicyclo[4.1.0]heptenone
systems with higher levels of functionality. Work toward selective
cyclopropane ring opening either providing the tropolone
structures or highly substituted benzene systems and studies
aimed at advancing these bicyclic systems for further more
transformations is being actively pursued.
Scheme 5 Synthesis of bicyclo[4.1.0]heptenone derivatives 8a, 8a-isomer, 8k.
investigated the addition reactions of indole to these bicyclic
systems and contemplate that their addition products may
possibly be of potential use in medicinal chemistry. To begin
with, reaction of compound 1a with indole (9a) in the presence of
Acknowledgements
We thank Mr. R. Kuppusamy for carrying out a couple of
experiments. Thanks are due to Ms. Marcella Powell and Mr.
Cortney Poirier for obtaining few analytical data. The authors
sincerely thank Dr Anjan Chakrabarti and Dr Takeshi Yura for
encourangement.
Notes and references
{ General procedure for the preparation of sulfonium bromide ‘a’: To
phenacyl bromide (1.0 g) was added dimethyl sulfide (10 mL) and was
stirred for 16 h at room temperature. Excess dimethyl sulfide was
evaporated under rotory evaporation. The residual solid was triturated with
methyl t-butyl ether and dried under vacuum to provide 1.1 g (85%) of
dimethylphenacylsulfonium bromide (a).
General procedure for the synthesis of bicyclo[4.1.0]heptenone derivative
1a: To a stirred solution of MOB 1 (75 mg, 0.41 mmol) and S-ylide
precursor ‘a’ (128 mg, 0.49 mmol) in CH3CN (3 mL) was added K2CO3 (140
mg, 1.02 mmol) at room temperature. The reaction mixture was stirred for
12 h at room temperature. After the aqueous workup and column
chromatographic purification (hexanes/ethylacetate) gave 1a (111 mg,
91%).
1a: 1H NMR (300 MHZ, CDCl3): d = 7.95–7.99 (m, 2H), 7.57–7.64 (m, 1H),
7.46–7.53 (m, 2H), 5.41 (d, J = 5.4 Hz, 1H), 3.70 (t, J = 4.2 Hz, 1H), 3.68 (s,
3H), 3.42 (s, 3H), 3.30 (s, 3H), 2.83 (ddd, J = 0.6, 4.2, 8.1 Hz, 1H), 2.62 (ddd, J
= 4.2, 5.4, 8.1 Hz, 1H). 13C NMR (75 MHz, CDCl3): d = 197.9 (C), 194.1 (C),
153.4 (C), 136.7 (C), 133.6 (CH), 128.8 (2 6 CH), 128.3 (2 6 CH), 99.7 (CH),
96.2 (C), 55.6 (CH3), 52.7 (CH3), 51.8 (CH3), 40.6 (CH), 33.2 (CH), 25.9 (CH)
ppm. HRMS (ESI ): m/z calcd. for C H O Na [M + Na] 325.1052; found
3
17 18
5
325.1062.
1e: 1H NMR (300 MHZ, CDCl3): d = 7.15 (d, J = 3.3 Hz, 1H), 7.05 (dd, J =
3.3, 9.3 Hz, 1H), 6.92 (d, J = 9.3 Hz, 1H), 5.40 (d, J = 5.7 Hz, 1H), 3.88 (t, J =
4.5 Hz, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 3.65 (s, 3H), 3.39 (s, 3H), 3.28 (s, 3H),
2.81 (app dd, J = 4.5, 7.8 Hz, 1H), 2.60 (ddd, J = 4.5, 5.7, 7.8 Hz,1H). 13C
NMR (75 MHz, CDCl3): d = 198.3 (C), 195.9 (C), 153.5 (C), 153.4 (C), 152.9
(C), 127.9 (C), 120.7 (CH), 113.9 (CH), 113.4 (CH), 100.2 (CH), 96.0 (C), 56.2
(CH3), 55.8 (CH3), 55.5 (CH3), 52.5 (CH3), 51.7 (CH3), 44.8 (CH), 33.8 (CH),
26.1 (CH). HRMS (ESI ): m/z calcd. for C H O [M + H] 363.1444; found
3
19 23
7
363.1454.
1j: 1H NMR (300 MHZ, CDCl3): d = 7.58 (d, J = 3.9 Hz, 1H), 7.00 (d, J = 3.9
Hz, 1H), 5.38 (d, J = 5.4 Hz, 1H), 3.67 (s, 3H), 3.45 (t, J = 4.2 Hz, 1H), 3.41 (s,
3H), 3.29 (s, 3H), 2.78 (ddd, J = 0.6, 4.2, 7.8 Hz,1H), 2.63 (ddd, J = 4.2, 5.4,
7.8 Hz, 1H). 13C NMR (75 MHz, CDCl3): d = 197.5 (C), 185.6 (C), 153.5 (C),
142.3 (C), 140.8 (C), 131.9 (CH), 127.9 (CH), 99.3 (CH), 96.1 (C), 55.6 (CH3),
Scheme 6 Synthesis of indolyl bicyclo[4.1.0]heptenones 10a–10f.
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52.6 (CH3), 51.7 (CH3), 40.4 (CH), 32.7 (CH), 25.4 (CH). HRMS (ESI ): m/z
3
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calcd. for C15H15ClO5SNa [M + Na] 365.0226; found 365.0236.
1k: 1H NMR (300 MHZ, CDCl3): d = 5.34 (d, J = 5.7 Hz, 1H), 3.65 (s, 3H),
3.36 (s, 3H), 3.26 (s, 3H), 3.18 (t, J = 4.2 Hz, 1H), 2.53 (dd, J = 4.2, 8.1Hz, 1H)
2.38 (ddd, J = 4.2, 5.7, 8.1 Hz, 1H), 1.18 (s, 9H). 13C NMR (75 MHz, CDCl3): d
= 209.1 (C), 198.1 (C), 153.1 (C), 99.6 (CH), 96.1 (C), 55.6 (CH3), 52.7 (CH3),
51.6 (CH3), 44.1 (C), 39.6 (CH), 33.0 (CH), 25.9 (3 6 CH3), 24.9 (CH). HRMS
(ESI ): m/z calcd. for C H O Na [M + Na] 305.1365; found 305.1377.
3
15 22
5
4j: 1H NMR (300 MHZ, CDCl3): d = 7.61 (d, J = 3.9 Hz, 1H), 7.02 (d, J = 3.9
Hz, 1H), 6.89 (dd, J = 0.6, 5.1 Hz,1H), 3.53 (t, J = 4.5 Hz,1H), 3.43 (s, 3H),
3.29 (s, 3H), 2.83 (ddd, J = 0.6, 4.5, 7.8 Hz, 1H), 2.67 (ddd, J = 4.2, 5.4, 7.5
Hz, 1H). 13C NMR (75 MHz, CDCl3): d = 195.0 (C), 184.8 (C), 141.8 (C), 141.5
(C), 135.2 (CH), 132.4 (CH), 128.0 (CH), 123.8 (C), 95.6 (C), 52.7 (CH3), 51.7
(CH3), 39.0 (CH), 33.2 (CH), 28.4 (CH). HRMS (ESI ): m/z calcd. for
3
C14H12BrClO4SNa [M + Na] 412.9226; found 412.9233.
4k: 1H NMR (300 MHZ, CDCl3): d = 6.85 (dd, J = 0.6, 5.4,1H), 3.39 (s, 3H),
3.25 (s, 3H), 3.24–3.28 (m, 1H), 2.57 (ddd, J = 0.6, 4.5, 7.5 Hz, 1H), 2.45
(ddd, J = 4.5, 5.4, 7.5 Hz, 1H), 1.19 (s, 9H). 13C NMR (75 MHz, CDCl3): d =
208.5 (C), 195.5 (C), 135.6 (CH), 123.3 (C), 95.7 (C), 52.7 (CH3), 51.6 (CH3),
44.3 (C), 38.2 (CH), 33.5 (CH), 28.1 (CH), 25.8 (3 6 CH3). HRMS (ESI ): m/z
3
calcd. for C14H20O4Br [M + H] 331.0545; found 331.0558.
10b: 1H NMR (300 MHz, DMSO-d6): d =11.52 (brs, 1H), 8.13–8.15 (m, 2H),
7.69–7.72 (m, 1H), 7.57–7.60 (m, 2H), 7.45 (t, J = 4.2 Hz, 1H), 7.23 (dd, J =
0.8, 7.6 Hz, 1H), 7.14 (s, 1H), 7.05 (t, J = 8.0 Hz, 1H), 5.43 (s, 1H), 3.77 (s,
3H), 3.64 (s, 3H), 3.51–3.53 (m, 1H), 2.36 (ddd, J = 1.2, 3.6, 4.8 Hz, 1H), 2.27
(ddd, J = 0.8, 4.4, 5.2 Hz, 1H). 13C NMR (75 MHz, DMSO-d6): d = 195.9 (C),
188.9 (C), 160.2 (C), 138.1 (C), 136.4 (C), 134.8 (C), 133.7 (CH), 128.9 (2 6
CH), 128.5 (2 6 CH), 124.5 (CH), 123.5 (CH), 122.9 (CH), 122.9 (C) 114.7
(C), 112.1 (C), 111.9 (CH), 59.5 (CH3), 57.0 (CH3), 33.0 (CH), 32.9 (CH), 31.5
(CH), 30.8 (CH). MS (ESI ): m/z found C H BrNO [M + 2 + H] 468.
3
24 21
4
1
10d: H NMR (300 MHZ, CDCl3): d = 8.36 (brs, 1H), 7.96–8.02 (m, 2H),
7.57–7.66 (m, 2H), 7.46–7.55 (m, 2H), 7.36–7.43 (m, 1H), 7.18 (d, J = 2.4 Hz,
1H), 7.04 (t, J = 7.8 Hz, 1H), 4.46 (s, 1H), 3.86 (s, 3H),3.74 (s, 3H), 3.13 (dd, J
= 3.6, 4.8 Hz, 1H), 2.75 (ddd, J = 1.5, 3.6, 8.1 Hz, 1H), 2.55 (ddd, J = 1.2, 4.8,
8.1 Hz, 1H). 13C NMR (75 MHz, CDCl3): d = 195.6 (C), 190.5 (C), 159.9 (C),
137.0 (C), 135.1 (C), 134.7 (C), 133.5 (CH), 128.8 (2 6 CH), 128.3 (2 6 CH),
126.8 (C), 125.1 (CH), 122.8 (CH), 121.3 (CH), 117.8 (CH), 117.0 (C), 105.2
(C), 60.6 (CH3), 58.7 (CH3), 35.7 (CH), 34.9 (CH), 32.3 (CH), 28.2 (CH). MS
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