Synthesis and oxidation reactions of cycloheptatrienyl sulfones

Article abstract of DOI:10.1016/S0040-4039(00)01386-1

Inexpensive cycloheptatriene is regiospecifically converted to all three phenylsulfonyl substituted cycloheptatrienes. Epoxidation of these materials with achiral reagents is shown to be relatively regiospecific. Reasonable levels of enantiomeric excess (?63, 78%) are achieved by Sharpless asymmetric dihydroxylation of a pair of 3-substituted trienes. Crystallization of these sulfones provides the diols in enantiomeric excesses greater than 90%. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01386-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7795–7799
Synthesis and oxidation reactions of cycloheptatrienyl
sulfones
Zhiwei Tong, Yuzhong Chen, Martin F. Hentemann and Philip L. Fuchs*
Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
Received 8 August 2000; accepted 14 August 2000
Abstract
Inexpensive cycloheptatriene is regiospecifically converted to all three phenylsulfonyl substituted
cycloheptatrienes. Epoxidation of these materials with achiral reagents is shown to be relatively regiospe-
cific. Reasonable levels of enantiomeric excess (ꢀ63,78%) are achieved by Sharpless asymmetric dihydrox-
ylation of a pair of 3-substituted trienes. Crystallization of these sulfones provides the diols in
enantiomeric excesses greater than 90%. © 2000 Published by Elsevier Science Ltd.
Multiply convergent synthetic strategies place high value upon efficient construction of
assemblies such as 1, which are typically employed as sub-goals as a prelude to assembly of the
final target. We are currently exploring the synthesis of optically pure termini-differentiated
hexyl (1a, n=6) and heptyl (1b, n=7) compounds bearing up to five contiguous chiral centers
(Fig. 1).1
Figure 1.
Preparation of the full family of prochiral trienyl sulfones from inexpensive cycloheptatriene
is of general significance since these materials may now be examined as starting materials for a
variety of potentially enantiospecific cycloaddition and conjugate–addition/alkylation reactions.
For example, we speculated that trienyl sulfones such as 4 might serve as substrates for a
sequence of nucleophilic and electrophilic functionalizations which ultimately afford generic
* Corresponding author. Tel: +1 765 494 5242; fax: +1 765 494 7679; e-mail: pfuchs@purdue.edu
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01386-1

7796
sulfone 5 after elimination of a molecule of HE3. Completion of the hypothetical synthesis
would then involve oxidative scission of the vinyl sulfone functionality to deliver substrate 6
appropriately functionalized for further connective operations. Clearly, such an approach raises
a myriad of enantio-, stereo-, regio-, and chemoselectivity questions, but before these can be
addressed, effective access to this unknown class of compounds needed to be achieved (Fig. 2).
Figure 2.
Cycloheptatriene 7 is an ideal substrate for synthesis of multiply-functionalized 7-membered
ring vinylsulfones because of its insignificant cost and high oxidation state.2 Reaction of 7 with
phenylsulfenylchloride, prepared in situ from thiophenol and N-chlorosuccinimide,3 afforded a
mixture of adducts which were not separated, but directly oxidized to the chlorosulfones and
treated with triethylamine to converge to 1-substituted trienylsulfone 4 as a single regioisomer in
68% overall yield (Fig. 3).
Figure 3.
Synthesis of the 2-substituted triene 8 in 57% overall yield was accomplished by addition of
the Back phenylselenylsulfonate reagent4 to cycloheptatriene 7 followed by oxidation and
elimination with hydrogen peroxide. Synthesis of the 3-substituted triene 12 was more difficult.
Treatment of cycloheptatriene 7 to generate tropylium fluoroborate5 followed by addition of
thiophenol provided 7-thiophenyl cycloheptatriene 96 in 71% yield. Thermal rearrangement of
0.05 M triene 9 with 0.05 equiv. hydroquinone in benzene at 185°C for 1 h (sealed tube)
provided 3-thiophenyl-cycloheptatriene 10 in a modest 46% yield along with 43% recovered 10.
Extending the reaction time to 19 h delivers 1-thiophenyl-cycloheptatriene 11 in 41% along with
19% recovered 9, but only traces of 10 remain. Relative Rf values (SiO2–100% hexane) for 9, 10,
and 11 are 0.25, 0.49, and 0.51, respectively, which allows ready separation of 9 and 10.
Oxidation of 10 gives the requisite sulfone 12 in 89% yield (Fig. 4).
Figure 4.

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Epoxidation of the three cycloheptenyl sulfones was evaluated using both achiral and chiral
reagents. The trienyl substrates were substantially less reactive than the parent 2-phenylsulfonyl-
cyclohepta-1,3-diene 3b. While 3b is a premier substrate for Jacobsen epoxidation,1c it is clear
from Table 1 that addition of the third double bond deactivates the substrate and serves to
decrease the facial specificity, presumably due to resonance-related flattening of the cyclohepta-
triene ring (Table 1).
Table 1
Achiral and Jacobsen epoxidationsa
SM
Conditions
Product(s)
Yield (%)
SM
Conditions
Product(s)
Yield (%)
4
4
4
8
8
8
12
12
A
B
C
B
G
I
13
13
13
15
16
17
–
40 (41% ee)
40 (37% ee)
38
33
87
95
4
4
8
8
8
12
12
12
E
D
A
F
H
A
J
13:14 (2.3:1)
13
15
15
17
–
75
23
28
85
65
12 recovered
89
10
B
E
12 recovered
85
18:20 (1.3:1)
18:19 (2:1)
20:21 (12:1)
C
a Conditions: A: (R,R)-Jac. cat. (0.08 equiv.), P3NO (0.32 equiv.), 12% bleach (3 equiv.), MC, 0°C, 5 h; B:
(S,S)-Jac. cat. (0.08 equiv.), P3NO (0.32 equiv.), 12% bleach (3 equiv.), MC, 0°C, 5 h; C: (R,R)-Jac. cat. (0.2 equiv.),
NH4OAc (0.25 equiv.), 30% H2O2 (3 equiv.), MC–MeOH (1:1), 0°C, 6 h; D: (S,S)-Jac. cat. (0.2 equiv.), NH4OAc
(0.25 equiv.), 30% H2O2 (3 equiv.), MC–MeOH (1:1), 0°C, 6 h; E: Na2EDTA (0.003 equiv.), trifluoroacetone (10
equiv.), Oxone® (7.8 equiv.), NaHCO3 (5 equiv.), MeCN, 0°C, 1 h; F: m-CPBA (2.5 equiv.), MC, rt, 28 h; G:
Na2EDTA (0.003 equiv.), trifluoroacetone (10 equiv.), Oxone® (7.8 equiv.), NaHCO3 (5 equiv.), MeCN, 0°C, 0.5 h;
H: 30% H2O2 (5 equiv.), NaOH (1 equiv.), MeOH; I: n-BuLi (1.2 equiv.), t-BuOOH (1.5 equiv.), THF, −40°C, 3 h;
J: m-CPBA (2.5 equiv.), MC, rt, 12 h; 0°C, 7 h.
Sharpless asymmetric dihydroxylation of trienyl sulfones 4 and 8 was also disappointing. In
contrast, although slow, reaction of 12 and 25 provided reasonable levels of asymmetric
induction. In fact, one recrystallization of diol 27 served to remove crystalline racemic material
providing 27 with >90% ee as the ‘crystallization residue’ (Table 2).
Synthesis of chlorinated trienylsulfone 25 was accomplished by treatment of cycloheptane-1,3-
dione 287 with oxalyl chloride to give vinylogous acid halide 29. Bis-sulfenylation of 29 with
phenylsulfenyl chloride in THF afforded thioacetal 30 in 70% yield. DIBAl-H reduction of 30
smoothly provided allylic alcohol 31 in near-quantitative yield. Compound 31 is thus conve-
niently prepared on a 25 g scale.

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Table 2
Sharpless dihydroxylationa
SM
Reaction time (h)
Product(s)
Yield (%)
ee (%)
4
8
12
25
46
46
10
22:23 (4:1)
75
73
51
45b
36
38
63
78
24
26
27
120
a Conditions: (DHQ)2PHAL (0.1 equiv.) or (DHQD)2PHAL (0.1 equiv.), K3Fe(CN)6 (3 equiv.), K2CO3 (3 equiv.),
OsO4 (0.1 equiv.), MeSO2NH2 (3 equiv.), t-BuOH/H2O, 0°C.
b Based upon recovered starting material; 18% absolute yield, (DHQ)2PHAL as ligand.
The key reaction in this sequence is the reaction of 31 with three equivalents of m-CPBA
which provides vinylsulfone 32, presumably regiospecific via loss of sulfinic acid from the
a-sulfinylsulfone intermediate. Treatment of alcohol 32 with mesyl chloride in the presence of
excess triethylamine effects 1,4-elimination to chloro-substituted triene 258 as a single regioiso-
mer. This specificity results from the inductive acidification of the sulfone-bearing g-hydrogen
(Fig. 5).
Figure 5. Conditions: A: (COCl)2 (1.2 equiv.), CHCl3, rt, 5 h; B: PhSCl (2.2 equiv.), THF–HMPA (10:1), 0°C, 2 h;
C: DIBAl-H (1.5 equiv.), MC. −78°C, 2 h; D: m-CPBA, MC, rt, 1 h; E: MsCl (1.5 equiv.), Et3N (3 equiv.), MC, 0°C,
0.5 h

7799
Acknowledgements
We acknowledge Arlene Rothwell and Karl Wood for mass spectral data and the NIH for
partial support of this project (GMc 32693).
References
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8. 1-Benzenesulfonyl-1,3,5-cycloheptatriene (4): H NMR (500 MHz, CDCl3): 7.91–7.94 (m, 2H), 7.51–7.64 (m, 3H),
1
7.26 (d, J=0.48 Hz, 1H), 6.76 (q, J=5.62 Hz, 1H), 6.62–6.66 (m, 1H), 6.21 (dd, J=5.62 and 9.52 Hz, 1H),
5.33–5.38 (m, J=0.49, 6.84, and 9.52 Hz, 1H), and 2.59 (d, J=6.84 Hz, 2H); 2-benzenesulfonyl-1,3,5-cyclohepta-
1
triene (8): H NMR (500 MHz, CDCl3): 7.75–7.79 (m, 2H), 7.44–7.59 (m, 3H), 6.84 (dt, J=0.46 and 11.44 Hz,
1H), 6.71–6.79 (m, J=5.49, 5.65 and 11.44 Hz, 1H), 6.48 (td, J=0.46 and 7.44, 1H), 6.13 (dd, J=5.49 and 9.46
Hz, 1H), 5.46 (dt, J=6.57 and 9.46 Hz, 1H), and 2.41 (dd, J=6.87 and 7.17 Hz, 2H); 3-benzenesulfonyl-1,3,5-
1
cycloheptatriene (12): H NMR (300 MHz, CDCl3): 7.91–7.95 (m, 2H), 7.73 (d, J=6.87 Hz, 1H), 7.55–7.58 (m,
3H), 6.53 (d, J=9.61 Hz, 1H), 6.37 (dd, J=5.96 and 9.31 Hz, 1H), 5.62 (dt, J=6.87 and 9.31 Hz, 1H), 5.43 (dt,
J=6.87 and 9.61 Hz, 1H), and 2.25 (t, J=6.87, 2H); 5,6-epoxy-2-benzenesulfonyl-1,3-cycloheptadiene (15): 1H
NMR (500 MHz, CDCl3): 7.85–7.89 (m, 2H), 7.09 (t, 1H), 7.49–7.63 (m, 3H), 3.53–3.57 (m, 1H), 6.17–6.27 (m,
J=5.62 and 11.72 Hz, 2H), 3.09 (dt, J=3.18 and 3.42 Hz, 1H), 2.93 (ddd, J=2.93, 5.62 and 14.89 Hz, 1H), and
2.65 (ddd, J=5.62, 7.57 and 14.77 Hz, 1H); 5,6-dihydroxyl-1-benzenesulfonyl-1,3-cycloheptadiene (22): 1H NMR
(500 MHz, CDCl3): 7.84–7.88 (m, 2H), 7.50–7.64 (m, 3H), 7.16 (dt, J=3.51 Hz, 1H), 6.08 (q, 2H), 4.31–4.33 (m,
1H), 3.95–4.00 (m, 1H), 2.65 (dd, J=0.92 and 6.41 Hz, 2H), and 2.24 (s, br, ꢀOH); 5,6-dihdroxyl-2-benzenesulfonyl-
1
1,3-cycloheptadiene (24): H NMR (500 MHz, CDCl3): 7.83–7.89 (m, 2H), 7.50–7.65 (m, 3H), 7.26 (t, 1H), 6.18 (d,
1H), 5.97 (dd, 1H), 4.77 (s, br, ꢀOH), 4.25 (s, br, 1H), 4.08–4.14 (m, 1H), 2.71 (t, 2H); 1-chloro-4-benzenesulfonyl-
1
cyclohepta-1,3,5-triene (25): H NMR (300 MHz, CDCl3): 7.88–7.92 (m, 2H), 7.52–7.63 (m, 4H), 6.61 (d, J=9.3
Hz, 1H), 6.54 (d, J=6.6 Hz, 1H), 5.65 (dt, J=9.3, 6.9 Hz, 1H), and 2.76 (d, J=6.9 Hz, 2H). 1-chloro-4-benzene-
sulfonyl-5,6-dihydroxy-cyclohepta-1,3-diene (27): 1H NMR (300 MHz, C6D6): 7.90–7.96 (m, 2H), 7.10–7.15 (m,
3H), 7.01 (d, J=8.7 Hz, 1H), 5.81 (dd, J=2.7, 8.7 Hz, 1H), 4.85 (br s, 1H), 3.93 (br s, 1H), 3.59 (br d, J=11.1
Hz, 1H), 3.32 (ddd, J=2.7, 11.1, 18.3 Hz, 1H), 3.05 (br s, 1H), 2.63 (br d, J=18.3 Hz, 1H).
.
.