Methylsulfonyl and hydroxyl substituents induce Z-stereocontrol in the McMurry olefination reaction

Article abstract of DOI:10.1055/s-2004-829087

Aryl ketones possessing methylsulfonyl and hydroxyl substituents, that induce stereocontrol, selectively afford Z-olefins using a Zn-TiCl₄ catalyzed McMurry reaction.

Full text of DOI:10.1055/s-2004-829087

LETTER
1513
Methylsulfonyl and Hydroxyl Substituents Induce Z-Stereocontrol in the
McMurry Olefination Reaction
Z-Stereocontrol inthe
d
McMurryO
l
.
e
fination
Re
J
action ashim Uddin, P. N. Praveen Rao, Edward E. Knaus*
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, T6G 2N8, Canada
Fax +1(780)4921217; E-mail: eknaus@pharmacy.ualberta.ca
Received 3 February 2004
n-Pr, n-pentyl, n-hexyl, n-nonyl) in 63–72% overall yield
Abstract: Aryl ketones possessing methylsulfonyl and hydroxyl
substituents, that induce stereocontrol, selectively afford Z-olefins
using a Zn–TiCl4 catalyzed McMurry reaction.
(Scheme 1).17
Accordingly, we are pleased to report that the cross-cou-
pling reaction of two aryl ketones functionalized by a sul-
fonyl and a hydroxyl group, proceeds in a stereocontrolled
manner to afford the target Z-olefinic products 4
(Table 1). The structure of the starting materials 1, the
isolated intermediates 3, and the final products 4 were
consistent with their spectral (IR, 1H NMR, 13C NMR) and
microanalytical data. The absolute stereochemistry of (Z)-
4l (R2 = n-Pr) was unambiguously confirmed by a single
crystal X-ray analysis (Figure 1).
Key words: McMurry olefination, stereocontrol, Z-olefins, acety-
lation
Condensation of carbonyl compounds as a method to syn-
thesize olefins using the McMurry reaction is a useful
transformation in organic synthesis.1 In this regard, mech-
anistic aspects2–5 of the McMurry reaction were studied in
considerable detail. Coe and Scriven6 reported a low va-
lent titanium-mediated McMurry reaction which afforded
(Z)-tamoxifen as the predominant stereoisomer (ratio
Z:E = 9:1). Other studies subsequently showed that steric
hindrance seems to be an important factor that affects the
stereoselectivity of the McMurry reaction since deoxy-
genation of the pinacolic intermediate results in preferen-
tial formation of the olefin in which the bulkier and
smaller substituents are cis to each other.7 We now report
a practical stereocontrol approach involving a McMurry
reaction using functionalized aryl ketones that coordinate
with metallic titanium to induce a high level of Z-selectiv-
ity.
The stereocontrol achieved in this McMurry olefination
reaction is attributed to a polydentate transient pinacolic
intermediate which is formed by homolytic coupling of a
radical anion species generated from reduction of the car-
bonyl compounds 1 (R1 = SO2Me, R2 = H, Me, Et, n-Pr,
n-pentyl, n-hexyl, n-nonyl) and 2 (R3 = 4-hydroxyphenyl,
R4 = Ph) by Ti0.1 The Z-conformer likely arises from a
consecutive surface induction of active Ti0 to the polyden-
tate pinacolic intermediate, that is followed by subsequent
demetallation and deoxygenation reactions.4 In this re-
gard, the ‘phenoxy-Ti-sulfone’ induction plays an impor-
tant role for Z-stereoselection by forcing the sulfonyl and
phenoxy moieties to be positioned on the same side
(Figure 2). This explanation depicting the stereochemical
role of phenoxy and sulfone groups is consistent with the
stereochemical outcome observed for a set of control
reactions (see Table 1). For example, irrespective of
As a part of our ongoing program to develop novel and
highly selective COX-2 inhibitors,8–10 we required a
method to prepare (Z)-monoacetoxyphenyl analogs of the
very potent and highly selective COX-2 inhibitor 1,1-
diphenyl-2-(4-methylsulfonyl)hex-1-ene.11 In this regard,
carbonyl compounds 1 (R1 = SO2Me, R2 = H, Me, Et, n-
Pr, n-pentyl, n-hexyl, n-nonyl) required for these synthe-
ses were prepared in 85–92% yield by oxidation of the re-
spective methylthio compounds11–13 using either MCPBA
or Oxone®.14
The intermediate Z-olefin products 3 (R1 = SO2Me,
R2 = H, Me, Et, n-Pr, n-pentyl, n-hexyl, n-nonyl, R3 = 4-
hydroxyphenyl, R4 = Ph) were generated in situ using a
McMurry olefination reaction15 by Zn–TiCl4 catalyzed re-
ductive cross-coupling of compounds 1 (R1 = SO2Me,
R2 = H, Me, Et, n-Pr, n-pentyl, n-hexyl, n-nonyl) with 4-
hydroxybenzophenone (2, R3 = 4-hydroxyphenyl, R4 =
Ph). Subsequent acetylation of intermediates 316 afforded
the target (Z)-acetoxyphenyl products 4 (R2 = H, Me, Et,
R1
R3
R4
a
O
O
+
R2
1
2
MeO2S
b
OAc
R1
R3
R4
R2
R2
4
3
SYNLETT 2004, No. 9, pp 1513–1516
2
2.
0
7.
2
0
0
4
Scheme 1 Reagents and conditions: (a) Zn, TiCl4, THF, reflux 4.5
h; (b) AcCl, TEA, Et2O, 25 °C, 1.5 h.
Advanced online publication: 29.06.2004
DOI: 10.1055/s-2004-829087; Art ID: S01004ST
© Georg Thieme Verlag Stuttgart · New York

1514
Md. J. Uddin et al.
LETTER
Table 1 Stereoselective Synthesis of Z-Olefins Using a McMurry Reaction
R1
R3
R4
R1
R2
No.
3a
3b
3c
3d
3e
3f
R2
R3
R4
Ph
Ph
Ph
Ph
Ph
Ph
H
Yield (%)
64
Z (%)a
<56
<65
<66
<60
<53
<61
<65
<51
>99
>99
>90
>90
>99
>99
>99
>99
SO2Me
SMe
H
(4-Br)Ph
(4-Me)Ph
(4-Me)Ph
(4-Me)Ph
Naphthyl
Naphthyl
Ph
Me
65
SO2Me
SMe
Me
64
Et
60
SO2Me
SO2Me
SMe
H
68
n-Pentyl
n-Heptyl
H
68
3g
3h
3i
61
SMe
(4-OH)Ph
(4-OH)Ph
(4-OAc)Ph
(4-OAc)Ph
(4-OAc)Ph
(4-OAc)Ph
(4-OAc)Ph
(4-OAc)Ph
(4-OAc)Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
63
SO2Me
SO2Me
SO2Me
SO2Me
SO2Me
SO2Me
SO2Me
SO2Me
Et
75
4i
Et
72
4j
Me
67
4k
4l
H
67
n-Pr
n-Pentyl
n-Hexyl
n-Nonyl
68
4m
4n
4o
70
70
63
a Determined by 1H NMR.
whether the ketones 1 possessed a R1 SO2Me or SMe
substituent, the cross-coupled reaction with ketones 2
(R3 = 4-bromophenyl, 4-methylphenyl, napthyl or phe-
nyl; R4 = H or Ph) all afforded a mixture of stereoisomers
3 in which the E:Z ratio was about 2:3 (see products 3a–g
in Table 1). A similar reaction of ketone 1 (R1 = SMe;
R2 = H) with ketone 2 (R3 = 4-hydroxyphenyl; R4 = Ph)
furnished 3h with a E:Z ratio of about 1:1. In contrast, the
cross-coupled reaction of the ketone 1 (R1 = SO2Me;
R2 = Et) with the ketone 2 (R3 = 4-hydroxyphenyl,
R4 = phenyl) afforded the Z-olefin 3i exclusively (>99%)
since none of the E-stereoisomer was detected in the prod-
uct. These data indicate that a sulfonyl moiety in one car-
bonyl compound 1 and a hydroxyl moiety in the other
carbonyl compound 2 is a requirement for high Z-stereo-
selectivity [see Z-products 4i–o that were isolated after
acetylation of the corresponding R3 hydroxyphenyl com-
pounds 3]. Further studies are currently in progress utiliz-
ing this stereocontrolled McMurry olefination reaction.
Figure 1 X-Ray crystal structure of (Z)-4l.18
In conclusion, a new methodology has been developed to
control the stereochemistry of the McMurry olefination
reaction that will have a wide range of synthetic applica-
tions.
Synlett 2004, No. 9, 1513–1516 © Thieme Stuttgart · New York

LETTER
Z-Stereocontrol in the McMurry Olefination Reaction
1515
The solvent was removed in vacuo, H2O (20 mL) was added
to the residue, and the mixture was extracted with EtOAc
(3 × 30 mL). The combined EtOAc extracts were washed
with H2O, the EtOAc fraction was dried (Na2SO4), and the
solvent was removed in vacuo to afford a white solid which
was purified by recrystallization from CH2Cl2n-hexane (1:9,
v/v) to afford 1 (R1 = SO2Me, R2 = n-Pr) in 89% yield as
white needles; mp 86–88 °C. IR (film): 1148, 1313 (SO2),
1698 (C=O) cm–1. 1H NMR (300 MHz, CDCl3): d = 1.02 (t,
3 H, J = 7.3 Hz, CH3), 1.73–1.85 (m, 2 H, CH2), 2.90 (t, 2 H,
J = 7.0 Hz, COCH2), 3.09 (s, 3 H, SO2CH3), 8.04 (d, 2 H,
J = 8.5 Hz, 4-methylsulfonylphenyl H-2, H-6), 8.13 (d, 2 H,
J = 8.5 Hz, 4-methylsulfonylphenyl H-3, H-5). Anal. Calcd
for C11H14O3S·1/6H2O: C, 57.61; H, 6.25. Found: C, 57.89;
H, 6.25.
Ti
O O
O
S
O
O
Figure 2 Proposed mechanism for stereoselective Z-olefin formati-
on as illustrated for (Z)-1-(4-hydroxyphenyl)-1-phenyl-2-(4-methyl-
sulfonylphenyl)pent-1-ene: A surface induction pattern involving
metallic titanium and the polydentate pinacolic intermediate.1,4
(15) Rubin, V. N.; Ruenitz, P. C.; Boudinot, F. D.; Boyd, J. L.
Bioorg. Med. Chem. 2001, 9, 1579.
(16) Strazzolini, P.; Verardo, G.; Giumanini, A. G. J. Org. Chem.
1988, 53, 3321.
Acknowledgment
(17) General Procedure for Synthesis of Compounds 4.
Synthesis of (Z)-1-(4-acetoxyphenyl)-1-phenyl-2-(4-
methylsulfonylphenyl)pent-1-ene [(Z)-4l]: TiCl4 (1.83 mL,
13 mmol) was added drop wise to a stirred suspension of Zn
powder (1.7 g, 26.5 mmol) in dry THF (30 mL) under argon
at –10 °C, and this mixture was refluxed for 2 h. A solution
of 4-(methylsulfonyl)butyrophenone (1, R1 = SO2Me,
R2 = n-Pr) (0.75 g, 3.3 mmol) and 4-hydroxybenzophenone
(2, R3 = 4-hydroxyphenyl, R4 = Ph) (0.66 g, 3.3 mmol) in
THF (65 mL) was added to the cooled suspension of the
titanium reagent at 0 °C, and the reaction mixture was
refluxed for 2.5 h. After cooling to 25 °C, the reaction
mixture was poured into a 10% aq K2CO3 solution (100 mL),
vigorous stirring was maintained for 5 min, and the
dispersed insoluble material was removed by vacuum
filtration using Celite 545. The organic layer was separated
and the aqueous layer was extracted with EtOAc (3 × 50
mL). The combined EtOAc extracts were dried (Na2SO4),
the solvent was removed in vacuo to afford the olefinic
intermediate 3 (R1 = SO2Me, R2 = n-Pr, R3 = 4-hydroxy-
phenyl, R4 = Ph), which was dissolved in Et2O (10 mL), and
Et3N (0.5 g, 5.0 mmol) was added. Acetyl chloride (0.39 g,
5.0 mmol) was added drop wise at 0 °C, and the reaction was
allowed to proceed for 1.5 h at 25 °C with stirring prior to
quenching with H2O (20 mL). The organic layer was
separated, the aqueous layer was extracted with EtOAc
(3 × 30 mL), the combined organic fractions were washed
with H2O, and the organic fraction was dried (Na2SO4).
Removal of the solvent in vacuo gave a solid that was
purified by flash silica gel column chromatography using n-
hexaneEtOAc (3:1, v/v) as eluant to afford (Z)-4l (R = n-Pr)
as colorless crystals (0.97 g, 68%); mp 132–134 °C. IR
(film): 1142, 1322 (SO2), 1585 (C=C), 1757 (C=O of OAc)
cm–1. 1H NMR (300 MHz, CDCl3): d = 0.82 (t, 3 H, J = 7.3
Hz, CH2CH3), 1.25–1.40 (m, 2 H, CH2CH3), 2.23 (s, 3 H,
OCOCH3), 2.44 (t, 2 H, J = 7.9 Hz, C=C-CH2), 3.04 (s, 3 H,
SO2CH3), 6.76 (d, 2 H, J = 8.5 Hz, 4-acetoxyphenyl H-3,
H-5), 6.85 (d, 2 H, J = 8.5 Hz, 4-acetoxyphenyl H-2, H-6),
7.20–7.40 (m, 7 H, phenyl hydrogens, and 4-methylsulfonyl-
phenyl H-2, H-6), 7.74 (d, 2 H, J = 8.5 Hz, 4-methyl-
sulfonylphenyl H-3, H-5). 13C NMR (75 MHz, CDCl3):
d = 14.10 (CH2CH2CH3), 17.77 (CH3C=O), 21.16
We are grateful to the Canadian Institutes of Health Research
(CIHR) (MOP-14712) for financial support of this research, to the
Alberta Heritage Foundation for Medical Research (AHFMR) for a
postdoctoral fellowship (to M. J. Uddin) and for a graduate scholar-
ship (to P.N. P. Rao), and to Bob McDonald for acquiring the X-ray
crystal structure data.
References
(1) McMurry, J. E. Chem. Rev. 1989, 89, 1513.
(2) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S. J. Org.
Chem. 1976, 41, 260.
(3) McMurry, J. E.; Krepski, L. R. J. Org. Chem. 1976, 41,
3929.
(4) McMurry, J. E.; Fleming, M. P.; Kees, K. L.; Krepski, L. R.
J. Org. Chem. 1978, 43, 3255.
(5) Dams, R.; Malinowski, M.; Westdrop, I.; Geise, H. Y. J.
Org. Chem. 1982, 47, 248.
(6) Coe, P. L.; Scriven, C. E. J. Chem. Soc., Perkin Trans. 1
1986, 475.
(7) (a) Gauthier, S.; Sancéau, J.-Y.; Mailhot, J.; Caron, B.;
Cloutier, J. Tetrahedron 2000, 56, 703. (b) Detsi, A.;
Koufaki, M.; Calogeropoulou, T. J. Org. Chem. 2002, 67,
4608.
(8) Habeeb, A. G.; Rao, P. N. P.; Knaus, E. E. J. Med. Chem.
2001, 44, 3039.
(9) Rahim, M. A.; Rao, P. N. P.; Knaus, E. E. Bioorg. Med.
Chem. Lett. 2002, 12, 2753.
(10) Rao, P. N. P.; Amini, M.; Li, H.; Habbeb, A. G.; Knaus, E.
E. J. Med. Chem. 2003, 46, 4872.
(11) Uddin, M. J.; Rao, P. N. P.; Knaus, E. E. Bioorg. Med. Chem.
Lett. 2004, 14, 1953.
(12) Huang, H.-C.; Li, J. J.; Garland, D. J.; Chamberlain, T. S.;
Reinhard, E. J.; Manning, R. E.; Seibert, K.; Koboldt, C. M.;
Gregory, S. A.; Anderson, G. D.; Veenhuizen, A. W.; Zhang,
Y.; Perkins, W. E.; Burton, E. G.; Cogburn, J. N.; Isakson, P.
C.; Reitz, D. B. J. Med. Chem. 1996, 39, 253.
(13) Buu-Hoi, N. P.; Hoan, N. J. Org. Chem. 1952, 17, 350.
(14) (a) Fringuelli, F.; Pellegrino, R.; Piermatti, O.; Pizzo, F.
Synth. Commun. 1994, 18, 2665. (b) Habeeb, A. G.; Rao, P.
N. P.; Knaus, E. E. J. Med. Chem. 2001, 44, 2921.
(c) General Procedure for the Synthesis of Compounds 1.
Synthesis of 4-(Methylsulfonyl)butyrophenone (1,
R1 = SO2Me, R2 = n-Pr): A solution of Oxone® (potassium
peroxymonosulfate) (4.06 g, 6.6 mmol) in H2O (20 mL) was
added to a stirred solution of 4-(methylthio)butyrophenone13
(0.64 g, 3.3 mmol) in 50% THF–MeOH (1:1, v/v; 10 mL) at
0 °C, and the reaction mixture was stirred for 15 h at 25 °C.
(CH2CH2CH3), 37.64 (CH2CH2CH3), 44.53 (SO2CH3),
120.69, 126.99, 127.11, 128.26, 129.23, 130.44, 131.46
(Carom-H), 138.03, 139.44, 139.53, 140.53, 142.22, 148.64,
148.96 (Carom-C, Colefin-C, Carom-O, Carom-S), 169.00
(CH3C=O). Anal. Calcd for C26H26O4S: C, 71.86; H, 6.03; S,
7.38. Found: C, 71.74; H, 5.96; S, 7.27.
Synlett 2004, No. 9, 1513–1516 © Thieme Stuttgart · New York

1516
Md. J. Uddin et al.
LETTER
independent reflections were collected to a maximum 2q
limit at 52.9°. The structure was solved by direct methods.
Refinement of atomic parameters was carried out by using
full-matrix least-squares on F2 (SHELXL-93), giving final
agreement factor (R indices) of R1 = 0.0484 and
(18) Crystal data for (Z)-4l: Molecular formula: C26H26O4S,
formula weight: 434.53, crystal system: monoclinic, space
group: P21/c(14) with unit cell dimensions a = 8.0403 (6) Å,
b = 14.5485 (12) Å, c = 19.9285 (16) Å, b = 101.4182 (15)º,
V = 2285.0 (3) Å3, Z = 4, = 1.263 gcm–3, m = 0.171 mm–1. A
crystal fragment of approximate dimensions(mm3) 0.73 ×
0.40 × 0.04 was mounted in a nonspecific orientation on
Bruker PLATFORM/SMART 1000 CCD diffractometer.
All intensity measurements were performed using Mo Ka
radiation (l = 0.71073 Å) with a graphite crystal incident
beam monochromator. The intensity data were collected at
–80 °C using an w scan (0.3º) (10 s exposures). A total 4675
wR2 = 0.1116. Crystallographic data (excluding structure
factors) have been deposited at the Cambridge
Crystallographic Data Centre as supplementary publication
number CCDC 228635. Copies of the data can be obtained
free of charge by application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: 44(1223)336033 or e-mail:
deposit@ccdc.cam.ac.uk).
Synlett 2004, No. 9, 1513–1516 © Thieme Stuttgart · New York