Substitution of β-Halostyrenes by MeS-

Full text of DOI:10.1021/jo9804083

5684
J . Org. Chem. 1998, 63, 5684-5686
Su bstitu tion of â-Ha lostyr en es by MeS-
cal answer to the mechanistic question. Since both
concerted routes involve cleavage of the C-halogen bond
in the rate-determining step, the study of the “element
effect”7 i.e., the relative reactivity of a vinyl bromide vs
the corresponding vinyl chloride, could detect a C-halo-
gen rate-determining bond cleavage. Both the stereo-
chemical and the element effect criteria are necessary for
distinguishing a concerted from a stepwise vinylic sub-
stitution via addition-elimination.
We therefore decided to further investigate the mech-
anism of the reaction since a concerted in-plane bimo-
lecular vinylic substitution6 may be observed in an
inactivated system, and â-halostyrenes should indeed be
relatively inactivated in comparison with YCHdCHHal
(Hal ) Cl, Br) where Y is a good electron-withdrawing
group such as CN, CO2R′. Moreover, substitution of
â-halostyrenes by lithium dimethylcuprate gave both
retained products and a considerable element effect: kBr/
kCl of ca. 102 whereas â-fluorostyrene was unreactive.8
We applied several mechanistic criteria, i.e., the kBr/kCl
element effect, the cis/trans relative ratio, the stereo-
chemistry, the effect of a p-MeO substituent, and the
effect of a radical scavenger on the reaction rate of
â-bromostyrenes with the MeS- ion.
Xin Chen and Zvi Rappoport*
Department of Organic Chemistry, The Hebrew University,
J erusalem 91904, Israel
Received March 3, 1998
In 1983 Tiecco and co-workers reported vinylic substi-
tution of relatively inactive vinyl halides.1 E-â-bromosty-
rene (E-Br ) reacted rapidly with MeS- or i-PrS- in
HMPA at room temperature to give g95% of the substi-
tution product E-SR with g98% retained configuration.
The Z isomer, Z-Br , gave g95% of the >95% retained
substitution product Z-SR (eq 1). In DMSO or DMF high
yields but lower stereospecificities were observed, i.e., 9:1
and 2:8 E-SR:Z-SR (R ) Me) ratios, starting from E-Br
and Z-Br , respectively. In EtOH Z-Br reacted much
slower and E-Br did not react at all. Based on the
retention stereochemistry, an addition-elimination vi-
nylic substitution route,2 without further mechanistic
details, was suggested.1
Resu lts a n d Discu ssion
E- and Z-â-bromostyrenes were prepared according to
Cristol9a and Grovenstein9b and a 1:1 E-Cl:Z-Cl mixture
was prepared from trans-cinnamic acid.10 The reactions
1
were followed directly in an NMR tube. The H NMR
spectra of reactants and products are given in Table 1.
Ster eoch em istr y of th e Su bstitu tion . We con-
firmed the previous observations that the reaction is fast
and gives retained products.1 The direct observation of
the reaction mixture enabled us to determine both
features at reaction times earlier than previously re-
ported. The reaction of a solution of 0.2 M of the Z-Br
with 0.22 M of NaSMe in DMSO-d6 at 295 K showed that
<8% of Z-Br remained after e3 min reaction time, and
that the rest was converted to the retained substitution
product, Z-SMe. No E-SMe was detected. After 8 min
no Z-Br was detected and after 13 min the inverted
product, E-SMe was formed in <0.16%. Hence, the
reaction is faster and more stereoselective than reported
by Tiecco.1
Reaction of 0.2 M of each of a 95:5 E-Br :Z-Br mixture
and MeSNa in DMSO-d6 at 295 K was somewhat slower.
A 40% amount of the vinyl bromide was converted to the
pure E-thioether E-SMe in 3 min. After standing
overnight, no E-Br remained, and the products were
95.8: 4.2 E-SMe:Z-SMe. Hence, the reaction is highly
stereoselective, and the overall substitution is stereospe-
cific.
This finding is of interest for two reasons. First,
â-bromostyrene should be relatively inactivated to nu-
cleophilic vinylic substitution, judging by the pKa of
toluene (41.2)3 which should serve as a rough measure
for the dispersal of the negative charge formed in the
transition state or the intermediate formed in the sub-
stitution. Hence, other mechanistic routes such as
elimination-addition via phenylacetylene,4,5 and an SRN
V
route,5 which are known for this system may be opera-
tive. Second, there is a recent interest in the operation
of a single step nucleophilic vinylic substitution,6 and the
main experimental evidence for it comes from inversion
during the substitution. However, whereas inversion is
the predicted outcome of an in-plane concerted substitu-
tion, a concerted substitution with retention by a per-
pendicular attack on the π* orbital is also a possibility.
Hence, stereochemistry alone does not give an unequivo-
(1) Tiecco, M.; Testaferri, L.; Tingoli, M.; Chianelli, D.; Montanucci,
M. J . Org. Chem. 1983, 48, 4795.
(2) Rappoport, Z. Adv. Phys. Org. Chem. 1969, 7, 1. Acc. Chem. Res.
1981, 14, 7, and references therein.
We conducted analogous reactions of the Z- and E-â-
chlorostyrenes with a 1:1.9 Z-Cl:E -Cl mixture. The
(3) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in
Organic Chemistry, 3rd ed.; Harper and Row: New York, 1987; p 294.
(4) Rappoport, Z. Recl. Trav. Chim. Pays-Bas 1985, 104, 309.
(5) Galli, C.; Gentili, P.; Rappoport, Z. J . Org. Chem. 1994, 59, 6786.
(6) (a) Ochiai, M.; Oshima, K.; Masaki, Y. J . Am. Chem. Soc. 1991,
113, 7059. (b) Shainyan, B. A.; Rappoport, Z. J . Org. Chem. 1993, 58,
3421. (c) Glukhovtsev, M. N.; Pross, A.; Radom, L. J . Am. Chem. Soc.
1994, 116, 5961. (d) Lucchini, V.; Modena, G.; Pasquato, L. J . Am.
Chem. Soc. 1993, 115, 4527; 1995, 117, 2297. (e) Okuyama, T.; Ochiai,
M. J . Am. Chem. Soc. 1997, 119, 4785. (f) Beit-Yannai, M.; Rappoport,
Z.; Shainyan, B. A.; Danilevich, Y. S. J . Org. Chem. 1997, 62, 8049.
(7) Bunnett, J . F.; Garbisch, E. W., J r.; Pruitt, K. M. J . Am. Chem.
Soc. 1957, 79, 385.
(8) Maffeo, C. V.; Marchese, G.; Naso, F.; Ronzini, L. J . Chem. Soc.,
Perkin Trans 1 1979, 92.
(9) (a) Cristol, S. J .; Norris, W. P. J . Am. Chem. Soc. 1953, 75, 2645.
(b) Grovenstein, E., J r.; Lee, D. E. J . Am. Chem. Soc. 1953, 75, 2639.
(10) Blitz, H. J ustus Liebig’s Ann. Chem. 1897, 296, 263.
S0022-3263(98)00408-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/09/1998

Notes
J . Org. Chem., Vol. 63, No. 16, 1998 5685
Ta ble 1. 1H NMR Sp ectr a of P h CHdCHR
δ, ppm (J , Hz)
Ta ble 2. kZ-Br /kZ-Cl Ra tios in DMSO-d 6:CD3OD Mixtu r e
DMSO-d6:CD3OD
reaction time, min
kZ-Br /kZ-Cl
R
isomer
solvent
vinyl-Ha
Ph-Hb
95:5
5:1
5:2
2-17a
2-97b
1.0 ( 0.1
1.4 ( 0.1
2.8 ( 0.3
c
Cl
E
Z
CDCl3
6.64, 6.84 (13.7)
6.26, 6.64 (8.16)
7.24-7.41
2-115c
7.24-7.41 (3H),
7.64-7.70 (2H)
7.28-7.47
a
b
All the Z-Br was consumed after 17 min. All the Z-Br was
consumed after 156 min. c All the Z-Br was consumed overnight,
when 30% of Z-Cl still remained.
E
Z
DMSO-d6 6.94, 7.15 (13.7)
6.56, 6.85 (8.04)
7.29-7.48 (3H),
7.67-7.69 (2H)
7.27-7.45
c
Ta ble 3. 1H NMR Sp ectr a of An CHdCHR
δ, ppm (J , Hz)
Br
E
Z
CDCl3
6.78, 7.12 (14.0)
6.46, 7.09 (8.13)
7.32-7.44 (3H),
7.70-7.73 (2H)
7.30-7.38 (3H),
7.45-7.48 (2H)
7.35-7.45 (3H),
7.67-7.71 (2H)
7.15-7.39 (5H)
7.10-7.45
E
Z
DMSO-d6 7.19, 7.28 (14.0)
R
isomer solvent
dCHa
Ar-Hb MeO MeS
Br
E
Z
E
Z
E
Z
E
Z
CDCl3
6.61, 7.04 (13.9) 6.85, 7.23 3.81
6.31, 7.00 (8.08) 6.91, 7.68 3.83
DMSO-d6 7.06, 7.12 (13.9) 6.90, 7.40 3.75
6.54, 7.17 (7.9) 6.98, 7.68 3.77
DMSO-d6 6.25, 6.27 (15.3) 6.85, 7.31 3.73 2.32
6.21, 6.37 (10.8) 6.92, 7.37 3.75 2.37
6.72, 7.26 (7.95)
d
MeS
E
Z
DMSO-d6 6.31, 7.08 (15.6)
DMSO-d6 6.40, 6.44 (10.9)
e
SMe
a
b
d
e
1H doublet. Multiplet. c Reference 11. δMe ) 2.36. δMe
)
CDCl3
6.29, 6.63 (15.4) 6.84, 7.24 3.80 2.37
6.08, 6.39 (10.8) 6.90, 7.43 3.82 2.39
2.41.
a
b
1H doublet. Each signal is an AA′BB′ multiplet.
Z-SMe:E-SMe product ratio decreased with time from
3.6 after 3 min to 2.8, 2.2, 2.0, and 1.8 after 7, 11, 15,
and 900 min, respectively. The Z-Cl was completely
consumed after 11 min, whereas none of the E-Cl
remained after 20 h (although it was presumably con-
sumed earlier). The final Z-SMe:E-SMe ratio of 1.8 is
close to the initial 1.9 ratio in this experiment. A similar
behavior was shown by using a Z-Cl:E-Cl ratio of 0.94.
The Z-SMe:E-SMe ratios were 2.2, 2.2, 1.7, 1.4, and 1.1
after 3, 5, 7, 14, and 900 min, i.e., the ratio approached
the initial Z-Cl:E-Cl ratio within the integration experi-
mental error.
different volumes of CD3OD, addition of which decrease
appreciably the substitution rate. When 1:1.1 Z-Br :Z-
Cl mixtures were used the observed kBr/kCl element
effects increased on increasing percentage of CD3OD in
the solvent (Table 2).
p -Meth oxy-â-br om ostyr en es. An E:Z mixture of
p-methoxy-â-bromostyrenes was prepared by bromina-
tion/dehydrobromination of p-methoxycinnamic acid. Chro-
matography gave the pure cis-isomer (Z-An , Br ), and
recrystallization of another fraction gave the pure trans
isomer (E-An , Br ). NMR data are given in Table 3. On
substitution with MeSNa in DMSO-d6 under conditions
similar to those described above, the reaction of Z-An ,
Br was complete in 15 min but was qualitatively slower
than that of Z-Br . The reaction was stereospecific. The
only product observed was the retained thioether Z-An ,
SMe.
The product ratio changes due to the higher reactivity
of Z-Cl. From the values given above the approximate
k(Z-Cl)/k(E-Cl) ratios are 1.7 ( 0.2 in the first experi-
ment and 2.1 ( 0.2 in the second experiment.
Th e Z-Br :E-Br Rea ctivity Ra tio. A 1.8:1 Z-Br :E-
Br mixture was reacted with 0.5 mol equiv of MeSNa.
As with the analogous chlorides the Z isomer was more
reactive: the k(Z-Br ):k(E-Br ) ratios were 2.6 ( 0.1
between 3 and 18 min. The corresponding Z-SMe:E-SMe
ratio is 4.6 ( 0.2 which drops to 4.1 after standing
overnight (when 90-100% of NaSMe was consumed).
Rea ction of P h en yla cetylen e w ith MeSNa . An
R,â-elimination-addition via an intermediate phenyl-
acetylene is inconsistent with the stereochemistry of the
reaction. When we searched during the reaction for a
phenylacetylene signal (at δ (DMSO) 3.42 ppm) in the
mixture, none was found. Likewise, no R-(methylthio)-
styrene, the regioisomer which may have been formed
by addition of MeSH to phenylacetylene, was observed.
Addition of 0.2 M MeSNa to 0.2 M phenylacetylene in
DMSO-d6 under the usual reaction conditions was fol-
lowed independently. After 0.5 or 1 h only 1-2% of a
ca. 1:5 E-SMe:Z-SMe ratio was observed. After the
mixture stood overnight at room temperature, followed
by 1 h at 50 °C, the amount of the â-(methylthio)styrenes
did not increase, but a deep red color, which was not
investigated further, was developed. We conclude that
the addition to the phenylacetylene is much slower than
the overall substitution reaction, thus excluding the
elimination-addition route.
Similar reaction of the E-isomer E-An , Br was slower
than that of Z-An , Br . It was complete after standing
overnight at 295 K. No Z-An , SMe was obtained.
Unfortunately, the coupling pattern of the vinylic sub-
stitution product E-An , SMe was too complicated for
obtaining the stereochemistry of the reaction.
kH/kp-MeO Rea ctivity Ra tio. A 1.4:1 Z-Br to Z-An ,
Br mixture in 95:5 DMSO-d6:CD3OD gave with MeSNa
the two substitution products. A reactivity ratio kH/
kp-MeO (i.e. kZ-Br /kZ-An ,Br ) of 1.60 ( 0.16 was evaluated
from the decrease in the intensity of the precursor
signals, which were used since the signals of Z-An , SMe
and Z-SMe overlapped in the δ 6.40 ppm region.
Rea ction in th e P r esen ce of a Ra d ica l Sca ven ger .
The possibility that the substitution of these relatively
inactivated substrates proceeds via a single electron (SE)
transfer with the strong SE reductant MeS- cannot be
excluded, and hence 0.2 M Z-Br or E-Br was reacted with
0.2 M MeSNa in the presence of 0.06 M of the free radical
scavenger TEMPO (2,2,6,6-tetramethylpiperidine N-ox-
ide) in DMSO-d6 at 295 K.
When TEMPO and Z-Br were mixed first and then
MeS- was added, the reaction rate and stereochemistry
remained unchanged. However, the reaction was slower
when the TEMPO and MeS- were mixed before the
reaction with Z-Br .
Th e Elem en t Effect. There are two element effects:
Z-Br vs Z-Cl and E-Br vs E-Cl. The reactions are too
fast to follow conveniently in DMSO-d6 and in order to
run the two reactions under close conditions we added
Con cer ted vs Step w ise Su bstitu tion . The nearly
complete retention stereochemistry for both isomers is

5686 J . Org. Chem., Vol. 63, No. 16, 1998
Notes
consistent with both a concerted and stepwise perpen-
dicular nucleophilic attack.12 The same applied for the
lower reactivity of the p-methoxy derivative compared
with the unsubstituted derivative and for the higher
reactivity of the Z isomer which is ascribed to its higher
ground state energy due to a vicinal Ar/Br steric interac-
tion. Only the element effect distinguishes between the
two routes,2,4 and the close to unity kZ-Br/kZ-Cl value
points unequivocally to a rate-determining nucleophilic
attack not involving C-halogen bond cleavage, i.e., to the
multistep route2 (eq 2).
aprotic solvent and to the low steric effect in its approach
to the vinylic system. The importance of steric effects
in reducing the vinylic substitution rates was recently
demonstrated.15
Exp er im en ta l Section
Su bstr a tes, Solven ts, a n d Meth od s. The â-halostyrenes
were prepared according to literature procedures as given above.
cis- and trans-p-methoxy-â-bromostyrenes were prepared by
bromination of p-methoxycinnamic acid, dehydrobromination of
the 5:95 erythro/threo dibromides mixture with sodium bicar-
bonate in acetone, separation of the cis-p-methoxy-â-bromosty-
rene,16 by chromatography and recrystallization of trans-p-
methoxy-â-bromostyrene from ethanol, mp 58-9 °C (lit. 55.0-
55.5 °C).17 The cis- and trans-p-methoxystyryl methyl sulfides
had NMR spectra similar with that in the literature.18 NaSMe
and the solvents were commercial products (Aldrich). NMR
analysis was performed with a Bruker AMX 400 instrument.
Su bstitu tion Exp er im en ts. (1) The reactions of the vinyl
halide with NaSMe in DMSO at 22 °C were carried out in NMR
Con clu sion . The retention stereochemistry, the ele-
ment effect, the slower reactions of the p-MeO derivative,
and the slower reaction in the presence of added CD3OD
are consistent with Tiecco’s suggestion that even this
system, which is activated by a single phenyl group,
reacts via the nucleophilic addition-elimination multi-
step route.2 The slower reaction in the presence of
TEMPO suggests the involvement of radicals in the
reaction. However, since we expect that in a process
involving a radical intermediate the stereochemistry will
be lost,13 in contrast with the observation, and since the
reaction was unaffected when TEMPO and Z-Br were
first mixed, we tentatively suggest that the TEMPO
reacts with MeS- before the substitution. Indeed, we
recently found that TEMPO reacts with i-PrS- in MeCN.14
The relatively high reactivity of the â-halostyrenes
with MeS- in DMSO is ascribed to a combination of an
excellent nucleophile, which is “naked” in the dipolar
1
tubes and followed directly by H NMR spectroscopy every 1-3
min without workup.
(2) The reaction of Z-Br with NaSMe (0.2 M each) in DMSO-
d6 was studied with or without added TEMPO, and the products
were analyzed by HPLC. Without adding TEMPO the reaction
was 95% complete within 5 min. When styrene Z-Br and
TEMPO were first mixed and the NaSMe was added afterward,
the result was identical. However, when TEMPO and NaSMe
were mixed first and Z-Br was added to this mixture, the
reaction rate was slower: 70% of unreacted styrene still remained
after 20 min.
Ack n ow led gm en t. This work was supported by the
United States-Israel Binational Science Foundation
(BSF), J erusalem, to which we are indebted.
J O9804083
(15) Bernasconi, C. F.; Schuck, D. F.; Ketner, R. J .; Weiss, M.;
Rappoport, Z. J . Am. Chem. Soc. 1994, 116, 11764.
(16) Shinozi, H.; Kubota, M.; Yagi, O.; Tada, M. Bull. Chem. Soc.
J pn. 1976, 49, 2280.
(11) Karpaty, M.; Davidson, M.; Hellin, M.; Coussemant, F. Bull.
Soc. Chim. Fr. 1971, 1731.
(12) Apeloig, Y.; Rappoport, Z. J . Am. Chem. Soc. 1979, 101, 5095.
(13) Galli, C.; Guarnieri, A.; Koch, H.; Mencarelli, P.; Rappoport, Z.
J . Org. Chem. 1997, 62, 4072.
(17) Trumbull, E. R.; Finn, R. T.; Ibne-Rasa, K. M.; Sauers, C. K. J .
Org. Chem. 1962, 27, 2339.
(18) Caserio, M. C.; Pratt, R. E.; Hollard, R. J . J . Am. Chem. Soc.
1966, 88, 5747.
(14) Beit-Yannai, M., unpublished results.