Regioselective ring-opening α-methylenation of aryl epoxides to conjugated allyl alcohols utilizing n-BuLi and Me2S=CH2 reagents

Article abstract of DOI:10.1016/j.tetlet.2014.04.076

In the presence of a mixture of n-BuLi and Me₂SCH₂ reagents, aryl epoxides underwent a novel ring-opening α-methylenation providing conjugated allyl alcohols with an unusual regioselective pattern.

Full text of DOI:10.1016/j.tetlet.2014.04.076

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective ring-opening
a-methylenation of aryl epoxides to
conjugated allyl alcohols utilizing n-BuLi and Me2S@CH2 reagents
⇑
Takashi Tomioka , Rambabu Sankranti, Amber M. James, Daniell L. Mattern
Department of Chemistry and Biochemistry, University of Mississippi, University, MS 38677, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
In the presence of a mixture of n-BuLi and Me2S@CH2 reagents, aryl epoxides underwent a novel ring-
Received 10 April 2014
Accepted 21 April 2014
Available online xxxx
opening
a
-methylenation providing conjugated allyl alcohols with an unusual regioselective pattern.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
a-Methylenation
One-carbon homologation
Dimethylsulfonium methylide
Aryl epoxide
Allyl alcohol
Allyl alcohols and their derivatives are of great importance in
organic synthesis. Indeed, a number of different methods/routes
to access those have been extensively studied over the years.1
Recently, our group serendipitously discovered a novel transfor-
mation of styrene oxide to 2-phenyl-2-propen-1-ol in the presence
of lithioacetonitrile (LiCH2CN). Further investigation of this finding
eventually revealed that the use of a 1:1 mixture of n-BuLi and
LiCH2CN effectively converted such an aryl epoxide to the corre-
sponding one-carbon homologated allyl alcohol 1 with a high reg-
ioselectivity (Scheme 1).2
Our prior experiments also indicated that this one-carbon
homologation was likely to proceed by way of a unique carbene-
mediated mechanism (Scheme 2)3 and was potentially useful for
various synthetic applications. However, the elimination step
(2 ? 3) causes the production of a cyanide ion in a stoichiometric
manner. This toxic side-product unfortunately hinders further
practical uses of this protocol. In order to avoid this potential
drawback, an alternative ‘cyanide-free’ approach was therefore
sought in our group. Herein, we describe a regioselective sulfur-
a less substituted epoxide site, that is, b-carbon, and eventually
produces allyl alcohol 4 as a major regioisomer (Scheme 3, Eq. 1).
Importantly, the by-product of the reaction is only dimethyl sul-
fide. Based on such nature of this reagent, we assumed that if Me2-
S@CH2 was able to react with carbene (or carbenoid) species 5, it
could be used as an alternative ‘cyanide-free’ reagent to LiCH2CN
and still selectively provide allyl alcohol 1, instead of 4, along with
dimethyl sulfide (Scheme 3, Eq. 2).
To test whether this proposed a-methylenation works (Table 1),
we first took advantage of our previously reported protocol that
was used for n-BuLi–LiCH2CN homologation system.2 That is, a
mixture of styrene oxide (1.0 equiv) and Me3S+IÀ (1.05 equiv) in
THF was simply treated with n-BuLi (2.1 equiv) at À78 °C (entry
1). The conditions should generate one equivalent of Me2S@CH2
reagent in situ, while the remaining one equivalent of n-BuLi will
be used for the generation of carbene 5. Excitingly, the desired
product 1a was successfully obtained as a major regioisomer; how-
ever, the yield was only 28%. The amount of Me2S@CH2 was there-
fore increased (entries 2–4). When two equivalents of Me2S@CH2
were used (entry 3), the yield of 1a was maximized to 55%. The
ylide mediated a-methylenation of an aryl epoxide leading an allyl
alcohol 1.
use of TMEDA as an additive entirely prevented both a- and b-
Dimethylsulfonium methylide, Me2S@CH2, is a well-known
one-carbon homologation reagent for various epoxides4,5 and can
be readily prepared in situ from trimethylsulfonium iodide, Me3S+-
IÀ, in the presence of an appropriate base (e.g., n-BuLi). This
reagent nucleophilically reacts with an aryl epoxide, normally, at
methylenation (entry 5). When Me2S@CH2 (2.0 equiv) was pre-
⇑
Corresponding author. Tel.: +1 662 915 7301.
E-mail address: tomioka@olemiss.edu (T. Tomioka).
Scheme 1. One-carbon homologation of aryl epoxide.
http://dx.doi.org/10.1016/j.tetlet.2014.04.076
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
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2
T. Tomioka et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Table 2
n-BuLi–Me2S@CH2 mediated
a
-methylenation of aryl epoxidea
O
n-BuLi
Me3S+I-
OH
+
Ar
Ar
THF, -78ºC to r.t.
1
Entry
1
Aryl epoxide
Allyl alcohol 1
% yieldb,c
O
OH
1b
1c
51 (81)
50 (72)
40 (51)
53
CH3
O
CH3
OH
Scheme 2. Plausible reaction mechanism.
2
3
4
CH3
CH3
O
OH
1d
t-Bu
t-Bu
O
OH
1e
1f
SiMe3
O
SiMe3
OH
Scheme 3.
a/b-Methylenation of aryl epoxide.
5
6
7
51 (60)
39
OMe
OMe
O
OH
Table 1
Screening optimal conditions
1g
F
F
OH
O
O
n-BuLi
Me3S+I-
+
OH
OH
+
Ph
Ph
Ph
THF
1h
36
(2.0 mmol)
1a
4a
-78ºC to r.t.
CF3
CF3
Me3S+I- (mmol)
n
1a (%)a
4a (%)a
Entry
-BuLi (mmol)
Aryl epoxide (2.0 mmol), Me3S+IÀ (4.1 mmol), n-BuLi (6.2 mmol), THF (3 mL).
Isolated yield.
Yields in parentheses were obtained under the n-BuLi–LiCH2CN conditions.
a
b
c
1
2.1
3.1
4.1
5.1
4.1
4.0
4.2
5.2
6.2
7.2
6.2
4.0
28
36
55
53
0
19
24
12
8
2
3
S@CH2 conditions do not generate a toxic cyanide ion and are still
a useful alternative in some cases from the practical/safety aspects.
In summary, the use of an in situ generated sulfur based ylide,
Me2S@CH2, as a methylenation reagent in the presence of n-BuLi
successfully converted a series of aryl epoxides into conjugated
allyl alcohols 1 in an unusual regioselective manner. This ‘cya-
nide-free’ protocol also overcame the previous major issues
encountered in the n-BuLi–LiCH2CN system. For further applica-
tions, we are currently investigating the reactivity and compatibil-
ity of various ylide species other than Me2S@CH2 under the
conditions.
4
5b
6
0
29
53
CH2I2 (mmol)
7
8
2.1
4.1
4.1
6.1
N/Ac
N/Ac
a
b
c
By NMR (internal standard).
Used TMEDA.
Styrene oxide mostly recovered, along with minor side-products.
Acknowledgments
pared by using a stoichiometric ratio of Me3S+IÀ and n-BuLi (1:1),
the regioselectivity was, as expected, reversed (entry 6). Thus, like
n-BuLi–LiCH2CN system, the presence of one equivalent of n-BuLi is
We thank Dr. Amal Dass and Mr. Vijay Reddy Jupally for their
analytical assistance. We gratefully acknowledge the National Sci-
ence Foundation (1153105) for financial support.
highly essential to lead an
a-methylenation product. Another
potential ‘cyanide-free’ reagent, LiCH2I, was also tested, but no
desired product was given (entries 7 and 8).
References and notes
The scope and generality under the optimized conditions were
subsequently investigated (Table 2).6 Aryl epoxides having an alkyl
group on the ortho, meta, or para position (entries 1–3) readily pro-
vided the desired allyl alcohols in fair yields. Functionalized aryl
epoxides including both electron-donating and electron-with-
drawing groups (entries 4–7) also moderately underwent the
methylenation. Although the yields are inferior to the ones
observed in the n-BuLi–LiCH2CN system by 10–30% presumably
due to the solubility problem of the salt reagent, the n-BuLi–Me2
1. Larock, R. C. Comprehensive Organic Transformations: a Guide to Functional Groups
Preparations, 2nd ed.; Wiley-VCH: New York, 1999.
2. Tomioka, T.; Sankranti, R.; Yamada, T.; Clark, C. Org. Lett. 2013, 15, 5099.
3. The existence of the carbene species was previously confirmed by conducting an
intramolecular cyclopropanation reaction (see Ref. 2).
4. Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, I. P.; La Gall, T.; Shin, D.-S.;
Falck, J. R. Tetrahedron Lett. 1994, 35, 5449.
5. For recent examples, see: (a) Camps Bres, F.; Guerard-Helaine, C.; Fernandes, C.;
Castillo, J. A.; Lemaire, M. Tetrahedron: Asymmetry 2013, 24, 1075; (b)
Kumaraswamy, G.; Narayana Murthy, A.; Narayanarao, V.; Vemulapalli, S. P.
Please cite this article in press as: Tomioka, T.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.076

T. Tomioka et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
B.; Bharatam, J. Org. Biomol. Chem. 2013, 11, 6751; (c) Reddy, B. V. S.; Reddy, P. S.;
Reddy, B. P.; Yadav, J. S.; Al Khazim Al Ghamdi, A. Tetrahedron Lett. 2013, 54,
5758; (d) Hwang, M.-H.; Han, S.-J.; Lee, D.-H. Org. Lett. 2013, 15, 3318; (e)
Kumar, T. V.; Reddy, G. V.; Babu, K. S.; Rao, J. M. Tetrahedron: Asymmetry 2013,
24, 594; (f) Kumar, T. V.; Shankaraiah, G.; Babu, K. S.; Rao, J. M. Tetrahedron Lett.
2013, 54, 1397; (g) Underwood, B. S.; Tanuwidjaja, J.; Ng, S.-S.; Jamison, T. F.
Tetrahedron 2013, 69, 5205; (h) Reddy, C. R.; Dilipkumar, U.; Reddy, M. D.; Rao,
N. N. Org. Biomol. Chem. 2013, 11, 3355; (i) Kumar, D. A.; Meshram, H. M. Synth.
Commun. 2013, 43, 1145; (j) Choi, J.; Kim, H.; Park, S.; Tae, J. Synlett 2013, 379;
(k) Arlt, A.; Benson, S.; Schulthoff, S.; Gabor, B.; Fuerstner, A. Chem. Eur. J. 2013,
19, 3596.
chromatography using hexanes–EtOAc as eluents. Note: allyl alcohols except
1e and 1h are known. NMR spectra are identical to the reported values: 81a–
1d,2 1f,2 1g.7
2-(3-(Trimethylsilyl)phenyl)prop-2-en-1-ol (1e): Column chromatography yielded
1e as a light yellowish liquid (218 mg, 53%). Rf 0.46 (hex/EtOAc = 7:3); 1H NMR
(300 MHz, CDCl3) d 7.62–7.58 (m, 1H), 7.56–7.28 (m, 3H), 5.47 (d, J = 0.9 Hz, 1H),
5.38 (d, J = 1.2 Hz, 1H), 4.58 (d, J = 5.7 Hz, 2H), 1.55 (t, J = 6.0 Hz, 1H), 0.30 (s,
9H); 13C NMR (75 MHz, CDCl3) d 147.8, 140.8, 137.9, 132.9, 130.9, 127.8, 126.6,
112.5, 65.1, 0.0; HRMS (TOF MS ES+) calcd for C12H18OSi 206.1127 [M]+, found
206.1109.
2-(4-Fluorophenyl)prop-2-en-1-ol (1h): Column chromatography yielded 1h as a
colorless liquid (150 mg, 37%). Rf 0.28 (hex/EtOAc = 7:3); 1H NMR (300 MHz,
CDCl3) d 7.71–7.44 (m, 4H), 5.54 (d, J = 0.9 Hz, 1H), 5.46 (d, J = 0.9 Hz, 1H), 4.57
(d, J = 5.4 Hz, 2H), 1.55 (t, J = 6.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 146.1,
6. General procedure for the preparation of 1a–1h: Into a mixture of aryl epoxide
(2.0 mmol) and trimethylsulfonium iodide (4.1 mmol) in dry THF (3.0 mL) was
added n-BuLi (6.2 mmol) slowly at À78 °C under argon. The resulting mixture
was stirred overnight while the temperature rose gradually to room
temperature. The reaction mixture was then quenched with a saturated aq.
NaHCO3 (3.0 mL). After the phase separation, the aqueous layer was extracted
with Et2O (Â2). The combined organics were then dried over MgSO4 and
2
3
139.4, 130.8 (q, JCF = 31.8 Hz), 129.4, 128.9, 124.5 (q, JCF = 3.7 Hz), 124.1 (q,
1JCF = 270.6 Hz), 122.8 (q, 3JCF = 3.8 Hz), 114.3, 64.7; HRMS (TOF MS ES+) calcd for
C
10H9F3O 201.0527 [MÀH]+, found 201.0520.
7. Mo, J.; Xu, L.; Ruan, J.; Liu, S.; Xiao, J. Chem. Commun. 2006, 3591.
concentrated in vacuo. The crude was purified with
a silica-gel column
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