Tungsten-, molybdenum-, and cerium-promoted regioselective and stereospecific halogenation of 2,3-epoxy alcohols and 2,3-epoxy sulfonamides

Article abstract of DOI:10.1021/ol503091n

The first catalytic regioselective and stereospecific halogenation of 2,3-epoxy alcohols and 2,3-epoxy sulfonamides has been developed. Under the catalysis of commercially available W- or Mo-salts, complemented by the method using cerium halides, the C-3

Full text of DOI:10.1021/ol503091n

Letter
pubs.acs.org/OrgLett
Tungsten‑, Molybdenum‑, and Cerium-Promoted Regioselective and
Stereospecific Halogenation of 2,3-Epoxy Alcohols and 2,3-Epoxy
Sulfonamides
Chuan Wang† and Hisashi Yamamoto*,†,‡
†Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue, Chicago, Illinois 60637, United States
‡Molecular Catalyst Research Center, Chubu University, 1200 Matsumoto, Kasugai, Aichi 487-8501, Japan
S
* Supporting Information
ABSTRACT: The first catalytic regioselective and stereo-
specific halogenation of 2,3-epoxy alcohols and 2,3-epoxy
sulfonamides has been developed. Under the catalysis of
commercially available W- or Mo-salts, complemented by the
method using cerium halides, the C-3 selective ring opening of
structurally diverse epoxides with Cl-, Br-, and I-nucleophiles
afforded various halohydrins in good yields and high regioselectivities.
ince a plethora of methods for asymmetric epoxidation of
allylic alcohols have been developed over the last decades,
sterically hindering 2,3-epoxy farnesol 1m was also successfully
used as precursor for the chlorination reaction furnishing the
product 2m bearing two quaternary and tertiary stereocenters
in complete regioselectivity. When aliphatic 2,3-disbustituted
epoxides were employed as substrate, only low regioselectivities
could be achieved.
Furthermore, the substrate spectrum of the regioselective
chlorination of 2,3-epoxy sulfonamides 3 was investigated
(Scheme 2). In the cases of trans-, terminal-, and trisubstituted
epoxides 3a−j complete regioselectivities were obtained, while
the reaction using cis-epoxide 3k as precursor gave the product
with relatively low regiocontrol.
Moreover, we studied the use of LiBr and LiI as nucleophiles
for the ring opening reaction. In this case WO2Cl2 turned out
to be unsuitable since Br−Cl and I−Cl exchange between the
catalyst and the lithium salts was observed, which resulted in a
mixture of chlorohydrin and bromohydrin or chlorohydrin and
iodohydrin as products. A brief screening of chlorine-free W-
and Mo-salts revealed that the best outcome was achieved when
MoO2(acac)2 was used as catalyst. Under the optimum
conditions terminal 2,3-epoxy alcohols and 2,3-epoxy sulfona-
mides were successfully employed as precursors for the ring
opening reaction furnishing the products 5a−i in high yields
and complete regioselectivities (Scheme 3). Unfortunately, this
method was not applicable to epoxides of other substitution
patterns, which led to low regioselectivities.
As mentioned above the W- and Mo-catalyzed halogenation
of 2,3-epoxy alcohols and 2,3-epoxy sulfonamides was not
applicable to aliphatic 2,3-disubstitued epoxides. In order to
expand the substrate scope of the ring opening reaction we
screened some other metal chlorides as nucleophiles.
Interestingly, cerium(III) halides turned out to be able to
S
regioselective and enantiospecific ring opening of readily
available enantioenriched 2,3-epoxy alcohols provides diverse
chiral building blocks for the synthesis of biologically active
compounds.1−3 Recently, our group developed an enantiose-
lective epoxidation of sulfonamides4 providing a possibility to
access various optically active polyfunctionalized compounds
through nucleophilic ring opening of 2,3-epoxy sulfonamides.
Hitherto, regioselective ring opening of 2,3-epxoy alcohols with
halides as nucleophiles are only accomplished employing
stoichiometric promoters with limited substrate scope,5−7
whereas the regioselective halogenations of 2,3-epoxy sulfona-
mides remain elusive. More recently, our group discovered that
W-salts are capable of catalyzing C-3 selective cleavage of 2,3-
epoxy alcohols and 2,3-epoxy sulfonamides with various N- and
O-nucleophiles.8 As a continuation of our research in this area,
herein we report a W-, Mo-, and Ce-mediated C-3 selective,
stereospecific halogenations of structurally diverse 2,3-epoxy
alcohols and 2,3-epoxy sulfonamides.
For optimization of the reaction conditions, we used racemic
trans-2,3-epoxy cinnamyl alcohol (1a) as standard substrate and
lithium chloride as the Cl-source. After careful screening of
solvents and W- or Mo-salts, the best yield was achieved when
the reaction was carried out in monoglyme employing WO2Cl2
as catalyst.9
After the optimum conditions were established, we started to
evaluate the substrate scope of this chlorination reaction. First,
we varied the structure of the 2,3-epoxy alcohols, and the
results are summarized in Scheme 1. In the cases of trans
aromatic epoxides 1a−d with primary alcohol as directing
group, the reactions proceeded with complete regioselectivities,
while the reaction employing the aromatic epoxide 1e with
tertiary alcohol-moiety gave the product 2e with relatively low
regiocontrol. For the terminal epoxides 1f−l all the reactions
afforded only one regioisomer as the product. Notably, the
Received: October 22, 2014
Published: November 10, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Scheme 1. W-Catalyzed Regioselective Chlorination of 2,3-
Epoxy Alcohols
Scheme 2. W-Catalyzed Regioselective Chlorination of 2,3-
Epoxy Sulfonamides
a
,b
10
a 10
,b
a
Unless otherwise specified, reactions were performed on a 0.25 mmol
scale of racemic 2,3-epoxy sulfonamides 3 using 4.0 equiv of LiCl and
a
b
Unless otherwise specified, reactions were performed on a 0.25 mmol
scale of racemic 2,3-epoxy alcohols 1 using 4.0 equiv of LiCl and 25
25 mol % WO2Cl2 at 55 °C in 2.5 mL of monoglyme for 1 d. All
1
c
regiomeric ratios were determined by H-NMR-spectroscopy. Reac-
tion was performed with 5 mol % WO2Cl2 at room temperature.
Reaction time: 7 h. dMonoglyme was used as solvent. eMbs: 4-
methoxybenzenesulfonyl.
b
mol % WO2Cl2 at 55 °C in 2.5 mL of monoglyme for 1 d. All
regiomeric ratios were determined by H-NMR-spectroscopy. Fifteen
mol % WO2Cl2 was used. MeCN was employed as solvent. Thirty
mol % WO2Cl2 was used.
1
c
d
e
Scheme 3. Mo-Catalyzed Regioselective Bromination and
Iodination of Terminal 2,3-Epoxy Alcohols and 2,3-Epoxy
Sulfonamides
mediate the ring opening reaction of aliphatic 2,3-disubstituted
2,3-epoxy alcohols and 2,3-epoxy sulfonamides smoothly at
room temperature under catalyst-free conditions, furnishing the
products in high to complete regioselectivities (Scheme 4).
Notably, only a substoichiometric amount of cerium halide (0.4
equiv) was necessary to achieve complete conversion of the
ring-opening reaction.
a
10
,b
To gain more insight into the directing effect of the OH- and
NH-sulfonyl moiety, we performed a control reaction using Ac-
protected epoxy alcohols and Boc-protected sulfonamide as
substrates (Scheme 5). The results obtained indicated that the
ring opening of terminal epoxides 9a and 9b could proceed
with complete regioselectivities even in the absence of OH-
moiety. In contrast, the regioselectivity of the trans-aromatic
epoxide 7 diminished when OH was protected. In both cases
mentioned above the reactions proceeded with significantly
lower efficiency. Furthermore, protecting the NHTs-moiety still
allowed the ring-opening to proceed with complete regiocon-
trol suggesting that the sulfonyl-group, instead of the amide
nitrogen, plays a crucial role as the directing group.
In addition, we have also studied the stereospecificity of this
ring opening reaction by employing enantioenriched epoxides
as starting materials. To our delight, all the reactions afforded
the products 2a, 4c, 4g, and 6b with identical enantiomeric
excesses in comparison to their epoxide precursors.11
In conclusion we have developed the first catalytic
regioselective and stereospecific halogenations of 2,3-epoxy
alcohols and 2,3-epoxy sulfonamides. This process was
efficiently promoted by commercially available W- and Mo-
a
Unless otherwise specified, reactions were performed on a 0.25 mmol
scale of racemic 2,3-epoxy alcohols 1 or 2,3-epoxy sulfonamides 3
using 4.0 equiv of LiBr or LiI and 25 mol % MoO2(acac)2 at 55 °C in
2.5 mL of monoglyme for 1 d. bAll regiomeric ratios were determined
1
by H-NMR-spectroscopy.
salts using simple lithium halide as nucleophiles and applicable
to a variety of epoxides furnishing various halohydrins in good
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Organic Letters
Letter
Scheme 4. Ce-Mediated Regioselective Halogenation of 2,3-
Epoxy Alcohols and 2,3-Epoxy Sulfonamides
AUTHOR INFORMATION
Corresponding Author
■
a
,b
10
*E-mail: yamamoto@uchicago.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Japan Society for the Promotion of Science (JSP-ACT-C) is
greatly appreciated for providing financial support. C.W. thanks
the Alexander von Humboldt Foundation for his postdoctoral
fellowship.
REFERENCES
■
(1) For recent selected general reviews on asymmetric epoxidation,
see: (a) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1. (b) Katsuki,
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Katsuki, T. J. Am. Chem. Soc. 2010, 132, 5886. (d) Olivares-Romero, J.
L.; Li, Z.; Yamamoto, H. J. Am. Chem. Soc. 2013, 135, 3411. (e) Wang,
C.; Yamamoto, H. J. Am. Chem. Soc. 2014, 136, 1222.
a
Unless otherwise specified, reactions were performed on a 0.25 mmol
scale of racemic 2,3-epoxy alcohols 1 or 2,3-epoxy sulfonamides 3
using 0.4 equiv of cerium(III) halide at rt in 2.5 mL of monoglyme.
bAll regiomeric ratios were determined by H-NMR-spectroscopy.
1
(3) For reviews on regioselective ring-opening of 2,3-epoxy alcohols,
see: (a) Hanson, R. M. Chem. Rev. 1991, 91, 437. (b) Pena, P. C. A.;
Roberts, S. M. Curr. Org. Chem. 2003, 7, 555.
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2012, 134, 5440.
Scheme 5. W-Catalyzed Chlorination of 2,3-Epoxy Acetates
and Boc-Protected 2,3-Epoxy Sulfonamide
(5) For a review on regioselective ring-opening of epoxides with
halides as nucleophiles, see: Bonini, C.; Righi, G. Synthesis 1994, 16,
225.
(6) For examples on regioselective ring-opening of 2,3-epoxy
alcohols with halide-nucleophiles, see: (a) Caron, M.; Sharpless, K.
B. J. Org. Chem. 1985, 50, 1557. (b) Onaka, M.; Sugita, K.; Takeuchi,
H.; Izumi, Y. J. Chem. Soc., Chem. Commun. 1988, 117. (c) Gao, L.-X.;
Murai, A. Chem. Lett. 1989, 18, 357. (d) Gao, L.-X.; Murai, A. Chem.
Lett. 1991, 20, 1503. (e) Alvarez, E.; Nunez, M. T.; Martin, V. S. J. Org.
̃
Chem. 1990, 55, 3429. (f) Gao, L.-X.; Saitoh, H.; Feng, F.; Murai, A.
Chem. Lett. 1991, 20, 1787. (g) Bonini, C.; Righi, G.; Sotgiu, G. J. Org.
Chem. 1991, 55, 6206. (h) Reifeld, Y. E.; Nikitenko, A. A.; Arshava, B.
M. Tetrahedron: Asymmetry 1991, 2, 1083. (i) Bovicelli, P.; Mincione,
E.; Ortaggi, G. Tetrahedron Lett. 1992, 33, 6181. (j) Shimizu, M.;
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(7) For an example on stereospecific chlorinolysis of 2,3-epoxy
alcohol in complex molecule, see: Nilewski, C.; Deprez, N. R.; Fessard,
T. C.; Li, D. B.; Geisser, R. W.; Carreira, E. M. Angew. Chem., Int. Ed.
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(8) Wang, C.; Yamamoto, H. J. Am. Chem. Soc. 2014, 136, 6888.
(9) For details, see Supporting Information, Page 3.
(10) The ring-opening products were assigned by analogy assuming a
common SN-2-type reaction pathway.
(11) For details, see Supporting Information, Page 20.
to high yields and in most cases with excellent regiocontrol.
Especially, the successful use of challenging trisubstituted
epoxides allows the construction of two consecutive quaternary
and tertiary centers. Furthermore, being complementary to the
W- and Mo-catalyzed halogenation, cerium(III) halides are
capable of mediating the highly regioselective ring-opening of
aliphatic 2,3-disubstituted 2,3-epoxy alcohols and 2,3-epoxy
sulfonamides.
ASSOCIATED CONTENT
* Supporting Information
■
S
Representative experimental procedures and necessary charac-
terization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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