Cooperative bronsted acid-type organocatalysis: alcoholysis of sytrene oxides

Article abstract of DOI:10.1021/ol800149y

We present a mild and efficient method for the completely regioselective alcoholysis of styrene oxides utilizing a cooperative Bronsted acid- type organocatalytic system comprised of mandelic acid (1 mol %) and N,N'-bis-[3,5-bis-(trifluoromethyl)phenyl]-thiourea (1 mol %). Various styrene oxides are readily transformed into their corresponding ss-alkoxy alcohols in good to excellent yields at full conversion. Simple aliphatic and sterically demanding, as well as unsaturated and acid-sensitive alcohols can be employed.

Full text of DOI:10.1021/ol800149y

ORGANIC
LETTERS
2008
Vol. 10, No. 8
1513-1516
Cooperative Brønsted Acid-Type
Organocatalysis: Alcoholysis of Styrene
Oxides
Torsten Weil, Mike Kotke, Christian M. Kleiner, and Peter R. Schreiner*
Justus-Liebig-UniVersita¨t, Institut fu¨r Organische Chemie, Heinrich-Buff-Ring 58,
D-35392 Giessen, Germany
prs@org.chemie.uni-giessen.de
Received January 22, 2008
ABSTRACT
We present a mild and efficient method for the completely regioselective alcoholysis of styrene oxides utilizing a cooperative Brønsted acid-
type organocatalytic system comprised of mandelic acid (1 mol %) and N,N -bis-[3,5-bis-(trifluoromethyl)phenyl]-thiourea (1 mol %). Various
styrene oxides are readily transformed into their corresponding -alkoxy alcohols in good to excellent yields at full conversion. Simple aliphatic
and sterically demanding, as well as unsaturated and acid-sensitive alcohols can be employed.
′
â
Catalytic epoxide ring opening reactions with neutral1-3 and
charged nucleophiles1,2,4,5 provide access to a broad spectrum
of valuable intermediates; the addition of alcohols leads to
the synthetically important class of â-alkoxy alcohols.2,4,6,7
Classical Brønsted acid catalysis is the most widely used
method for epoxide openings through protonation of the basic
epoxide oxygen that facilitates the ring opening with the
nucleophile.8 The use of strong mineral acids is naturally
limited to acid-stable compounds; Lewis acids have also been
widely used as catalysts for epoxide ring openings.2,6 Nature,
however, uses an entirely different path for epoxide hydroly-
sis, which is key for removing unsaturated toxic organic
compounds (through epoxidation and subsequent hydroly-
sis).9 There are numerous enzymes that catalyze this reaction,
and a common motif is the activation of the epoxide through
(double) hydrogen bonding to, e.g., tyrosine residues.10 Such
enzymatic ring opening reactions are mild but also often
sensitive toward pH and solvent.11,12 Recently, we have
successfully utilized this motif, inter alia,13 for epoxide
(1) Schneider, C. Synthesis 2006, 3919-3944.
(2) Moghadam, M.; Tangestaninejad, S.; Mirkhani, V.; Shaibani, R.
Tetrahedron 2004, 60, 6105-6111. Firouzabadi, H.; Iranpoor, N.; Jafari,
A. A.; Makarem, S. J. Mol. Catal. A-Chem. 2006, 250, 237-242.
(3) Reetz, M. T.; Torre, C.; Eipper, A.; Lohmer, R.; Hermes, M.; Brunner,
B.; Maichele, A.; Bocola, M.; Arand, M.; Cronin, A.; Genzel, Y.; Archelas,
A.; Furstoss, R. Org. Lett. 2004, 6, 177-180. Yang, M. H.; Zhu, C. J.;
Yuan, F.; Huang, Y. J.; Pan, Y. Org. Lett. 2005, 7, 1927-1930. Desai, H.;
D’Souza, B. R.; Foether, D.; Johnson, B. F.; Lindsay, H. A. Synthesis 2007,
902-910. Arai, K.; Salter, M. M.; Yamashita, Y.; Kobayashi, S. Angew.
Chem., Int. Ed. 2007, 46, 955-957. Yadav, J. S.; Reddy, A. R.; Narsaiah,
A. V.; Reddy, B. V. S. J. Mol. Catal. A: Chem. 2007, 261, 207-212.
(4) Yarapathi, R. V.; Reddy, S. M.; Tammishetti, S. React. Funct. Polym.
2005, 64, 157-161.
(6) Prestat, G.; Baylon, C.; Heck, M. P.; Mioskowski, C., Tetrahedron
Lett. 2000, 41, 3829-3831. Chandrasekhar, S.; Reddy, C. R.; Babu, B. N.;
Chandrashekar, G. Tetrahedron Lett. 2002, 43, 3801-3803. Kantam, M.
L.; Jeyalakshmi, K. A. K.; Likhar, P. R. Catal. Lett. 2003, 89, 95-97.
Bradley, D.; Williams, G.; Lawton, M. Org. Biomol. Chem. 2005, 3, 3269-
3272. Gallo, J. M. R.; Teixeira, S.; Schuchardt, U. Appl. Catal. A 2006,
311, 199-203. Solodenko, W.; Jas, G.; Kunz, U.; Kirschning, A. Synthesis
2007, 583-589.
(7) Iranpoor, N.; Mohammadpour Baltork, I. Tetrahedron Lett. 1990,
31, 735-738. Garcia, R.; Martinez, M.; Aracil, J. Chem. Eng. Technol.
1999, 22, 987-990. Matsunaga, S.; Ohshima, T.; Shibasaki, M. AdV. Synth.
Catal. 2002, 344, 3-15. Robinson, M. W. C.; Buckle, R.; Mabbett, I.; Grant,
G. M.; Graham, A. E. Tetrahedron Lett. 2007, 48, 4723-4725.
(8) Chapman, N. B.; Biggs, J.; Finch, A.; Wray, V. J. Chem. Soc. B
1971, 55-63. Coxon, J. M.; Townsend, M. A. E. Tetrahedron 2007, 63,
5665-5668.
(5) Vandeweghe, P.; Collin, J. Tetrahedron Lett. 1995, 36, 1649-1652.
Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. 1996, 35, 1995-
1995. Albanese, D.; Landini, D.; Penso, M. Tetrahedron 1997, 53, 4787-
4790. Schaus, S. E.; Jacobsen, E. N. Org. Lett. 2000, 2, 1001-1004. Lau,
E. Y.; Newby, Z. E.; Bruice, T. C. J. Am. Chem. Soc. 2001, 123, 3350-
3357. Sabitha, G.; Babu, R. S.; Rajkumar, M.; Reddy, C. S.; Yadav, J. S.
Tetrahedron Lett. 2001, 42, 3955-3958. Reddy, M. A.; Surendra, K.;
Bhanumathi, N.; Rao, K. R. Tetrahedron 2003, 59, 2363-2363. Smitha,
G.; Reddy, C. S. J. Chem. Res., Synop. 2004, 300-301. Belokon, Y. N.;
Chusov, D.; Borkin, D. A.; Yashkina, L. V.; Dmitriev, A. V.; Katayev, D.;
North, M. Tetrahedron: Asymmetry 2006, 17, 2328-2333. Das, B.; Reddy,
V. S.; Tehseen, F.; Krishnaiah, M. Synthesis 2007, 666-668.
10.1021/ol800149y CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/27/2008

hydrogen-bonding catalysts. With regards to the choice of
mildacid(5)tobeusedwithN,N′-bis-[3,5-bis-(trifluoromethyl)phen-
yl]-thiourea (3),15 we were helped by the fact that we ob-
served that undistilled styrene oxide (1a) readily reacted with
various alcohols while freshly distilled 1a did not. As the
oxidation product of 1a is mandelic acid (5a),9,16 this acid
was our first choice. The initial results were very promising
and encouraged us to examine this remarkable reaction
further.
Table 1. Alcoholysis of Styrene Oxides with Mandelic Acid
(5a)
While carboxylic acids are known to increase the reaction
rates of some nucleophilic organocatalytic reactions17 this
is a rare example of a cooperative Brønsted acid-type
organocatalytic system.18 Optimization of the reaction condi-
tions led to a protocol that utilizes 12 equiv of the alcohol
as nucleophile and solvent; this effectively suppresses the
formation of byproducts resulting from attack of the product
on 1 (see Supporting Information for details).
Styrene oxides can readily be transformed into â-alkoxy
alcohols in good to excellent yields; all catalyzed reactions
are completely regioselective and show full conversion. Both
simple aliphatic and sterically demanding (Table 1, entries
1-10), as well as unsaturated (entries 12, 13) and especially
acid-labile alcohols (entries 14-18) can be utilized. In
general, the reaction times depend more on the nature of
the epoxide substrate (1) than on the alcohol (2). The more
reactive 1c leads nearly in all cases to faster conversions
(Table 1, entries 4 and 8); the sole exception is the reaction
of cinnamyl alcohol (2k) with 1c. An electron-deficient
styrene oxide (1b) leads to longer reaction times and lower
yields. The reactions of styrene oxides with tert-butanol (2d,
entries 6-8) were all carried out at 50 °C and afforded yields
from 57% to 74% without byproduct formation. All reference
experiments for these reactions (entries 6-8) showed no
conversion; even after 17 days the reference experiment of
entry 8 without 3 showed less than 5% conversion. No
decomposition or polymerization reactions could be detected
for the acid-labile substrates 2j, 2k, and 2l.
a Reaction conditions: 1 equiv of 1, 12 equiv of alcohol, and 1 mol %
of 3 and 5a respectively; rt. All catalyzed reactions were accompanied by
parallel reference experiments without 3, as well as experiments with 3
and without acid co-catalyst under identical reaction conditions. No polymers
of styrene oxide were detected. All reference experiments showed no
conversion at the presented reaction time if not otherwise noted. Reactions
were monitored by GC/MS. Regiochemistry was determined by NMR
experiments (3J CH-coupling) and fragmentation in MS. b At 50 °C. c 3
mol % of 5a; 2 equiv of alcohol; at 50 °C. d Yield of isolated product.
Table 2. Solvent Effect on the Alcoholysis of Styrene Oxide
with Ethanola
openings with strong nucleophiles. We demonstrated that the
effects of hydrogen-bonding organocatalysis and water as
the solvent are cooperatiVe and termed this “hydrophobic
amplification”.14 Apparently, the approximately neutral pH
and the presence of water also are key factors in THP-
templated epoxide openings in cascade reactions leading to
structures akin to Brevetoxin A.12 As water can effectively
compete with weaker nucleophiles, we set out to develop
an alternative approach that relies on using two cooperative
solvent
time [h]
temp. [°C]
conv. of 1 [%]
ethanol
22
48
20
48
20
16
48
rt
rt
>99
-
acetonitrile
acetonitrile
THF
50
rt
∼9
>99
-
toluene
rt
toluene
50
rt
>99
>99
n-hexane
a Reaction conditions: 1 equiv of 1, 2 equiv of 2b, 2 vol equiv of solvent,
and 1 mol % of 3 and 5a, respectively, rt.
(9) Korn, M.; Wodarz, R.; Schoknecht, W.; Weichardt, H.; Bayer, E.
Arch. Toxicol. 1984, 55, 59-63.
We examined various solvents for the conversion of solid
alcohols or epoxides (Table 2) with our test reaction and
(10) Gallimore, A. R.; Stark, C. B. W.; Bhatt, A.; Harvey, B. M.;
Demydchuk, Y.; Bolanos-Garcia, V.; Fowler, D. J.; Staunton, J.; Leadlay,
P. F.; Spencer, J. B. Chem. Biol. 2006, 13, 453-460.
(11) Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217-220.
Schreiner, P. R., Chem. Soc. ReV. 2003, 32, 289-296. Wittkopp, A.;
Schreiner, P. R., Chem. Eur. J. 2003, 9, 407-414.
(15) Pihko, P. M. Angew. Chem., Int. Ed. 2004, 43, 2062-2064.
Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299-4306. Doyle, A. G.;
Jacobsen, E. N., Chem. ReV. 2007, 107, 5713-5743.
(12) Vilotijevic, I.; Jamison, T. F. Science 2007, 317, 1189-1192.
(13) Kotke, M.; Schreiner, P. R. Tetrahedron 2006, 62, 434-439. Kotke,
M.; Schreiner, P. R. Synthesis 2007, 779-790. Zhang, Z.; Schreiner, P. R.,
Synlett 2007, 1455-1457.
(16) Ensign, S. A.; Allen, J. R. Annu. ReV. Biochem. 2003, 72, 55-76.
(17) Cao, C. L.; Ye, M. C.; Sun, X. L.; Tang, Y. Org. Lett. 2006, 8,
2901-2904.
(18) Yong-Ling Shi, M. S. AdV. Synth. Catal. 2007, 349, 2129-2135.
Zuend, S. J.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 15872-15883.
(14) Kleiner, C. M.; Schreiner, P. R. Chem. Commun. 2006, 4315-4317.
1514
Org. Lett., Vol. 10, No. 8, 2008

found a remarkable solvent effect. Reactions in ethanol were
more than two times faster than reactions in nonpolar or
aprotic solvents.19 To optimize our cooperative catalyst
system, we also varied the ratio between 3 and 5a20 and
utilized various mandelic acid derivatives.21
Scheme 1. Proposed Catalytic Cycle for Epoxide Alcoholysis
through H-Bonding-Mediated Cooperative Catalysis
Further Brønsted acid screening (Table 3) revealed that
Table 3. Brønsted Acid Screening
It is likely that co-catalyst 3 coordinates to the acid 5a
through double H-bonding, stabilizes 5a in the chelate-like
a Reaction conditions: 1 equiv of 1, 12 equiv of ethanol, and 1 mol %
of 3 and 5a-l, respectively, rt. All catalyzed reactions were accompanied
by parallel reference experiments without 3, as well as experiments with 3
and without acid co-catalyst under identical reaction conditions. Reference
experiments showed no conversion. b Reactions were monitored by GC/
MS. c Reference without 3 showed 12% conversion after 18 h. d Reference
without 3 showed 80% conversion after 15 h; remarkably, the reaction does
not run to completion even after 3 days. e Calculated data. f No experimental
or calculated data available.
only aromatic acids bearing a second coordination center in
the R-position (hydroxy or carbonyl) led to appreciable
conversions (entries 1-3, 9). The removal or blocking of
the R-coordination center (5j and 5e) or removal of the
aromatic system dramatically reduces the conversion rates.
Aqueous acidity (pKa) appears not to be a good predictor
for catalyst activity (entry 12).
Figure 1. Minimum-energy structures of monomers 1a, 3, and
5a, binary (1a‚3, 5a‚3, and 1a‚5a) and ternary complexes (1a‚5a‚
3) optimized at B3LYP/6-31+G(d,p).
cis-hydroxy conformation, and acidifies the R-OH proton via
an additional intramolecular H-bond. The epoxide then is
activated by a single-point hydrogen bond that facilitates
regioselective nucleophilic attack of the alcohol at the ben-
zylic position. Such monodentate binding was recently sug-
gested for diol catalysts.22 The incipient oxonium ion repro-
tonates the mandelate and affords the â-alkoxy alcohol
product.
Our experimental findings suggest an H-bonding-mediated
cooperative Brønsted-acid catalysis mechanism (Scheme 1).
(19) Park, K. S.; Kim, J.; Choo, H.; Chong, Y. Synlett 2007, 395-398.
Shirakawa, S.; Shimizu, S. Synlett 2007, 3160-3164.
(20) Suprisingly, reaction times in all cases are nearly equal, although
GC/MS analysis after 15 h showed more than two times faster conversion
in case of 7 mol % of 3 than in case of our standard protocol (1 mol % of
3). The results are available in the Supporting Information.
(21) We observed a nonlinear catalytic effect for the ethanolysis of 1
with a notable rate enhancement in the second half of the reaction period.
This is apparently not a case of autocatalysis through product 4b because
addition of 20 mol% of 4b to our standard test reaction showed no variation
relative to our standard protocol. Further mechanistic investigations are
currently underway.
(22) McGilvra, J. D.; Unni, A. K.; Modi, K.; Rawal, V. H. Angew. Chem.,
Int. Ed. 2006, 45, 6130-6133.
(23) Frisch; et al. Gaussian 03 (for full reference see Supporting
Information).
(24) Becke, A. D. Phys. ReV. A 1988, 38, 3098-3100. Lee, C.; Yang,
W.; Parr, R. G. Phys. ReV. B 1988, 37, 785-789.
Org. Lett., Vol. 10, No. 8, 2008
1515

(Figure 1, Table 4). The rather strong complexation of
epoxides with thiourea derivatives was recently found by
us14 and Connon et al.25 The ternary complex has an overall
binding energy relative to its components of remarkable 20.0
kcal/mol, and this explains the concept of cooperativity of
the two catalysts. This prompted us to use an NMR titration
to determine the 5a‚3 complexation energy but found, even
upon inclusion of elaborate DOSY experiments, that the
binding is too strong to be measured with conventional
means. Further experimental and computational studies are
underway.
Table 4. Stabilization Energies, H-Bond Distances and Bond
Lengths at B3LYP/6-31+G(d,p)
complex ∆H0 [kcal/mol] HB distance [Å] bond length [Å]
1a‚3
5a‚3
1a‚5a
-9.2
-11.9
-5.7
NH‚‚‚O 2.109
NH‚‚‚O 2.019
N-H 1.017
N-H 1.019
C1-O 1.463
C2-O 1.444
NH1‚‚‚O1 2.131
NH2‚‚‚O2 1.984
N-H1 1.018
N-H2 1.018
O-H 0.973
O-H (R) 0.968
O-H 0.986
O-H (R) 0.974
C1-O 1.455
C2-O 1.442
N-H2 1.022
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (SPP 1179) and the Fonds
der Chemischen Industrie. We thank Dr. Heike Hausmann
(JLU) for carrying out extensive NMR experiments and
Volker Lutz (JLU) for helpful discussions and support in
computational questions.
OH‚‚‚O 1.769
NH2‚‚‚O2 1.943
OH (R)‚‚‚O 1.781 O-H 0.985
O-H (R) 0.982
C1-O 1.458
Supporting Information Available: Experimental and
computational details as well as characterization of all new
compounds. This material is free of charge via the Internet
at http://pubs.acs.org.
C2-O 1.443
N-H1 1.015
1a‚5a‚3
-20.0
NH1‚‚‚O1 2.339
DFT computations lend credibility to the suggested mech-
anism. At the B3LYP/6-31+G(d,p) level23,24 a binary com-
plex between 3 and 5a is thermochemically favored by 2.7
and 6.2 kcal/mol as compared to complexes 1a‚3 and 1a‚5a
OL800149Y
(25) Fleming, E. M.; Quigley, C.; Rozas, I.; Connon, S. J. J. Org. Chem.
2008, 73, 948-956.
1516
Org. Lett., Vol. 10, No. 8, 2008