Alkene dihydroxylation with malonoyl peroxides: Catalysis using fluorinated alcohols

Article abstract of DOI:10.1021/ol3030154

The effect of fluorinated alcohols on the dihydroxylation of alkenes using cyclopropyl malonoyl peroxide is described. Addition of perfluoro-tert-butyl alcohol to a toluene solution of alkene and peroxide increases the rate of product formation and the stereoselectivity observed, providing a simple and effective method for acceleration of this important class of reaction. Basic hydrolysis of the crude reaction mixture provides access to syn-diols in high yield and stereoselectivity.

Full text of DOI:10.1021/ol3030154

ORGANIC
LETTERS
2012
Vol. 14, No. 24
6250–6253
Alkene Dihydroxylation with Malonoyl
Peroxides: Catalysis Using Fluorinated
Alcohols
Sylvain Picon,† Michael Rawling,‡ Matthew Campbell,§ and
Nicholas C. O. Tomkinson*,‡
School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff, CF10
3AT, U.K., GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire,
SG1 2NY, U.K., and WestCHEM, Department of Pure and Applied Chemistry, Thomas
Graham Building, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, U.K.
Nicholas.Tomkinson@strath.ac.uk
Received November 2, 2012
ABSTRACT
The effect of fluorinated alcohols on the dihydroxylation of alkenes using cyclopropyl malonoyl peroxide is described. Addition of perfluoro-
tert-butyl alcohol to a toluene solution of alkene and peroxide increases the rate of product formation and the stereoselectivity observed,
providing a simple and effective method for acceleration of this important class of reaction. Basic hydrolysis of the crude reaction mixture
provides access to syn-diols in high yield and stereoselectivity.
Alkene dihydroxylation is central in synthetic chemistry.
The gold-standard Sharpless asymmetric dihydroxylation
represents an outstanding method for performing this
reaction, providing the products in excellent yields and
high levels of asymmetric induction.1 Despite the over-
whelming acceptance of this reaction, the toxicity and
expense of osmium(VIII) has provided an impetus for
the development of alternative methods.2 Notable success
has been achieved with transition metals including
palladium,3 iron,4 ruthenium,5 manganese,6 and copper.7
Metal-free methods have also been reported. However,
this area is considerably less established than their metal-
based counterparts.8,9 To date, the development of a
catalytic asymmetric, metal-free method for the dihydrox-
ylation of alkenes remains an elusive and attractive target.
We recently described a simple and effective method for
the transition-metal free syn-dihydroxylation of alkenes
† Cardiff University.
(6) (a) Boer, J. W.; Brinksma, J.; Browne, W. R.; Meetsma, A.;
Alsters, P. L.; Hage, R.; Feringa, B. L. J. Am. Chem. Soc. 2005, 127,
7990. (b) Boer, J. W.; Brinksma, J.; Browne, W. R.; Harutyunyan, S. R.;
Bini, L.; Tiemersma-Weyman, T. D.; Alsters, P. L.; Hage, R.; Feringa,
B. L. Chem. Commun. 2008, 3747.
‡ University of Strathclyde.
§ GlaxoSmithKline.
(1) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483.
(2) (a) Bataille, C. J. R.; Donohoe, T. J. Chem. Soc. Rev. 2011, 40,
114. (b) Asghar, S. F.; Lewis, S. E. Annu. Rep. Prog. Chem., Sect. B: Org.
Chem. 2011, 107, 34. (c) Christie, S. D. R.; Warrington, A. D. Synthesis
2008, 1325.
(7) Seayad, J.; Seayad, A. M.; Chai, C. L. L. Org. Lett. 2010, 12, 1412.
(8) (a) Schmidt, V. A.; Alexanian, E. J. Angew. Chem., Int. Ed. 2010,
49, 4491. (b) Giglio, B. C.; Schmidt, V. A.; Alexanian, E. J. J. Am. Chem.
Soc. 2011, 133, 13320.
(3) (a) Li, Y.; Song, D.; Dong, Vy. M. J. Am. Chem. Soc. 2008, 130,
2962. (b) Wang, A.; Jiang, H.; Chen, H. J. Am. Chem. Soc. 2009, 131,
3846. (c) Wang, W.; Wang, F.; Shi, M. Organometallics 2010, 29, 928.
(4) (a) Chen, K.; Costas, M.; Kim, J.; Tipton, A. K.; Que, L., Jr.
J. Am. Chem. Soc. 2002, 124, 3026. (b) Oldenburg, P. D.; Que, L., Jr.
Catal. Today 2006, 117, 15.
(5) (a) Plietker, B.; Niggemann, A.; Pollrich, A. Org. Biomol. Chem.
2004, 2, 1116. (b) Plietker, B.; Niggemann, A. J. Org. Chem. 2005, 70,
2402. (c) Plietker, B.; Neisius, N. M. J. Org. Chem. 2008, 73, 3218.
(9) (a) Emmanuvel, L.; Shaikh, T. M. A.; Sudalai, A. Org. Lett. 2005,
7, 5071. (b) C-elik, M.; Alp, C.; Cos-kun, B.; Gultekin, M. S.; Balci, M.
€
Tetrahedron Lett. 2006, 47, 3659. (c) Santoro, S.; Santi, C.; Sabatini, M.;
Testaferri, L.; Tiecco, M. Adv. Synth. Catal. 2008, 350, 2881. (d) Fujita,
M.; Wakita, M.; Sugimura, T. Chem. Commun. 2011, 47, 3983. (e) Zhong,
W.; Yang, J.; Meng, X.; Li, Z. J. Org. Chem. 2011, 76, 9997. (f) Yuan, C.;
Axelrod, A.; Varela, M.; Danysh, L.; Siegel, D. Tetrahedron Lett. 2011, 52,
2540. (g) Zhong, W.; Liu, S.; Yang, J.; Meng, X.; Li, Z. Org. Lett. 2012, 14,
3336.
r
10.1021/ol3030154
Published on Web 11/30/2012
2012 American Chemical Society

using cyclic malonoyl peroxides.10 For example, reac-
tion of cyclopropyl malonoyl peroxide 1 (1.2 equiv) with
styrene in the presence of 1 equiv of water leads to
intermediate esters 2 and 3. Removal of the solvent
followed by basic hydrolysis of the crude reaction mixture
provides diol 4 (89%) and diacid 5 (87%) (Scheme 1).
Within this paper we describe successful efforts to catalyze
this reaction using fluorinated alcohols.
Scheme 2. Possible Mechanism for the Reaction of Styrene with
Cyclopropyl Malonoyl Peroxide 1
Scheme 1. Dihydroxylation of Styrene with Cyclopropyl Mal-
onoyl Peroxide 1
A potential mechanism for the transformation is out-
lined in Scheme 2. Reaction of alkene and peroxide 1 leads
to 6 which undergoes ring closure, forming dioxonium
species 7. Hydrolysis with the molecule of water necessary
to bring about reaction gives observed esters 2 and 3.
Interestingly, without water, the overall rate of reaction
is considerably reduced (see Supporting Information for
details). This suggested water could be playing a dual role
within the reaction, hydrolyzing intermediate 7 and acti-
vating peroxide 1, stabilizing a developing negative charge
on oxygen (i.e., 6).
Water has limited solubility in chloroform (mole frac-
tion 0.005),11 such that under the reaction conditions the
concentration of water in solution would be less than that
of the reagents. Reasoning that alternative H-bond donors
which were soluble in chloroform could activate peroxide
1, and stabilize intermediates 6 and 7, we examined the
effect of alcohols on the reaction rate. Adam has shown
di-n-butylmalonoyl peroxide reacts with methanol and
ethanol.12 We therefore considered that the less nucleophilic
fluorinated alcohols trifluoroethanol (TFE), hexafluoroi-
sopropanol (HFP), and perfluoro-tert-butyl alcohol (PFB)
might accelerate the reaction (Figure 1).
It is clear from Figure 1 that in the presence of a fluori-
nated alcohol (1.2 equiv) the rate of product formation
in chloroform is enhanced. Increasing the acidity of the
alcohol TFEfHFPfPFB13 increases the rate. These re-
sults are consistent with the alcohol acting as a H-bond
donor, activating peroxide 1.
Figure 1. Relative rates of product formation for the reaction
of 1 with styrene in the presence of fluorinated alcohols. All
reactions performed in CHCl3 [0.65 M] at 25 °C in the presence
of H2O (1.0 equiv) and fluorinated alcohol (1.2 equiv). ([) No
alcohol; (9) trifluoroethanol (TFE); (2) hexafluoroisopropanol
(HFP); (Â) perfluoro-tert-butyl alcohol (PFB).
In developing the reaction,10 a number of solvents were
examined with chloroform emerging as the most effective
with respect to rate and yield. We were unable to rationa-
lize this finding at the time. Based upon the results above
(Figure 1), it is possible that chloroform may also act as
a H-bond donor in a similar manner to the fluorinated
alcohols.14,15
(10) (a) Griffith, J. C.; Jones, K. M.; Picon, S.; Rawling, M. J.;
Kariuki, B. M.; Campbell, M.; Tomkinson, N. C. O. J. Am. Chem. Soc.
2010, 132, 14409. (b) Jones, K. M.; Tomkinson, N. C. O. J. Org. Chem.
2012, 77, 921.
(11) Donahue, D. J.; Bartell, F. E. J. Phys. Chem. 1952, 56, 480.
€
(12) Adam, W.; Rucktaschel, R. J. Org. Chem. 1972, 37, 4128.
(13) The pKa’s of these fluorinated alcohols in DMSO are: TFE 23.5;
HFP 17.9; PFB 10.7. See: (a) Bordwell, F. G. Acc. Chem. Res. 1988, 21,
456. (b) Taft, R. W. Acc. Chem. Res. 1988, 21, 463.
(14) Similar reaction rate profiles for “bench” chloroform and base
washed chloroform were observed; see Supporting Information for full
details.
Org. Lett., Vol. 14, No. 24, 2012
6251

In an effort to slow down the background reaction we
examined toluene as the reaction medium (Figure 2).
Consistent with the hypothesis that chloroform was acting
as a H-bond donor, the rate of reaction in toluene was
substantially reduced. It is also noteworthy that water
is less soluble in toluene (mole fraction 0.0025)11 when
compared to chloroform, which can also account for the
reduced rate. Importantly, theuseofPFB (Â; 1.2equiv) led
to a significantly enhanced rate of product formation.
Reducing the loading of PFB (2; 0.2 equiv) also showed
an improved reaction rate.
under anhydrous reaction conditions (2) as both the
peroxide 1 and water would compete to H-bond with the
fluorinated alcohol when water is present (b).
Figure 3. Effect on rate of water and PFB in toluene. All
reactions performed in PhMe [0.3 M] at 25 °C. ([) No water
and no PFB; (9) 1 equiv of water and no PFB; (b) 1 equiv of
water and 1 equiv of PFB; (2) no water and 1 equiv of PFB.
Table 1. Effect of Fluorinated Alcohols on Stereoselectivity in
the Reaction of 1 with β-Substituted Alkenesa
Figure 2. Acceleration of reaction of stilbene and 1 in the
presence of PFB. Average of two runs in PhMe [0.6 M] at
25 °C in the presence of H2O (1.0 equiv). ([) No alcohol; (Â) 1.2
equiv of PFB; (9) 1.0 equiv of PFB; (2) 0.2 equiv of PFB.
The potential existed for the fluorinated alcohol to
increase the solubility (and hence concentration) of water
in the reaction solvent, and it was this factor which was
responsible for rate enhancement. In order to examine this,
we monitored the consumption of peroxide in the presence
and absence of both water and PFB (Figure 3). Without
PFB present similar rates for peroxide consumption were
observed, in both the absence ([) and presence (9) of
water, suggesting that water has little effect on the rate in
toluene. In the presence of PFB and water (b) the rate of
peroxide consumption was significantly increased. This
rate increased further in the presence of PFB and absence
of water (2). If the origin of rate enhancement by PFB
addition was due to an increased concentration of water
in the reaction medium it would be expected that under
anhydrous reaction conditions (2) the rate of peroxide
consumption would be slower. This is not the case. It is
thought that the rate of peroxide consumption is greater
entry
alcohol
R1
R2
syn/antib
% yieldc
1
none
TFE
HFP
PFB
none
PFB
none
PFB
none
PFB
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Me
Me
13:1
17:1
17:1
19:1
31:1
49:1
4:1
78
84
81
85
76
79
77
78
74
74
2
3
4
5
6
7d
8d
9
4:1
4-BrC6H4
4-BrC6H4
10:1
15:1
10
a All reactions performed in PhMe [0.6 M] at 25 °C in the presence
of H2O (1.0 equiv) and fluorinated alcohol (1.2 equiv). b Determined
by 1H NMR spectroscopy of crude reaction mixture. c Isolated yield.
d cis-Stilbene used as substrate.
Finally, further evidence for the intimate involvement
of the H-bond donor within the transition state came
from examining the effect of fluorinated alcohols on the
(15) For a discussion of chloroform as a H-bond donor, see: Kwak,
K.; Rosenfeld, D. E.; Chung, J. K.; Fayer, M. D. J. Phys. Chem. B 2008,
112, 13906.
6252
Org. Lett., Vol. 14, No. 24, 2012

stereoselectivity of dihydroxylation (Table 1). In the ab-
sence of an alcohol additive, reaction of trans-β-methyl-
styrene was slow, providing the product in a respectable
78% yield and a syn/anti ratio of 13:1 (entry 1). Addition of
TFE, HFB, and PFB (1.2 equiv) consistently gave the
product in higher yield and a higher syn/anti ratio (entries
2À4). This observation also held true for the reaction of
trans-stilbene 10 (entries 5 and 6) and 4-bromo-β-methyl-
styrene (entries 9 and 10). With more challenging substrates
such as cis-stilbene (entries 7 and 8), reactions were faster but
levels of selectivity still did not reach those required by
contemporary standards. The precise origin of this remark-
able effect is not apparent. However, the ability to signifi-
cantly affect the stereoselectivity of the reaction by addition
of a fluorinated alcohol further increases the power of this
simple and effective dihydroxylation process.
fluorinated alcohols can significantly enhance the stereo-
selectivity of the reaction with 1,2-disubstituted alkenes.
This highly practical syn-dihydroxylation procedure, which
proceeds at room temperature in the presence of moisture
and air, provides a powerful and robust method to carry out
this important class of transformation. Current efforts focus
on the use of chiral H-bond donors to provide a catalytic
asymmetric protocol.
Acknowledgment. The authors thank the Leverhulme
Trust, EPSRC, and GlaxoSmithKline for financial support
and the Mass Spectrometry Service, Swansea for high-
resolution spectra.
Supporting Information Available. Analytical data,
experimental procedures, and NMR spectra for all com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
In summary, we have shown that fluorinated alcohols
accelerate the reaction between alkenes and cyclo-
propyl malonoyl peroxide providing a catalytic transition-
metal-free syn-dihydroxylation procedure. In addition,
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 24, 2012
6253