Enantioselective synthesis of trifluoromethyl-substituted cyclopropanes

Article abstract of DOI:10.1021/ol070714f

Equation Presented The reaction of 1-aryl-2,2,2-trifluorodiazoethanes with alkenes, catalyzed by the adamantylglycine-derived dirhodium complex Rh ₂(R-PTAD)₄, generates trifluoromethyl-substituted cyclopropanes with high diastereosel

Full text of DOI:10.1021/ol070714f

ORGANIC
LETTERS
2
007
Vol. 9, No. 14
625-2628
Enantioselective Synthesis of
Trifluoromethyl-Substituted
Cyclopropanes
2
Justin R. Denton, Dinesh Sukumaran, and Huw M. L. Davies*
Department of Chemistry, UniVersity at Buffalo, The State UniVersity of New York,
Buffalo, New York 14260-3000
hdaVies@acsu.buffalo.edu
Received March 23, 2007
ABSTRACT
The reaction of 1-aryl-2,2,2-trifluorodiazoethanes with alkenes, catalyzed by the adamantylglycine-derived dirhodium complex Rh
2 4
(R-PTAD) ,
generates trifluoromethyl-substituted cyclopropanes with high diastereoselectivity (>94%) and enantioselectivity (88 >98%).
−
The presence of fluorine functionality in organic compounds
can have profound effects on their physical and chemical
The development of enantioselective transformations with
these trifluoromethyl reagents is an attractive challenge. So
far, enantioselective reactions have been limited to two
systems. The rhodium(II)-catalyzed cyclopropanations con-
ducted with ethyl 3,3,3-trifluoro-2-diazopropionate (1) gener-
ated cyclopropanes 2 in moderate yields (24-72%), di-
astereoselectivity (0-30% de), and enantioselectivity (0-
1
properties. Fluorinated derivatives of pharmaceutical agents
2
3
can modulate pharmacokinetic, electronic, lipophilic, and
4
steric properties. These effects can ultimately lead to
improved efficacy of the therapeutic agent. Consequently,
5
there is considerable interest in developing new methods for
the selective introduction of fluorinated groups into organic
compounds.
6
a
50% ee) (Scheme 1). The generally poor results were
2,2,2-Trifluorodiazoethanes have recently been recognized
as attractive reagents for introduction of a trifluoromethyl
group. On metal-catalyzed extrusion of nitrogen, the resulting
metal carbenoid has been shown to be effective at cyclo-
Scheme 1
6
7
8
propanation, ylide generation, and X-H insertion.
(1) (a) Hiyama, T. Organofluorine Compounds. Chemistry and Applica-
tions; Springer: New York, 2000. (b) O’Hagan, D.; Harper, D. B. J.
Fluorine Chem. 1999, 100, 127.
(
2) (a) Chambers, R. D. Fluorine in Organic Chemistry; Blackwell: Boca
Raton, Fl, 2004. (b) Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2005,
4, 214.
4
(
(
3) Smart, B. E. J. Fluorine Chem. 2001, 109, 3.
4) Park, B. K.; Kitteringham, N. R.; O’Niel, P. M. Ann. ReV. Pharmacol.
Toxicol. 2001, 41, 443.
(
5) Ismail, F. J. Fluorine Chem. 2002, 118, 27.
(6) (a) M u¨ ller, P.; Grass, S.; Shahi, S. P.; Bernardinelli, G. Tetrahedron
2
2
2
004, 60, 4755. (b) Le Maux, P.; Juillard, S.; Simonneaux, G. Synthesis
006, 10, 1701. (c) Wang, Y.; Zhu, S.; Zhu, G.; Huang, Q. Tetrahedron
001, 57, 7337.
ascribed to the fact that the rhodium carbenoid would be
highly electrophilic due to the presence of two electron-
1
0.1021/ol070714f CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/07/2007

withdrawing substituents. Somewhat better results were
obtained with iron and ruthenium porphyrin catalyzed
cyclopropanations of 2,2,2-trifluorodiazoethane (3). The
cyclopropanes 4 were formed with high diastereoselectivity
compound was prepared from the corresponding tosylhy-
drazone in about 40% yield, but due to its high volatility, it
was difficult to remove all traces of solvent from 9. The
effect of different catalysts (2 mol %) was explored in a
standard reaction between 9 and styrene (5 equiv) to generate
the trifluoromethyl-substituted cyclopropane 10a (Table 1).
(
up to 98% de) and moderate enantioselectivity (17-75%
6b
ee). The asymmetric induction is still inferior to the
reactions of the more traditional carbenoid source, ethyl
diazoacetate.9
In recent years, considerable attention has been directed
toward the chemistry of donor/acceptor-substituted rhodium
carbenoids (5) (Figure 1). These carbenoids are more stable
Table 1. Catalyst Optimization Studies
10
Rh(II) catalyst
solvent
de (%)a
ee (%)b
yield (%)c
d
Rh2(S-DOSP)4
Rh2(S-DOSP)4
Rh2(S-PTTL)4
Rh2(S-PTTL)4
Rh2(S-PTAD)4
hexanes
TFT
TFT
DCM
TFT
94
90
>94
>94
>94
40
37
97
86
>98
80
60
95
96
94
d
a
de determined by 1H NMR of crude material. b ee determined by a
chiral HPLC OJ column. c Estimated isolated yields of 10a after purification
by column chromatography because 9 was contaminated with traces of
1
d
pentane (<5% by H NMR). Opposite enantiomer preferentially formed.
TFT ) R,R,R-trifluorotoluene.
2
Rh (S-DOSP)
4
was not especially effective in this reaction
(
60% yield, 90% de, 37% ee), but much better results were
14
achieved with Hashimoto’s catalyst Rh
2
(S-PTTL)
4
(95%
(S-
gave even better results (94% yield, >94% de,
Figure 1. Carbenoid and catalyst structures.
yield, >94% de, 97% ee). The adamantyl derivative Rh
PTAD)
98% ee). As previously noted, Rh
S-PTAD) result in opposite asymmetric induction. Lower-
2
4
1
2
>
(
2 4 2
(S-DOSP) and Rh -
than the conventional carbenoids, lacking a donor group, and
4
are capable of a range of highly selective reactions. Rh
2
(S-
ing the rhodium(II) catalyst loading to 1 mol % had a
negative effect on the yield and enantioselectivity (39% yield,
DOSP) is ideally suited for the reactions of diazo esters 6,
4
and high enantioselectivity is routinely achieved in substrates
with a range of aryl and vinyl functionality as the electron-
donating group.11 In contrast, the nature of the electron-
withdrawing group dramatically influences the effectiveness
7
4% ee).
2
of the chiral catalyst. With the diazophosphonates 7, Rh -
Table 2. Optimization of a Two-Step Sequence
12
4
(S-PTAD) is the most effective catalyst. In this paper, we
describe exploratory studies on the cyclopropanation chem-
istry of the trifluoromethyl derivatives 8.
The initial screen of the influence of the trifluoromethyl
group on the reactions of donor/acceptor carbenoids was
13
conducted on 1-phenyl-2,2,2-trifluorodiazoethane (9). This
(7) (a) Jiang, B.; Zhang, X.; Luo, Z. Org. Lett. 2002, 4, 2453. (b) Zhu,
S.; Zhu, S.; Liao, Y. J. Fluorine Chem. 2004, 125, 1071. (c) Zhu, S.; Xing,
C.; Zhu, S. Tetrahedron 2006, 62, 829. (d) Titanyuk, I. D.; Vorob’eva, D.
V.; Osipov, S. N.; Beletskaya, I. P. Synlett 2006, 1355.
(
8) (a) Kale, T. A.; Distefano, M. D. Org. Lett. 2003, 5, 609. (b) Brunner,
J.; Senn, H.; Richards, F. M. J. Biol. Chem. 1980, 255, 3313.
9) (a) Lou, Y.; Remarchuk, T. P.; Corey, E. J. J. Am. Chem. Soc. 2005,
27, 14223.
10) (a) Davies, H. M. L.; Antoulinakis, E. G. Org. React. 2001, 57, 1.
(
1
(
(
b) Davies, H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103, 2861. (c)
Davies, H. M. L.; Lee, G. H. Org. Lett. 2004, 6, 2117. (d) Davies, H. M.
L.; Dai, X.; Long, M. S. J. Am. Chem. Soc. 2006, 128, 2485.
(
11) Davies, H. M. L. Eur. J. Org. Chem. 1999, 9, 2459.
(12) Reddy, R. P.; Lee, G. H.; Davies, H. M. L. Org. Lett. 2006, 8,
3
437.
13) (a) Shepard, R. A.; Wentworth, S. E. J. Org. Chem. 1967, 32, 3197.
b) Shi, G.; Xu, Y. J. Fluorine Chem. 1989, 44, 161. (c) Shi, G.; Xu, Y. J.
Fluorine Chem. 1990, 46, 173.
a
1
b
(
de determined by H NMR of crude material. Isolated yields after
column chromatography purification. c N′N′N′N′-Tetramethylguanidine.
(
2626
Org. Lett., Vol. 9, No. 14, 2007

Further optimization studies were then conducted using a
two-step sequence, to avoid isolation of the diazo compound
The reaction could be extended to a range of trifluoro-
methyl hydrazones (Table 4). The hydrazones 13a-c were
1
5
9
.
A summary of the key results is given in Table 2.
13a
Reaction of the tosylhydrazone 11 with NaH generated
the diazo compound 9 in situ, which was then exposed to
the cyclopropanation conditions to give 10a in 45-50%
combined yield and >94% de. Oxidation of the hydrazone
16
12 was an alternative process, and when this was conducted
17
with MnO
2
in trifluorotoluene (TFT) followed by a 3 h
syringe pump addition of the resulting orange filtrate to Rh
OAc) and styrene, 10a was isolated in an overall 73% yield
and >94% de.
The two-step process is effective with a range of styrene
derivatives (Table 3). In the Rh (R-PTAD) -catalyzed reac-
2
-
(
4
2
4
Table 3. Cyclopropanation of Various Styrenes with 12
19
1
Figure 2. F{ H} HOESY spectra of 14b.
product temp (°C)
R
de (%)a ee (%)b yield (%)c
1
1
1
1
1
1
0a
0b
0c
0d
0e
0f
rt
C
6
H
5
>94
>94
>94
>94
>94
>94
>94
-
>98
90
71
72
76
64
61
75
72
20
rt
p-MeC
6
H
6
4
H
formed easily from the corresponding trifluoromethyl ketones
by condensation of hydrazine in ethanol with a catalytic
amount of acetic acid. The two-step process (oxidation/
cyclopropanation) was then performed on 13a-c to form
the cyclopropanes 14a-c in 71-78% yield, >94% de and
rt
p-MeOC
p-ClC
p-CF
2-naphthyl
2-naphthyl
n-octyl
4
88
rt
6
H
6
4
H
90
d
rt
3
C
4
>94
89
rt
0
90
-
e
1
0g
reflux
a
de determined by 1H NMR of crude material. ee determined by a
b
9
7->98% ee. The data show that electron-withdrawing
c
chiral HPLC OJ column. Isolated yield after column chromatography
purification. Due to the broad nature of the peaks, the signal for the minor
enantiomer was not observed. Reaction was conducted with the achiral
catalyst Rh2(OAc)4.
d
substituents on the phenyl ring increase the yield of the
cyclopropane but slightly lower the enantioselectivity.
e
Table 5. Rh
2
4
(R-PTAD) -Catalyzed Cyclopropanation by 13c
tions of 12, the cyclopropanes 10a-f were formed in 61-
76% yield, >94% de, and 88->98% ee. The reaction was
Table 4. Cyclopropanation of Styrene with 13a-c
product
R1
R2
yield (%)a
de (%)b
ee (%)c
1
1
1
5a
5b
5c
p-BrC6H4
p-NO2C6H4
2-naphthyl
Ph
H
H
H
Ph
78
75
80
75
>94
>94
>94
-
>98
>98
98
1
3
14
yield (%)
a
a
de (%)b
ee (%)c
compd
R
yield (%)
15d
>98
a
b
c
p-MeC
6
H
H
4
4
91
90
91
75
78
77
>94
>94
>94
>98
97
98
a
b
Isolated yields after column chromatography purification.
de
p-FC
6
1
c
determined by H NMR of crude material. ee determined by a chiral HPLC
OJ column.
d
p-BrC
6
H
4
a
b
Isolated yields after column chromatography purification. de deter-
1
c
mined by H NMR of crude material. ee determined by a chiral HPLC
OJ column. Slight impurities were seen in H NMR of isolated material.
d
1
A 19F{ H} HOESY NMR experiment on cyclopropane
1
18
14b was performed to determine its relative stereochemistry
2 4
far less effective with unactivated olefins as the Rh (OAc) -
(15) Diazo compounds should always be handled with care. In this case,
catalyzed cyclopropanation of 1-decene (5 equiv) went in
only 20% yield, even under refluxing conditions.
we did not observe any instability problems with 9, but it was difficult to
obtain in a pure form because it was relatively volatile.
(16) (a) Walker, J. W.; Reid, G. P.; McCray, J. A.; Trentham, D. R. J.
Am. Chem. Soc. 1988, 110, 7170. (b) Holton, T. L.; Shechter, H. J. Org.
Chem. 1995, 60, 4725.
(17) Nagai, W.; Hirata, Y. J. Org. Chem. 1989, 54, 635.
(
14) Watanabe, N.; Ogawa, T.; Ohtake, Y.; Ikegami, S.; Hashimoto, S.-
I. Synlett 1996, 85.
Org. Lett., Vol. 9, No. 14, 2007
2627

illustrate the potential of this chemistry as the cyclopropanes
1
5a-d were obtained in 98% ee and above.
Scheme 2
After considerable experimentation, a crystalline product
was obtained by reduction of the enantiomerically pure
nitrocyclopropane 15b with SnCl to the aniline, followed
2
by N-acylation to form 16 (Scheme 2). X-ray crystallographic
analysis of crystals of 16 revealed that the absolute config-
uration was (1R,2S). All other trifluoromethyl-substituted
cyclopropanes were tentatively assigned the same relative
and absolute configuration by analogy.
2 4
In conclusion, Rh (R-PTAD) has shown to be an effective
chiral catalyst in the decomposition of 1-phenyl-2,2,2-
trifluorodiazoethane and its derivatives to form chiral trif-
luoromethyl-substituted cyclopropanes with very high enan-
tioselectivity. These studies further broaden the range of
donor/acceptor-substituted rhodium carbenoids that are ca-
pable of highly stereoselective transformations.
(
Figure 2). The spectrum shows direct correlations of the
trifluoromethyl group at -69.8 ppm with two cyclopropane
protons at 2.84 and 1.88 ppm. No correlation was observed
for the cyclopropane proton at 1.65 ppm. It was concluded
that the relative stereochemistry of 14b was the expected
(Z)-diarylcyclopropane. Thus, as is typical for donor/acceptor
carbenoids, the major cyclopropane formed has the donor
group cis to the alkene substituent.
Acknowledgment. Financial support of this work by the
National Science Foundation (CHE-0350536) is gratefully
acknowledged. We thank Dr. Mateusz Pitak, University at
Buffalo, for the X-ray analysis.
To verify the absolute configuration of the cyclopropane,
the bromophenyl hydrazone 13c was reacted with a variety
of alkenes with the goal of generating a crystalline product
suitable for X-ray analysis (Table 5). None of the products
gave suitable crystalline material, but these efforts further
Supporting Information Available: Experimental data
for the reported reactions and a CIF file for the X-ray
crystallographic data for 16. This material is available free
of charge via the Internet at http://pubs.acs.org.
(18) (a) Bellachioma, G.; Cardaci, G.; D’Onofrio, F.; Macchioni, A.;
Sabatini, S.; Zuccaccia, C. Eur. J. Inorg. Chem. 2001, 1605. (b) Hughes,
R. P.; Zhang, D.; Ward, A. J.; Zakharov, L. N.; Rheingold, A. L. J. Am.
Chem. Soc. 2004, 126, 6169.
OL070714F
2628
Org. Lett., Vol. 9, No. 14, 2007