Transition Metal-Catalyzed Cyclopropanation of Alkenes in Water: Catalyst Efficiency and in Situ Generation of the Diazo Reagent

Article abstract of DOI:10.1021/ol0270879

(Matrix Presented) A cyclopropanation reaction involving ethyl diazoacetate and olefins proceeds with surprisingly high efficiency in aqueous media using| Rn(II) carboxylates. Nishiyama's Ru(II) Py box and Katsuki's Co(II) Salen complexes that allow for highly enantioselective cyclopropanations in organic solvents can also be applied to aqueous cyclopropanations with similar results. In situ generate of ethyl diazoacetate and cyclopropanation also proceeds efficiently. A chemoselective O-H insertion is also possible in water when hydrophobic catalysts and alcohols are used.

Full text of DOI:10.1021/ol0270879

ORGANIC
LETTERS
2002
Vol. 4, No. 25
4531-4533
Transition Metal-Catalyzed
Cyclopropanation of Alkenes in Water:
Catalyst Efficiency and in Situ
Generation of the Diazo Reagent
Ryan P. Wurz and Andre´ B. Charette*
De´partement de Chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
andre.charette@umontreal.ca
Received October 11, 2002
ABSTRACT
A cyclopropanation reaction involving ethyl diazoacetate and olefins proceeds with surprisingly high efficiency in aqueous media using Rh(II)
carboxylates. Nishiyama’s Ru(II) Py-box and Katsuki’s Co(II) Salen complexes that allow for highly enantioselective cyclopropanations in
organic solvents can also be applied to aqueous cyclopropanations with similar results. In situ generation of ethyl diazoacetate and
cyclopropanation also proceeds efficiently. A chemoselective O−H insertion is also possible in water when hydrophobic catalysts and alcohols
are used.
Over the years, our group has been interested in the
preparation of cyclopropanes because of their applications
in pharmaceuticals,1 presence in naturally occurring prod-
ucts,2 and use as synthetic intermediates.3 Transition-metal-
catalyzed cyclopropanation of alkenes with diazo compounds
represents a direct approach for their preparation. Although
diazo reagents have been sporadically used for the large-
scale preparation of cyclopropanes, the potential hazardous
nature of the sulfonyl azide precursor4 has led researchers
to find alternative methods for their manipulation.5
In an attempt to improve the viability of large-scale diazo-
mediated cyclopropanation reactions and make their use more
appealing, we turned to water as a reaction solvent due to
its low toxicity and inertness.6 Furthermore, we reasoned that
the use of hydrophobic catalysts and non-water-soluble
(4) For an excellent discussion on the hazardous properties of sulfonyl
azide reagents, see: Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds: From
Cyclopropanes to Ylides; Wiley: New York, 1998.
(5) (a) Aggarwal, V. K.; de Vicente, J.; Bonnert, R. V. Org. Lett. 2001,
3, 2785. (b) Aggarwal, V. K.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.;
Porcelloni, M. Angew. Chem., Int. Ed. 2001, 40, 1433. (c) For a recent
report on the large scale generation of ethyl diazoacetate and its direct use
in solution without isolation in neat form see: Scott, J. W. Organ. Chem.
(Abstr. Am. Chem. Soc. DiV. Org. Chem.) 2002, 186, 223.
(1) Biochemistry of the Cyclopropyl Group. In The Chemistry of the
Cyclopropyl Group, Patai, S., Rappoport, Z., Eds.; Wiley: New York 1987;
Chapter 16, p 959.
(2) Taber, D. F. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 3, p 1045.
(3) Carbocyclic Three- and Four-Membered Ring Compounds. In
Methods of Organic Chemistry (Houben-Weyl); de Meijere, A., Ed.;
Verlag: New York, 1997; Vols. E17a,b. Small Ring Compounds in Organic
Synthesis VI. In Topics in Current Chemistry; de Meijere, A., Ed.;
Springer: New York, 2000; Vol. 207.
(6) For recent reviews on carrying stereoselective transformations in
water, see: (a) Lindstro¨m, U. M. Chem. ReV. 2002, 102, 2751. (b) Grieco,
P. A., Ed. Organic Synthesis in Water; Blackie Academic & Professional:
London, 1998. (c) Li, C.-J.; Chan, T.-H. Organic Reactions in Aqueous
Media; John Wiley & Sons: New York, 1997. (d) Cornils, B.; Hermann,
W. A. Aqueous-Phase Organometallic Catalysis: Concepts and Applica-
tions; Wiley-VCH: New York, 1998.
10.1021/ol0270879 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/15/2002

alkenes would lead to small alkene/catalyst beads or micelles
in water. Since ethyl diazoacetate is quite soluble in water,
its concentration in the alkene beads would be relatively low
and the reagent should slowly diffuse into the alkene layer
as the reaction proceeds. This approach contrasts those using
catalysts bearing hydrophilic ligands to increase their water
solubilities.7 Generally, cyclopropanations employing diazo
substrates are performed under anhydrous conditions due to
the competing O-H insertion reaction affording 2 (eq 1).8
However, we believed that this pathway should be suppressed
if the reaction occurs in the alkene/catalyst beads.
Table 2. Reaction Scope of Cyclopropanationa
yield (%)
ratio trans/cis
(CH2Cl2)
entry
(CH2Cl2)
styrene (a )
a
61 (72)
72 (84)b
73 (77)
72 (75)
53 (55)
52 (57)c
49 (64)b
59 (64)
56 (61)b
1.5 (1.5)
1.5 (1.5)
1.5 (1.3)
1.1 (1.2)
2.2 (2.0)
1.5 (1.5)
1.5 (1.5)
1.5 (1.5)
1.0 (1.1)
4-Cl-styrene (b)
R-methylstyrene (c)
cyclohexa-1,4-diene (d )
2-vinylnaphthalene (e)
e
(E)-PhCHdCH2CHdCH2 (f)
f
To illustrate this idea, a number of Rh(II) carboxylate
catalysts were screened for their cyclopropanation activity
with styrene in water (see Table 1).
a Reaction conditions: a 0.18 M solution of 1 was added over 1 h to
[Rh(OPiv)2]2 and alkene and then stirred for an additional 2 h. b In this
case, [Rh(C7H15CO2)2]2 was used as the catalyst. c The alkene was dissolved
in 0.5 mL of toluene.
Table 1. Effect of Rh(II) Catalyst on Cyclopropanation Yieldsa
The results in Table 2 suggest that under the same addition
times of the diazo substrate, the aqueous-based cyclopropa-
nation proceeds with efficiency similar to that performed in
anhydrous CH2Cl2 (yields and ratios shown in parentheses
are for the reactions run in CH2Cl2). Additionally, the
diastereoselectivities of the products are nearly identical.
Solid substrates such as 2-vinylnaphthalene (4e) can also be
submitted to this cyclopropanation by using a small amount
of toluene, thereby creating a liquid organic phase.
The success of this cyclopropanation may possibly result
from the biphasic nature of the reaction. Hydrophobic
catalysts migrate into the alkene substrate leading to a high
effective concentration of alkene. Upon diffusion of 1 into
the organic phase, cyclopropanes are formed preferentially.
Jessop et al. have reported that the dielectric constant of
the solvent can have a negative effect on the enantioselec-
tivities of a cyclopropanation reaction with certain diazo
substrates.10 Thus, we became interested in determining
whether asymmetric cyclopropanations in aqueous media
were possible.5,11 Unfortunately, few intermolecular cyclo-
propanations with Rh(II) type catalysts are known to cyclo-
propanate with 1 in high diastereoselectivities and enanti-
oselectivities.12 This prompted us to try other known
cyclopropanation catalysts (Figure 1) for their compatibility
with water (see Table 3).
entry
catalyst
[Rh(OAc)2]2
yield 3 (%) ratio trans/cis
1
2
3
4
5
6
26
11
72
47b
61
58
1.6
1.0
1.5
1.4
1.5
1.5
[Rh(CF3CO2)2]2
Rh(C7H15CO2)2]2
Rh(C7H15CO2)2]2
[Rh(OPiv)2]2
[Rh(1-adamantylCO2)2]2
a Reaction conditions: a 0.18 M solution of 1 was added over 1 h to the
catalyst and alkene and then stirred for an additional 2 h. b 1 equiv of styrene
was used.
The yields of the desired cyclopropane were highly
dependent upon the nature of the carboxylate used. Low
yields were observed with water-soluble catalysts (entries 1
and 2), while higher yields were obtained with hydrophobic
catalysts (entries 3-6). The Rh(II) octanoate catalyst (Table
1, entry 3) was the most efficient with this substrate,9 even
affording a 47% yield of cyclopropane3 when only 1 equiv
of styrene was used (Table 1, entry 4).
To further examine the generality of this reaction, other
substrates were also tested (Table 2) with the two most
efficient catalysts. For comparison, the reactions were also
performed in CH2Cl2 using the same alkene equivalents and
catalyst loadings.
Ruthenium(II)based catalyst 5 reported by Nishiyama et
al. was also found to be effective in aqueous media, affording
highly diastereoselective and enantioselective formation of
cyclopropanes 4a-h, nearly identical to the reaction per-
(7) For a water-soluble Ru(II) catalyst, see: Iwasa, S.; Takezawa, F.;
Tuchiya, Y.; Nishiyama, H. Chem. Commun. 2001, 59.
(8) Paulissen, R.; Reimlinger, H.; Hayez, E.; Hubert, A. J.; Teyssie´, P.
Tetrahedron Lett. 1973, 14, 2233.
(9) The Rh(II) hexanoate catalyst shows slightly improved yields
compared to that of the pivalate when styrene is used as a substrate; see:
Anciaux, A. J.; Hubert, A. J.; Noels, A. F.; Petiniot, N.; Teyssie´, P. J. Org.
Chem. 1980, 45, 695.
(10) Wynne, D. C.; Olmstead, M. M.; Jessop, P. G. J. Am. Chem. Soc.
2000, 122, 7638.
(11) For Co(II) cat. cyclopropanations in 5% aqueous solvents, see:
Ikeno, T.; Nishizuka, A.; Sato, M.; Yamada, T. Synlett 2001, 406.
(12) (a) Doyle, M. P.; Davies, S. B.; Hu, W. Chem. Commun. 2000,
867. (b) Barberis, M.; Lahuerta, P.; Pe´rez-Prieto, J.; Sanau´, M. Chem.
Commun. 2001, 439.
4532
Org. Lett., Vol. 4, No. 25, 2002

Table 4. In Situ Generation of Ethyl Diazoacetatea
entry
styrene (equiv)
yield of 3b (%)
ratio trans/cis
1
2
3
4
3
2
2c
1
70
66
54
45
1.5:1
1.3:1
1.1:1
1.2:1
Figure 1. Catalysts for asymmetric cyclopropanation.
formed in CH2Cl2 (yields in parentheses).13 In the case of
the Co(II)-type catalysts 6 popularized by Katsuki,14 an
improvement in reaction yields was often observed in
aqueous media, although the reaction had to be performed
in argon-purged water.
a Reaction conditions: a 0.7 M solution of 7 and a 0.8 M solution of
NaNO2 were added to the catalyst and styrene at 0 °C. b Isolated yield of
chromatographically pure cyclopropane. c Reaction time: 5 h.
The reaction yields compare nicely with those reported in
Table 1, although slightly longer reaction times are required
for higher yields. The reaction has been successfully
performed on a 3 g scale and this method represents a cost
efficient source of ethyl diazoacetate without the disadvan-
tages of its handling and purification.
Table 3. Asymmetric Aqueous Cyclopropanationsa
Finally, a selective O-H insertion of a primary alcohol
in water can also be achieved if the combination of
hydrophobic catalyst and hydrophobic substrate is used (eq
2).
yield (%) of 4
ratio trans/cis
(in CH2Cl2)
ee (trans)
alkene
cat.
(in CH2Cl2)
(in CH2Cl2)
a
b
gb
h c
a
5
5
5
5
6d
6d,e
6d,e
46 (48)
31 (40)
42 (77)
44 (74)
61 (20)f
80 (62)f
60 (76)f
19:1 (24:1)
24:1 (24:1)
19:1 (19:1)
90 (86)
83 (89)
87 (85)
86 (83)
22 (nd)
47 (56)
47 (46)
2.0:1 (nd)
1.5:1 (1.5:1)
1.8:1 (1.3:1)
a
b
a A 0.18 M solution of 1 was added over 2 h to a mixture of 5 and the
alkene, and the reaction mixture was stirred for an additional 4 h, or a 0.18
M solution of 1 was added in one portion to a mixture of 6 and the alkene.
The mixture was stirred under argon for 24 h. b g: 4-methoxystyrene. c h:
1,1-diphenylethene. d 5 mol % of catalyst was used in argon-purged H2O.
e 10% N-methylimidazole was used as an additive. f The yield in parentheses
is for the reaction in THF.
Although the yield of 8 was a modest 45% based on 1,
when the corresponding reaction was performed with 2 equiv
of EtOH as a substrate (a more hydrophilic alcohol), only
trace amounts of the corresponding ethanol O-H insertion
product resulted.
In conclusion, we have shown that water is a suitable
solvent to use for the cyclopropanation of alkenes with
R-diazoester reagents. This novel procedure also allows the
in situ generation and reaction of the diazo compound without
the need to isolate the sensitive reagent.
To address the explosive nature of the 1, we believed in
situ diazo generation followed by cyclopropanation15 would
eliminate the necessity of handling the reagent. Treatment
of 7 with sodium nitrite affords 116 and is rapidly consumed
upon formation yielding the cyclopropane 3 (Table 4).
Acknowledgment. This work was supported by the
E.W.R. Steacie Fund, NSERC, Merck Frosst Canada, Boe-
hringer Ingelheim, and the Universite´ de Montre´al. R.W.
thanks NSERC for a postgraduate (PGS B) fellowship.
(13) Nishiyama, H.; Itoh, Y.; Matsumoto, H.; Park. S.-B.; Itoh, K. J.
Am. Chem. Soc. 1994, 116, 2223.
(14) Niimi, T.; Uchida, T.; Irie, R.; Katsuki, T. Tetrahedron Lett. 2000,
41, 3647.
(15) Compound 7 was treated with NaNO2 in 10:1 CH2Cl2/H2O, 10 equiv
of alkene, 0.5% TPPRhI, 4 days; see: Barrett, A. G. M.; Braddock, D. C.;
Lenoir, I.; Tone, H. J. Org. Chem. 2001, 66, 8260. It was also claimed that
Rh2(OAc)4 was not an effective catalyst under these conditions.
(16) Nomack, E. B.; Nelson, A. B. Org. Synth. 1964, C. V. 3, 392.
(17) A preferable method for generation of 1 involves using Na2B4O7‚
10H2O as a buffer and a 2% H3PO4 solution as the catalyst (see ref 5c).
The cyclopropanation proceeds with equal or better yields than those
reported in Table 4. See the Supporting Information for details.
Supporting Information Available: Spectral data for all
new compounds (1H NMR, 13C NMR, IR, HRMS) and SFC
traces for enantioselective cyclopropanations. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0270879
Org. Lett., Vol. 4, No. 25, 2002
4533