Catalytic cyclopropanation of alkenes using diazo compounds generated in situ. A novel route to 2-arylcyclopropylamines

Article abstract of DOI:10.1021/ol0164177

(Equation presented) A user-friendly, one-pot process for catalytic cyclopropanation of alkenes from tosylhydrazones is described. The cyclopropanation of N-vinylphthalimide provides a new route to 2-arylcyclopropylamines, and this is exemplified in the efficient synthesis of the HIV-1 reverse transcriptase inhibitor 6.

Full text of DOI:10.1021/ol0164177

ORGANIC
LETTERS
2001
Vol. 3, No. 17
2785-2788
Catalytic Cyclopropanation of Alkenes
Using Diazo Compounds Generated in
Situ. A Novel Route to
2-Arylcyclopropylamines
Varinder K. Aggarwal,* Javier de Vicente, and Roger V. Bonnert†
School of Chemistry, Bristol UniVersity, Cantock’s Close, Bristol BS8 1TS, U.K.
V.aggarwal@bristol.ac.uk
Received July 10, 2001
ABSTRACT
A user-friendly, one-pot process for catalytic cyclopropanation of alkenes from tosylhydrazones is described. The cyclopropanation of
N-vinylphthalimide provides a new route to 2-arylcyclopropylamines, and this is exemplified in the efficient synthesis of the HIV-1 reverse
transcriptase inhibitor 6.
Transition-metal-catalyzed cyclopropanation of alkenes using
diazo compounds is not only highly efficient but also,
through developments in chiral catalysts, control over relative
and absolute stereochemistry can now be achieved in many
cases.1 However, to date developments in cyclopropanation
have been restricted to diazo esters and R-substituted
analogues for two reasons: (i) diazo esters are more stable
(ethyl diazoacetate is commercially available) and therefore
easier to handle than aryl-, alkenyl-, or alkynyldi-
azomethanes, which are unstable and potentially explosive,2,3
and (ii) diazo esters are much less prone to metal-catalyzed
diazo dimerization than the above diazo compounds. In fact,
to achieve reasonable yields in cyclopropanation of alkenes
with phenyldiazomethane, slow addition of this substrate is
required (to minimize the concentration of PhCHN2, thereby
slowing the rate of path B, Scheme 1) together with a large
Scheme 1
† AstraZeneca R&D Charnwood, Medicinal Chemistry, Bakewell Road,
Loughborough, Leics LE11 5RH, U.K.
(1) For recent reviews, see: Doyle, M. P.; McKervey, M. A.; Ye, T.
Modern Catalytic Methods for Organic Synthesis with Diazo Compounds:
From Cyclopropanes to Ylides; Wiley-Interscience: New York, 1998. (b)
Do¨rwald, F. Z. Metal Carbenes in Organic Synthesis; Wiley-VCH: New
York, 1998. (c) Doyle, M. P. In ComprehensiVe Organometallic Chemistry
II; Hedegeus, L. S., Ed.; Pergamon Press: New York, 1995; Vol. 12;
Chapters 5.1 and 5.2. (d) Davies, H. M. L. Eur. J. Org. Chem. 1999, 2459.
(e) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911.
(2) Apart from diazomethane, diazoalkanes are not usually successful
in cyclopropanation, as the metal carbene readily undergoes 1,2-hydrogen
shifts to give alkenes: Doyle, M. P.; High, K. G.; Oon, H. S.-M.; Osborn,
A. K. Tetrahedron Lett. 1989, 30, 3049. See also ref 1a.
excess of the alkene (to maximize the rate of cyclopropa-
nation, path A); otherwise, stilbenes are the dominant
product.4
(3) Regitz, M.; Maas, G. Diazo Compounds: Properties and Synthesis;
Academic Press: London, 1996.
(4) Doyle, M. P.; Griffin, J. H.; Bagheri, V.; Dorow, R. L. Organome-
tallics 1984, 3, 53.
10.1021/ol0164177 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/03/2001

We recently reported a new method for generating aryl-
and alkenyl diazomethanes from stable hydrazone derivatives
and their use in catalytic epoxidation of carbonyl com-
pounds.5 As the diazo compounds were consumed as they
were formed, their concentration in the reaction was always
low and so there were no issues associated with handling or
building up of these unstable intermediates.3 Furthermore,
as the diazo compounds were generated essentially one
molecule at a time, their concentration in the reaction was
always low. We were therefore keen to examine whether
this new process could solve some of the traditional problems
inherent in cyclopropanation of electron-rich alkenes. In this
paper we report our success in achieving this goal and the
development of a new user-friendly, one-pot cyclopropana-
tion process in which the diazo compound is generated in
situ.
(entry 9). Interestingly, rhodium acetate gave predominantly
cis selectivity, while the iron porphyrin gave largely trans
selectivity.
As rhodium acetate and the iron porphyrin gave the two
highest yields and complementary selectivity (vide infra),
these two catalysts were tested with a range of alkenes (Table
2). Moderate to good yields were achieved with most of the
Table 2. Yields and Ratios of Cyclopropanes Formed from
Alkenes and Benzaldehyde Tosylhydrazone Sodium Salt Using
Rh2(OAc)4 and ClFeTPP
We began our studies with styrene, Rh2(OAc)4, and the
sodium salt of benzaldehyde tosylhydrazone and varied the
solvent, the amount of PTC, and the temperature. From these
studies we found that using either 1,4-dioxane and 10% PTC
at 30 °C (conditions A) or toluene and 5% PTC at 40 °C
(conditions B) gave the best results. We then screened a
series of metal catalysts under both sets of conditions (Table
1). Contrary to expectation, copper catalysts, which are
Table 1. Catalyst Influence in the in Situ Cyclopropanation
entry
catalysta
conditionsb yield (%)c trans:cisd
1
2
3
4
5
6
7
8
9
Cu(MeCN)4PF6
Cu(OTf)2
A
A
B
B
A
A
A
B
B
traces
13
87:13
67:33
63:37
71:29
PdCl2(PhCN)2
Pd2(dba)3‚CHCl3
Pd(PPh3)4
13
35
20
Rh2(cap)4
traces
48
Rh2(OAc)4
23:77
91:9
Rh2(pfb)4
traces
73
ClFeTPP
a Abbreviations: cap ) caprolactam, pfb ) perfluorobutyrate, TPP )
tetraphenylporphyrin. b All the catalysts were tested using conditions A (1,4-
dioxane, 10 mol % PTC, 30 °C) and B (toluene, 5 mol % PTC, 40 °C), but
only the best results are given in the table. c Isolated yields. d Determined
by GC.
a A 5-fold excess of alkenes was employed, except in entries 9-12, where
10 equiv was used. b Reactions with different catalysts were performed
according to the optimal conditions described in Table 1. c Isolated yields.
d Determined by GC.
commonly employed in cyclopropation,1 gave much poorer
results (entries 1 and 2) than palladium catalysts6 (entries
3-5). Rhodium acetate was superior to other rhodium salts
(entries 6-8), and the iron porphyrin gave the highest yield
alkenes tested,7 although, as expected, electron-rich alkenes
performed better than less electron rich substrates (compare
entries 3 and 4 with 9 and 10).8 Dienes were also suitable
substrates, and complete regioselectivity in favor of attack
at the terminal alkene was observed with 1-methoxybutadiene
(entries 13 and 14). Although N-vinylformamide gave poor
yields in cyclopropanation, N-vinylphthalimide performed
well and gave high cis selectivity with rhodium acetate (entry
15). This is the first example of the use of enamides in
(5) Aggarwal, V. K.; Alonso, E.; Hynd, G.; Lydon, K. M.; Palmer, M.
J.; Porcelloni, M.; Studley, J. R. Angew. Chem., Int. Ed. 2001, 40, 1430.
We have also used this procedure for aziridination of imines and cyclo-
propanation of electron-deficient alkenes: Aggarwal, V. K.; Alonso, E.;
Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew. Chem., Int. Ed.
2001, 40, 1433. In addition, this procedure has been utilized for homolo-
gation of aldehydes: Aggarwal, V. K.; de Vicente, J.; Pelotier, B.; Holmes,
I. H.; Bonnert, R. V. Tetrahedron Lett. 2000, 41, 10327.
2786
Org. Lett., Vol. 3, No. 17, 2001

cyclopropanation, and we were surprised to find that they
had not previously been employed, especially as there are a
number of biologically important cyclopropylamines (vide
infra).
Table 3. Yields and Ratios of Cyclopropanes Formed from
Different Hydrazones and N-Vinylphthalimide Using Rh2(OAc)4
and ClFeTPP
Using the Rh- and Fe-based catalyst, complementary
diastereoselectivity was observed in most cases.9 Only
alkenes bearing â-carbonyl groups showed cis selectivity
with both metals (entries 9, 10, 15, and 16). The observed
diastereoselectivity with rhodium1a,4,10 and iron11 is largely
in keeping with the literature. The iron porphyrin gives trans
selectivity because it is a less electrophilic carbene and so
has a later (more product-like) transition state.11,12 The
rhodium carbene, being more electrophilic, has an earlier
transition state and cyclopropanation is less synchronous.4,13
We have also found that the tosylhydrazone salt can be
generated in situ from the corresponding tosylhydrazone and
base, and in fact, improved yields were obtained (Table 3).
Several other diazo precursors were employed with N-
vinylphthalimide, showing the generality of the new proce-
dure.14
2-Arylcyclopropylamines and derivatives have received
considerable attention following the introduction of trans-
2-phenylcyclopropylamine for the treatment of depression
in 1961.15 They have also been found to be potent agonists
for the 5-hydroxytryptamine (5-HT) receptor,16 and more
recently urea derivatives of arylcyclopropylamines have
a Reactions with different catalysts were performed according to the
optimal conditions described in Table 1. b Isolated yields. c Determined by
GC.
emerged as a new class of highly effective HIV-1 reverse
transcriptase inhibitors.17 Arylcyclopropylamines are gener-
ally prepared from the corresponding ester using a three-
step sequence (Scheme 2):18 basic hydrolysis of the ester,
(6) Palladium(II) salts have been used extensively in the cyclopropanation
of electron-deficient alkenes with diazomethane: Denmark, S. E.; Stavenger,
R. A.; Faucher, A. M.; Edwards, J. P. J. Org. Chem. 1997, 62, 3375 and
references therein. They have also occasionally been employed in cyclo-
propanation of electron-rich alkenes with ethyl diazoacetate: Miller, K. J.;
Baag, J. H.; Abu-Omar, M. M. Inorg. Chem. 1999, 38, 4510 and references
therein. However, there are only sporadic examples of the use of Pd(0) in
cyclopropanation: Nakamura, A.; Koyama, T.; Otsuka, S. Bull. Chem. Soc.
Jpn. 1978, 51, 593. Anciaux, A. J.; Hubert, A. J.; Noels, A. F.; Petiniot,
N.; Teyssie´, P. J. Org. Chem. 1980, 45, 695.
Scheme 2
(7) It has been reported that 1,2-disubstituted alkenes are poor substrates
with iron porphyrin catalysts,10 hence the low yield with dihydropyran (entry
2).
(8) 1-Octene, cyclohexene, and 1-methyl-1-cyclohexene were poor
substrates. This is keeping with Doyle’s observations.4
(9) The assignment of the cis and trans isomers of the unknown
cyclopropanes synthesized was determined by 1H NMR on the basis of the
diamagnetic anisotropy effect in the chemical shift caused by the aryl group
(δcis > δtrans) and confirmed by the coupling constans (Jcis > Jtrans). The
relative stereochemistry of cis- and trans-2-isopropenyl-2-methyl-1-phen-
ylcyclopropane (entries 11 and 12, Table 2) was also confirmed by NOE
experiments.
(10) de Meijere, A.; Schulz, T.-J.; Kostikov, R. R.; Graupner, F.; Murr,
T.; Bielfeldt, T. Synthesis 1991, 547.
(11) Wolf, J. R.; Hamaker, C. G.; Djukic, J.-P.; Kodadek, T.; Woo, L.
K. J. Am. Chem. Soc. 1995, 117, 9194.
(12) In contrast to iron porphyrins, Hossain’s iron Lewis acid [(η5-
C5H5)Fe(CO)2THF] give largely cis cyclopropanes with PhCHN2: Seitz,
W. J.; Hossain, M. M. Tetrahedron Lett. 1994, 35, 7561. For a discussion
on the mechanism, see ref 1a.
Curtius rearrangement, and finally hydrolysis of the iso-
cyanate. The cyclopropyl ester is prepared by either metal-
catalyzed cyclopropanation of ethyl diazoacetate with styrene
or that of diazomethane with ethyl cinnamate (4 steps in
total). The former, more commonly used process is usually
moderately trans selective ((50:50)-(75:25)).1,19 Our pro-
(13) Similar diastereoselectivity was originally found by Casey using
an electrophilic tungsten phenylcarbene: Casey, C. P.; Polichnowski, S.
W.; Shusterman, A. J.; Jones, C. R. J. Am. Chem. Soc. 1979, 101, 7282.
(14) None of the reactions presented in Table 3 have been optimized.
(15) (a) Zirkle, C. L.; Kaiser, C.; Tedeschi, D. H.; Tedeschi, R. E.; Burger,
A. J. Med. Chem. 1962, 5, 1265. (b) Baldessarini, R. J. In The Pharma-
cological Basis of Therapeutics, 7th ed.; Gilman, A. G., Goodman, L. S.,
Rall, T. W., Murad, F., Eds.; Macmillan: New York, 1985; Chapter 19.
(16) (a) Arvidson, L.-E.; Johanson, A. M.; Hacksell, U.; Nilsson, J. L.-
G.; Svensson, K.; Hjorth, S.; Magnusson, T.; Carlsson, A.; Lindberg, P.;
Andersson, B.; Sanchez, D.; Wikstro¨m, H.; Sundell, S. J. Med. Chem. 1988,
31, 92. (b) Vallgårda, J.; Appelberg, U.; Arvidsson, L.-E.; Hjorth, S.;
Svensson, B. E.; Hacksell, U. J. Med. Chem. 1996, 39, 1485. (c) Appelberg,
U.; Mohell, N.; Hacksell, U. Bioorg. Med. Chem. Lett. 1996, 6, 415.
(17) (a) Sahlberg, C.; Nore´en, R.; Engelhardt, P.; Ho¨gberg, M.; Kan-
gasmetsa¨, J.; Vrang, L.; Zhang, H. Bioorg. Med. Chem. Lett. 1998, 8, 1511.
(b) Ho¨gberg, M.; Sahlberg, C.; Engelhardt, P.; Nore´en, R.; Kangasmetsa¨,
J.; Johansson, N. G.; O¨ berg, B.; Vrang, L.; Zhang, H.; Sahlberg, B.-L.;
Unge, T.; Lo¨vgren, S.; Fridborg, K.; Ba¨ckbro, K. J. Med. Chem. 1999, 42,
4150.
(18) Kaiser, C.; Weinstock, J. Org. Synth. 1971, 51, 48.
Org. Lett., Vol. 3, No. 17, 2001
2787

(Scheme 2). Furthermore, this process provides a route to
the less easily accessible cis isomer with high diastereo-
selectivity.
Scheme 3a
The process has been further exemplified in the efficient
synthesis of 6, which is one of the most active members of
the class of HIV-1 reverse transcriptase inhibitors17 (Scheme
3). Aldehyde 2 was prepared from the commercially available
phenol 1 in two steps and converted into the tosylhydrazone
3. Deprotonation with LiHMDS and treatment with N-
vinylphthalimide, PTC, and rhodium acetate20 gave the
cyclopropane 4 in 76% yield and as an 85:15 mixture in
favor of the required cis isomer. We were pleased to note
that even though a hindered 2,3,6-trisubstituted arylhydrazone
was employed, high yield and high cis selectiVity was still
achieVed. Following hydrazinolysis, the amine was coupled
with 2-amino-5-cyanopyridine in the presence of triphosgene
to give the urea 6. This compound was spectroscopically
identical with that reported.17b Our overall yield (18%) is
markedly higher than that reported (0.7%).
In summary, we have developed a highly practical one-
pot process for catalytic cyclopropanation of alkenes by in
situ generation of the diazo compound. Furthermore, we have
designed the simplest route to access cis-arylcyclopropyl-
amines by a unique cyclopropanation of an enamide. This
strategy was successfully employed as the key step in the
synthesis of HIV-1 reverse transcriptase inhibitor 6 in 18%
overall yield.
a Reaction conditions: (a) ethyl iodide, acetone, K2CO3, 55 °C,
100%; (b) n-BuLi, THF, -65 °C, followed by DMF, THF -65 °C
to room temperature, 87%; (c) TsNHNH2, MeOH, room temper-
ature, 72%; (d) LiHMDS, THF, -78 °C to room temperature, then
N-vinylphthalimide, Rh2(OAc)4, 10% PTC, 1,4-dioxane, room
temperature, trans:cis 15:85, 76%; (e) H2NNH2‚H2O, EtOH, 40 °C,
then 1 M HCl, EtOH, 78%; (f) 2-amino-5-cyanopyridine, triphos-
gene, THF, -78 °C to room temperature, 56%.
posed route involves two simple steps: cyclopropanation
using a diazo compound generated in situ followed by
hydrazinolysis, and both steps have proved to be efficient
Acknowledgment. We gratefully thank AstraZeneca for
support of a studentship (J.d.V.).
(19) During the course of this work, Pe´rez described a cis selective
cyclopropanation of styrene with ethyl diazoacetate using a copper(I) tris-
(pyrazoyl)borate species: D´ıaz-Requejo, M. M.; Beldera´ın, T. R.; Trofi-
menko, S.; Pe´rez, P. J. J. Am. Chem. Soc. 2001, 123, 3167.
(20) Commercially available chiral Rh2(S-DOSP)4 catalyst only gave low
enantioselectivity.
Supporting Information Available: Experimental details
and characterization data for the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0164177
2788
Org. Lett., Vol. 3, No. 17, 2001