Enantioselective palladium-catalyzed carbozincation of cyclopropenes

Article abstract of DOI:10.1021/ol1029904

A highly enantioselective palladium-catalyzed carbozincation of cyclopropenes has been developed. The intermediate cyclopropylzinc species, after transmetalation with copper, were trapped with various electrophiles. This one-pot procedure furnished functionalizied cyclopropenes with excellent diastereo-and enantioselectivity.

Full text of DOI:10.1021/ol1029904

ORGANIC
LETTERS
2011
Vol. 13, No. 4
819–821
Enantioselective Palladium-Catalyzed
Carbozincation of Cyclopropenes
€
Katja Kramer, Paul Leong, and Mark Lautens*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario
M5S 3H6, Canada
mlautens@chem.utoronto.ca
Received December 9, 2010
ABSTRACT
A highly enantioselective palladium-catalyzed carbozincation of cyclopropenes has been developed. The intermediate cyclopropylzinc species,
after transmetalation with copper, were trapped with various electrophiles. This one-pot procedure furnished functionalizied cyclopropenes with
excellent diastereo- and enantioselectivity.
Functionalized cyclopropanes are highly attractive tar-
gets in organic synthesis because they are structural com-
ponents of many biologically relevant materials.1,2 Asym-
metric transition-metal catalyzed additions to the double
bond of cyclopropenes are powerful reactions for the
construction of such cyclopropanes since desymmetriza-
tion leads to multiple stereocenters in one step. In the past
few years, several new catalytic asymmetric addition reac-
tions to cyclopropenes have been developed.3
tion reactions such as hydroboration,4 -stannation,5,6 -silyla-
tion, and -germylation.6 More recently rhodium-cata-
lyzed hydroformylation7 and hydroacylation8 reactions of
cyclopropenes were described. Palladium-catalyzed addi-
tions to cyclopropenes such as hydrophosphorination,
hydrophosphinylation9 and the addition of alkynes have
appeared.10 Carbometalation, on the other hand, offers the
possibility to directly functionalize two carbon atoms in a
single pot. In 2000 Nakamura has shown an enantioselective
iron-catalyzed system for the addition of diorganozinc
reagents to cyclopropenone ketals.11 Later Fox reported
a directed carbomagnesation of hydroxymethylcyclo-
propenes in the presence of copper catalysts.12 Marek
In the early 2000s, Gevorgyan reported on highly stereo-
and regioselective transition-metal catalyzed hydrometala-
(1) Fox, J. M.; Yan, N. Curr. Org. Chem. 2005, 9, 719.
(2) (a) Pietruszka, J. Chem. Rev. 2003, 103, 1051. (b) Wessjohann,
€
L. A.; Brandt, W. Chem. Rev. 2003, 103, 1625. (c) Salaun, J. Top. Curr.
(6) Trofimov, A.; Rubina, M.; Gevorgyan, V. J. Org. Chem. 2007, 72,
8910.
(7) Sherrill, W. M.; Rubin, M. J. Am. Chem. Soc. 2008, 130, 13804.
(8) Phan, D. H. T.; Kou, K. G. M.; Dong, V. M. J. Am. Chem. Soc.
2010, 132, 16354.
(9) Alnasleh, B. K.; Sherrill, W. M; Rubin, M. Org. Lett. 2008, 10,
3231.
(10) Yin, J.; Chisholm, J. D. Chem. Commun. 2006, 632.
(11) (a) Nakamura, E.; Yoshikai, N. J. Org. Chem. 2010, 75, 6061.
(b) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 2000,
122, 978.
Chem. 2000, 207, 1. (d) Liu, H.; Walsh, C. T. Biochemistry of the
Cyclopropyl Group. In The Chemistry of the Cyclopropyl Group; Patai,
S., Rappaport, Z., Eds.; Wiley: Chichester, 1987; p 959.
(3) Recent reviews of cyclopropene chemistry: (a) Marek, I.; Simaan,
S.; Masarwa, A. Angew. Chem., Int. Ed. 2007, 46, 7364. (b) Rubin, M.;
Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107, 3117. (c) Rubin, M.;
Rubina, M.; Gevorgyan, V. Synthesis 2006, 1221. (d) Fox, J. M.; Yan, N.
Curr. Org. Chem. 2005, 9, 719. (e) Nakamura, M.; Isobe, H.; Nakamura,
E. Chem. Rev. 2003, 103, 1295.
(4) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2003,
125, 7198.
(5) (a) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc.
2004, 126, 3688. (b) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am.
Chem. Soc. 2002, 124, 11566.
(12) (a) Liao, L.; Fox, J. M. J. Am. Chem. Soc. 2002, 124, 14322.
(b) Liu, X.; Fox, J. M. J. Am. Chem. Soc. 2006, 128, 5600. (c) Yan, N.;
Liu, X.; Fox, J. M. J. Org. Chem. 2008, 73, 563.
r
10.1021/ol1029904
2011 American Chemical Society
Published on Web 01/20/2011

trapping of the cyclopropylzinc intermediate with acid
gave promising results, and with Tol-BINAP, cyclopro-
pane 5a could be obtained with 91% ee (Table 1).
Table 1. Enantioselective Pd-Catalyzed Carbozincation
The use of unsymmetrical substituted cyclopropenes in
the palladium-catalyzed carbozincation yielded the prod-
ucts with moderate enantioselectivity.16,18 Therefore we
focused our investigations toward broadening the sub-
strate scope on further symmetrical substituted cyclopro-
penes (Table 1). The carbozincation protocol was applied
to cyclopropenes 2a-d bearing different protecting groups
providing the cyclopropanes 6a-d with low to moderate
enantioselectivities. The comparison showed that with the
Bz group the product with the highest enantioselectivity
was obtained, albeit in a moderate yield. Next, we sub-
jected cyclopropene 3 to a carbozincation. Cyclopropane 7
a Isolated yields. b Not determined.
Table 2. Investigation of Trapping Reactions
demonstrated a copper-catalyzed carbomagnesation reac-
tion of chiral cyclopropenylcarbinol derivatives.13 Recently
a copper-catalyzed facially selective carbozincation of
cyclopropenes was reported.14 Noteworthy in this connec-
tionare as well the dimetalation reactionsofcyclopropenes
described by Gevorgyan.5b,6 However, there are few asym-
metric carbozincation reactions.11,14 Herein, we report an
efficient approach to highly functionalized cyclopropanes
by enantio- and diastereoselective palladium-catalyzed
carbozincation of cyclopropenes and stereospecific trans-
formation of the cyclopropylzinc intermediates.
Stimulated by our longstanding interest in the addition
of organometallic reagents to strained alkenes,15,16 we
initiated our studies with 3,3-disubstituted cyclopropene
1 and ZnEt2 in CH2Cl2 in the presence of Pd(dppb)Cl2.17
Under these reaction conditions, the carbometalation was
found to proceed at low temperature. The choice of solvent
proved to be crucial. While the reaction occurred in
CH2Cl2 with cosolvents such as diethyl ether or pentane,
the use of more coordinating solvents such as THF or
NMP inhibited catalysis.18 We noticed variability in our
reactions, but the addition of Zn(OTf)2 solved this prob-
lem. The zinc salt seems to increase the reaction rate of the
carbometalation step. This finding suggests the formation
of a more reactive cationic palladium(II) species.15a,c Ex-
ploring an asymmetric variant, ligand-screening18 under
palladium-catalyzed reaction conditions, and subsequent
(13) Simaan, S.; Masarwa, A.; Zahor, E.; Stanger, A.; Bertus, P.;
Marek, I. Chem.;Eur. J. 2009, 15, 8449.
(14) Tarwade, V.; Liu, X.; Yan, N.; Fox, J. M. J. Am. Chem. Soc.
2009, 131, 5382.
(15) Selected examples for oxabicycles: For alkylzinc compounds,
see: (a) Lautens, M.; Hiebert, S. J. Am. Chem. Soc. 2004, 126, 1437. (b)
Lautens, M.; Hiebert, S.; Renaud, J.-L. J. Am. Chem. Soc. 2001, 123,
6834. (c) Lautens, M.; Hiebert, S.; Renaud, J.-L. Org. Lett. 2000, 2, 1971.
(d) Lautens, M.; Renaud, J.-L.; Hiebert, S. J. Am. Chem. Soc. 2000, 122,
1804. For review, see:(e) Lautens, M.; Fagnou, K.; Hiebert, S. Acc.
Chem. Res. 2003, 36, 48.
(16) For cyclopropenes, see: Hierbert, S. PhD Thesis, Toronto 2003,
184.
(17) The use of Pd(PPh3)4 afforded only starting material.
(18) Leong, P. PhD Thesis, Toronto 2007, 196 and Supporting
Information.
a Isolated yields. b Cis/trans. c No transmetalation to copper. d Pd((S)-
Tol-BINAP))Cl2 was used. e Ratio of branched:linear product = 86:14.
f Mixture of diastereomers at the exo position, dr (3,10) = 85:15, relative
configuration not assigned.
820
Org. Lett., Vol. 13, No. 4, 2011

was obtained only with 20% yield due to rearrangement of 3.
The reaction with cyclopropene 4 did not provide the
desired product. However, the best results were observed
with cyclopropene 1.
Encouraged by the results with cyclopropene 1, we
investigated other trapping reactions of the cyclopropyl-
zinc intermediates (Table 2). Reaction with iodine yielded
the desired product 5b as a single diastereomer with an
enantioselectivity of 90%. An excess of nucleophile was
used to quench unreacted diethylzinc. For the capture with
X-ray analysis of compound 5g confirmed the stereochem-
istry of the substituents (Figure 1).20
After exploring the scope of the electrophilic capture, we
investigated the ability to modify the products selectively.
Reduction of ketone 5d with sodium borohydride afforded
alcohol 9, which is the formal adduct of the addition of the
cyclopropyl metal intermediate to propionaldehyde, as a
single diastereomer (Scheme 1, eq 1). Ozonolysis of com-
pound 5i and reductive workup afforded 10 in 61% yield
(eq 2).
carbon electrophiles, transmetalation with CuCN 2LiCl
3
was necessary and a range of electrophiles could be success-
fully19 reacted with the corresponding copper derivative,
providing the products in high yields and with excellent
diastereo- and enantioselectivities ranging from 90 to 93%.
Scheme 1. Derivatization of 5d and 5i
a Dr (3,10), mixture of diastereomers at the exo position, relative
configuration not assigned; dr (2,3-cis,trans) > 95:5
In summary, a novel enantio- and diastereoselective
palladium-catalyzed protocol for the carbozincation of
cyclopropenes has been developed, and the intermediate
cyclopropylzinc species were successfully trapped with a
range of electrophiles. For the capture with carbon elec-
trophiles, a transmetalation to copper was found to be
necessary. Further investigations to expand the scope of
the reaction are currently underway.
Figure 1. X-ray structure of 5g.
Reaction with benzoyl chloride and propionyl chloride in a
one-pot procedure provided 5c and 5d, respectively. Treat-
ment with 2-bromo-1-phenylacetylene furnished the alkyny-
lated product 5e in 81% yield. Capture with 1-bromo-2-
pentyne led to allene 5f from an SN20 pathway, which is
known for organocopper reagents prepared from organozinc
species. Finally, the copper intermediate could be smoothly
allylated with allyl bromide, ethyl 2-(bromomethyl)acrylate,
and cinnamyl bromide. In the latter case we observed an
86:14 mixture of branched and linear products. Single crystal
Acknowledgment. This work is supported by NSERC
(Canada), Merck Frosst (IRC), and the University of
Toronto. K.K. thanks the Deutsche Forschungs-
gemeinschaft (DFG) for a postdoctoral fellowship. We
acknowledge Dr. Sheldon Hiebert (University of Toronto)
for preliminary experiments, Dr. Mathieu Blanchot
(University of Toronto) and Dr. Alistair Boyer (University
of Toronto) for repeating some experiments, and Dr. Alan
Lough (University of Toronto) for X-ray analysis.
(19) Attempts to react the cyclopropylzinc intermediate, after trans-
metalation using copper salts, with aldehydes (benzaldehyde,
butyraldehyde) were unsuccessful. Neither activation by Lewis acids
[BF3.OEt2, Ti(OiPr)4] nor transmetalation to a more reactive titanium
species with ClTi(OiPr)3 afforded the desired product. Likewise it was
not possible to capture the cyclopropyl copper compound with Michael
acceptors like cyclohexenone, ethyl acrylate, or nitroalkenes in the
Supporting Information Available. Experimental pro-
cedures and characterization data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
presence of TMSCl or BF3 OEt2. Moreover, the copper species failed
3
to undergo addition to alkynes. Only 5a was obtained in these reactions.
(20) For analytical reasons we synthesized racemic materials as an
HPLC reference by using rac-BINAP as a ligand.
Org. Lett., Vol. 13, No. 4, 2011
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