Palladium-catalyzed catellani aminocyclopropanation reactions with vinyl halides

Article abstract of DOI:10.1021/ol401383m

Palladium is shown to catalyze an intramolecular aminocyclopropanation of norbornenes with aliphatic vinyl halides in good yields. The reaction tolerates a variety of amine substituents and gives good results with a variety of carbocyclic and oxabicyclic [2.2.1] alkene acceptors. Notably, stabilized enolate nucleophiles were also employed in cyclopropanation reactions.

Full text of DOI:10.1021/ol401383m

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Palladium-Catalyzed Catellani
Aminocyclopropanation Reactions
with Vinyl Halides
Avinash Khanna,† Ilandari Dewage Udara Anulal Premachandra,† Paul D. Sung, and
David L. Van Vranken*
Department of Chemistry, University of California at Irvine, Irvine,
California 92697-2025, United States
david.vv@uci.edu
Received May 16, 2013
ABSTRACT
Palladium is shown to catalyze an intramolecular aminocyclopropanation of norbornenes with aliphatic vinyl halides in good yields. The reaction
tolerates a variety of amine substituents and gives good results with a variety of carbocyclic and oxabicyclic [2.2.1] alkene acceptors. Notably,
stabilized enolate nucleophiles were also employed in cyclopropanation reactions.
Norbornenes are gaining increasing attention for their
participation in metal-catalyzed reactions, for example as
traceless participants in CÀH activation reactions1 and as
ligands for asymmetric catalysis.2 Norbornenes are also
exceptional substrates for cyclopropanation. Palladium(0)
can catalyze the cyclopropanation of norbornenes using
traditional carbene precursors such as R-diazo esters3 and
various carbenoid precursors.4
Vinyl halides have received scant attention as reagents
for cyclopropanation. In the 1980s Catellani and co-work-
ers reported that tandem Heck reactions of vinyl bromides
with norbornene generate three types of cyclopropane
products (Scheme 1). In the presence of potassium acetate,
1-bromo-1-octene reacts via β-hydride elimination to gen-
erate vinylcyclopropane 1.5 β-Styryl bromide generates
intermediates that can be trapped with hydride donors or
secondary amines such as benzylcyclopropane 2 and cyclo-
propylcarbinylamine 3.6 It was proposed that all three pro-
ducts arise from a tandem reaction involving intermolecular
carbopalladation of norbornene to give vinylnorbornane 4,
† A.K. and I.D.U.A.P. contributed equally to this work.
(1) (a) Catellani, M.; Motti, N.; Della Ca’, N. Acc. Chem. Res. 2008,
41, 1512–1522. (b) Martins, A.; Mariampillai, B.; Lautens, M. Top.
Curr. Chem. 2010, 292, 1–33. (c) Faccini, F.; Motti, E.; Catellani, M.
J. Am. Chem. Soc. 2004, 126, 78–79. (d) Jiao, L.; Herdtweck, E.; Bach, T.
J. Am. Chem. Soc. 2012, 134, 14563–14572. (e) Sehnal, P.; Taylor,
R. J. K.; Fairlamb, I. J. S. Chem. Rev. 2010, 110, 824–889. (f) Elena
Motti, E.; Della Ca’, N.; Xu, D.; Armani, S.; Aresta, B. M.; Catellani, M.
Tetrahedron 2013, 69, 4421–4428.
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Chem. Soc. 2003, 125, 11508–11509.
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10.1021/ol401383m
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followed by intramolecular carbopalladation to give cyclo-
propylcarbinylpalladium intermediate 5.7
Table 1. Optimization of the Aminocyclopropanation of
Norbornadiene
Scheme 1. Common Reactive Intermediates in Catellani
Cyclopropanations Can Generate Three Different Products
equiv
equiv
equiv
nbd
entry Ph3P
amine
PTC
temp vessel yield
1
0.4 2 Et3N
2
5
80 °C
80 °C
80 °C
39%
52%
64%
73%
79%
57%
56%
21%
36%
56%
2
0.8 2 Et2NH
0.8 2 Et2NH
0.8 2 Et2NH
0.8 2 Et2NH
0.8 2 Et2NH
0.4 2 Et2NH
3
10
10
10
10
10
10
10
10
10
10
10
10
10
4
Bu4NCl 66 °C
Bu4NCl 80 °C
Bu4NCl 100 °C
Bu4NCl 80 °C
Bu4NCl 80 °C
Bu4NCl 80 °C
Bu4NCl 80 °C
80 °C sealed 66%
Bu4NCl 80 °C sealed 81%
Bu4NCl 80 °C sealed 82%
Bu4NCl 80 °C sealed 70%
Bu4NCl 80 °C sealed 72%
5
6
7
8
0.8
À
9
0.8 2 Bu3N
0.8 2 Et3N
Other than styryl bromide, no other vinyl halides have
been shown to generate cyclopropylcarbinylamines, pre-
sumably due to facile β-hydride elimination that leads to
formation of vinylcyclopropanes analogous to 1. We set
out to explore this distinctive aminocyclopropanation
reaction using vinyl halides other than styryl bromides.
10
11
12
13
14
15
0.8 2 Et2NH
0.8 2 Et2NH
0.8 3 Et2NH
0.8 1 Et2NH
0.8 2 n-PrNH2
Thereactioniscompleteinlessthan1hwithalargeexcess
of norbornadiene and additional phosphine (Table 1, en-
tries 1À3). The yields slightly improved in the presence of
the phase transfer catalyst tetra-n-butylammonium chloride
(entry 2 and 4), and the optimal temperature was 80 °C
(entries 4À6). Unfortunately, the reaction was less efficient
when the amount of triphenylphosphine was reduced
(entries 5 and 7). The optimal stoichiometry was found to
be 2 equiv of diethylamine, and secondary amine additives
were superior to tertiary or primary amines (entries 8À15).
To better accommodate the volatile reaction components,
the reaction was carried out in sealed tubes, ultimately
providing yields over 80% (entries 12 and 13). The opti-
mized conditions (entry 12) favor the participation of an
amine nucleophile in the cyclopropanation reaction as
opposed to β-hydride elimination.
Scheme 2. Aminocyclopropanation Reactions
In order to favor this unique aminocyclopropanation
reaction, we turned to a vinyl iodide substrate 6a with a
pendant secondary amine. Under the conditions reported
for styryl bromide, none of the cyclopropylcarbinylamine
7a was observed and we isolated only (E)-vinylcyclopro-
pane 8a, resulting from β-hydride elimination (Scheme 2).
In order to promote the formation of pyrrolidine 7a, we
changed both the alkene acceptor and the reaction conditions.
We substituted norbornadiene for norbornene since it has
been reported to provide higher yields in palladium-catalyzed
cyclopropanation reactions with diazo compounds.3a We also
changed the reaction conditions to those reported by Torii for
reductive trapping of a putative cyclopropylcarbinylpalla-
dium intermediate using formic acid as a hydride source.8
In a footnote, Torii and co-workers reported the isolation of a
cyclopropane in 84% yield by reacting a vinyl iodide, nor-
bornene, Ph3P, Pd(OAc)2, and Et3N in DMF. Therefore, we
set out to optimize the aminocyclopropanation of norborna-
diene under the Torii conditions (Table 1).
The relative stereochemistry of the amine product 9a
was established by the presence of a positive steady state
NOE from oneofthe protons on the norbornene bridgeC7
to one of the cyclopropane protons and an absence of
NOEs between the proton at C8 and the protons at C2 and
C3 (Figure 1).
(8) (a) Torii, S.; Okumoto, H.; Ozaki, H.; Nakayasu, S.; Tadokoro,
T.; Kotani, T. Tetrahedron Lett. 1992, 33, 3499–3502. The cyclopropa-
nation reaction was mentioned in ref 8a without a full description of the
reaction conditions. (b) Torii, S.; Okumoto, H.; Ozaki, H.; Nakayusu,
S.; Kotani, T. Tetrahedron Lett. 1990, 31, 5319–5322.
Figure 1. Establishing the relative stereochemistry.
Org. Lett., Vol. XX, No. XX, XXXX
B

With optimized conditions in hand, we next explored the
tolerance of the amine nitrogen substituent to varying
degrees of steric hindrance (Scheme 3). The reaction con-
ditions led to chemoselective cyclopropanation of the
nobornadiene acceptor without a competing reaction of
a pendant cinnamyl group in 9b. The reaction furnished
cyclopropanes in yields up to 87%. As expected, the bulky
N-cyclopentylamine 9d was formed in lower yield. The
exceedingly hindered adamantyl group of adamantylamine
6e led to a slower reaction and an inseparable 2:1 mixture
of pyrrolidine 9e and vinylcylopropane 9f in 56% yield. The
N-benzyl vinyl bromide corresponding to 6a also provided
the cyclopropylcarbinylamine 9a in 53% yield.
We set out to test carbon nucleophiles in the Catellani
cyclopropanation. The malonate anion 10, generated with
sodium hydride, produces the corresponding cyclopro-
pane adduct 11 in 60% yield under the optimized condi-
tions (Scheme 5).
Scheme 5. Carbon Nucleophiles Generate Carbocyclic Rings in
Conjunction with Cyclopropanation
The mechanism of these unique cyclizations and cyclo-
propanations is still unclear. In their seminal report Ca-
tellani and co-workers proposed the intermediacy of
cyclopropylcarbinylpalladium intermediate 5 (Scheme 1)
in the aminocyclopropanation reaction.6 The first step
involves an oxidative addition to form vinylpalladium
halide b (Scheme 6), followed by intermolecular carbopal-
ladation across the norbornene double bond to give exo-
norbornylpalladium intermediate c. The exo palladium
atom is unable to undergo syn β-hydride elimination but
is poised to carbopalladate across the exo vinyl group to
produce cyclopropylcarbinylpalladium intermediate e.
CarbonÀnitrogen bond formation could occur via a re-
ductive elimination6 or ionization of XPdÀ to give a
cyclopropylcarbinyl cation, both of which would generate
the aminocyclopropane product. Reductive elimination
seems less likely as a mechanism for CÀN bond formation
given the challenges that have been documented11 with
Scheme 3. Intramolecular Aminocyclopropanation with Varia-
tions in the Amine Substituent
We next set out to explore variations in the alkene acceptor.
Norbornene and dicyclopentadiene were slightly less efficient
than norbornadiene (Scheme 4). The adduct of dicyclopen-
tadiene 7b was obtained as an inseparable 1:1 mixture of
diastereomers. An oxabicyclic [2.2.1] substrate generated the
aminocyclopropane 7c in 69% yield.9 The cyclic alkene
acenaphthylene, which has been shown to resist β-hydride
elimination, generated none of the cyclopropane 7d.10
Scheme 6. Mechanistic Models for Intramolecular Aminocy-
clopropanation
Scheme 4. Scope of Alkene Acceptor
(9) The substrate is known to undergo cyclopropanation reactions
with high exo selectivity: Tenaglia, A.; Marc, S. J. Org. Chem. 2006, 71,
3569–3575.
(10) Dyker, G. J. Org. Chem. 1993, 58, 234–238.
Org. Lett., Vol. XX, No. XX, XXXX
C

BuchwaldÀHartwig aminations. However, the olefin and
palladium groups in norbornylpalladium intermediate c
are poised for an aminopalladation to give palladacyclo-
butane d. Palladacyclobutanes have previously been
invoked in the mechanisms for palladium catalyzed cyclo-
propanation.4g,12 In previous studies of aminopallada-
tions, N-alkylamines have been shown to aminopalladate
anti13 whereas N-aryl and N-sulfonylamines have been
shown to aminopalladate syn.14 Moreover, the participa-
tionofmalonateanionsisconsistentwiththewell-accepted
anti-carbopalladation mechanism.15
In summary, we show for the first time that the Catellani
reaction can be applied to aliphatic vinyl halides;not just
styryl bromide;and can even engagestabilizedenolates as
well as amine nucleophiles. The reaction is selective for
norbornenes over other alkenes, even acenaphthylene,
which, like norbornenes, should generate palladium inter-
mediates that resist β-hydride elimination. Ultimately, the
mechanism of the reaction is unclear, but given the parti-
cipation of both alkylamines and stabilized enolates as
nucleophiles, we favor a mechanism involving palladacy-
clobutanes such as d in Scheme 6.
~
(11) Hartwig, J. F.; Richards, S.; Baranano, D.; Paul, F. J. Am.
Chem. Soc. 1996, 118, 3626–3633.
Acknowledgment. A.K. is supported by a graduate
fellowship from the National Science Foundation.
(12) Straub, B. F. J. Am. Chem. Soc. 2002, 124, 14195–14201.
˚
€
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K.; Zetterberg, K. Tetrahedron Lett. 1974, 15, 1363–1366. (b) Arnek, R.;
Zetterberg, K. Organometallics 1987, 6, 1230–1235.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) (a) Ney, J. E.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 8644–
8651. (c) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328–6335. (c)
Minatti, A.; Muniz, K. Chem. Soc. Rev. 2007, 36, 1142–1152.
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2366–2447. (b) Holton, R. A.; Zoeller, J. R. J. Am. Chem. Soc. 1985, 107,
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The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX