Synthesis and reactivity of azapalladacyclobutanes

Article abstract of DOI:10.1021/ja0660756

N-Sulfonyl aziridines undergo oxidative addition to palladium(O) complexes generated in situ from mixtures of Pd₂(dba)₃ and 1,10-phenanthroline. The resulting azapalladacyclobutane complexes undergo intramolecular carbopalladation in

Full text of DOI:10.1021/ja0660756

Published on Web 11/10/2006
Synthesis and Reactivity of Azapalladacyclobutanes
Joshua E. Ney and John P. Wolfe*
Contribution from the Department of Chemistry, UniVersity of Michigan, 930 North UniVersity
AVenue, Ann Arbor, Michigan, 48109-1055
Received August 21, 2006; E-mail: jpwolfe@umich.edu
Abstract: N-Sulfonyl aziridines undergo oxidative addition to palladium(0) complexes generated in situ
from mixtures of Pd2(dba)3 and 1,10-phenanthroline. The resulting azapalladacyclobutane complexes
undergo intramolecular carbopalladation in the presence of copper(I) iodide to afford azapalladabicyclo-
[3.2.1]octanes. A deuterium-labeling experiment indicates that the oxidative addition proceeds via SN2-
type attack of palladium(0) on the less-hindered carbon of the aziridine ring and that alkene insertion occurs
in a syn fashion. The azapalladabicyclo[3.2.1]octane complexes undergo oxidative palladium-carbon bond
functionalization in the presence of copper(II) bromide.
Introduction
low-valent late transition metal complexes have been invoked
as plausible intermediates in these transformations,1,2 although
experimental evidence for these species is limited.
The oxidative addition of aziridines to late transition metal
complexes has been implicated as a key step in a number of
useful metal-catalyzed reactions. For example, transition metal-
catalyzed carbonylations of unactivated aziridines have been
employed for the construction of â-lactams (eq 1),1-7 and the
Pd-catalyzed isomerization of N-tosylaziridines to N-tosyl-
ketimines is also believed to proceed via oxidative addition of
In addition to the established transformations described above,
azametallacyclobutanes could potentially serve as intermediates
in metal-catalyzed [3 + 2] coupling reactions between aziridines
and alkenes that would afford substituted pyrrolidine products.9
As shown in Scheme 1, oxidative addition of an aziridine to a
metal complex could generate azametallacyclobutane 1, which
could undergo insertion of an alkene into either the M-N
bond10,11 to afford 2 or the M-C bond12,13 to provide 3.
Subsequent C-C14 or C-N15,16 bond-forming reductive elimi-
nation of 2 or 3, respectively, would give a pyrrolidine product
(4). However, several of the key steps in this process are
(6) Several Lewis acid-catalyzed cycloadditions of aziridines and hetero-
cumulenes employing palladium(II) complexes have been reported. See:
(a) Baeg, J.-O.; Alper, H. J. Org. Chem. 1992, 57, 157-162. (b) Baeg,
J.-O.; Bensimon, C.; Alper, H. J. Am. Chem. Soc. 1995, 117, 4700-4701.
(c) Maas, H.; Bensimon, C.; Alper, H. J. Org. Chem. 1998, 63, 17-20.
(7) 2-Vinylaziridines, which are activated for oxidative addition, have also been
shown to undergo palladium-catalyzed insertions of carbon monoxide,
isocyanates, phenyl isothiocyanate, carbodiimides, and alkylidene malonates.
These reactions are believed to proceed via intermediate allylpalladium
complexes. See: (a) Butler, D. C. D.; Inman, G. A.; Alper, H. J. Org.
Chem. 2000, 65, 5887-5890. (b) Dong, C.; Alper, H. Tetrahedron:
Asymmetry 2004, 15, 1537-1540. (c) Trost, B. M.; Fandrick, D. R. J. Am.
Chem. Soc. 2003, 125, 11836-11837. (d) Trost, B. M.; Fandrick, D. R.
Org. Lett. 2005, 7, 823-826. (e) Spears, G. W.; Nakanishi, K.; Ohfune,
Y. Synlett 1991, 91-92. (f) Tanner, D.; Somfai, P. Bioorg. Med. Chem.
Lett. 1993, 3, 2415-2418. (g) Aoyagi, K.; Nakamura, H.; Yamamoto, Y.
J. Org. Chem. 2002, 67, 5977-5980.
an aziridine to Pd(0) (eq 2).8 In some instances azametallacy-
clobutanes that derive from oxidative addition of aziridines to
(1) For examples of reactions employing rhodium catalysts see: (a) Alper,
H.; Urso, F.; Smith, D. J. H. J. Am. Chem. Soc. 1983, 105, 6737-6738.
(b) Calet, S.; Urso, F.; Alper, H. J. Am. Chem. Soc. 1989, 111, 931-934.
(c) Khumtaveeporn, K.; Alper, H. Acc. Chem. Res. 1995, 28, 414-422.
(d) Lu, S.-M.; Alper, H. J. Org. Chem. 2004, 69, 3558-3561.
(2) For examples of reactions employing cobalt catalysts see: (a) Piotti, M.
E.; Alper, H. J. Am. Chem. Soc. 1996, 118, 111-116. (b) Davoli, P.;
Moretti, I.; Prati, F.; Alper, H. J. Org. Chem. 1999, 64, 518-521. (c)
Mahadevan, V.; Getzler, Y. D. Y. L.; Coates, G. W. Angew. Chem. Int.
Ed. 2002, 41, 2781-2784.
(8) A portion of this work has been previously communicated. See: Wolfe, J.
P.; Ney, J. E. Org. Lett. 2003, 5, 4607-4610.
(3) For palladium-catalyzed carbonylations of methyleneaziridines see: Alper,
H.; Hamel, N. Tetrahedron Lett. 1987, 28, 3237-3240.
(9) The synthesis of tetrahydrofuran via Rh-catalyzed insertion of ethylene into
ethylene oxide has been previously described, but this reaction has not
been demonstrated with other alkenes or epoxides. See: Collman, J. P.;
Hegedus, L. S.; Norton, J. R.; Finke, R. G. Principles and Applications of
Organotransition Metal Chemistry; University Science Books: Mill Valley,
CA, 1987; pp 640-641.
(10) For examples of olefin or alkyne insertion into isolated transition metal
amido complexes see: (a) Cowan, R. L.; Trogler, W. C. Organometallics
1987, 6, 2451-2453. (b) Cowan, R. L.; Trogler, W. C. J. Am. Chem. Soc.
1989, 111, 4750-4761. (c) Villanueva, L. A.; Abboud, K. A.; Boncella, J.
M. Organometallics 1992, 11, 2963-2965. (d) VanderLende, D. D.;
Abboud, K. A.; Boncella, J. M. Inorg. Chem. 1995, 34, 5319-5326. (e)
Dahlenburg, L.; Herbst, K. J. Chem. Soc., Dalton Trans. 1999, 3935-
3939. (f) Zhao, P.; Krug, C.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127,
12066-12073.
(4) For a stoichiometric nickel-mediated aziridine carbonylation see: Cham-
chaang, W.; Pinhas, A. R. J. Org. Chem. 1990, 55, 2943-2950.
(5) For related carboxylations and carbonylations of unactivated epoxides
see: (a) De Pasquale, R. J. J. Chem. Soc., Chem. Commun. 1973, 157-
158. (b) Kamiya, Y.; Kawato, K.; Ohta, H. Chem. Lett. 1980, 1549-1552.
(c) Ref 1c. (d) Ref 2c. (e) Lee, J. T.; Thomas, P. J.; Alper, H. J. Org.
Chem. 2001, 66, 5424-5426. (f) Getzler, Y. D. Y. L.; Mahadevan, V.;
Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2002, 124, 1174-
1175. (g) Schmidt, J. A. R.; Mahadevan, V.; Getzler, Y. D. Y. L.; Coates,
G. W. Org. Lett. 2004, 6, 373-376. (h) Getzler, Y. D. Y. L.; Mahadevan,
V.; Lobkovsky, E. B.; Coates, G. W. Pure Appl. Chem. 2004, 76, 557-
564. (i) Schmidt, J. A. R.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem.
Soc. 2005, 127, 11426-11435.
9
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J. AM. CHEM. SOC. 2006, 128, 15415-15422
15415

A R T I C L E S
Scheme 1
Ney and Wolfe
in 1988.17 The C-H activation of tert-butylamine with Cp*-
(PMe3)IrH2 provided an azairidacyclobutane complex, which
was found to undergo insertion of tert-butylisocyanide into the
Ir-N bond. In the second study, Hillhouse reported that N-tosyl-
2-alkylaziridines undergo oxidative addition to (bpy)Ni(COD)
or (bpy)NiEt2 to afford azanickelacyclobutanes via an SN2
mechanism.18 Although small-molecule insertion chemistry of
the nickel complexes was not reported, treatment with oxygen
led to C-N bond-forming reductive elimination that regenerated
the substituted aziridines. The experiments described by Hill-
house represent the first and only examples of oxidative addition
reactions between aziridines and late transition metal complexes
that afford isolable azametallacyclobutane products.
unprecedented (e.g., the conversion of 1 to 2 or 3) or have not
been thoroughly explored (e.g., the formation of 1 from an
aziridine).
Only two studies have examined the synthesis and reactivity
of late transition metal azametallacyclobutane complexes that
contain an anionic amido group and a saturated backbone (e.g.,
1).17-22 The first example of the synthesis and isolation of an
azametallacyclobutane of this type was reported by Bergman
In this Article we describe the first syntheses of azapallada-
cyclobutane complexes of the general structure 1,21,22 which
were accomplished through the oxidative addition of aziridines
to Pd(0) complexes derived from Pd2(dba)3 and 1,10-phenath-
roline (phen). We also demonstrate the unprecedented CuI-
catalyzed insertion of alkenes into the azametallacyclobutanes,
which occurs in an intramolecular fashion to provide unusual
bridged bicyclic palladacycles. The azapalladabicyclo[3.2.1]-
octane products of these reactions undergo C-X (X ) Br, OAc)
bond-forming reductive elimination upon treatment with CuBr2
or PhI(OAc)2 to provide substituted cyclopentylamine deriva-
tives in moderate yield.
(11) For catalytic reactions involving olefin or alkyne insertion into transition
metal amido complexes see: (a) Casalnuovo, A. L.; Calabrese, J. C.;
Milstein, D. J. Am. Chem. Soc. 1988, 110, 6738-6744. (b) Tsutsui, H.;
Narasaka, K. Chem. Lett. 1999, 45-46. (c) Kitamura, M.; Zaman, S.;
Narasaka, K. Synlett 2001, 974-976. (d) Helaja, J.; Go¨ttlich, R. Chem.
Commun. 2002, 720-721. (e) Ney, J. E.; Wolfe, J. P. Angew. Chem. Int.
Ed. 2004, 43, 3605-3608. (f) Bertrand, M. B.; Wolfe, J. P. Tetrahedron
2005, 61, 6447-6459. (g) Ney, J. E.; Wolfe, J. P. J. Am. Chem. Soc. 2005,
127, 8644-8651. (h) Nakhla, J. S.; Kampf, J. W.; Wolfe, J. P. J. Am. Chem.
Soc. 2006, 128, 2893-2901. (i) Brice, J. L.; Harang, J. E.; Timokhin, V.
I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 2868-2869.
(j) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 7179-7181.
(12) For general reviews covering the insertion of olefins into metal-carbon
bonds see: (a) Yamamoto, A. J. Chem. Soc., Dalton Trans. 1999, 1027-
1037. (b) Yamamoto, A.; Kayaki, Y.; Nagayama, K.; Shimizu, I. Synlett
2000, 925-937. (c) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000,
100, 3009-3066.
(13) For catalytic reactions involving olefin insertions into metal alkyls bearing
â-hydrogen atoms see: (a) Rix, F. C.; Brookhart, M. J. Am. Chem. Soc.
1995, 117, 1137-1138. (b) Johnson, L. K.; Killian, C. M.; Brookhart, M.
J. Am. Chem. Soc. 1995, 117, 6414-6415. (c) Gottfried, A. C.; Brookhart,
M. Macromolecules 2001, 34, 1140-1142. (d) Oh, C. H.; Rhim, C. Y.;
Kang, J. H.; Kim, A.; Park, B. S.; Seo, Y. Tetrahedron Lett. 1996, 37,
8875-8878. (e) Schweizer, S.; Song, Z.-Z.; Meyer, F. E.; Parsons, P. J.;
De Meijere, A. Angew. Chem. Int. Ed. 1999, 38, 1452-1454. (f) Quan, L.
G.; Cha, J. K. J. Am. Chem. Soc. 2002, 124, 12424-12425. (g) Widen-
hoefer, R. A. Acc. Chem. Res. 2002, 35, 905-913 and references therein.
(h) Perch, N. S.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 6332-
6346.
Results
Oxidative Addition Reactions. In our preliminary experi-
ments, we sought to examine the synthesis of azapalladacy-
clobutane complexes via the oxidative addition of aziridines to
Pd(0). Palladium was chosen for these studies due to its
demonstrated utility in catalytic cross-coupling reactions that
involve oxidative addition, small-molecule insertion, and reduc-
tive elimination processes. We initially examined the stoichio-
metric reaction of N-tosyl-2-butylaziridine (5) with Pd/phosphine
complexes or mixtures of Pd2(dba)3 and phosphine or amine
ligands. As shown in Table 1, treatment of 5 with Pd[PCy3]2 or
Pd[P(t-Bu)2Me]2 provided N-tosylimine 6, which presumably
results from oxidative addition followed by â-hydride elimina-
tion, as the sole detectable product (entries 3 and 4).23
Interestingly, although no reaction occurred between 5 and
mixtures of Pd2(dba)3/phen (entry 5),24 subjection of the
(14) (a) Cardenas, D. J. Angew. Chem. Int. Ed. 1999, 38, 3018-3020. (b)
Cardenas, D. J. Angew. Chem. Int. Ed. 2003, 42, 384-387. (c) Luh, T.-Y.;
Leung, M.-K.; Wong, K.-T. Chem. ReV. 2000, 100, 3187-3204. (d)
Netherton, M. R.; Fu, G. C. AdV. Synth. Catal. 2004, 346, 1525-1532. (e)
Netherton, M. R.; Fu, G. C. Top. Organomet. Chem. 2005, 14, 85-108.
(15) Catalytic reactions involving C(sp2)-N bond-forming reductive elimination
are well-known. For reviews see: (a) Muci, A. R.; Buchwald, S. L. Top.
Curr. Chem. 2002, 219, 131-209. (b) Hartwig, J. F. Pure Appl. Chem.
1999, 71, 1417-1423. (c) Barluenga, J.; Valdes, C. Chem. Commun. 2005,
4891-4901.
(21) Azapalladacyclobutanes and azaplatinacyclobutanes that contain a neutral
amino group with the general structure 1a have been prepared via
aminopalladation or aminoplatination of alkenes. See: (a) Briggs, J. R.;
Crocker, C.; McDonald, W. S.; Shaw, B. L. J. Chem. Soc., Dalton Trans.
1981, 575-580. (b) Green, M.; Sarhan, J. K. K.; Al-Najjar, I. M.
Organometallics 1984, 3, 520-524 and references therein. (c) De Renzi,
A.; Di Blasio, B.; Morelli, G.; Vitagliano, A. Inorg. Chim. Acta 1982, 63,
233-241. (d) Åkermark, B.; Zetterberg, K. J. Am. Chem. Soc. 1984, 106,
5560-5561. (e) Hegedus, L. S.; Åkermark, B.; Zetterberg, K.; Olsson, L.
F. J. Am. Chem. Soc. 1984, 106, 7122-7126. (f) Arnek, R.; Zetterberg, K.
Organometallics 1987, 6, 1230-1235. (g) Zhang, L.; Zetterberg, K.
Organometallics 1991, 10, 3806-3813.
(16) Reductive elimination reactions that form C(sp3)-N bonds are rare and
often require oxidative conditions; for examples see: (a) Ba¨ckvall, J.-E.
Tetrahedron Lett. 1978, 19, 163-166. (b) Koo, K.; Hillhouse, G. L.
Organometallics 1995, 14, 4421-4423. (c) Zabawa, T. P.; Kasi, D.;
Chemler, S. R. J. Am. Chem. Soc. 2005, 127, 11250-11251. (d) Streuff,
J.; Ho¨velmann, C. H.; Nieger, M.; Muniz, K. J. Am. Chem. Soc. 2005,
127, 14586-14587. (e) Ref 11i.
(17) Klein, D. P.; Hayes, J. C.; Bergman, R. G. J. Am. Chem. Soc. 1988, 110,
3704-3706.
(18) Lin, B. L.; Clough, C. R.; Hillhouse, G. L. J. Am. Chem. Soc. 2002, 124,
2890-2891.
(19) The oxidative addition of ethyleneimine to K2PtCl4 in aqueous HCl has
been reported to afford KPt(CH2CH2N+H3)Cl5. See: Mitchenko, S. A.;
Slinkin, S. M.; Vdovichenko, A. N.; Zamashchikov, V. V. Metallorg. Khim.
1991, 4, 1031-1035.
(20) For a discussion of the synthesis and reactivity of oxymetallacyclobutanes
of Rh, Ir, Pt, and Ru see: (a) Schlodder, R.; Ibers, J. A.; Lenarda, M.;
Graziani, M. J. Am. Chem. Soc. 1974, 96, 6893-6900. (b) Lenarda, M.;
Ros, R.; Traverso, O.; Pitts, W. D.; Baddley, W. H.; Graziani, M. Inorg.
Chem. 1977, 16, 3178-3182. (c) Zlota, A. A.; Frolow, F.; Milstein, D. J.
Am. Chem. Soc. 1990, 112, 6411-6413. (d) Calhorda, M. J.; Galvao, A.
M.; Unaleroglu, C.; Zlota, A. A.; Frolow, F.; Milstein, D. Organometallics
1993, 12, 3316-3325. (e) Hartwig, J. F.; Bergman, R. G.; Andersen, R.
A. Organometallics 1991, 10, 3326-3344. (f) Hartwig, J. F.; Bergman, R.
G.; Andersen, R. A. Organometallics 1991, 10, 3344-3362.
(22) For examples of four-membered platinalactam and palladalactam complexes
see: (a) Henderson, W.; Oliver, A. G.; Nicholson, B. K. Inorg. Chim. Acta
2000, 298, 84-89. (b) Henderson, W.; Nicholson, B. K.; Oliver, A. G. J.
Chem. Soc., Dalton Trans. 1994, 1831-1835. (c) Henderson, W.; Fawcett,
J.; Kemmitt, R. D. W.; Proctor, C.; Russell, D. R. J. Chem. Soc., Dalton
Trans. 1994, 3085-3090.
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Synthesis and Reactivity of Azapalladacyclobutanes
A R T I C L E S
Table 1. Ligand Effectsa
Table 2. Synthesis of Azapalladacyclobutanes from
N-Sulfonylaziridines and Pd0/Phena,b
a Conditions: 1.0-1.5 equiv aziridine, 0.5 equiv Pd2(dba)3 (1.0 equiv
Pd), 1.0 equiv phen, THF (0.01 M in Pd), 65 °C. b Ns ) 4-nitrobenzene-
sulfonyl.
contrast, the reaction of 2-methylaziridine derivative 10, which
bears a more strongly activating N-nosyl substituent (nosyl =
4-nitrophenylsulfonyl)26 afforded metallacycle 15 in 44%
isolated yield (entry 2). The reactivity of the aziridine substrates
toward oxidative addition to Pd(0) was dependent on both the
steric and electronic properties of the tethered alkene. For
example, aziridine 11, which bears an electron-deficient internal
olefin, underwent facile oxidative addition to afford 16 (entry
3). However, aziridine substrates bearing internal alkenes
substituted with a methyl group (12) or a silyloxy group (13)
did not react (entries 4 and 5). The reactivity of the aziridine
toward Pd/phen was also dependent on the length of the tether
between the alkene and the aziridine. The butenyl-containing
substrate 7 underwent clean oxidative addition to Pd(0) (Table
1, entry 6), but no reaction was observed between the Pd/phen
mixture and pentenyl-substituted aziridine 14 (Table 2, entry
6).
Olefin Insertion Reactions of Azapalladacyclobutane
Complexes. With azapalladacyclobutane complexes 8, 15, and
16 in hand, we sought to develop conditions that would effect
intramolecular migratory insertion of the tethered olefin. Met-
allacycle 8 failed to undergo intramolecular olefin insertion when
heated to temperatures up to 70 °C in a variety of solvents
including benzene, chlorobenzene, DME, acetonitrile, and
DMSO. However, treatment of a methylene chloride solution
of 8 with a catalytic amount of copper(I) iodide resulted in clean
intramolecular carbopalladation of the alkene to provide bridged
bicyclic complex 17 in 72% yield as an air-stable orange solid
(eq 3).27 Analysis of 17 by 1H NMR, 13C NMR, COSY, HSQC,
difference NOE, IR, and HRMS confirmed the structure shown
below.
a Conditions: 1.0-1.5 equiv aziridine, 0.5 equiv Pd2(dba)3 (1.0 equiv
Pd), 2.0 equiv monodentate ligands, 1.0 equiv bidentate ligands, THF or
C6D6 (0.01 M in Pd), 65-70 °C.
unsaturated N-tosyl-2-but-3-enylaziridine 7 to these conditions
afforded azametallacyclobutane 8 in 45% isolated yield as an
air-stable yellow solid (entry 6). The structure of metallacycle
8, which results from oxidative addition of the less-hindered
1
C-N bond in 7 to palladium(0), was established through H
NMR, 13C NMR, COSY, IR, and HRMS analysis. Efforts to
prepare the analogous azapalladacyclobutane complex bearing
PCy3 ligands from 7 and Pd[PCy3]2 provided complex mixtures
of products (entry 9); neither the desired metallacycle nor
2-(toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane25 (the product
that would result from oxidative addition, alkene insertion, and
reductive elimination as described in Scheme 1) was observed.
The oxidative addition of 7 failed to proceed when the
bisphosphines dppe, dppf, and dcpe were employed as ligands
(entries 10-12).24 Surprisingly, bpy24 was also not an effective
ligand for the oxidative addition of 7; the aziridine was
recovered unchanged from this reaction (entry 7).
To assess the scope and limitations of this oxidative addition
reaction, a series of N-sulfonylaziridine substrates (9-14) was
prepared and treated with mixtures of Pd2(dba)3 and phen. As
shown in Table 2, N-tosylaziridines lacking a tethered olefin,
such as 9, were inert to the reaction conditions (entry 1). In
(23) Control experiments demonstrated that the aziridine did not isomerize when
heated for 15 h at 70 °C in C6D6 with 1 equiv of tricyclohexylphosphine
in the absence of Pd.
(24) Phen ) 1,10-phenanthroline, dppe ) 1,2-bis(diphenylphospino)ethane, dppf
) 1,1′-bis(diphenylphosphino)ferrocene, dppb ) 1,4-bis(diphenylphos-
phino)butane, dcpe ) 1,2-bis(dicyclohexylphosphino)ethane, bpy ) 2,2′-
bipyridine.
(26) Maligres, P. E.; See, M. M.; Askin, D.; Reider, P. J. Tetrahedron Lett.
1997, 38, 5253-5256.
(25) Heesing, A.; Herdering, W. Chem. Ber. 1983, 116, 1081-1096.
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A R T I C L E S
Ney and Wolfe
hexadiene (21)31 (obtained with ca. 5:1 E/Z selectivity) was
subjected to Evans aziridination conditions32 to generate an
N-tosyl-2-(but-3-enyl)aziridine (22) that was stereoselectively
and regioselectively deuterated at C1 and C6 (Scheme 3). This
material was obtained as a 5:1 mixture of trans/cis aziridines
and a ca. 5:1 mixture of alkene isomers. Oxidative addition of
22 to Pd(0)/phen afforded azapalladacyclobutane 23 as a 5:1
mixture of cis/trans metallacycles and a 5:1 mixture of alkene
isomers. Thus, the oxidative addition occurs with clean inversion
of configuration at the reacting methylene carbon. Treatment
of azametallacyclobutane 23 with a catalytic amount of CuI in
methylene chloride afforded 24, the product of intramolecular
syn carbopalladation, as a 5:1 mixture of C3 epimers and a 5:1
mixture of C8 epimers.33
Treatment of 8 with several other late transition metal salts,
including gold(I) chloride, palladium(II) acetate, and zinc(II)
iodide, provided detectable amounts of 17. However, these
transformations were more sluggish and/or less clean than the
CuI-catalyzed process. Use of other copper salts such as CuBr
or CuCl gave results similar to those obtained with CuI.
Treatment of 8 with sodium iodide or tetrabutylammonium
iodide did not lead to any observable reaction, which suggests
that the insertion is facilitated by a soft Lewis acid rather than
a halide or other anionic species.
Scheme 3
Intramolecular carbopalladation of metallacycle 16 required
more forcing conditions than were employed for the transforma-
tion of 8 to 17;28 complete conversion of 16 to C-bound
palladium enolate 18 was achieved using a stoichiometric
amount of CuI at 65 °C (Scheme 2). The bicyclic complex 18
was obtained as a single stereoisomer, which was determined
to contain a C-bound enolate and exo orientation of the ester
substituent, through 13C NMR and NOE analysis, respectively.
This stereochemical outcome corresponds to apparent syn
carbopalladation of the E-olefin in 16. However, initial formation
of the endo isomer 19 followed by conversion to 18 via O-bound
enolate 20 could not be unambiguously ruled out in this
system.29,30 Subsequent deuterium-labeling experiments con-
firmed that alkene insertion most likely occurs through a syn
carbopalladation pathway (see below).
The stereochemistry of azapalladacyclobutane 23 was estab-
lished through two-dimensional H NMR analysis of the all-
1
proteo analogue 8. The proton resonances observed at δ 4.51-
4.45, 1.12, and 0.57 ppm were assigned to HA, HB, and HC,
respectively, through COSY analysis. A cross-peak between the
resonances attributed to HA and HB was observed in the 2D-
NOESY spectrum of 8, which established the cis relationship
Scheme 2
1
between these protons. The H NMR spectrum of 23 lacked
(27) Azanickelacyclobutane 8a, which was prepared from 7 using Hillhouse’s
conditions, did not undergo intramolecular alkene insertion under thermal
or Cu-mediated conditions.
(28) Insertion reactions of internal alkenes are usually slower than insertion
reactions of terminal alkenes. For selected examples see: (a) Gu¨rtler, C.;
Buchwald, S. L. Chem.sEur. J. 1999, 5, 3107-3112. (b) Littke, A. F.;
Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989-7000.
(29) For an example of partial stereochemical scrambling at the palladium-bound
carbon in a C-bound palladium enolate see: Lu, G.; Malinakova, H. C. J.
Org. Chem. 2004, 69, 8266-8279.
Although 8 and 16 were found to undergo intramolecular Cu-
catalyzed olefin insertion, efforts to induce intermolecular olefin
insertion with a variety of different alkenes were unsuccessful.
Similarly, metallacycle 15, which is derived from N-nosyl-2-
methylaziridine (10), also failed to participate in intermolecular
insertion reactions with a variety of olefins, including 1-decene,
styrene, and butyl acrylate. Reactions were conducted in both
methylene chloride and THF, with and without added CuI.
(30) For examples of O-bound palladium enolate complexes see: (a) Ito, Y.;
Nakatsuka, M.; Kise, N.; Saegusa, T. Tetrahedron Lett. 1980, 21, 2873-
2876. (b) Bouaoud, S. E.; Braunstein, P.; Grandjean, D.; Matt, D.; Nobel,
D. J. Chem. Soc., Chem. Commun. 1987, 488-490. (c) Bouaoud, S.-E.;
Braunstein, P.; Grandjean, D.; Matt, D.; Nobel, D. Inorg. Chem. 1988, 27,
2279-2286. (d) Andrieu, J.; Braunstein, P.; Dusausoy, Y.; Ghermani, N.
E. Inorg. Chem. 1996, 35, 7174-7180. (e) Sodeoka, M.; Tokunoh, R.;
Miyazaki, F.; Hagiwara, E.; Shibasaki, M. Synlett 1997, 463-466. (f)
Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 5816-5817.
(g) Culkin, D. A.; Hartwig, J. F. Organometallics 2004, 23, 3398-3416.
(h) Braunstein, P. Chem. ReV. 2006, 106, 134-159.
(31) Piers, W. E.; Bercaw, J. E. J. Am. Chem. Soc. 1990, 112, 9406-9407.
(32) Evans, D. A.; Bilodeau, M. T.; Faul, M. M. J. Am. Chem. Soc. 1994, 116,
2742-2753.
Stereochemistry of Oxidative Addition and Olefin Inser-
tion. To explore the mechanistic details of the oxidative addition
and olefin insertion reactions described above, (E,E)-1,6-d2-1,5-
(33) See the Supporting Information for copies of the 1H NMR spectra obtained
for 8, 17, 18, 22, 23, and 24 along with selected 2D NMR spectra for 8,
17, and 18.
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Synthesis and Reactivity of Azapalladacyclobutanes
A R T I C L E S
to promote any reaction (oxone, O2). Complex 17 was also
unreactive toward intermolecular insertion of alkenes or alkynes,
including 1-decene and diethyl acetylenedicarboxylate. Treat-
ment of 18 with CuBr2 afforded a complex mixture of
products.36
Figure 1.
Discussion
Oxidative Addition of Aziridines to Pd(0). The reactivity
of N-sulfonyl aziridines toward Pd(0) complexes is highly
dependent on two structural features of the aziridine moiety:
sterics and electrophilicity. In all cases examined (Tables 1 and
2), oxidative addition occurred exclusively via attack on the
less-substituted carbon of the aziridine, and sterically bulky 1,1-
or 1,2-disubstituted aziridines were unreactive. Use of a more
electron-deficient group on the nitrogen atom led to increased
reactivity as demonstrated by the observation that the more
electrophilic N-nosyl-2-methylaziridine (10) readily undergoes
oxidative addition to Pd2(dba)3/phen, whereas N-tosyl-2-
methylaziridine (9) is unreactive under these conditions (Table
2).
Figure 2.
the resonance at δ 0.57, which is consistent with the structure
shown in Figure 1.33
The presence of a tethered alkene also facilitates the oxidative
addition reaction. For example, N-tosyl-2-but-3-enylaziridine 7
undergoes oxidative addition to Pd2(dba)3/phen, whereas N-
tosyl-2-butylaziridine 5 does not. One possible explanation for
this effect is that precoordination of the tethered olefin to
palladium(0) facilitates chelate-directed oxidative addition to
the aziridine (Scheme 4, 27).37 The relative reactivities of
The stereochemistry of 24 was established in a similar
fashion. The resonances in the H NMR spectrum of 17 were
1
assigned on the basis of COSY, HSQC, and difference NOE
1
spectroscopy as shown in Figure 2. The H NMR spectrum of
24 lacked the resonances attributable to HA and HC, establishing
the stereochemical configuration of this complex.
Reactivity of Bicyclic Palladium Complex 17. Having
prepared azapalladabicyclo[3.2.1]octane derivatives 17 and 18,
we sought to probe whether these complexes could be induced
to undergo C-N bond-forming reductive elimination to generate
azanorbornane products under thermal or oxidative conditions.16
No reaction was observed when a solution of 17 in toluene-d8
was heated to 120 °C. However, treatment of 17 with 2 equiv
of copper(II) bromide afforded a 49% isolated yield of 25, the
product of carbon-bromine bond formation (eq 4).34 Similarly,
treatment of 17 with 1 equiv of PhI(OAc)2 provided acetate 26
in 32% yield.35 The use of other oxidants resulted in the
formation of complex mixtures of products (m-CPBA) or failed
Scheme 4
internal olefin-containing substrates 11-13 are consistent with
this model. Electron-deficient olefins are known to bind strongly
to palladium(0).38 Accordingly, acrylate-containing aziridine 11
underwent oxidative addition to form 16 (Table 2, entry 3).39
Electron-rich internal olefins, in contrast to terminal and
electron-deficient internal alkenes, bind weakly to palladium-
(0).38 As a result, 12 and 13 were inert to the reaction conditions
(Table 2, entries 4 and 5). The length of the tether between the
aziridine and the olefin also affected the reactivity of the azirdine
(34) (a) Henry, P. M. J. Org. Chem. 1967, 32, 2575-2580. (b) Henry, P. M. J.
Org. Chem. 1974, 39, 3871-3874 and references therein. (c) Budnik, R.
A.; Kochi, J. K. J. Organomet. Chem. 1976, 116, C3-C6. (d) Ba¨ckvall,
J.-E. Tetrahedron Lett. 1977, 18, 467-468. (e) Ba¨ckvall, J.-E. Acc. Chem.
Res. 1983, 16, 335-342. (f) Zhu, G.; Ma, S.; Lu, X.; Huang, Q. J. Chem.
Soc., Chem. Commun. 1995, 271-273 and references therein.
(35) (a) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126,
9542-9543. (b) Dick, A. R.; Kampf, J. W.; Sanford, M. S. J. Am. Chem.
Soc. 2005, 127, 12790-12791 and references therein.
(36) The major products appear to be two R-bromoester stereoisomers that would
result from oxidative bromination of 18 in a manner analogous to 17. These
assignments were made on the basis of 1H NMR and COSY analysis of an
inseparable mixture of the two stereoisomers that was contaminated with
ca. 20% of an unidentified impurity. A third product that was isolated in
(38) (a) Ozawa, F.; Ito, T.; Nakamura, Y.; Yamamoto, A. J. Organomet. Chem.
1979, 168, 375-391. (b) Canovese, L.; Visentin, F.; Uguagliati, P.;
Crociani, B. J. Chem. Soc., Dalton Trans. 1996, 1921-1926. (c) Stahl, S.
S.; Thorman, J. L.; de Silva, N.; Guzei, I. A.; Clark, R. W. J. Am. Chem.
Soc. 2003, 125, 12-13. (d) Popp, B. V.; Thorman, J. L.; Morales, C. M.;
Landis, C. R.; Stahl, S. S. J. Am. Chem. Soc. 2004, 126, 14832-14842.
(39) In our system, the ability of the alkene to bind to Pd(0) appears to override
the tendency of electron-poor alkenes to decrease the reactivity of Pd(0)
complexes in oxidative addition reactions. See: (a) Amatore, C.; Carre,
E.; Jutand, A.; Medjour, Y. Organometallics 2002, 21, 4540-4545. (b)
Scrivanti, A.; Beghetto, V.; Matteoli, U.; Antonaroli, S.; Marini, A.;
Crociani, B. Tetrahedron 2005, 61, 9752-9758.
1
small quantities (ca. 5%) has tentatively been assigned on the basis of H
NMR and COSY analysis to be an R,â-unsaturated ester that would derive
from loss of HBr from the R-bromoester. Small amounts of several other
unidentified products were also observed.
(37) For an example of chelation-assisted oxidative addition of an alkyl chloride
to Pd(0), see: Portnoy, M.; Ben-David, Y.; Milstein, D. J. Organomet.
Chem. 1995, 503, 149-153.
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A R T I C L E S
Ney and Wolfe
substrates. The two-carbon tether present in 7, which would
lead to nucleophilic attack via a six-membered chelate, led to
good reactivity (Scheme 4, 27). However, the three-carbon tether
present in 14 did not promote reactivity via a seven-membered
chelate (Scheme 4, 28).
electron-rich monodentate phosphine ligands PCy3 and P(t-Bu)2-
Me are sufficiently reactive to promote the oxidative addition
of N-tosylaziridines without the requirement for precomplexation
to a tethered alkene on the substrate, but the resulting intermedi-
ate 29 is unstable and is ultimately converted to the N-tosylimine
(31). In contrast, the complex derived from mixtures of Pd2-
(dba)3/phen is less reactive, and chelation assistance is required
to facilitate oxidative addition. However, the resulting inter-
mediate 29 is sufficiently stable toward â-hydride elimination
to allow for σ-bond rotation and capture by the sulfonamide
group to afford the azametallacyclobutane (32).
Intramolecular Alkene Insertion of Azapalladacyclobu-
tane Complexes. Azapalladacyclobutanes 8 and 16 undergo
intramolecular syn carbopalladation of the pendant alkene to
provide the unusual azapalladabicyclo[3.2.1]octane derivatives
17 and 18. Reactivity toward alkene insertion is only observed
in the presence of soft Lewis acids, with optimal results obtained
using added CuI. These reactions are the first examples of olefin
insertion into azametallacyclobutane complexes, and to the best
of our knowledge, they are also the first reported instances in
which an added metal salt facilitates the migratory insertion of
an alkene into a Pd-C bond.
The direct, uncatalyzed insertion of the alkene into the
azametallacyclobutane was not observed. This lack of reactivity
under thermal conditions may be due to the anti-Bredt character
of the transition state for insertion. As shown in Scheme 6,
insertion of the alkene into either the Pd-C or Pd-N bond of
8 would proceed via transition state 33 or 34, respectively. Both
transition states contain partial double bond character between
a bridgehead atom and the adjacent C2 atom. These transition
states would likely be high in energy; thus, low reactivity is
observed.
The ability of Pd(0) complexes to undergo oxidative addition
to N-sulfonylaziridines also appears to be dependent on both
the steric and electronic properties of the metal complex. For
example, N-tosyl-2-but-3-enylaziridine 7 undergoes addition to
Pd2(dba)3/phen but not to the complex generated from Pd2(dba)3
and the less electron-rich 5-nitro-phen (Table 1, entry 8). A
similar electronic effect is observed in the conversion of N-tosyl-
2-butylaziridine 5 to N-tosylketimine 6 via oxidative addition
followed by â-hydride elimination. The reaction is facilitated
by the electron-rich Pd(0) complexes Pd[PCy3]2 and
Pd[P(t-Bu2)Me]2, but no reaction is observed with the less
nucleophilic Pd2(dba)3/P(o-tol)3 mixture (Table 1, entry 1). Use
of very bulky Pd complexes (e.g., Pd[P(t-Bu)3]2) also inhibits
oxidative addition (Table 1, entry 2); the steric bulk of the
complex presumably hinders approach of the metal to the
electrophile.
The results described above are most consistent with a
mechanism for oxidative addition that involves a nucleophilic
SN2-type attack of the Pd(0) complex on the aziridine. This
nucleophilic attack would initially generate a zwitterionic
intermediate (29) that can react further via one of two pathways
(Scheme 5). Intermediate 29 can undergo a σ-bond rotation
followed by nucleophilic attack of the anionic sulfonamide
nitrogen on the cationic palladium center to generate azamet-
allacyclobutane 32, or it can undergo â-hydride elimination to
provide anionic enamine 30, which is protonated to generate
an N-tosylimine (31).8 This mechanistic hypothesis is supported
by the observed inversion of configuration in the oxidative
addition of deuterated aziridine 22 to Pd2(dba)3/phen, which is
consistent with SN2 substitution.
Scheme 7
Scheme 5
The structural features of the metal complex have a large
impact on the nature of the products that are isolated from the
oxidative addition reactions. This effect is presumably a
reflection of the stability of intermediate 29 toward â-hydride
elimination and/or its reactivity toward ring closure. The
The unexpected effect of copper on this otherwise unfavorable
olefin insertion reaction could arise from two plausible scenarios,
which can be distinguished by analysis of the insertion stere-
ochemistry of deuterated azametallacyclobutane 23. One pos-
Scheme 6
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Synthesis and Reactivity of Azapalladacyclobutanes
A R T I C L E S
Scheme 8
sible mechanistic pathway would involve coordination of
copper(I) to the olefin to provide 35,40 which may be activated
for nucleophilic attack by the palladium-bound alkyl (Scheme
7). Transmetalation of the resulting copper(I) alkyl species (36)
to palladium would afford 37,41 the product of formal anti
carbopalladation. This mechanistic pathway can be ruled out,
as 37 is not generated. Instead, product 24, which formally
derives from syn carbopalladation, is formed.
A more plausible pathway that is consistent with the formation
of a product resulting from syn carbopalladation is shown in
Scheme 8. Initial transmetalation of the palladium tosylamide
ligand of 23 to copper(I) could afford an alkylpalladium(II)
iodide intermediate (38).42 This species could then undergo syn
carbopalladation via conformation 38ax, which is unstrained and
does not possess the anti-Bredt characteristics that are exhibited
in transition state 33 described above (Scheme 6). The carbo-
palladation would provide 39, which could undergo transmeta-
lation of the copper(I) tosylamide to yield the observed product
24.42,43
to provide 24. Instead, 40 would be expected to undergo
competing â-hydride elimination to generate methylenecyclo-
pentane product 41. One possible explanation for this observa-
tion is that the pseudoaxial orientation of the -N(Ts)Cu group
could be favored by bridging of the iodide ligand between the
Cu and Pd centers in 38ax. Alternatively, 38ax may simply be
the more reactive conformation for the alkene insertion process.
Oxidatively Induced Reductive Elimination of 17. Treat-
ment of bicyclic palladium complex 17 with CuBr2 or PhI(OAc)2
effected C-X bond-forming reductive elimination to provide
bromide 25 or acetate 26, respectively. Interestingly, carbon-
nitrogen bond-forming reductive elimination to afford azanor-
bornane 43 was not observed with these or other oxidants. This
may be due to a high transition state energy for the formation
of the strained product via an inner-sphere reductive elimination.11i
Alternatively if the reductive elimination proceeds through an
outer-sphere mechanism,16a-d,18 conversion of 17 to 43 would
involve dissociation of the tosylamide ligand from palladium
to afford aminocyclopentane intermediate 42 followed by SN2-
type C-N bond-forming reductive elimination (Scheme 9).44
This pathway would also require a strained transition state in
which both groups occupy pseudoaxial orientations. In contrast,
reductive elimination to generate a C-Br or C-OAc bond
through either an inner-sphere or outer-sphere process would
not require a similarly strained transition state and should be
more facile than C-N bond formation in this system.
Curiously, the most plausible conformation through which
intermediate 38 would be transformed to the observed product
bears the -N(Ts)Cu substituent in a pseudoaxial position (38ax).
Cyclization via conformer 38eq, in which the -N(Ts)Cu group
is pseudoequatorial, would afford 40. This complex contains a
trans relationship between the Pd group and the copper-
sulfonamide moiety and therefore could not undergo cyclization
Scheme 9
(40) For a review on the chemistry of Cu(I) alkene complexes see: Wang,
X.-S.; Zhao, H.; Li, Y.-H.; Xiong, R.-G.; You, X.-Z. Top. Catal. 2005, 35,
43-61.
(41) The stereochemical outcome of transmetalation reactions between well-
defined alkylcopper(I) reagents and palladium has not been established.
However, related Cu-mediated transmetalation reactions between alkyltin
reagents have been shown to proceed with retention of configuration and
are believed to proceed through intermediate alkylcopper species. Direct
transmetalation of alkyl Sn, B, and Si reagents to Pd are also known to
proceed with retention of configuration. See: (a) Ridgway, B. H.; Woerpel,
K. A. J. Org. Chem. 1998, 63, 458-460. (b) Matos, K.; Soderquist, J. A.
J. Org. Chem. 1998, 63, 461-470. (c) Hatanaka, Y.; Hiyama, T. J. Am.
Chem. Soc. 1990, 112, 7793-7794. (d) Ye, J.; Bhatt, R. K.; Falck, J. R. J.
Am. Chem. Soc. 1994, 116, 1-5. (e) Falck, J. R.; Bhatt, R. K.; Ye, J. J.
Am. Chem. Soc. 1995, 117, 5973-5982.
(42) For examples of reversible transmetalation reactions of palladium amido
complexes see: (a) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1995,
117, 4708-4709. (b) Louie, J.; Hartwig, J. F. J. Am. Chem. Soc. 1995,
117, 11598-11599.
(43) An alternative mechanism could involve Cu-mediated dechelation of one
nitrogen atom in the phenanthroline ligand to afford a coordinatively
unsaturated complex, which would be expected to be more reactive towards
alkene insertion. Although we cannot unambiguously rule out this pos-
sibility, the intermediate azametallacyclobutane-alkene complex appears
to be strained, and the transition state for insertion via this pathway would
possess anti-Bredt characteristics similar to those described above in Scheme
6.
Summary of Pd-Mediated Conversion of 7 to 25. Overall,
the transformations described in Table 1, entry 6, and eqs 3
and 4 result in a three-step conversion of aziridine 7 to bromide
(44) To the best of our knowledge, no related examples of SN2-type ring closure
to form azanorbornane structures have been reported. However, the
intramolecular O-alkylation of cis-3-hydoxymethylcyclopentanol to afford
2-oxanorbornane has been described. See: Kirmse, W.; Mrotzeck, U. Chem.
Ber. 1988, 121, 485-492.
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A R T I C L E S
Ney and Wolfe
mixture was then cooled to room temperature and transferred to a clean,
flame-dried Schlenk flask via cannula filtration under nitrogen. The
solution was concentrated under reduced pressure to a volume of 5-10
mL, and ether (50 mL) was added to afford a yellow precipitate. The
solid material was collected by vacuum filtration, washed with ether
(4 × 50 mL) and hexane (2 × 50 mL), and dried in vacuo.
25 (Scheme 10) that would be difficult to achieve using other
methods. These three reactions effect difunctionalization of the
alkene with 1,2-addition of a Br atom and the C1 atom, which
can be viewed as a formal reversal of polarity of the electrophilic
aziridine carbon. Although this process is not yet catalytic, the
individual transformations all occur under mild and essentially
neutral reaction conditions. The overall process should be of
significant interest if catalytic conditions can be developed, as
molecules that are structurally related to 25 have been employed
as intermediates in the construction of natural products and other
biologically active molecules.45
(Phen)Pd{NTsCH(CH2CH2CHCH2)CH2} (8). Reaction of 377 mg
(1.5 mmol) of 7 with 458 mg (0.5 mmol) of Pd2(dba)3 and 180 mg
(1.0 mmol) of 1,10-phenanthroline following the general procedure
afforded 262 mg (49%) of the title compound as a yellow solid, mp
1
185 °C (decomp). H NMR (500 MHz, CDCl3) δ 10.06 (dd, J ) 1.5,
5.0 Hz, 1 H), 8.54 (dd, J ) 1.5, 5.0 Hz, 1 H), 8.49 (dd, J ) 1.5, 8.5
Hz, 1 H), 8.40 (dd, J ) 1.5, 8.5 Hz, 1 H), 8.09 (d, J ) 8.5 Hz, 2 H),
7.92 (s, 2 H), 7.84 (dd, J ) 5.0, 8.0 Hz, 1 H), 7.68 (dd, J ) 5.0, 8.5
Hz, 1 H), 7.16 (d, J ) 8.0 Hz, 2 H), 5.79-5.70 (m, 1 H), 4.97-4.84
(m, 2 H), 4.51-4.45 (m, 1 H), 2.34 (s, 3 H), 2.08-1.93 (m, 2 H),
1.61-1.48 (m, 2 H), 1.12 (dd, J ) 5.0, 8.0 Hz, 1 H), 0.57 (app t, J )
5.0 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 153.4, 149.4, 146.8,
144.7, 141.7, 140.6, 139.5, 137.5, 137.1, 129.9, 129.3, 128.9, 128.0,
127.8, 126.5, 126.1, 124.8, 113.9, 68.7, 38.5, 29.1, 21.6, -6.0; IR (film)
1127, 1084 cm-1; MS (ESI) m/z 560.0613 (560.0600 calcd for
C25H25N3O2PdS, M + Na+).
Scheme 10
(Phen)Pd{NTsCH(CH2CH2)CH2CHCH2} (17). A flame-dried
Schlenk flask equipped with a magnetic stir bar was charged with CuI
(15 mg, 0.078 mmol). The flask was purged with nitrogen, and then a
solution of 8 (210 mg, 0.39 mmol) in 39 mL of CH2Cl2 was added.
The reaction mixture was stirred at room temperature for 20 h and
then transferred to a clean, flame-dried Schlenk flask via cannula
filtration under nitrogen. The solution was concentrated under reduced
pressure to a volume of 3 mL, and ether (50 mL) was added to afford
an orange precipitate. The solid material was collected by vacuum
filtration, washed with ether (4 × 50 mL) and hexane (2 × 50 mL),
and dried in vacuo to afford the title compound (171 mg, 81%) as an
Conclusions
In conclusion, we have described the first syntheses of
azapalladacyclobutane complexes 1, which are effected via
oxidative addition of N-sulfonylaziridines to mixtures of Pd2-
(dba)3/phen. These metallacycles undergo intramolecular syn
carbopalladation in the presence of copper(I) iodide to afford
azapalladabicyclo[3.2.1]octanes in the first examples of alkene
insertions into azametallacyclobutanes. The unusual bridging
bicyclic complexes generated in the insertion reactions undergo
oxidative cleavage of the palladium-carbon bond to afford
substituted cyclopentylamine derivatives. These transformations
have the potential for application to the development of new
metal-catalyzed ring expansion reactions of aziridines and
represent an unusual three-step umpolung process in which the
polarization of the aziridine C1 atom is formally reversed.
Efforts to render these reactions catalytic and to expand the
scope of the oxidative addition and insertion chemistry are
currently underway.
1
orange solid, mp 185 °C (decomp). H NMR (500 MHz, CDCl3) δ
9.64 (d, J ) 4.0 Hz, 1 H), 8.84 (d, J ) 4.5 Hz, 1 H), 8.48 (d, J ) 8.0
Hz, 1 H), 8.36 (d, J ) 7.5 Hz, 1 H), 8.12 (d, J ) 8.0 Hz, 2 H), 7.90-
7.82 (m, 3 H), 7.76 (dd, J ) 5.0, 8.0 Hz, 1 H), 7.22 (d, J ) 7.5 Hz, 2
H), 3.87-3.83 (m, 1 H), 2.39 (s, 3 H), 2.05-1.97 (m, 1 H), 1.92-
1.84 (m, 1 H), 1.84-1.81 (m, 1 H), 1.81-1.74 (m, 1 H), 1.68-1.63
(m, 1 H), 1.63-1.58 (m, 1 H), 1.45-1.40 (m, 1 H), 1.22-1.15 (m, 1
H), 1.09-1.04 (m, 1 H); 13C NMR (125 MHz, CDCl3) δ 151.5, 148.0,
147.9, 144.5, 143.5, 140.0, 137.8, 136.7, 130.0, 129.2, 128.8, 128.3,
127.5, 126.3, 125.4, 124.5, 56.6, 39.6, 38.3, 34.4, 30.6, 27.8, 21.6; IR
(film) 1263, 1132, 1092 cm-1; MS (ESI) m/z 560.0604 (560.0600 calcd
for C25H25N3O2PdS, M + Na+).
Acknowledgment. The authors thank Eli Lilly (Grantee
Award), Research Corporation (Innovation Award), The Camille
and Henry Dreyfus Foundation (New Faculty Award, Camille
Dreyfus Teacher-Scholar Award), Amgen, and 3M for financial
support of this work. J.E.N. acknowledges the University of
Michigan for a Regents Fellowship, Pfizer for a Graduate
Research Fellowship, and the American Chemical Society
Division of Organic Chemistry for a Graduate Fellowship.
Experimental Section
General Procedure for the Synthesis of Azapalladacyclobutanes.46
A flame-dried Schlenk flask equipped with a magnetic stir bar was
charged with Pd2(dba)3 (0.5 mmol, 1.0 mmol Pd) and 1,10-phenan-
throline (1.0 mmol). The flask was purged with nitrogen, THF (50 mL)
was added, and the mixture was stirred at room temperature for 1 min.
A solution of the aziridine (1.0-1.5 mmol) in THF (50 mL) was added,
and the reaction mixture was heated to 65 °C with stirring for 5 h. The
Supporting Information Available: Experimental procedures,
characterization data for all new compounds, descriptions of
deuterium-labeling experiments, descriptions of structural and
stereochemical assignments, and selected one- and two-
dimensional NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(45) (a) Trost, B. M.; Madsen, R.; Guile, S. D.; Brown, B. J. Am. Chem. Soc.
2000, 122, 5947-5956. (b) Trost, B. M.; Madsen, R.; Guile, S. D.
Tetrahedron Lett. 1997, 38, 1707-1710.
(46) The yields reported in the Experimental Section and the Supporting
Information describe the result of a single experiment, whereas the yields
reported in Tables 1 and 2, Schemes 2 and 3, and eqs 3 and 4 are average
yields of two or more experiments. Thus, the yields reported in the
Experimental Section and Supporting Information may differ from those
shown in Tables 1 and 2, Schemes 2 and 3, and eqs 3 and 4.
JA0660756
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15422 J. AM. CHEM. SOC. VOL. 128, NO. 48, 2006