generation of seven-membered heterocycles via this strategy
would be quite challenging, as both yields and reaction rates
diminish with increasing ring size. This appears to be due to
two main problems related to the mechanism of these
transformations: as ring size increases, (a) Syn-aminopal-
ladation of the alkene (Scheme 1), 6f7, becomes more
difficult due to entropic and stereoelectronic effects;9,10 and
(b) competing formation of enamine side products 9ꢀ10,
via β-hydride elimination from intermediate 7, becomes
more problematic.9,10 The application of this methodology
to the construction of seven-membered rings has not pre-
viously been demonstrated, and the formation of seven-
membered nitrogen heterocycles via other metal-catalyzed
alkene difunctionalization reactions is very rare.12 For
example, Michael has described a conceptually related
Pd(II)-catalyzed CꢀH activation/carboamination of a
N-allyl-2-(aminomethyl)aniline derivative that afforded a
3-substituted 1,4-benzodiazepine. However, only a single
example was reported, and the yield was modest (53%).12c
Pd-catalyzed N-arylation of methyl-2-aminobenzoate.13
Saponification of the ester followed by coupling of the
resulting acid 12 with an allylic amine provided amides 13.
Reduction of the amides with LiAlH4 then afforded 14 in
moderate to good yield.
Scheme 2. Synthesis of Substrates
In our preliminary experiments we examined the Pd-
catalyzed coupling of 14a with 4-bromobiphenyl (Table 1).
Our previous studies indicated that use of P(2-fur)3 as
a ligand gave satisfactory results in six-membered ring
forming reactions.9 However, use of this ligand in a reaction
of 14a provided desired product 15 in a modest 58% NMR
yield, along with 13% of ketone 16. This side product
presumably results from hydrolysis of an enamine (9, n =
3), which is generated via a competing β-hydride elimination
pathway (Scheme 1). In order to minimize this side reaction,
Scheme 1. Mechanism and Competing Pathways
To determine the feasibility of forming seven-membered
nitrogen heterocycles via Pd-catalyzed carboamination
reactions, we elected to examine the synthesis of saturated
1,4-benzodiazepines. The substrates 14 for these studies
were prepared in three steps from readily available diary-
lamines 11 (Scheme 2), which can be generated via
Table 1. Optimization of Reaction Conditionsa
(8) Pyrrolidines: (a) Ney, J. E.; Wolfe, J. P. Angew. Chem., Int. Ed.
2004, 43, 3605. (b) Bertrand, M. B.; Neukom, J. D.; Wolfe, J. P. J. Org.
Chem. 2008, 73, 8851. (c) Lemen, G. S.; Wolfe, J. P. Org. Lett. 2010, 12,
2322. Pyrazolidines: (d) Giampietro, N. C.; Wolfe, J. P. J. Am. Chem.
Soc. 2008, 130, 12907. Isoxazolidines: (e) Lemen, G. S.; Giampietro,
N. C.; Hay, M. B.; Wolfe, J. P. J. Org. Chem. 2009, 74, 2533.
Imidazolidin-2-ones: (f) Fritz, J. A.; Wolfe, J. P. Tetrahedron 2008, 64,
6838.
(9) Piperazines: (a) Nakhla, J. S.; Schultz, D. M.; Wolfe, J. P.
Tetrahedron 2009, 65, 6549. Morpholines: (b) Leathen, M. L.; Rosen,
B. R.; Wolfe, J. P. J. Org. Chem. 2009, 74, 5107.
(10) Reviews: (a) Wolfe, J. P. Eur. J. Org. Chem. 2007, 571. (b) Wolfe,
J. P. Synlett 2008, 2913.
yield 15 yield 16
Pd-source
Pd2(dba)3
ligand
conversion (%)
(%)b
(%)b
P(2-fur)3
S-Phos
91
100
100
100
100
58
13
0c
8
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
0
PCy2Ph
PPh2Cy
46
79
79 (65)d
6
PdCl2(MeCN)2 PPh2Cy
4
a Conditions: 1.0 equiv of 14a, 2.0 equiv of 4-bromobiphenyl, 2.0
equiv of NaOtBu, 2 mol % [Pd], 4 mol % ligand. Product 15 was formed
with >20:1 dr. b Yields were determined by 1H NMR analysis of crude
reaction mixtures using phenanthrene as an internal standard. c The
major product resulted from N-arylation of the starting material.
d Isolated yield (average of two experiments).
(11) For Cu- or Au-catalyzed carboamination reactions that afford
2-(arylmethyl)pyrrolidines and related heterocycles, see: (a) Chemler,
S. R. Org. Biomol. Chem. 2009, 7, 3009. (b) Zhang, G.; Cui, L.; Wang, Y.;
Zhang, L. J. Am. Chem. Soc. 2010, 132, 1474. For alkene carboamina-
tion reactions involving solvent CꢀH bond functionalization, see: (c)
Rosewall, C. F.; Sibbald, P. A.; Liskin, D. V.; Michael, F. E. J. Am.
Chem. Soc. 2009, 131, 9488.
(12) For hydroamination reactions, see: (a) Leitch, D. C.; Payne,
P. R.; Dunbar, C. R.; Schafer, L. L. J. Am. Chem. Soc. 2009, 131, 18246.
(b) Reznichenko, A. L.; Hultzsch, K. C. Organometallics 2010, 29, 24. (c)
several other monodentate ligands were examined. Use of
S-Phos failed to afford the desired product.14 Instead,
ꢀ
Gagne, M. R.; Stern, C. L.; Marks, T. J. J. Am. Chem. Soc. 1992, 114,
€
275. For diamination reactions, see: (d) Streuff, J.; Hovelmann, C. H.;
~
Nieger, M.; Muniz, K. J. Am. Chem. Soc. 2005, 127, 14586. For Cope-
(13) Wolfe, J. P.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6359.
type hydroamination reactions, see: (e) Roveda, J.-G.; Clavette, C.;
Hunt, A. D.; Gorelsky, S. I.; Whipp, C. J.; Beauchemin, A. M. J. Am.
Chem. Soc. 2009, 131, 8740.
(14) S-Phos
=
2-dicyclohexylphosphino-20,60-di-isopropoxy-1,10-
biphenyl.
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