C O M M U N I C A T I O N S
Scheme 1. One-Pot Synthesis of ꢀ-Lactamsa
Table 2. Expanding the Scope of the Lactamization Reactiona,b
a Reaction conditions: (1) 0.5 mmol of substrate, 10 mol % Pd(OAc)2, 1.5
equiv of CuCl2, 2.0 equiv of AgOAc, DCE, 100 °C, N2, 10 h. (2) 4 equiv of
CsF, 0.18 equiv of benzyltriethyl ammonium chloride, 100 °C, 12 h.
Scheme 2. Mechanistic Studiesa
a Reaction conditions: 0.5 mmol of substrate, 10 mol % Pd(OAc)2, 1.5 equiv
of CuCl2, 2.0 equiv of AgOAc, DCE, 100 °C, N2, 10 h.
Second, lactam 21b did not form when substrate 21 was subjected to
the standard conditions (Scheme 2). These observations argue against
a sequential chlorination-amination pathway in these reactions.
In summary, we have developed a novel catalytic C-H lactamiza-
tion reaction using a Pd(II) catalyst. The reaction provides new access
to a range of lactams. We are currently developing an intermolecular
C-H amination protocol using this catalysis.
Acknowledgment. We thank The Scripps Research Institute, the
U.S. National Science Foundation (NSF CHE-0615716), and Amgen
Inc. for financial support and A. P. Sloan Foundation for a Fellowship
(J.-Q.Y.).
Supporting Information Available: Experimental procedure and
characterization of all new compounds. This material is available free of
References
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Li, J.-J.; Mei, T.-S.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 6452.
(4) For the preparation of γ-benzolactams via Pd-catalyzed C-H activation/
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a Conditions: 0.5 mmol of substrate, 10 mol% Pd(OAc)2, 1.5 equiv of
CuCl2, 2.0 equiv of AgOAc, 10 mL of dichloroethane, N2, 100 °C, 10 h.
b For entry 5, 4:1 mixture of E-Z isomers was used. For entry 6, 6:1 mixure
of E-Z isomers was used.
(5) For the intramolecular carbene insertion into C-H bonds adjacent to
nitrogen atoms of diazoacetamides catalyzed by dirhodium(II) carboxylates,
see: (a) Watanabe, N.; Anada, M.; Hashimoto, S.-i.; Ikegami, S. Synlett
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7190.
C-H bonds could be achieved by using an N-benzyloxy amide. At
this stage, the exact mechanistic nature of this sp3 C-H activation
remains to be elucidated.
When substrate 20 was treated with our standard lactamization
conditions, only ꢀ-chlorinated products were obtained (Scheme 1). This
is not surprising since the reductive elimination of the five-membered
palladacycle to form four-membered ꢀ-lactam is less favored due to a
strained transition state structure, and therefore the reductive elimination
of the alkyl chloride from the Pd(IV) intermediate occurs. Importantly,
ꢀ-lactams can be readily obtained by treating the reaction mixture with
CsF and triethylbenzyl quaternary ammonium salt in one pot (Scheme
1).
(7) For CuCl2-catalyzed C-H bond chlorination, see: Chen, X.; Goodhue, C. E.;
Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790.
(8) For the use of a combination of Pd(OAc)2/CuCl2 for C-H bond chlorination,
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Chem. 1996, 32, 89. (b) Wan, X.; Ma, Z.; Li, B.; Zhang, K.; Cao, S.; Zhang,
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(11) Kawase, M.; Kitamura, T.; Kikugawa, Y. J. Org. Chem. 1989, 54, 3394–
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Preliminary mechanistic studies were also carried out. First, the
ortho-chlorinated substrate 21 (Scheme 2) did not undergo intramo-
lecular amination under treatment with CuCl in DCE at 100 °C.
(12) Yang, H. W.; Romo, D. J. Org. Chem. 1999, 64, 7657.
(13) Bachrach, S. M. J. Org. Chem. 2008, 73, 2466.
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J. AM. CHEM. SOC. VOL. 130, NO. 43, 2008 14059