Selective and catalytic arylation of N-phenylpyrrolidine: sp3 C-H bond functionalization in the absence of a directing group

Article abstract of DOI:10.1021/ja050269o

We herein describe our studies on arylation of N-phenylpyrrolidine, which led to the development of a new transformation for the direct and selective arylation of sp³ C-H bonds in the absence of a directing group. In this method, Ru(H)₂(CO)(PCy₃)₃ 4 was used as the catalyst, and preliminary mechanistic studies suggested that Ru(Ph)(I)(CO)(PCy₃)₂ 5 is the key intermediate of the catalytic cycle. A large kinetic isotope effect (k_H/k_D = 5.4) was observed, which supports the proposal that C-H bond metalation is the slow step. Preliminary examination of the substrate scope showed that in addition to N-phenylpyrrolidine, N-methyl- and N-benzylpyrrolidine, as well as N-benzoylpyrrolidine, were arylated under the reaction conditions. Copyright

Full text of DOI:10.1021/ja050269o

Published on Web 03/23/2005
Selective and Catalytic Arylation of N-Phenylpyrrolidine: sp3 C-H Bond
Functionalization in the Absence of a Directing Group
Bengu¨ Sezen and Dalibor Sames*
Department of Chemistry, Columbia UniVersity, 3000 Broadway, New York, New York 10027
Received January 14, 2005; E-mail: sames@chem.columbia.edu
This paper was retracted on March 1, 2006 (J. Am. Chem. Soc. 2006, 128, 3102).
Despite significant progress in the area of C-H bond function-
alization, catalytic intermolecular transformations of sp3 C-H bonds
to C-C bonds still remain rare.1 These few examples depend on
the presence of a suitably situated directing group and, hence, suffer
from a limited substrate scope.2,3 In this paper, we report our studies
Figure 1. Challenges: (a) sp3 versus sp2 C-H bond arylation; (b)
on arylation of N-phenylpyrrolidine, which led to the development
competing pathways following the C-H bond activation step; i. â-H
of a new catalytic system capable of selective arylation of sp3 C-H
elimination, ii. dehalogenation of PhX, and iii. C-C bond formation.
bonds in the absence of a directing group.4
The direct coupling of an sp3 C-H bond and a haloarene requires
Although the involvement of the carbene complexes seemed
unlikely, our interest in ruthenium complexes was not diminished,
due to their low propensity for â-hydride elimination.8 The first
lead was obtained with Ru(H)2(CO)(PPh3)3, which not only showed
good selectivity for the R-CH2 position but also underwent catalytic
turnover (14% yield, Table 1). Encouraged by this exciting dis-
covery, we modified the catalyst by replacing triphenylphosphine
with more electron donating and bulkier phosphine ligands, with
the aim to stabilize the higher oxidation state intermediates and
favor the reductive elimination of the product. Indeed, these alter-
ations led to an improved catalyst as Ru(H)2(CO)(PCy3)3 afforded
the desired product in 32% yield.
the introduction of an aryl group to the metal system (via oxidative
addition of Ar-X) either before or after the C-H bond activation
step (eq 1). To translate this simple scheme to practice, however,
multiple challenges need to be addressed: (1) the selectivity for
sp3 C-H bonds over arene sp2 bonds; (2) the suppression of
â-hydride elimination; and (3) the suppression of dehalogenation
in favor of C-C bond formation (Figure 1).
Subsequently, we undertook preliminary mechanistic studies to
determine the order of two key steps, namely, the oxidative addition
of PhI and the C-H bond activation (eq 1). As the reactions in the
absence of iodobenzene yielded no insight, we directed our efforts
toward the sequence wherein C-I addition precedes the C-H
activation.
The feasibility of this scenario was documented by in situ NMR
analysis, which revealed the formation of complex 5 upon heating
of the reaction mixture, presumably via elimination of hydrogen
followed by oxidative addition of iodobenzene (Figure 2).9 More-
over, complex 5, prepared through an independent procedure,
reacted with N-phenylpyrrolidine directly, furnishing the product
in 71% yield (eq 3). Further analysis revealed nearly identical
behavior (yields and kinetics) of 4 and 5 in both catalytic and
stoichiometric reactions (for details, see Supporting Information).10
N-Phenylpyrrolidine was chosen as a suitable substrate for our
studies. Although the higher reactivity of the methylene group
adjacent to the amine (“activated” C-H bonds) is well recognized,
a direct arylation of this position has not been achieved.5 Our initial
results with Cp*M(H)2PR3 complexes6 highlighted the selectivity
issue discussed above as the arylation occurred predominantly on
the phenyl ring (eq 2). The product distribution was in accord with
the well-documented thermodynamic preference for the metalation
of sp2 over sp3 C-H bonds.7 Noteworthy is the fact, however, that
the phenylation did occur, and these preliminary studies demon-
strated the feasibility of intermolecular arylation of benzene rings
in the absence of a directing group. It should be noted that the key
to success was the judicious choice of base and solvent.
To confirm that this transformation did not proceed via an en-
amine intermediate formed by â-hydride elimination, N-phenylpyr-
rolidine deuterated at both â-positions was prepared. As expected,
no hydrogen incorporation in the product was observed (eq 4).
With the focus on sp3 C-H bonds, however, we decided to
explore ruthenium-pyrrolidine carbene complexes, prepared by
metalation of pyrrolidines in Caulton’s group8 as possible inter-
mediates in the arylation reaction. Having failed to obtain any stable
complexes from the reaction of N-phenylpyrrolidine with the
Caulton complex {Ru(H)(Cl)[P(iPr)3]2}2, we turned our attention
to the known carbene complex, derived from N-methylpyrrolidine.
When treated with iodobenzene, this complex gave only traces of
the arylation products (Supporting Information).
On the basis of these observations, we propose the following
mechanistic model (Figure 2). The reaction is initiated by the
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C O M M U N I C A T I O N S
Table 1. Identification of the Active Catalyst Systema
Last, a preliminary examination of the substrate scope showed
that in addition to N-phenylpyrrolidine, N-methyl- and N-benzyl-
pyrrolidine, as well as N-benzoylpyrrolidine, were arylated under
the reaction conditions. In the case of N-benzylpyrrolidine, phenyl-
ation occurred preferentially at the R-methylene groups, confirming
the selectivity of this system for sp3 over sp2 C-H bonds (eq 5;
for details, see Supporting Information).
[M]
1 / 2 / 3
Ru(H)2(CO)(PPh3)3
14 / 3 / 2
26 / 4 / 3
28 / 4 / 2
32 / 6 / 4
34 / 5 / 4
Ru(H)2(CO)(PCyPh2)3
Ru(H)2(CO)(PCy2Ph)3
Ru(H)2(CO)(PCy3)3 (4)
Ru(Ph)(I)(CO)(PCy3)2 (5)
a Conditions: N-phenylpyrrolidine (1 equiv), PhI (1.2 equiv), [Ru] (5
mol % Ru), Cs2CO3 (1.2 equiv), tert-BuOH, 150 °C, 18 h. The given yields
are the average of three runs with deviation of 2-3%. Purification of
reagents and anhydrous conditions are required (see Supporting Information
for details).
In summary, a novel transformation was identified to achieve
the direct and selective arylation of sp3 C-H bonds in the absence of
a directing group. Although rudimentary in its efficiency, this cata-
lytic system sets the precedent for future development in this area.
Acknowledgment. This work was supported by the NIGMS.
D.S. is a recipient of the Bristol-Myers Squibb Unrestricted Grants
in Synthetic Organic Chemistry Award and Pfizer Award for
Creativity in Organic Chemistry. B.S. is a recipient of the Bristol-
Myers Squibb graduate fellowship. We thank GlaxoSmithKline,
Merck Research Laboratories, Dr. J. B. Schwarz (editorial as-
sistance), and Vitas Votier Chmelar (intellectual support).
Figure 2. Proposed mechanistic scheme.
Table 2. Catalyst Improvementa
Supporting Information Available: Experimental procedures,
spectral data for all products, kinetics of stoichiometric and catalytic
experiments with complexes 4 and 5 (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
References
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[M]
1 / 2 / 3
Ru(H2)(H)2(PCy3)3
Ru(H2)2(H)2(PCy3)2
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