Palladium-catalyzed alkylation of aryl C-H bonds with sp3 organotin reagents using benzoquinone as a crucial promoter

Article abstract of DOI:10.1021/ja0570943

The combination of directed C-H activation, batch-wise addition of tetraalkyltin reagents, and rate enhancement by benzoquinone and microwave irradiation provides a promising strategy for the direct coupling of C-H bonds with organometallic reagents. A variety of tetraalkyltins were coupled to C-H bonds to give the alkylated products in good yields by using 5 mol % Pd(OAc)₂ as the catalyst. Benzoquinone was shown to be essential for the C-H activation when substrates containing non-π-conjugated chelating groups are used. Monitoring the formation and reductive elimination of the Pd(Ar)(Me)L₂ complex also revealed that benzoquinone promotes the reductive elimination step. Microwave irradiation enhances the reaction rate drastically. The versatility of this protocol was demonstrated by using substrates containing either oxazoline or pyridine as directing groups. Copyright

Full text of DOI:10.1021/ja0570943

Published on Web 12/08/2005
Palladium-Catalyzed Alkylation of Aryl C-H Bonds with sp3 Organotin
Reagents Using Benzoquinone as a Crucial Promoter
Xiao Chen, Jiao-Jie Li, Xue-Shi Hao, Charles E. Goodhue, and Jin-Quan Yu*
Department of Chemistry MS015, Brandeis UniVersity, Waltham, Massachusetts 02454-9110
Received October 24, 2005; E-mail: yu200@brandeis.edu
Scheme 1. Benzoquinone-Promoted Stoichiometric Coupling
The direct coupling of C-H bonds with organometallic reagents
is an attractive C-C bond-forming method that compliments the
widely used cross-coupling reactions of Ar-X bonds (X ) halide,
OTf, OMs, OP(O)(OR)2, OR, SR, and N2BF4) (eq 1).1 Pyridine-
and carbonyl-directed arylation of o-aryl C-H bonds using RhCl-
(PPh3)3/Ph4Sn and RuH2(CO)(PPh3)3/arylboronates, respectively,
illustrate the feasibility of this approach.2 Sames’ Pd(OAc)2-
Scheme 2. Catalytic Methylation of Aryl C-H Bonds
catalyzed arylation of sp3 C-H bonds in a bisdentate chelating
substrate using Ph2Si(OH)Me as a coupling partner represents an
important step forward in developing this strategy.3
In contrast to the remarkable progress in the Pd0-catalyzed cross-
coupling reactions of aryl or alkyl halides with organometallic
reagents,4 the development of PdII-catalyzed coupling of C-H
bonds with organotin still faces the following two challenges:5-7
(a) the PdII species required for C-H activation causes rapid homo-
coupling of the organotin reagent,8 (b) the C-H activation reaction
conditions are often not compatible with the transmetalation step
or the reoxidation of the Pd0 in the catalytic cycle (eq 1). In this
communication, we disclose the first protocol for PdII-catalyzed
alkylations of aryl C-H bonds with a variety of primary-alkyl tin
and the reoxidation step to complete. After 10 batches of Me4Sn
regents using a combination of directed C-H activation and batch-
wise addition of the organotin reagent.
(0.75 equiv in total) were added, the reaction mixture was subjected
1
to a workup procedure and analyzed by H NMR.
Various protocols for the reoxidation of Pd0 to PdII in catalysis
have been developed;13 however, most of the conditions involving
the use of acetic acid, DMF, and DMSO are not compatible with
either the C-H activation or the transmetalation step in our experi-
ments. It was decided to focus on the most commonly used oxida-
tion system Cu(OAc)2/air/benzoquinone. We found that catalytic
alkylation of 1 can be achieved by using 1 equiv of Cu(OAc)2 and
Recently, we reported the palladium-catalyzed 2-oxazoline
directed stereoselective iodination and oxygenation of unactivated
C-H bonds.9 Inspired by the early observation of a stoichiometric
phenylation reaction of a tri-o-tolyphosphane-bound palladium
0.5 equiv of benzoquinone in CH2Cl2 under air to afford mainly
complex with Me3SnPh by Hartwig,10 we decided to explore Pd-
the dialkylated product 1d (Scheme 2). Further screening of solvents
(OAc)2-catalyzed coupling of aryl C-H bonds with sp3 organotin
then established that MeCN is the best solvent for this catalytic
reagents. We envisioned that the undesired homo-coupling of tin
reaction.
reagents mediated by PdII could be avoided by adding the organotin
coupling partner batch-wise if C-H cleavage and reoxidation of
As previously pointed out by Murai and co-workers, directed
C-H activation of aryl C-H bonds are favored by a σ-chelating
heteroatom that is conjugated to the aryl rings as in 1 and 2, and
the non-π-conjugated chelation-assisted catalytic C-H activation/
C-C bond-forming reactions are still relatively rare.14 We were
pleased to find that the coupling reactions of 2-benzyloxazolines
3-7 containing one carbon atom between the aryl ring and the
σ-chelating group proceeded smoothly to give the desired methy-
lation products in the presence of 1 equiv of benzoquinone (Table
1). In contrast to 1 and 2, the reactions of 3-7 give the mono-
methylation products 3a-7a exclusively. Importantly, our experi-
ments showed that the presence of 1 equiV of benzoquinone is
essential for C-H actiVation to occur with this type of substrate
(3-7) (see Supporting Information). Since the formation of a cyclic
trinuclear mixed metal acetate [Cu2Pd(OAc)6] was preViously
reported,15 it is possible that benzoquinone preVented the formation
of this complex which is not reactiVe for substrates 3-7.
Pd0 is sufficiently fast. To establish suitable conditions that are
compatible with each individual step, oxazoline substrate 1 was
stirred with 1 equiv of Pd(OAc)2 in CH2Cl2 at 100 °C for 3 h (in
a tube sealed with a Teflon cap) to afford the previously reported
dimeric complex 1a in 90% yield.11 Treatment of complex 1a with
0.75 equiv of Me4Sn under the same conditions gives the expected
methylation product 1b in 20% yield (Scheme 1). The use of 1
equiv of benzoquinone was found to improve the yield to 95%.
1
Monitoring the formation and reductiVe elimination of 1b by H
NMR reVealed that benzoquinone promotes the reductiVe elimina-
tion step (see Supporting Information).12
We next sought to identify a suitable oxidant to reoxidize Pd0
to PdII to close the catalytic cycle under the same conditions.
Reactions were carried out by stirring oxazoline substrates with
10 mol % Pd(OAc)2 in the presence of various oxidants, and 0.075
equiv of Me4Sn was added every 4 h to allow the C-H activation
9
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J. AM. CHEM. SOC. 2006, 128, 78-79
10.1021/ja0570943 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 5. Methylation Assisted by Microwave Irradiation
Table 1. Pd-catalyzed Alkylation of Aryl C-H Bondsa
a fast step. By using the microwave conditions, the reaction can be
carried out by adding the organotin every 0.5 h, thereby reducing the
overall reaction time to 10 h using 5 mol % Pd(OAc)2 (Scheme 5).
In summary, we have developed a protocol for PdII-catalyzed
alkylations of aryl C-H bonds. The combination of directed C-H
activation, batch-wise addition of tetraalkyltin reagents, and rate
enhancement by benzoquinone and microwave irradiation provides
a promising strategy for the development of C-C bond-forming
reactions via coupling of C-H bonds with organometallic reagents.
Future work will concentrate on the coupling of sp3 C-H bonds
and other environmentally benign organometallic reagents.
Acknowledgment. We thank Brandeis University for financial
support and the Camille and Henry Dreyfus Foundation for a New
Faculty Award.
Supporting Information Available: Experimental procedures and
characterization of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
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Scheme 3. Alkylation Using Various Primary Alkyl Tin Reagents
Scheme 4. Methylation Assisted by a Pyridine Directing Groupa
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a Reaction conditions: Pd(OAc)2 (5 mol %), Me4Sn (0.037 equiv × 20),
Cu(OAc)2 (1 equiv), benzoquinone (1 equiv), MeCN, 100 °C, 40 h.
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We further tested Et4Sn as a coupling partner, and satisfactory
yields were obtained, suggesting that the reductive elimination is
sufficiently faster than the undesired â-hydride elimination in the
presence of benzoquinone (Table 1, entries 8-14). By adding the
organotin reagents in 20 batches every 3 h, alkylation reactions
proceed smoothly in the presence of 5 mol % of Pd(OAc)2. A
variety of primary alkyl tin reagents were tested using these new
conditions, and the alkylated products were obtained in good yields
consistently (Scheme 3).16
These results encouraged us to extend our protocol to the
extensively investigated pyridine-directed C-H activation/C-C
bond-forming reactions of substrate 8 (Scheme 4).2,6c The advantage
is again demonstrated by coupling substrate 9 containing a pyridine
ring that is not conjugated to the aryl ring.
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(16) Fifteen percent of the alkylated product was obtained when substrate 4
and (i-Pr)4Sn were used.
The necessity for the addition of the tin reagent in batches results
in long reaction time, especially when Pd-loading is low. In principle
this could be circumvented by shortening the reaction time of the
C-H activation and reoxidation steps since the transmetalation is
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