Highly selective palladium-catalyzed oxidative Csp2-Csp 3 cross-coupling of arylzinc and alkylindium reagents through double transmetallation

Article abstract of DOI:10.1002/adsc.200800703

Using desyl chloride (2-chloro-1,2-diphenylethanone) as the oxidant, the palladium-catalyzed reaction of arylzinc with alkylindium reagents occurred smoothly in a highly selective manner to afford the products in 57-90% yields. Preliminary kinetic data in

Full text of DOI:10.1002/adsc.200800703

FULL PAPERS
DOI: 10.1002/adsc.200800703
2
3
À
Highly Selective Palladium-Catalyzed Oxidative Csp Csp Cross-
Coupling of Arylzinc and Alkylindium Reagents through Double
Transmetallation
Liqun Jin,a Yingsheng Zhao,a Lizheng Zhu,a Heng Zhang,a,* and Aiwen Leia,*
a
The College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, Hubei, Peopleꢀs Republic of China
Fax : (+86)-27-6875-4067; phone: (+86)-27-6875-4672; e-mail: aiwenlei@whu.edu.cn
Received: November 13, 2008; Revised: February 7, 2009; Published online: March 12, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800703.
Abstract: Using desyl chloride (2-chloro-1,2-diphen- highly favored for transmetallation with the alkoxy-
ACHTUNGTRENNUNGylethanone) as the oxidant, the palladium-catalyzed palladium moiety.
reaction of arylzinc with alkylindium reagents oc-
curred smoothly in a highly selective manner to
afford the products in 57–90% yields. Preliminary ki- Keywords: alkylindium reagents; arylzinc reagents;
netic data indicated that alkylindium reagents were cross-coupling reaction; palladium
Introduction
RalkylX were revolutionized by employing electron-
rich and sterically hindered phosphine ligands or car-
bene ligands, and showed good potential in organic
2
3
2A
Csp Csp bond formation, especially the Csp CTHNGUTRNE(NUG aryl)
À
À
Csp3 version, is a valuable tool of unfailing interest in synthesis.[7,10–20]
organic synthesis. This transformation could be realiz-
With our strong interest in Csp3-related coupling
ed via classic methods such as nucleophilic substitu- reactions, we recently developed an oxidative cross-
tion, Friedel–Crafts reaction, etc., or modern methods coupling reaction (shown in Scheme 1B), in which
involving transition metals as catalysts. Scheme 1A il- two nucleophiles, prepared readily from inexpensive
lustrates the latter strategies, in which either ArX or and abundant organic chlorides, could be coupled to-
À
R
alkylX could serve as the electrophile.[1] The ArX gether in the presence of an oxidant, A B. The strat-
option has been explored, in which RalkylM could be egy has been successfully applied in cross-coupling of
3
[21]
either alkylzinc reagents (Negishi reaction),[2–4] alkyl- Csp Sn reagents and Csp Zn reagents. Herein, we
À
À
boron reagents (Suzuki reaction)[5] or others. When report our extension to make Csp Csp bonds by
alkylX was the electrophile, the success was more lim- this strategy, in which arylzinc reagents and alkylindi-
2
3
À
R
ited due to the difficult oxidative addition of RalkylX um reagents were successfully cross-coupled with high
towards metal catalysts, and the fast but deleterious selectivities under mild conditions.
b-H elimination.[6–9] Recently, pioneered by Fu, Organ
and Nolan etc., cross-coupling reactions involving
Results and Discussion
Inspired by previous results, desyl chloride 3 (2-
chloro-1,2-diphenylethanone), which had successfully
3
promoted the Csp Csp oxidative cross-coupling,[21]
À
was chosen as the oxidant. Desyl chloride 3 was ex-
pected to add oxidatively to Pd(0) to form C-bonded
Pd-enolate 3-I, which could tautomerize possibly to
O-bonded Pd-enolate 3-II (Scheme 2). Both the chlo-
ride anion and C-enolate anion or O-enolate anion at-
tached to palladium in 3-I or 3-II could serve as leav-
2
3
À
Scheme 1. Strategies for Csp Csp bond formation.
ing groups, and their intrinsic different activities
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turned out to be a good option, and the combination
of (4-chlorophenyl)zinc(II) chloride 1b and triphen-
ACHUTNGRENeNUG thylindium 2f with PdCl2AHCTUNGTRNE(NUGN dppf) as catalyst displayed
a promising result. The cross-coupled product was ob-
tained in 78% yield (Table 1, entry 6). Reactions of
1b with alkylindium dichloride 2d or dialkylindium
chloride 2e gave moderate yields (Table 1, entries 4
and 5). On the other hand, reactions of arylindium re-
agent 2a, 2b or 2c with alkylzinc reagent 1a all result-
ed in poor yields (Table 1, entries 1–3).
Encouraged by the preliminary results, we investi-
gated the oxidative cross-coupling using various li-
gands. The effect of ligand was evaluated in the reac-
Scheme 2. Proposed mechanism of oxidative cross-coupling
reaction between ArZnX and R3In.
toward organometallic reagents would make a highly tion of 1b and 2f in THF at 608C (Table 2). Catalyst
selective transmetallation process possible.
precursors without added ligands such as PdCl2
LiX has been reported to promote Stille coupling
ACHTUNGNERT(NUGN CH3CN)2, PdAHCTUNRTEGGN(NNU dba)2 and PdACHTNGUTNER(NUGN OAc)2 gave moderate
of ArOTf with organostannane reagents.[22] This infor- yields of product 4 together with 19–21% yields of
À
mation along with the success of our previous Csp Sn side product 4a (Table 2, entries 1–3). Monophosphine
and Csp Zn oxidative cross-coupling, encouraged us L1 and monophosphite L2 ligands lowered the yields
3
À
to employ a tin reagent as a halophilic reagent. Un- and selectivities of 4 (Table 2, entries 4 and 5). Biden-
fortunately, all attempts using Ar Sn reagents and tate phosphine ligand Xantphos gave an even poorer
Ralkyl Zn reagents resulted in poor yields and poor se- result (Table 2, entry 6). However, DPEphos satisfac-
À
À
lectivities for cross-coupled products. Satisfactorily, torily improved the reaction results to 95% selectivity
organoindium reagents (R3In, R=alkyl, alkenyl, al- in 81% yield.
kynyl, aryl), possessing interesting chemical properties
including a low first oxidation potential, stability
Table 2. Ligands effects in the oxidative cross-coupling reac-
under aqueous conditions and low toxicity,[21,23–33]
tions.[a]
Table 1. Combination of different organometallic reagents
for palladium-catalyzed oxidative cross-coupling.[a]
[a]
[b]
[a]
[b]
Reaction conditions: The reactants 1, 2, and 3 (in a ratio
of 1.1:1.2:1) were mixed in THF in the presence of 5
mol% PdCl2ACHTUNGTRENNUNG(dppf) in 608C.
The yield was determined by GC after 5 h using naphtha-
lene as the internal standard.
Reaction conditions: The reactants 1b, 2f, and 3 (in a
ratio of 1.1:1.2:1) were mixed in THF in the presence of
5 mol% catalyst in 608C.
The yield was determined by GC after 5 h using naphtha-
lene as the internal standard.
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Table 3. Palladium-catalyzed oxidative cross-coupling reac-
tions.[a]
[a]
Reaction conditions: The reactants 1, 2, and 3 (in a ratio
of 1.1:1.1:1) were mixed in THF in the presence of 5
mol% PdCl2ACHTUNGTRENNUNG(CH3CN)2 and DPEphos in 608C except for
entries 5–10 which were run at room temperature.
The yield was determined by NMR in 5 h using dibromo-
methane as the internal standard.
[b]
The substrate scope of this reaction was further ex-
plored under the optimized conditions (Table 3). Both
primary and secondary alkylindium reagents reacted
smoothly, and it was noteworthy that bromo and
chloro substituents on the arylzinc reagents were well
tolerated (Table 3, entries 1–10). In all reactions,
2
3
À
Csp Csp cross-couplings were achieved selectively
with less than 5% homo-coupling products. Moreover,
(t-Bu)2RIn (R=PhCH2CH2 ), in place of trialkylindi-
um reagents R3In, provided good selectivity and yield
as well (83%).
À
To gain some understanding of the mechanism, the
entire catalytic process of the reaction between (3-
methoxyphenyl)zinc(II) chloride 1e and triphenyl-
ACHTUNGTRENNUNGethanylindium 2f was monitored by in-situ IR and
GC. The depletion of desyl chloride 3 and formation
of product 15 and a new species assigned as R’OInR2
a (compared to authentic sample, see Supporting In-
formation) were clearly observed. The kinetic profiles
are listed in Figure 1A. Rate constants kobs of the
Figure 1. A: The kinetic profiles of desyl chloride 3, In-eno-
late a and product 15, which were collected by ReactIR cali-
brated by GC (In-enolate was calibrated according to 1,2-di-
phenylethanone). B: Linear fitting of period I; C: Linear fit-
ting of period II.
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were preformed on a Varian GC 3900 gas chromatography
instrument with an FID detector and naphthalene was
added as internal standard. The IR spectra were recorded
using a ReactIR 4000 from Mettler-Toledo AutoChem fitted
with a silicon-tipped (SiComp) probe. Data manipulation
was carried out using the iC IR software, version 1.5.105.0.
three compounds were calculated through a linear fit
in the 1.0–1.5 min (Figure 1B) and 1.7–2.2 min re-
gions, respectively (Figure 1C). In both periods, the
kobs of desyl chloride 3, product 15 and In-enolate a
were in the same order of magnitude, and even the
numerical values were very close, indicating that 3, a
and 15 were associated in the same catalytic cycle.
Thus it was reasonable to suppose that the enolate
part of 3 was directly converted to a in the reaction
system, implying selective transmetallation between
R3In and the O-enolate anion OR’ attached to Pd(II).
Therefore, a plausible mechanism of this reaction
was proposed as shown in Scheme 2.
All common reagents were prepared in our lab or ob-
tained from commercial suppliers and were purified follow-
ing general procedures. All ligands were obtained from Sol-
vias AG and Strem Chemicals and used without further pu-
rification. THF were dried and distilled from sodium/benzo-
phenone ketyl under nitrogen.
Preparation of the Alkylindium Reagents
Oxidative addition of desyl chloride to a Pd(0) spe-
cies generated C-bound Pd-enolate chloride 3-I,
which could tautomerize possibly to O-bonded Pd-
enolate chloride 3-II (R’OPdCl). Then the trialkylin-
dium reagents selectively transmetallate with the OR’
group of 3-II and release R’OInR2 (vide supra). The
All of the organoindium reagents were prepared from reac-
tions of the corresponding Grignard reagents with indium-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
and THF (1 mL). The solution was cooled to 08C and tert-
butylmagnesium chloride (2.0 mL, 1M) was added dropwise
to the flask. The mixture was stirred for 2 h and then phene-
thylmagnesium chloride (1.0 mL, 1 mmol) was added drop-
wise. After that, the resultant solution was allowed to slowly
warm to the room temperature and was stirred for addition-
al 2 h.
À
À
second transmetallation between ArZn with R Pd
À
À
Cl would form the key intermediate R Pd Ar, and
the final reductive elimination would result in the de-
sired cross-coupled product, and regenerate the cata-
lytic specie.[34]
Preparation of the Arylzinc Reagents
Conclusions
The arylzinc reagents 1a, 1e were prepared from the corre-
sponding Grignard reagent with zinc chloride.
2
3
À
In conclusion, Csp Csp oxidative coupling was real-
ized for the first time and nucleophilic arylzinc re-
agents and alkylindium reagents were cross-coupled
with good selectivities and yields using PdCl2
(4-Chlorophenyl)zinc(II) chloride[38] (1b): To a 25-mL
Schlenk flask were added 1-bromo-4-chlorobenzene
(191.4 mg, 1 mmol) and THF (2 mL). The mixture was
cooled to À788C. After that, n-BuLi (0.4 mL, 2.5M,
1 mmol) was added to the mixture dropwise. The resultant
solution was stirred for 1 h at À788C. Then, ZnCl2 (2.0 mL,
1.0M in THF, 2.0 mmol) was added dropwise to the flask.
Afterwards the mixturee was allowed to slowly warm to
room temperature and stirred for additional 2 h.
ACHTUNGTRENNUNG(CH3CN)2 as catalyst precursor and DPEphos as
ligand. Preliminary kinetic studies were conducted
and a mechanism for the reaction was proposed. Cur-
rently, desyl chloride was used as the stoichiometric
oxidant in this transformation, which was not atom
economic. Other oxidants of lower molecular weight,
some of which have been used in homocoupling of ar-
ylboronic acids, would make this reaction greener.[35,36]
Oxidative cross-coupling employing lower molecular
weight oxidants including O2 or air are under investi-
gation in this laboratory and will be reported in due
course.
(4-Bromophenyl)zinc(II) chloride[39](1c): To
a diethyl
ether (4.5 mL) and THF (4.5 mL) solution of 1,4-dibromo-
benzene (236.0 mg, 1 mmol) was slowly added n-BuLi
(0.4 mL, 2.5M, 1 mmol) at À788C. The resultant solution
was stirred at À788C for 1 h. After that, ZnCl2 (2.0 mL,
1.0M in THF, 2.0 mmol) was added dropwise to the flask.
Afterwards the mixture was allowed to slowly warm to the
room temperature and stirred for additional 2 h.
(3,5-Dibromophenyl)zinc(II) chloride[40] (1d): To a THF
(10 mL) solution of 1,3,5-tribromobenzene (314.8 mg,
1 mmol) was slowly added n-BuLi (0.4 mL, 2.5M, 1 mmol)
at À788C . The resultant solution was stirred at À788C for
1 h. After that, ZnCl2 (2.0 mL, 1.0M in THF, 2.0 mmol) was
added dropwise to the flask. Afterwards the mixture was al-
lowed to slowly warm to the room temperature and stirred
for additional 2 h.
Experimental Section
All reactions and manipulations were performed in a nitro-
gen-filled glove-box or using standard Schlenk techniques.
Column chromatography was performed using EM silica gel
1
60 (230–400 mesh). H NMR and 13C NMR were recorded
on a Mercury 300 MHz spectrometer. GC-mass spectra were
recorded on a Varian GC-MS 3900–2100T. All H NMR ex-
General Procedure for the Cross Coupling Reaction
1
periments are reported in parts per million (ppm) downfield
Under the protection of nitrogen gas, to a 10-mL Schlenk
flask were added desyl chloride (230.7 mg, 1 mmol),
PdCl2CH3CN2 (12.9 mg, 0.05 mmol, 5 mol% Pd) and DPE-
of TMS. All 13C NMR spectra are reported in ppm and were
1
obtained with H decoupling. Gas chromatographic analysis
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phos (32.3 mg, 0.06 mmol, 6 mol% Pd). To the flask, the ar-
ylzinc reagent (1.1 mol) and the alkylindium reagent
(1.1 mmol) were added by syringe. Then the solution was
warmed to 608C (the reaction temperature with arylzinc re-
agents 1c and 1d is room temperature). 5 h later, the reac-
tion mixture was quenched by saturated NH4Cl solution and
extracted by ether. The organic layer was dried over sodium
sulfate, filtered, and concentrated. Purification of product
was accomplished by silica gel chromatography. The charac-
terization data are available in the Supporting Information
file.
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