Grignard-type arylation of aldehydes via a rhodium-catalyzed C-H activation under mild conditions

Article abstract of DOI:10.1002/adsc.201100232

An efficient Grignard-type arylation of aldehydes via aryl C-H activation was achieved under mild conditions catalyzed by rhodium. The reaction provides an easy access to a wide variety of benzyl alcohols and can tolerate various functional groups as well

Full text of DOI:10.1002/adsc.201100232

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DOI: 10.1002/adsc.201100232
Grignard-Type Arylation of Aldehydes via a Rhodium-Catalyzed
À
C H Activation under Mild Conditions
Luo Yang,a Camille A. Correia,a and Chao-Jun Lia,*
a
Department of Chemistry, McGill University, Montreal, QC, Canada H3A 2K6
Fax : (+01)-514-398-8457; phone: +01-514-398-3797; e-mail: cj.li@mcgill.ca
Received: February 18, 2011; Revised: March 30, 2011; Published online: May 17, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100232.
Abstract: An efficient Grignard-type arylation of
aldehydes via aryl C H activation was achieved
under mild conditions catalyzed by rhodium. The
reaction provides an easy access to a wide variety
of benzyl alcohols and can tolerate various func-
tional groups as well as air and water.
reagents is still required.[4] Alternatively, arylation of
aldehydes can be realized by the well known Friedel–
Crafts reaction,[5] which is limited to highly electron-
rich arenes and usually produces a mixture of re-
gioisomers (Scheme 1, route b). The development of
overall catalytic isomerization reactions is among the
greatest challenges in future synthetic chemistry.[6]
À
À
À
Keywords: aldehydes; arylation; C H activation;
With the recent great advances in catalytic arene C
Grignard-type reaction; rhodium catalysis
H
activations,[7] we envisioned an alternative
Grignard-type arylation of aldehdyes via the addition
of an organometallic species, generated in situ from
À
simple arenes via C H activation (Scheme 1, route c).
Herein we report an unprecedented Grignard-type ar-
À
The Grignard-type nucleophilic addition of organo- ylation of aldehydes via a rhodium-catalyzed aryl C
metallic reagents to aldehydes (and ketones) repre- H activation and subsequent nucleophilic addition
sents one of the most important developments in the under very mild reaction conditions. More important-
history of organic chemistry.[1] For Grignard-type ary- ly, the reaction can proceed efficiently in the presence
lations, it generally requires the pre-generation of an of water, in air, and can tolerate acidic functional
organometallic reagent such as arylmagnesium halide groups such as hydroxy groups without using protect-
from stoichiometric aryl halides and magnesium ing groups.
(Scheme 1, route a). In addition, the use of anhydrous
To begin our study, we first examined the reaction
solvents, inert atmosphere, and protection of acidic of 2-phenylpyridine (1a) and ethyl glyoxylate (2a)
functionalities such as hydroxy groups are essential.[2] using rhodium catalysts based on our early work on
To overcome the latter limitations, Grignard-type nu- related arylations with arylmetal reagents in air and
cleophilic additions of arylmetal reagents to alde- water.[8] To our delight, the desired nucleophilic addi-
ACHTUNGTRENNUNG
hydes in aqueous media[3] have been developed re- tion product 3a was obtained in the presence of a cat-
cently; however pre-formation of the organometallic alytic amount of (COD)2RhBF4, albeit the yield was
Scheme 1. Various arylation reactions of aldehydes.
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Luo Yang et al.
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Table 1. Optimization of the reaction conditions.[a]
Entry
Rh (mol%)
(COD)2Rh(BF4) (5)
G
E
N
N
G
Additive (mol%)
Solvent
Yield[b] [%]
1
2
3
4
5
6
7
8
G
G
–
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
DCE
5
0
84
76
AgOTf
AgBF4
AgPF6
AgSbF6
–
–
–
94
95
A
U
98[c]
96
A
U
9
A
U
94
10
11
12
13
14
15
16
N
G
–
–
–
–
–
–
THF
84
66
33
t-BuOH
toluene
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
17
96[d]
96[e]
95[f]
H2O (20 mL)
[a]
Conditions: 1a (0.1 mmol), 2 (0.15 mmol), [Rh], additive (10 mol%), solvent (1 mL), reacted at 508C for 12 h under
argon, unless otherwise noted.
Determined by H NMR analysis of the crude reaction mixture using an internal standard.
Reaction completed in 1 h.
408C, 5 h.
Room temperature, 24 h.
508C, 24 h under air.
[b]
[c]
[d]
[e]
[f]
1
rather low (Table 1, entry 1). During our study, Berg- uene as the solvent due to the low solubility of the
man[9] and Shi[10] independently reported the rhodi- Rh-catalyst in toluene. Acetonitrile was not a good
um-catalyzed nucleophilic addition of phenylpyridine solvent for the reaction, possibly due to coordination
to Boc- and Ts-aldimine derivatives, respectively. Sim- of the nitrile group to the rhodium catalyst, lowering
ilar to these studies, the use of [Cp*RhCl2]2 as a cata- its Lewis acidity. It is worth noting that this reaction
lyst did not generate any aldehyde-addition product can also be performed at 408C or even at room tem-
(entry 2), which can be attributed to the reduced perature with comparable yields after a longer reac-
Lewis acidity caused by the strong s bonding between tion time (entries 14 and 15). Furthermore, this reac-
rhodium and chlorine in [Cp*RhCl2]2. To increase its tion was not sensitive to either water or O2, and a
Lewis acidity, different silver salts were tested as the similar yield was obtained when the reaction was per-
chloride abstractor (entries 3–6). The yield increased formed in the presence of water and under air atmos-
dramatically from 5% to 84% on addition of AgOTf. phere (entry 16).
While AgBF4 and AgPF6 were also effective, AgSbF6
Under the optimized conditions, the substrate
was found to be the best one and the NMR yield of scope of this novel Grignard-type arylation of ethyl
À
the nucleophilic addition product 3a increased to glyoxylate (2) via C H activation was explored. As
95%. These positive results further prompted us to shown by the results in Table 2, all the 2-phenylpyri-
use the pre-purified (CH3CN)3Cp*RhACTHNUGTRNEUNG(SbF6)2 (Rh*; dine analogues tested (1a–1i) reacted with ethyl glyox-
Cp*=pentamethylcyclopentadienyl) as the catalyst ylate (2) smoothly to produce the corresponding alco-
directly, leading to near quantitative formation of hols efficiently, regardless whether the phenyl group
À
product 3a (entry 7). This C H activation and nucleo- was substituted by electron-withdrawing or electron-
philic addition process can be performed not only in donating groups. The influence of substituents at dif-
lower polarity solvent such as CH2Cl2, CHCl3 and ferent positions of the phenyl ring was also examined.
DCE, but also in much more polar THF and tert-butyl The ortho-methyl substrate 1f reacted with ethyl
alcohol (entries 8–13). The yield dropped on using tol- glyoxylate in high yield and the meta-methoxy sub-
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Grignard-Type Arylation of Aldehydes via a Rhodium-Catalyzed C H Activation
Table 2. The reaction of 2-phenylpyridine analogues with
responding arylation products 3l–3o were obtained in
moderate to high yields.
ethyl glyoxylate.[a]
Encouraged by the high yields between the reaction
of 2-phenylpyridine analogues and ethyl glyoxylate,
the application of this novel reaction to other alde-
hydes was investigated. However, under the opti-
mized reaction condtions (5 mol% Rh*, 508C, 5 h in
CH2Cl2), 2-phenylpyridine (1a) was not reactive to-
wards the unsubstituted benzaldehyde. Compared to
ethyl glyoxylate, benzaldehyde is much less nucleo-
philic, therefore aromatic aldehydes with electron-
withdrawing groups were tested next (Table 3). To
our delight, the reaction of 4-nitrobenzaldehyde (4a)
and 2-phenylpyridine produced 5a in 75% yield. 4-Tri-
fluoromethylbenzaldehyde (4b) and 4-methoxycarbo-
nylbenzaldehyde (4c) were also applicable, albeit re-
sulting in lower yields. Other electron-deficient aro-
matic aldehydes such as 3-nitrobenzaldehyde (4d) and
3,5-bis(trifluoromethyl)benzaldehyde (4e) reacted
with 2-phenylpyridine (1a) smoothly and good yields
were obtained in both cases. Interestingly, when ter-
ephthalaldehyde (4f) was used, only one aldehyde
functional group took part in this reaction and the
other remained intact, which renders the product for
further functionalizations readily.
Table 3. The reaction of 2-phenylpyridine and aromatic alde-
hydes.[a]
[a]
Conditions:
1a
(0.2 mmol),
2
(0.3 mmol),
(CH3CN)3Cp*Rh
AHCTUNGTRENNUNG
(2 mL), reacted at 508C for 5 h under argon, unless oth-
erwise noted. The yield of isolated product is reported.
Determined by H NMR analysis of the crude reaction
mixture.
Reacted at 508C for 48 h.
[b]
[c]
1
strate 1g gave two regioisomers with a ratio of 48:52
in 91% total yield. 2-b-Naphthylpyridine 1j was also
applicable to this reaction and only one nucleophilic
addition product was obtained. Pyridinyl directing
group with a methyl substituent at C-6 1k also
showed good reactivity, resulting in a 93% yield of
3k. Other nitrogen-containing heterocyclic substitu-
ents such as quinolinyl, pyrimidinyl, pyrazolyl and ox-
azolyl can also act as the directing group, and the cor-
[a]
Conditions:
(CH3CN)3Cp*Rh
(0.4 mL), reacted at 608C for 24 h under argon, unless
otherwise noted. The yield of isolated product is report-
ed.
1a
AHCTUNGTRENNUNG
(0.2 mmol),
4
(0.4 mmol),
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Luo Yang et al.
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To further demonstrate the potential applications arylrhodium complex 7 to produce arylrhodium com-
of this reaction, more challenging substrates contain- plex 8, which is followed by the nucleophilic addition
ing unprotected hydroxy groups were examined of the aryl species to the activated carbonyl group to
(Scheme 2). The 2-phenylpyridine analogue 1p bear- yield the rhodium alkoxide 9. Protonation of 9 releas-
ing a free hydroxy group reacted with ethyl glyoxylate es the nucleophilic addition product and regenerates
(2) to afford 3p in 91% yield. Likewise, 2-phenylpyri- of the rhodium catalyst (Rh*).
dine (1a) reacted with 3-hydroxy-4-nitrobenzaldehyde
to produce 5g in 71% yield.
In summary, we have developed an efficient
Grignard-type arylation of aldehyde via a rhodium-
À
A tentative mechanism to rationalize this novel catalyzed aryl C H activation and subsequent nucleo-
rhodium-catalyzed Grignard-type aldehyde-arylation philic addition under mild conditions. Unlike the clas-
À
reaction via C H activation is illustrated in Scheme 3. sical Grignard-type reaction, the current reaction
First, the coordination of rhodium catalyst (Rh*) to 2- does not require the pre-generation of a stoichiomet-
phenylpyridine and subsequent electrophilic substitu- ric quantity of organometallic reagents and can toler-
tion generates the arylrhodium complex 7, releasing ate a wide range of functional groups such as esters,
one equivalent of proton at the same time. Then, the halide, nitro, and an additional aldehyde. Compounds
carbonyl group of the aldehyde coordinates to the bearing free hydroxy groups can be used directly in
high yields without any protecting groups. Further-
more, the reaction can occur efficiently in the pres-
ence of water and under an air atmosphere. The
scope, mechanism, and application of this novel reac-
tion are under investigation.
Experimental Section
General Experimental Procedure
An oven-dried reaction vessel was charged with
(CH3CN)3Cp*RhACTHUNTRGNE(UNG SbF6)2 (Rh*, 8.4 mg, 5 mol%, 0.01 mmol),
CH2Cl2 (2 mL), 2-phenylpyridine (1a, 31 mg, 0.2 mmol) and
ethyl glyoxylate (2, 60 mL, 0.3 mmol, 50% solution in tolu-
ene) under argon. The vessel was sealed and heated at 508C
(oil bath temperature) for 5 h. The resulting mixture was
cooled to room temperature, filtered through a short silica
gel pad and transferred to silica gel column directly and
eluted with hexanes and ethyl acetate (1:1) to give product
3a; yield: 49 mg (95%).
Scheme 2. The arylation of aldehydes bearing unprotected
hydroxy groups.
Acknowledgements
We are grateful to the Canada Research Chair (Tier I) Foun-
dation (to CJL), CFI, and NSERC for partial support of our
research.
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