Palladium-Catalyzed ortho C?H Arylation of Benzaldehydes Using ortho-Sulfinyl Aniline as Transient Auxiliary

Article abstract of DOI:10.1002/asia.201800581

A Pd^II-catalyzed ortho-(Csp²)–H arylation reaction of benzaldehydes using a catalytic amount of 2-(methylsulfinyl)aniline as transient auxiliary was developed. This reaction is compatible with a broad range of benzaldehyde and aryl iodide substrates. Compared with other related reaction systems, an excellent regioselectivity for ortho-C(sp²)?H bonds over benzylic C(sp³)?H bonds was obtained for ortho-alkyl-benzaldehyde substrates.

Full text of DOI:10.1002/asia.201800581

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Palladium-Catalyzed ortho C−H Arylation of Benzaldehydes
Using ortho-Sulfinyl Aniline Transient Auxiliary
Authors: Delong Mu, Gang He, and Gong Chen
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To be cited as: Chem. Asian J. 10.1002/asia.201800581
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Palladium-Catalyzed ortho C−H Arylation of Benzaldehydes Using
ortho-Sulfinyl Aniline Transient Auxiliary
Delong Mu,[a] Gang He*[a] and Gong Chen*[a,b]
Abstract: A PdII-catalyzed ortho-(Csp2)−H arylation reaction of
A) C(sp3)−H arylation of ortho-alkyl benzaldehydes
benzaldehydes using catalytic amount of 2-methylsulfinyl-aniline as
N
Y
transient auxiliary was developed. This reaction is compatible with a
broad range of benzaldehyde and aryl iodide substrates. Compared
with other related reaction systems, an excellent regioselectivity for
ortho-C(sp2)−H bonds over benzylic C(sp3)−H bonds was obtained for
ortho-alkyl-benzaldehyde substrates.
Pd
H
H
O
H
O
H
H
H
Ar
I
+
H
Ar
H
Pd(OAc)2, Transient Auxiliary
H
O
N
H2N
H2N
OH
Yu (2016, ref 10)
O
2-Arylbenzaldehyde compounds are frequently encountered in
organic synthesis. While various metal-catalyzed cross coupling
reactions such as Suzuki−Miyaura coupling have been widely
utilized to prepare these compounds,[1] direct ortho C−H arylation
of benzaldehydes with suitable aryl coupling partners would
provide a more streamlined synthetic strategy. Despite the
significant advance of metal-catalyzed C−H functionalization
chemistry[2, 3], practical method for ortho C−H functionalization of
benzaldehydes remain challenging due to the relatively weak
coordinating ability of aldehyde group.[4] An alternative solution is
to convert the carbonyl group into imine or oxime, thus taking
advantage of the stronger directing ability of sp2 nitrogen to
facilitate the desired C−H functionalization.[5, 6] However, the need
to install and remove the directing group diminishes the overall
operational economy. Recently, a more attractive strategy using
catalytic amount of amine-based transient auxiliary (TA) has been
reported for C−H functionalization of benzaldehydes.[7-9] In these
reaction systems, an imine directing group was in situ generated
to facilitate metal-catalyzed ortho C−H activation and
subsequently hydrolyzed to release the functionalized products
and the transient auxiliary. For example, Yu[10] and Hu[11] reported
palladium-catalyzed C−H arylation reactions of 2-alkyl
benzaldehydes using unprotected glycine or acetohydrazone as
transient auxiliary respectively (Scheme 1A). Notably, the
arylation reactions preferentially take place at the benzylic
C(sp3)−H bonds over the ortho-(Csp2)−H bonds. More recently,
Yu reported a protocol for arylation of ortho-C(sp2)−H bond of
benzaldehydes using a 2-aminoisobutyric acid transient auxiliary
(Scheme 1B)[12]. Herein, we report a new protocol of PdII-
catalyzed ortho-C(sp2)−H arylation reaction of benzaldehydes
using a catalytic amount of 2-methylsulfinyl-aniline as transient
auxiliary group. A variety of benzaldehydes were arylated in good
yields and excellent regioselectivity. An exclusive selectivity for
ortho-C(sp2)−H bonds was observed for ortho-alkyl-
benzaldehyde substrates.
Hu (2016, ref 11)
B) ortho C(sp2)−H arylation of benzaldehydes
H
O
H
O
H2N
CO2H
Yu (2017, ref 12a)
Pd(OAc)2
H
Ar
Ar
I
+
R
R
C) This work:
O
S
H
O
H
O
NH2
Ar
(20 mol%)
H
R
Ar
I
+
R
Pd(OAc)2 (10 mol%)
Ag3PO4 (1.5 equiv)
R at o, m, and p
positions
(1.2 equiv)
(1.0 equiv)
HCl (aq. 12 M, 1.0 equiv)
HFIP, 110 oC, Ar, 12 h
Scheme 1. Pd-catalyzed C−H arylation of benzaldehydes using a transient
auxiliary.
We commenced our study by evaluating various alkyl and
arylamine-based transient auxiliaries for the arylation reaction of
2-methylbenzaldehyde 1 with 4-iodoanisole 2 in the presence of
10 mol% of Pd(OAc)2 catalyst and 1.5 equiv of Ag3PO4 in
hexafluoroisopropanol (HFIP) (Scheme 2). The reaction without
any additives gave no detectable arylated product 3. The addition
of 20 mol% of plain aniline (TA1) formed trace amount of 3. The
[a]
[b]
D. Mu, Prof. Dr. G. He, Prof. Dr. G. Chen
State Key Laboratory and Institute of Elemento-Organic Chemistry,
College of Chemistry, Nankai University, Tianjin 300071, China.
Email: hegang@nankai.edu.cn, gongchen@nankai.edu.cn
Prof. Dr. G. He, Prof. Dr. G. Chen
Collaborative Innovation Center of Chemical Science and Engineering
(Tianjin), Tianjin 300071, China
Supporting information for this article is given via a link at the end of the
document.
Scheme 2. Evaluation of transient auxiliaries for Pd-catalyzed ortho-C(sp2)−H
arylation of benzaldehyde 1. Yields are based on 1H-NMR analysis of crude
reaction mixture on a 0.2 mmol scale using 1,1,2,2-tetrachloroethane as internal
standard. NR: no reaction.
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Table 1. Pd-catalyzed ortho-C(sp2)−H arylation of benzaldehyde 1
TA7 (20 mol%)
Pd(OAc)2 (10 mol%)
Ag3PO4 (1.5 equiv)
I
CHO
Ar
CHO
Ar
I
Pd(OAc)2 (10 mol%)
TA7 (20 mol%)
Ar'
H
OMe
CHO
CHO
+
Ar'
base (1.5 equiv)
HCl (aq. 12 M, 1.0 equiv)
HFIP, 110 oC, Ar, 12 ha
H
+
solvent, Ar
(1 equiv)
(1.2 equiv)
CHO
110 oC, 12 h
OMe
1
2
3
Entry
Base
Additive (equiv)
Solvent
Yield (%)a
4e, R = p'-CO2Me, 54%b
4f, R = m'-CO2Me, 68%b,c
4g, R = m'-CH3CO, 62%b,c
4a, R = p'-Ph, 45%
4b, R = p'-OEt, 63%
4c, R = p'-Cl, 64%
4d, R = p'-Br, 61%
1
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
Ag2CO3
AgOAc
AgOTf
NONE
HFIP
43
R
4h, R = m'-Br,
60%b,c
2
NONE
dioxane
toluene
t-AmylOH
HFIP
<5
<5
<5
<5
<5
<5
6
3
NONE
CHO
4
NONE
CHO
CHO
5
NONE
6
NONE
HFIP
O
OMe
OMe
7
NONE
HFIP
6, NRd
5, 34%
7, 85%
8
AgF
NONE
HFIP
9
AgOTFA
K2CO3
NONE
HFIP
22
CHO
OMe
OMe
10
11
12
13
14
15
16
17
NONE
HFIP
<5
<5
80 (75)b
65
CHO
8a, R = o-Et,
61%
8b, R = o-OMe, 68%
8c, R = m-OMe, 63%b,c
8d, R = m-Me, 70%
Cs2CO3
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
NONE
HFIP
R
HCl (12 M, 1.0)
HCl (12 M, 2.0)
H3PO4 (1.0)
HOAc (1.0)
ZnCl2 (1.0)
FeCl3 (1.0)
HFIP
9, 15%e
OMe
CHO
HFIP
HFIP
20
OMe
OMe
HFIP
18
CHO
CHO
Br
HFIP
<5
<5
HFIP
F
12, 60%
11, 71%
10, 64%
Reaction conditions: 1 (0.24 mmol, 1.2 equiv), 2 (0.2 mmol, 1.0 equiv), TA7
(0.04 mmol, 0.2 equiv), base (0.3 mmol, 1.5 equiv), solvent (2 mL), 110 oC, Ar,
12 h. [a] Yields are based on 1H-NMR analysis of crude reaction mixture on a
0.2 mmol scale using 1,1,2,2-tetrachloroethane as internal standard. [b] Isolated
yield.
Scheme 3. Substrate scope of Pd-catalyzed ortho-C(sp2)−H arylation of
benzaldehydes. [a] Isolated yield. [b] 120 oC. [c] benzaldehyde (0.2 mmol, 1.0
equiv), ArI (0.24 mmol, 1.2 equiv). [d] NR: no reaction. [e] 9% of ortho di-arylated
product and 55% of benzaldehyde starting material were obtained.
use of N,N-bidentate compounds TA2-4, which have
demonstrated excellent directing ability in metal-catalyzed C−H
functionalization reactions of the corresponding carboxamide
substrates, did not give any desired product.[13] We were pleased
to find that 2-methylsulfinyl aniline (MSOA, TA7) gave the best
performance, forming 3 in 43% yield. Interestingly, ortho-
tolylsulfinyl aniline (TSOA, TA8) showed much lower reactivity. In
our previous study, we have shown that these two ortho-sulfinyl
aniline auxiliary group are particularly effective at facilitating Pd-
catalyzed b-C(sp3)-H arylation of the corresponding alkyl
carboxamides with sterically hindered aryl iodides.[14, 15]
on arenes were tolerated (4c, 4d). The steric effect of aryl iodide
also has a strong impact on their reactivity. Reaction of 1 with 2-
iodoacetophenone gave low yield (5). Product
6 with 2-
iodotoluene was not observed. As seen in compounds 8a-8d,
reactions of 4-iodoanisole 2 with ortho- and meta-substituted
benzaldehydes proceeded smoothly. The arylation of meta-
substituted benzaldehydes took place at the less hindered
position. For unclear reasons, para-substituted benzaldehydes
showed low reactivity under the standard conditions, forming a
mixture of mono- and di-arylated products in low yield along with
considerable amount of unreacted starting material (see 9). Multi-
substituted benzaldehydes were compatible (10-12). 2-
Naphthaldehyde was arylated selectively at the C3 position to give
7 in 85% yield.
The arylation conditions of 1 with 2 and TA7 were further
optimized (Table 1). Both HFIP solvent and Ag3PO4 base were
critical to obtain good yield (entries 1-11). Importantly, the addition
of 1 equiv of concentrated aqueous HCl solution significantly
improved the yield of 3 to 80% (75% isolated yield, entry 12). [10-
OMe
CHO
12]
The amount and type of acid was crucial, as the addition of 2
equiv of aq. HCl (entry 13) and other brønsted or Lewis acids
(entries 14-17) gave lower yield. Notably, no benzylic C(sp3)−H
arylation side product was observed under the conditions tested
above.
I
3, 70%
TA7
(20 mol%)
CHO
+
+
Pd(OAc)2 (10 mol%)
Ag3PO4 (1.5 equiv)
OMe
With the optimized conditions in hand, we next explored the
scope of aryl iodides and benzaldehydes (Scheme 3). Arylation of
2-methylbenzaldehyde 1 with electron rich aryl iodides proceeded
well, affording the desired products in moderate to good yields (4a,
4b). Electron deficient aryl iodides showed lower reactivity under
the standard conditions; synthetic useful yields could be obtained
at slightly higher temperature (4e-4h). Chloro and bromo groups
HCl (aq. 12 M, 1.0 equiv)
HFIP, 110 oC, Ar, 12 h
1
2
N
(8.4 mmol)
(7 mmol)
S
O
13, 5%
Scheme 4. Scale-up reaction.
As shown in Scheme 4, ortho-C(sp2)−H arylation of 1 with 2
on a 7 mmol scale under our standard conditions gave 3 in 70%
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isolated yield along with 5% of imine intermediate 13. As shown
in Scheme 5A, arylation of 13 with 4-iodoanisole 2 gave 36% yield
of 3 and 20% of 1 under standard conditions. Heating 13 with 1
equiv of Pd(OAc)2 in HFIP at 110 oC for 12 hours gave the
palladacycle intermediate 14 in 85% yield. The structure of 14 was
confirmed by X-ray crystallography (see Supporting information
for details).[16] Reaction of 14 with 4-iodoanisole 2 under the
standard conditions gave 3 in 27% yield along with compounds
13 and 1 (Scheme 5B).
temperature. The vial was purged with Ar and sealed with PTFE cap. The
reaction mixture was heated at 110 oC for 12 h. After being cooled to room
temperature, the reaction mixture was diluted with EtOAc (3 mL) and
filtered through a pad of Celite. The filtrate was concentrated in vacuo, and
the resulting residue was purified by flash chromatography to give the
desired product 3 in 75% yield as a yellow solid (Rf = 0.7, Hexanes:EtOAc
= 30:1).
Acknowledgements
A)
2 (1.2 equiv)
Pd(OAc)2 (10 mol%)
3, 36%
+
1, 20%
We greatly thank Natural Science Foundation of China (21421062,
21502098, 21672105), Natural Science Foundation of Tianjin
(17JCYBJC19700) and the State Key Laboratory of Elemento-Organic
Chemistry at Nankai University for financial support of this work.
(NMR yield)
Ag3PO4 (1.5 equiv)
HCl (1.0 equiv, aq. 12 M)
HFIP, 110 oC, Ar, 12 h
13
Pd(OAc)2 (1.0 equiv)
HFIP, 110 oC, Ar, 12 h
N
O
S
Pd
OAc
14, 85%
Conflict of interest
The authors declare no conflict of interest.
X-ray
structure
of 14
Keywords: C−H arylation • benzaldehyde •2-methylsulfinyl
aniline • transient auxiliary • palladium
B)
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OMe
14
CHO
(1.0 equiv)
standard conditions
+
2
3, 27%
(NMR yield)
(1.0 equiv)
Scheme 5. Mechanistic studies.
A PdII/IV catalytic cycle has been proposed for the arylation
reaction of 2-methylbenzaldehyde 1 with 2. 1 likely first reacts with
2-methylsulfinyl aniline (TA7) to generate an imine intermediate
13. C−H palladation of 13 directed by the N,S-chelation of imine
gives palladacycle intermediate 14. Oxidative addition of 14 with
4-iodoanisole 2 followed by reductive elimination gives the
arylated imine intermediate, which is then hydrolyzed to give the
final product 3 and release the transient auxiliary TA7.
In summary, we have developed a new protocol for PdII-
catalyzed ortho-C(sp2)−H arylation reaction of benzaldehydes
with aryl iodides using a catalytic amount of 2-methylsulfinyl-
aniline. The unique electron withdrawing property and metal-
coordination ability of the methylsulfinyl group was found critical
to the success of this aniline transient auxiliary. Compared with
other related reaction systems, an excellent regioselectivity for
ortho-C(sp2)−H bonds over benzylic C(sp3)−H bonds was
obtained for ortho-alkyl-benzaldehyde substrates.
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Experimental Section
A mixture of 2-methylbenzaldehyde 1 (28.8 mg, 0.24 mmol, 1.2 equiv), 4-
iodoanisole 2 (46.8 mg, 0.2 mmol, 1.0 equiv), Pd(OAc)2 (4.5 mg, 0.02
mmol, 0.1 equiv), 2-methylsulfinyl aniline TA7 (6.2 mg, 0.04 mmol, 0.2
equiv), Ag3PO4 (125 mg, 0.3 mmol, 1.5 equiv), aq. HCl (12 M, 17 μL, 0.2
mmol, 1.0 equiv) and HFIP (2 mL) was dispersed in a 8 mL vial at room
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10.1002/asia.201800581
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COMMUNICATION
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10.1002/asia.201800581
Chemistry - An Asian Journal
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Delong Mu,[a] Gang He*[a] and Gong
Chen*[a,b]
O
S
H
O
H
O
NH2
(20 mol%)
Page No. – Page No.
H
Ar
+
Ar
I
R
R
Palladium-Catalyzed ortho C−H
Arylation of Benzaldehydes Using
ortho-Sulfinyl Aniline Transient
Auxiliary
Pd(OAc)2 (10 mol%)
Ag3PO4 (1.5 equiv)
HCl (aq. 12 M, 1.0 equiv)
HFIP, 110 oC, Ar, 12 h
Text for Table of Contents
R at o, m, and p
positions
This article is protected by copyright. All rights reserved.