Palladium-catalyzed formylation of aryl halides with tert -butyl isocyanide

Article abstract of DOI:10.1021/ol5014262

A novel palladium-catalyzed formylation of aryl halides with isocyanide in the presence of Et₃SiH has been demonstrated, which provides a strategy toward important aldehydes with moderate to excellent yield. The advantage of this reaction includes milder conditions, convenient operation, lower toxicity, and wide functional group tolerance.

Full text of DOI:10.1021/ol5014262

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Formylation of Aryl Halides with tert-Butyl
Isocyanide
Xiao Jiang,† Jin-Mei Wang,† Ying Zhang,† Zhong Chen,† Yong-Ming Zhu,*,† and Shun-Jun Ji*,‡
†College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
‡College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, China
S
* Supporting Information
ABSTRACT: A novel palladium-catalyzed formylation of aryl halides
with isocyanide in the presence of Et3SiH has been demonstrated,
which provides a strategy toward important aldehydes with moderate
to excellent yield. The advantage of this reaction includes milder
conditions, convenient operation, lower toxicity, and wide functional group tolerance.
socyanides have been versatile C1 building blocks in organic
synthesis. In the past decades, isocyanide insertion has
Classical direct formylation of aryl halides involves a
halogen/metal exchange with nBuLi and subsequent formyla-
tion agents (e.g., DMF) added at low temperatures.7 Clearly,
the scope of functional groups are limited by tough
experimental conditions. Since the pioneering work of
Heck,8a many explorations for palladium-catalyzed synthesis
of aldehydes from aryl halides, which employs toxic CO, or CO
sources as a formyl source, hydrogen, formate salt, or silyl, and
tin hydrides as a reducing agent, have been reported8 (Scheme
2). However, the conditions of high pressure, high toxicity,
I
offered widespread application in the synthesis of nitrogen
compounds among all types of reactions involving isocyanides,
such as electrophilic and nucleophilic reactions, imidoylative
reactions, oxidation, etc.1 In the case of palladium-catalyzed
isocyanide insertion into C−X bonds2 to form amidines and
(thio)imidates, C-, N-, O-, and S-containing nucleophiles are
generally used (Scheme 1). In order to achieve carboxide,
Scheme 1. Catalytic Synthesis of Amidine or (Thio)Imidate
Scheme 2. Palladium-Catalyzed Formylation of Aryl Halides
further hydrolysis by losing tert-butylamine is sometimes
needed. Delightfully, our group has successfully built C−O
and C−C bonds to form the skeleton of isocounmarins,
phthalides,2i and alkynones2l through isocyanide insertion into
C−X bonds. Instead of carbon, oxygen, or nitrogen
nucleophiles, we speculated that the hydride ion could be
introduced to deliver valuable aldehydes, which would expand
the application of isocyanide insertion.
Aromatic aldehydes are an important class of compounds
widely used as an active formyl group for further trans-
formations, such as C−C, C−N, and C−S coupling reactions,
which can be readily employed in fine and pharmaceutical
chemicals, agricultural chemicals, perfumery, and dyestuff
industries.3 Conventional methods for synthesizing aromatic
aldehydes include Gattermann−Koch, Reimer−Tiemann,
Vilsmeier−Haag, Duff, and Rieche reactions;4 the reduction5
of carboxylic acids, chloride, esters, acylamide, or nitrile; and
the oxidation6 of benzyl alcohol. Unfortunately, these reactions
suffer from poor selectivity, low yield, harsh reaction
conditions, use of an environmentally hazardous reagent, and
production of significant quantities of waste.
difficult operation of CO, instability of formylating agents, and
limited functional group tolerance restricted their applications.
Thus, a more eco-benign, efficient procedure for their
construction will be greatly appreciated. As part of our interest
in isocyanide as a surrogate for toxic CO, herein, we provide a
new protocol for the synthesis of aldehyde via palladium-
catalyzed formylation of aryl halides with silane, an economical,
environmental, and high-activity hydrogen donor, following
tert-butyl isocyanide insertion into a carbon−halogen bond
(Scheme 3).
Initial investigations were carried out using 4-methoxy-
iodobenzene as a model substrate in the presence of Pd(OAc)2,
DPPB, Na2CO3, tert-butyl isocyanide, and Et3SiH (2 equiv) in
DMF for 8 h, and the desired 4-methoxybenzaldehyde was
Received: May 18, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol5014262 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
An investigation of hydrogen donors was also performed, and
3 equiv of Et3SiH resulted in a satisfactory reaction with a 92%
yield under the established conditions (Table 2, entries 1−5).
Scheme 3. Palladium-Catalyzed Formylation Strategy toward
Aldehyde from Aryl Halides
a
Table 2. Influence of Hydrogen Donors
obtained in 61% yield (Table 1, entry 1). Compared with other
solvents (Table 1, entries 2−5), DMF was optimal for this
b
entry
silane
Et3SiH
equiv
yield (%)
1
2
3
4
5
1
53
65
92
60
87
Et3SiH
1.5
3
a
Table 1. Optimization of Reaction Conditions
Et3SiH
PhSiH3
3
(Me2SiH)2O
2
a
Conditions: All reactions were performed with 1a (0.7 mmol), tert-
butyl isocyanide (1.2 equiv), Pd(OAc)2 (3 mol %), JohnPhos (4.5 mol
%), Na2CO3 (1 equiv), silane, and 2.0 mL of DMF under nitrogen at
65 °C for 8 h in a sealed tube unless otherwise noted. Isolated yield.
b
temp
(°C)
yield
(%)
b
entry
catalyst/ligand
base
solvent
1
Pd(OAc)2/DPPB
Pd(OAc)2/DPPB
Pd(OAc)2/DPPB
Pd(OAc)2/DPPB
Pd(OAc)2/DPPB
Pd(OAc)2/DPPB
Pd(OAc)2/DPPB
Pd(OAc)2/DPPB
Pd(OAc)2/DPPB
Pd(OAc)2/DPPB
Pd(OAc)2/DPPB
PdCl2/DPPB
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Cs2CO3
K2CO3
DMF
DMSO
toluene
THF
85
85
85
85
85
85
85
85
85
100
65
65
65
65
65
61
38
trace
trace
0
2
With the optimal conditions, namely treatment of aryl halide,
tert-butyl isocyanide (1.2 equiv), Pd(OAc)2 (3 mol %),
JohnPhos (4.5 mol %), Na2CO3 (1 equiv), and Et3SiH (2.1
mmol, 3 equiv) in DMF (2.0 mL) at 65 °C, in hand, we
explored the scope of the reaction. As shown in Scheme 4,
moderate to excellent yields were obtained. Electron-rich
phenyl halides (Scheme 4, 1b−4b, 10b, 16b, 18b, and 19b)
afforded higher yields than the electron-poor phenyl halides
(Scheme 4, 5b−9b, 11b, 14b, 15b, and 17b). Steric hindrance
has a slight effect on the reaction (Scheme 4, 2b, and 3b). The
reaction tolerates a variety of functional groups, such as
halogen, nitryl, ketone, ester, ether, and hydroxy (Scheme 4,
5b−7b and 14b−19b), affording the corresponding aldehydes
in moderate to good yields. A low yield of 17b was obtained
(Scheme 4, 17b), which resulted from the sensitivity of
isocyanide to the acidity of phenolic hydroxyl group. Notably,
4-iodobiphenyl and 1- and 2-naphthyl halides could not be
converted totally under our standard conditions. Satisfactory
results were obtained by a slight change of increasing the
amount of tert-butyl isocyanide (2 equiv), Pd(OAc)2 (6 mol
%), JohnPhos (9 mol %), and Na2CO3 (2 equiv) (Scheme 4,
8b, 12b, and 20b). Meanwhile, sterically hindered 9-
bromoanthracene was converted to the desired product in
65% yield. Heteroaromatic halides are suitable for this
transformation as well, giving moderate to good yields (Scheme
4, 13b, 22b−24b, and 26b). Interestingly, an 88% yield of
cinnamaldehyde was obtained by using our standard condition
(Scheme 4, 25b).
Amide was generated as the main product without a
hydrogen donor (Et3SiH) under our standard conditions,
which is in accordance with the report of Huang.2g And there
was no amide for our reaction. We speculate that palladium-
catalyzed hydride ion transfer is prior to the replacement of
halogen by hydroxyl. A plausible mechanism is depicted in
Scheme 5. Oxidative addition of ary halides to the Pd(0)
catalyst leads to a palladium complex 3, followed by tert-butyl
isocyanide insertion to form palladium(II) species 4. 4 could be
trapped by silane, and the desired aldehyde 1b is achieved via
palladium-catalyzed hydride transfer and subsequent reductive
elimination.
3
4
5
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
6
42
46
55
40
44
68
41
30
40
51
7
8
NaOAc
NaHCO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
9
10
11
12
13
14
15
Pd3(dba)2/DPPB
Pd(OAc)2/DPEPhos Na2CO3
Pd(OAc)2/
(R)-BINAP
Na2CO3
16
17
18
19
20
21
22
Pd(OAc)2/DPPF
Pd(OAc)2/PPh3
Pd(OAc)2/PCy3
Na2CO3
Na2CO3
Na2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
65
65
65
65
65
65
65
59
23
78
81
35
65
53
Pd(OAc)2/JohnPhos Na2CO3
Pd(OAc)2/TFP
Pd(OAc)2/SPhos
Pd(OAc)2/XPhos
Na2CO3
Na2CO3
Na2CO3
a
Conditions: All reactions were performed with 1a (0.7 mmol), tert-
butyl isocyanide (1.2 equiv), catalyst (3 mol %), ligand (4.5 mol %),
base (1 equiv), Et3SiH (2 equiv), and 2.0 mL of solvent under nitrogen
for 8 h in a sealed tube unless otherwise noted. DPPB = 1,4-
bis(diphenylphosphino)butane, DPEPhos = bis[(2-diphenylphos-
phino)phenyl]ether, (R)-BINAP = (R)-2,2′-bis(diphenylphosphino)-
1,1′-binaphthyl, DPPF = 1,1′-bis(diphenylphosphino)ferrocene, PPh3
= triphenylphosphine, PCy3 = tricyclohexylphosphine, JohnPhos =2-
(dicyclohexylphosphino)biphenyl, TFP = tri(2-furyl)phosphine, SPhos
= 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl, XPhos =2-
b
dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl. Isolated yield.
reaction. Na2CO3 was clearly superior to other bases (Table 1,
entries 6−9). Lowering the temperature led to an increase in
the yield (Table 1, entries 10 and 11). Switching to other
catalysts, such as PdCl2 and Pd3(dba)2, resulted in a lower yield
(Table 1, entries 12 and 13). Ligand screening showed that
PCy3 could also be used but less efficiently than JohnPhos
(Table 1, entries 14−22).
In summary, an efficient palladium-catalyzed method for
synthesizing aromatic aldehydes involving isocyanide insertion
B
dx.doi.org/10.1021/ol5014262 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Palladium-Catalyzed Formylation of Aryl
Halides
Scheme 5. Plausible Mechanism
a
,b
excellent yields. Compared to other reactions, the procedure is
more mild, general, and efficient. Furthermore, this new
perspective can expand the application of palladium-catalyzed
isocyanide insertion.
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and spectra data for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zhuyongming@suda.edu.cn.
*E-mail: shunjun@suda.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support by PAPD (A
Project Funded by the Priority Academic Program Develop-
ment of Jiangsu Higher Education Institutions) and NSFC
(National Nature Science Foundation of China, No.
21172162).
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