Palladium-Catalyzed Synthesis of Biaryl Ketones via tert -Butyl Isocyanide Insertion

Article abstract of DOI:10.1055/s-0033-1341244

A simple and efficient palladium-catalyzed carbonylative Suzuki coupling via tert-butyl isocyanide insertion has been developed, which demonstrates the utility of isocyanides in intermolecular C-C bond construction. This methodology provides a novel pathway for the synthesis of diaryl ketones in moderate to good yields. The approach is tolerant to a wide range of substrates and applicable to library synthesis. A possible reaction mechanism was proposed based on the experimental results. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1341244

LETTER
▌1425
letter
Palladium-Catalyzed Synthesis of Biaryl Ketones via tert-Butyl Isocyanide
Insertion
Carborylative Suzuki Coupling
Zhong Chen, Huaqing Duan, Xiao Jiang, Jinmei Wang, Yongming Zhu,* Shilin Yang
College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, P. R. of China
Fax +86(512)67166591; E-mail: zhuyongming@suda.edu.cn
Received: 26.02.2014; Accepted after revision: 25.03.2014
isocyanides represent an important class of reactive spe-
Abstract: A simple and efficient palladium-catalyzed carbonyla-
cies and synthons. This chemistry has seen a surge of in-
tive Suzuki coupling via tert-butyl isocyanide insertion has been de-
terest in recent years.12,13 Isocyanide is isoelectronic with
carbon monoxide and can be considered to replace carbon
veloped, which demonstrates the utility of isocyanides in
intermolecular C–C bond construction. This methodology provides
a novel pathway for the synthesis of diaryl ketones in moderate to monoxide in coupling reactions. In addition, isocyanides
good yields. The approach is tolerant to a wide range of substrates
and applicable to library synthesis. A possible reaction mechanism
was proposed based on the experimental results.
are easily to handle liquids or solids, which can be used in
stoichiometric quantities. So far, a lot of transition-metal-
catalyzed coupling reactions via the insertion of isocya-
nides to form C–N14,15 and C–O16 bonds have been inves-
Key words: isocyanide, carbonylative Suzuki coupling, palladium
catalyst, diaryl ketone, insertion reaction
tigated. However, reactions via isocyanide insertion to
form C–C bonds have been rarely described.17 For exam-
ple,17c the group of Suzuki reported a protocol for the cat-
Biaryl ketones are important building blocks in many nat-
ural products and pharmaceuticals.1 It is necessary to ex-
plore mild and high regioselective methods for the
preparation of diaryl ketones from commercially avail-
able simple starting materials. The traditional approach to
prepare biaryl ketones involves oxidation of diaryl
methanols2 or Friedel–Crafts acylation of substituted aro-
matic ring compounds with acyl halides. However, the
Friedel–Crafts acylation is incompatible with many func-
tional groups and the regioselectivity is limited to the para
position.3 In addition, the transition-metal-catalyzed di-
rect synthesis of biaryl ketones with aryl carboxylic acid
or aryl aldehydes as coupling partners has emerged as a
useful method. Various transition metals have been used
for these transformations, including cobalt,4 copper,5
nickel,6 rhodium,7 and palladium.8 Furthermore, an anoth-
er alternative approach is the carbonylative Suzuki cou-
pling. In 1986, Kojima and co-workers firstly reported the
carbonylative coupling of aryl iodides, carbon monoxide
(CO) with organoboranes in the presence of PdCl2(PPh3)2
as catalyst.9 Later, Suzuki and co-workers expanded the
aryl coupling partner from ArI to ArBr, ArOTf.10 Recent-
ly, many biaryl ketones have been successfully synthe-
sized by carbonylative Suzuki coupling reactions.11 The
common character of these reactions is that CO serves as
the carbonyl source. However, CO is a toxic gas usually
used in excess and under high pressures. Further, the reac-
tion is heterogeneous. All above drawbacks limits the ap-
plications.12
alytic reaction between haloarenes, t-BuNC and 9-alkyl-
9-BBN to synthesize alkyl aryl ketones. However, the re-
quired 9-alkyl-9-BBN were prepared in situ and used di-
rectly. Recently, our group developed a simple and
efficient palladium-catalyzed carbonylative Sonogashira
coupling reaction via tert-butyl isocyanide insertion,
which demonstrated the utility of isocyanides in inter-
molecular C–C bond construction.18 Enlightened by the
above literatures12–17 and the finding of our group,16b,18 we
surmised that it might be possible for the insertion of iso-
cyanides into aryliodo and arylboronic acid to construct
intermolecular C–C bonds to generate biaryl ketones. To
the best of our knowledge, there have been no reports of
carbonylative Suzuki coupling from isocyanides to gener-
ate biaryl ketones.
In a model experiment, phenylboronic acid and iodoben-
zene were reacted with tert-butyl isocyanide in Pd(OAc)2
and Ph3P with K2CO3 as base. The reaction was firstly
performed in dry toluene at 110 °C for four hours, then it
was hydrolyzed in HCl–THF, and the desired product
benzophenone was formed in 71% yield (Table 1, entry
1). The solvents for the activity of the reaction were exam-
ined. To our disappointment, the yields decreased from 4–
12% with dioxane or anisole as solvent comparing to tol-
uene, and the yield was 22% with DMSO as solvent (Ta-
ble 1, entries 2–4); however, only trace of the desired
product was isolated with THF as solvent (Table 1, entry
5), and most of the starting materials remained. In com-
parison with Pd(OAc)2, PdCl2 can slightly increase the
yield (Table 1, entry 6). Then we examined the influence
of base for the reaction activity. The desired product was
not appeared with NaOAc or CsF as base (Table 1, entries
7 and 8). To our delight, the yield was improved to 80%
when K3PO4 was used (Table 1, entry 9); the side product
biphenyl was also isolated, and the yield was 16%. When
Cs2CO3, KOt-Bu, Et3N, or DBU was used as base, the
Isocyanides are highly versatile reagents which have
found widespread applications in organic, medicinal, and
combinatorial chemistry. As valuable C1 building blocks,
SYNLETT 2014, 25, 1425–1430
Advanced online publication: 08.05.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1341244; Art ID: st-2014-w0167-l
© Georg Thieme Verlag Stuttgart · New York

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Z. Chen et al.
LETTER
Table 1 Condition Optimizationsa
1) Pd, ligand
base, solvent, 110 °C
I
O
C
B(OH)2
+
N
t-Bu
C–
2) HCl, THF, r.t.
Entry
Catalyst
Ligand
Base
Solvent
Yield (%)b
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
DPPF
DPEPhos
PCy3
TFP
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
toluene
dioxane
anisole
DMSO
THF
71
67
59
22
trace
74
0
3
4
5
6
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
7
PdCl2
NaOAc
CsF
8
PdCl2
0
9
PdCl2
K3PO4
Cs2CO3
KOt-Bu
Et3N
80
61
52
0
10
11
12
13
14
15
16
17
PdCl2
PdCl2
PdCl2
PdCl2
DBU
34
69
65
67
72
PdCl2
K3PO4
K3PO4
K3PO4
K3PO4
PdCl2
PdCl2
PdCl2
a Reaction conditions: All reactions were performed with iodobenzene (1.0 mmol), phenylboronic acid (1.2 mmol), tert-butyl isocyanide (1.2
mmol), catalyst (0.03 mmol), ligand (0.06mmol), and base (2.0 mmol) in solvent (4.0 mL) at 110 °C for 4 h, followed by stirring in THF–HCl
at r.t. for 2 h. Et3N = triethylamine; DBU = 1,5-diazabicyclo[5.4.0] undecen-5-ene; dppf = 1,1′-bis(diphenylphosphino)ferrocene; DPEPhos =
bis[(2-diphenylphosphino)phenyl]ether; PCy3 = tricyclohexylphosphine; TFP = tri(2-furyl)phosphine.
b Isolated yield.
yield was 61%, 52%, 0%, and 34%, respectively (Table 1, to the steric hindrance of 2-iodotoluene. 3,5-Dimethyl-
entries 10–13). Other commercially available mono- and iodobenzene gave a slightly lower yield of 62% (Table 2,
bidentate ligands were also tested to further improve the entry 5). The presence of the methoxy substituent on the
yield. But none of them was compared to Ph3P (Table 1, iodobenzene resulted in a decreased yield of 42% (Table
entries 14–17). Therefore, the optimal reaction conditions 2, entry 6). To our delight, iodobenzenes containing sen-
were PdCl2 (3 mol%) and Ph3P (6 mol%) as the catalyst sitive functional groups such as 4-CN and 4-CO2Me were
system, with K3PO4 (2 equiv) as the base and with toluene all coupled smoothly in moderate yields of 67% and 63%,
as the solvent.
respectively (Table 2, entries 7 and 8). Hence, the rela-
tionship between the nature of the substituent on the aryl
ring and the yield is unclear. In addition, thiophenyl and
naphthyl iodides afforded the desired biaryl ketones in
modest yields by use of the method (Table 2, entries 9 and
10). Furthermore, 1,4-diiodobenzene bearing two iodo
substituents could undergo isocyanide insertion twice and
produced the target product in 51% yield (Table 2, entry
11).
With optimal reaction conditions established, we turned
our focus to the effect of substituents on aryl iodide com-
pounds towards the coupling reaction (Table 2). The mod-
el reaction with iodobenzene led to the isolation of
benzophenone in 80% yield (Table 2, entry 1). Similarly,
2-, 3-, and 4-iodotoluene were converted into the corre-
sponding products in yields of 63%, 83%, and 81%, re-
spectively (Table 2, entries 2–4). The yield of entry 2
(Table 2) is lower than that of entries 3 and 4 (Table 2) due
Synlett 2014, 25, 1425–1430
© Georg Thieme Verlag Stuttgart · New York

LETTER
Carborylative Suzuki Coupling
1427
Table 2 Carbonylative Suzuki Coupling of Various Aryl Iodides with Phenylboronic Acid via tert-Butyl Isocyanide Insertiona
1) PdCl2, Ph3P
K3PO4, toluene
110 °C
O
+
N
Ar1I
t-Bu
C–
Ar1
C
B(OH)2
+
+
1a–k
2) HCl, THF, r.t.
3a–k
Entry
1
Substrate
Product
Time (h)
4
Yield (%)b
80
O
I
1a
1b
3a19
O
O
I
2
3
4
5
3b
22
7
63
83
81
62
I
1c
1d
1e
3c
3d
3e
O
O
I
I
4
5
O
I
6
7
1f
3f
24
6
42
67
MeO
MeO
NC
O
I
1g
3g
NC
O
I
MeO
8
9
1h
1i
3h
3i
22
22
63
64
MeO
O
O
I
I
S
S
O
O
10
1j
3j
22
41
© Georg Thieme Verlag Stuttgart · New York
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Z. Chen et al.
LETTER
Table 2 Carbonylative Suzuki Coupling of Various Aryl Iodides with Phenylboronic Acid via tert-Butyl Isocyanide Insertiona (continued)
1) PdCl2, Ph3P
K3PO4, toluene
110 °C
O
+
N
Ar1I
t-Bu
C–
Ar1
C
B(OH)2
+
+
1a–k
2) HCl, THF, r.t.
3a–k
Entry
11
Substrate
Product
Time (h)
23
Yield (%)b
O
O
1k
3k
51
I
I
a Reaction conditions: All reactions were performed under on a 1 mmol scale, using aryliodides (1.0 mmol), phenylboronic acid (1.2 mmol),
tert-butyl isocyanide (1.2 mmol), PdCl2 (0.03 mmol), Ph3P (0.06 mmol), and K3PO4 (2.0 mmol) in toluene at 110 °C for 4–23 h, followed by
stirring in THF–HCl at r.t. for 2 h.
b Isolated yield.
Next, we examined the effect of substituents on arylbo- 4–6). In addition, naphthalen-2-ylboronic acid was suc-
ronic acid towards the coupling reaction (Table 3). Elec- cessfully coupled with tert-butyl isocyanide and iodoben-
tron-rich substituents such as 4-Me, 4-OMe and 4-OBn zene in good yield (79%, Table 3, entry 7). Furthermore,
were tolerated and led to good or modest yields (Table 3, (4-vinylphenyl)boronic acid and methyl 4-(4-vinylbenzo-
entries 1–3). Besides, phenylboronic acid with electron- yl)benzoate could couple easily with tert-butyl isocyanide
withdrawing substituents such as 4-F, 4-Cl, and 4-vinyl and gave the desired product in 64% yield (Table 3, entry
reacted smoothly with iodobenzene under our standard 8).
conditions and resulted in 62–66% yields (Table 3, entries
Table 3 Carbonylative Suzuki Coupling of Iodobenzene with Various Arylboronic Acid via tert-Butyl Isocyanide Insertiona
1) PdCl2, Ph3P
K3PO4, toluene
110 °C
O
+
N
C–
Ar2
C
I
Ar2B(OH)2
t-Bu
2) HCl, THF
r.t.
2a–h
4a–h
Entry
1
Substrate
Product
Time (h)
12
Yield (%)b
86
O
B(OH)2
2a
4a
O
O
B(OH)2
2
3
4
5
2b
2c
2d
2e
4b
4c
4d
4e
12
12
12
12
54
61
62
66
MeO
BnO
F
MeO
BnO
F
B(OH)2
O
B(OH)2
O
B(OH)2
Cl
Cl
Synlett 2014, 25, 1425–1430
© Georg Thieme Verlag Stuttgart · New York

LETTER
Carborylative Suzuki Coupling
1429
Table 3 Carbonylative Suzuki Coupling of Iodobenzene with Various Arylboronic Acid via tert-Butyl Isocyanide Insertiona (continued)
1) PdCl2, Ph3P
K3PO4, toluene
110 °C
O
+
N
Ar2B(OH)2
Ar2
C
I
t-Bu
C–
2) HCl, THF
r.t.
2a–h
4a–h
Entry
6
Substrate
Product
Time (h)
22
Yield (%)b
64
O
O
O
B(OH)2
B(OH)2
2f
4f
7
8
2g
4g
22
22
79
B(OH)2
2h
4h
64c
OMe
O
a Reaction conditions: All reactions were performed on a 1 mmol scale, using iodobenzene (1.0 mmol), arylboronic acid (1.2 mmol), tert-butyl
isocyanide (1.2 mmol), PdCl2 (0.03mmol), Ph3P (0.06mmol), and K3PO4 (2.0 mmol) in toluene at 110 °C for 12–22 h, followed by stirring in
THF–HCl at r.t. for 2 h.
b Isolated yield.
c One of the coupling partners is methyl 4-iodobenzoate.
A plausible mechanism for this reaction is depicted in
L
Scheme 1. Oxidative addition of 1a to the palladium(0)
Ph—Pd—I
catalyst leads to the palladium complex 5, followed by
tert-butyl isocyanide insertion to form 6. With the assis-
tance of K3PO4, the iodine is exchanged by phenyl, which
leads to the generation of 7. Reductive elimination of 7
L
5
PhI
1a
L
t-Bu
N
gives the intermediate 8, which was detected by HRMS in
the reaction system.20 Intermediate 8 yields the target
product 3a by hydrochloric acid catalyzed hydrolysis.
Pd—I
L
Pd0 Ln
Ph
6
PhB(OH)2 + K3PO4
In conclusion, we have developed a simple and efficient
palladium-catalyzed carbonylative Suzuki coupling to
synthesize diaryl ketones via tert-butyl isocyanide inser-
tion and subsequent hydrochloric acid catalyzed hydroly-
sis. tert-Butyl isocyanide serves as carbonyl source in
catalytic C–C bond construction. Characterized by mild
reaction conditions, wide substrate scope and moderate to
good yields (42–86%), this protocol may aid the further
development of the isocyanides insertion reactions.
L
t-Bu
N
Pd—Ph
L
Ph
7
O
t-Bu
N
HCl, THF
Ph
Ph
Ph
Ph
8
3a
Acknowledgment
Scheme 1 Plausible mechanism for the synthesis of 3a
This project was funded by the Priority Academic Program Deve-
lopment of Jiangsu Higher Education Institutions (PAPD).
References and Notes
Supporting Information for this article is available online
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© Georg Thieme Verlag Stuttgart · New York
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LETTER
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(19) General Experimental Procedure
In a 15 mL sealed tube equipped with a magnetic stirring bar
were added iodobenzene (1.0 mmol, 112 μL), phenylboronic
acid (1.2 mmol, 146 mg), tert-butyl isocyanide (1.2 mmol,
136 μL), PdCl2 (0.03 mmol, 5 mg), Ph3P (0.06 mmol, 16
mg), K3PO4 (2.0 mmol, 424 mg), and anhydrous toluene (4.0
mL). The tube was purged with N2, and the contents were
stirred at 110 °C for 4 h. After completion of the reaction as
indicated by TLC, the mixture was filtered through neutral
Al2O3, and the solvent was removed under vacuum. Then,
the residue was stirred in THF (10 mL) and HCl (1 M, 3 mL)
for 2 h. Then, the mixture was extracted with EtOAc, dried
with Na2SO4, and evaporated. The residue was purified on a
silica gel column using PE–EtOAc (100:1) as the eluent to
give the pure product 3a.
Benzophenone (3a)
White solid; mp 48–50 °C. 1H NMR (300 MHz, CDCl3): δ =
7.79–7.82 (m, 4 H), 7.55–7.60 (m, 2 H), 7.45–7.49 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 196.7, 137.6, 132.4, 130.1,
128.3. ESI-MS: m/z = 183.0 [M + H]+.
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(20) Intermediate 8
HRMS (CI): m/z calcd for C17H19N [M]+: 237.1517; found:
237.1517. HRMS (CI): m/z calcd for C13H9N [M – C4H9]+:
180.0813; found: 180.0810.
Synlett 2014, 25, 1425–1430
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