Palladium-Catalyzed Insertion of Isocyanides into the C?S Bonds of Heteroaryl Sulfides

Article abstract of DOI:10.1002/anie.201802369

Insertion of tert-butyl isocyanide into the C(sp²)?S bonds of heteroaryl sulfides is catalyzed by a palladium diphosphine complex. Thioimidates generated through this reaction could be readily hydrolyzed under acidic conditions to yield the corresponding thioesters, which are of synthetic use. This insertion is useful because starting heteroaryl sulfides were readily prepared by either conventional ways or through sulfur-specific extended Pummerer reactions.

Full text of DOI:10.1002/anie.201802369

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Accepted Article
Title: Palladium-Catalyzed Insertion of Isocyanides into the C-S Bonds
of Heteroaryl Sulfides
Authors: Shinya Otsuka, Keisuke Nogi, and Hideki Yorimitsu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201802369
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Palladium-Catalyzed Insertion of Isocyanides into the C–S Bonds
of Heteroaryl Sulfides
Shinya Otsuka, Keisuke Nogi, and Hideki Yorimitsu*
Abstract: Insertion of tert-butyl isocyanide into the C(sp2)–S bonds of
heteroaryl sulfides proceeded catalyzed by a palladium–diphosphine
complex. Thioimidates generated through this reaction could be
readily hydrolyzed under acidic conditions to yield the corresponding
thioesters of synthetic use. This insertion is useful because starting
heteroaryl sulfides were readily prepared in conventional ways or
through sulfur-specific extended Pummerer reactions.
and Kambe succeeded in formal carbonyl insertion into the
C(=O)–S bonds of carbamoyl sulfides under palladium catalysis
(Scheme 1d).[11] However, insertion of CO or isocyanides into
aromatic C–S bonds has remained impractical.[12,13]
Along the line of our interest in catalytic C–S-bond
transformations,[5e,l–t] here we report that simple insertion of tert-
butyl isocyanide into the C–S bonds of heteroaryl sulfides
proceeded by means of a Pd catalyst to provide thioimidates
(Scheme 1e).
The resulting thioimidates could be easily
Palladium-catalyzed carbonylative transformations of aryl
halides have occupied an important position in the synthesis of
carbonyl compounds.[1] In the presence of nucleophiles such as
alcohols, amines, organoboronic acids, and hydrosilanes,
reactions of aryl halides with carbon monoxide (CO) or its
equivalents[2] affords esters, amides, ketones, and aldehydes,
respectively. Despite the utility of the transformations, a notable
limitation still remains: external nucleophiles are always
necessary. There are no precedent for simple insertion of CO into
the C–X bonds of aryl halides to provide aroyl halides of great
synthetic use. The reason for the lack would lie in the higher
reactivity of the resultant aroyl halides toward oxidative addition
than that of the starting aryl halides. In other words, catalyst
turnover would be difficult due to unfavorable reductive
elimination from aroylpalladium halides. Recently, Arndtsen
reported seminal elegant works on palladium-catalyzed synthesis
of aroyl chlorides from aryl iodides[3] or bromides.[4] However,
additional chloride anion was nevertheless required as an
external nucleophile.
converted to the corresponding thioesters by acidic hydrolysis.
Given that a wide variety of heteroaryl sulfides are easily
accessible,[14] this transformation would be useful in the synthesis
of heteroaromatic carbonyl compounds.
(a) Holmquist and Carnahan: aryl sulfide
O
SMe
cat. Co2(CO)8
SMe
21%
CO (1000 atm)
benzene, 300 °C
(b) Alper: reactive allylic and benzylic sulfides
O
cat. Pd/dppp
SR
SR
CO (68 atm)
toluene, 140 °C
S
NR2
cat. [Rh(cod)Cl]2
S
NR2
CO (53 atm)
O
benzene, 140 °C
(c) Komiya: strained thietane
S
cat. (dppe)Pt–Co(CO)4
S
O
CO (10 atm)
THF, 100 °C
Recently aryl sulfides have attracted great interest as aryl
pseudohalides in transition metal-catalyzed reactions.[5] Simple
insertion of CO into the C(sp2)–S bonds of aryl sulfides should
give aromatic thioesters, which are synthetically useful and
(d) Kuniyasu, Kambe: carbamoyl sulfide
O
O
cat. Pd/dppp
SAr
R2N
C=N(2,6-xylyl)
R2N
SAr
DMF, 110 °C
N(2,6-xylyl)
moisture-stable acyl cation synthons.[6]
However, such
(e) This work: heteroaryl sulfide
transformation has been very challenging. Although CO insertion
into the C–S bonds of phenyl sulfides was attempted, the highest
yield of the product was 21% even under extraordinarily harsh
conditions (1000 atm of CO pressure at 300 °C) (Scheme 1a).[7]
Therefore, CO insertion into C–S bonds is limited to several
reactive C–S bonds. Alper reported insertion of CO into reactive
C(sp3)–S bonds under Pd or Rh catalysis (Scheme 1b).[8] Komiya
developed insertion of CO into the strained C–S bond of thietane
NtBu
Y
Ar
Z
Y
Ar
Z
cat. Pd/dippf
SMe
C=NtBu
MeCN, 90–110 °C
SMe
Y = CH, N
Z = O, S
Scheme 1. Catalytic insertion of CO or its equivalents into C–S bonds.
In the presence of a Pd catalyst (5 mol%), Zn(OAc)2 (25
mol%), and K3PO4 (25 mol%), insertion of tert-butyl isocyanide
into the C–S bond of 2-(methylsulfanyl)benzothiazole (1a) was
tested (Table 1). After acidic workup, 18% of the corresponding
thioester 3a was obtained when Pd2(dba)3/dppf (dppf = 1,1'-
bis(diphenylphosphino)ferrocene) was used (entry 1). We then
screened analogues of dppf (entries 2–4). As a result, 1,1'-
bis(diisopropylphosphino)ferrocene (dippf) provided 3a in 80%
yield. Other bidentate phosphine (entries 5–8) as well as
monodentate phosphine or NHC ligands resulted in no or
negligible formation of the product (See Table S1 in the
Supporting Information). Interestingly, both of the additives,
Zn(OAc)2 and K3PO4, were indispensable for this transformation.
In the absence of one of these additives, the yield of 3a
catalyzed by
a
Pt-Co dinuclear complex (Scheme 1c).[9]
Nevertheless, high pressures of gaseous CO were required and
substrates were very limited. In this context, isocyanides are
regarded as intriguing surrogates of CO to avoid one to use high
pressure of CO.[1a,10] By employing 2,6-xylyl isocyanide, Kuniyasu
S. Otsuka, Dr. Keisuke Nogi, Prof. Dr. H. Yorimitsu
Department of Chemistry, Graduate School of Science
Kyoto University
Sakyo-ku, Kyoto 606-8502 (Japan)
E-mail: yori@kuchem.kyoto-u.ac.jp
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201802369
Angewandte Chemie International Edition
COMMUNICATION
dramatically dropped (entries 9 and 10).[15] The yield was
improved to 93% by increasing the amount of tert-butyl isocyanide
from 1.2 to 2.0 equivalents (entry 11). When Pd(PPh3)4 was used,
a catalyst loading could be reduced to 2 mol% without loss of the
yield (entry 12). The use of tert-butyl isocyanide is critical in this
Table 2. Scope of benzothiazolyl sulfides.
2 mol% Pd(PPh3)4
2 mol% dippf
2 equiv C=NtBu
25 mol% Zn(OAc)2
25 mol% K3PO4
Y
N
N
5
SR2
6
MeCN, 90 °C
SR2
reaction.
1,1,3,3-Tetramethylbutyl isocyanide and p-
S
S
R1
R1
toluenesulfonylmethyl isocyanide resulted in much poorer results
(See Table S1). Notably, completely no reaction took place under
CO atmosphere (1 atm) instead of using tert-butyl isocyanide.
1
Y = NtBu 2
H3O+
Y = O
3
isolated
yield
entry
R1
R2
1
3
Table 1. Optimization of reaction conditions.
1
2
3
H
Me
Me
Me
1a
1b
1c
3a
3b
3c
79%
94%
79%
5-CF3
6-F
2.5 mol% Pd2(dba)3
5 mol% ligand
1.2 equiv C=NtBu
25 mol% Zn(OAc)2
25 mol% K3PO4
4
5
6
7
6-(4-MeOC6H4)
Me
1d
1e
1f
3d
3e
3f
83%
66%
68%
67%
78%
79%
85%
85%
96%[a]
73%[a]
Y
N
N
S
6-(4-HCOC6H4)
Me
Me
SMe
MeCN, 110 °C
S
SMe
6-CO2Me
Y = NtBu 2a
1a
H3O+
6-(2-thienyl)
Me
1g
1h
1i
3g
3h
3i
Y = O
3a
8
9
5-Cl
H
Me
entry
ligand
NMR yield
18%
entry
ligand
dppb
NMR yield
2%
Et
1
2
3
dppf
dtbpf
dcypf
7
8
9[a]
10
11
12
13
H
C12H25
CH2Ph
4-MeOC6H4
CH2CH2CO2Me
1j
3j
38%
(rac)-BINAP
<1%
H
1k
1l
3k
(2l)
3m
58%
dippf
4%
H
4
5
dippf
dppe
dppp
80%
6%
10[b]
11[c]
12[c,d]
dippf
dippf
dippf
0%
H
1m
93%
96%
[a] 5 mol% of Pd(PPh3)4 and dippf.
6
6%
dtbpf
=
1,1'-bis(di-tert-butylphosphino)ferrocene, dcypf
=
1,1'-
5 mol% Pd(PPh3)4
10 mol% dippf
2 equiv C=NtBu
25 mol% Zn(OAc)2
bis(dicyclohexylphosphino)ferrocene. [a] Without Zn(OAc)2. [b] Without
K3PO4. [c] 2.0 equiv of tert-butyl isocyanide, 90 °C. [d] 2 mol% of Pd(PPh3)4
and dippf.
Y
Y
Ar
Z
Y
Ar
Z
25 mol% K3PO4
Y = NtBu 2
H3O+
SMe
Y = O
3
MeCN, 110 °C
SMe
With the optimized reaction conditions in hand, functional
group compatibility was examined (Table 2). Benzothiazolyl
methyl sulfides having an electron-withdrawing trifluoromethyl
and fluoro group reacted smoothly to provide 3b and 3c,
respectively, in excellent yields (entries 2 and 3). Benzothiazolyl
sulfide 1d containing an electron-donating methoxy group also
gave 3d in high yield (entry 4). Carbonyl groups such as formyl
and ester in 1e and 1f survived during the course of the reaction
(entries 5 and 6). To our delight, the C–Cl bond left untouched in
the reaction of 1h, which is beneficial for further transformations
(entry 8). The effect of the substituent R2 on the sulfur atom was
also investigated. S-Ethyl-, S-dodecyl-, and S-benzyl-substituted
benzothiazolyl sulfides 1i–1k were smoothly converted to the
corresponding thioesters in high yields (entries 9–11). Aromatic
p-anisyl-substituted 1l uneventfully underwent the isocyanide
insertion selectively into the benzothiazolyl–S bond (entry 12).[16]
Benzothiazolyl 2-(methoxycarbonyl)ethyl sulfide (1m) also
participated in the reaction to yield 3m, which can undergo retro-
Michael addition to generate thiocarboxylic acid (entry 13).[17]
Various heteroaryl sulfides were applicable to this
transformation (Scheme 2). Both π-extended naphthothiazolyl
sulfide 1n and simple thiazolyl sulfide 1o reacted smoothly. The
reaction of benzoxazolyl sulfide 1p was sluggish under the
optimized reaction conditions. However, by means of 5 mol% of
Pd(PPh3)4 and 10 mol% of dippf, 3p was obtained in 68% yield.
Gratifyingly, benzofuran 1q and benzothiophene 1r were also
converted into 3q and 3r in 73% and 71% yields, respectively,
under the modified reaction conditions.[18]
1
O
O
N
N
O
N
O
S
SMe
SMe
3o 64%[a]
3p 68%
S
SMe
3n 70%[a]
O
O
O
S
SMe
SMe
3r 71%
3q 73%
Scheme 2. Scope of sulfides. [a] 2 mol% of Pd(PPh3)4 and dippf, 90 °C.
Previously our group reported the concise synthesis of 2-
alkylsulfanylbenzothiophenes[19] and -benzofurans[5n,20] based on
extended Pummerer reactions of ketene dithioacetal monoxides.
We thus envisioned that the present isocyanide insertion would
be applicable to these heteroarenes. Indeed, benzofurans 4a–d
and benzothiophene 4e prepared through these sulfur-specific
Pummerer-type reactions were uneventfully converted to
thioesters 5a–e in good yields after hydrolysis (Schemes 3 and 4).
Furthermore, thioester 5d could be further derivatized to the
corresponding diaryl ketone
coupling[6d] with 4-methoxyphenylboronic acid (Scheme 5). This
three-step transformation including construction of
6 by Liebeskind-Srogl cross-
heteroaromatic core, isocyanide insertion, and Liebeskind-Srogl
cross-coupling would be a useful synthetic route to elaborate
unsymmetrical diaryl ketones which would be otherwise difficult to
construct.
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(a) Pd-catalyzed thiolate scrabmle between two benzothiazolyl sulfides
R
R
Tf2O or (CF3CO)2O
+
N
Ar
2 mol% Pd(PPh3)4
2 mol% dippf
25 mol% Zn(OAc)2
SMe
Ar
SMe
ref. [5m, 20]
SCD3
OH
MeS
O
S
1a-d: 46%
1t: 50%
1a: 50%
O
4a–d
1a-d
1t-d: 49%
R
MeCN
90 °C, 12 h
isocyanide insertion
then hydrolysis
N
recovered
exchanged
O
SCH3
Ar
S
without Zn(OAc)2: no scrambling
O
SMe
1t
5a–d
(b) Pd-catalyzed thiolate exchange with a thiol
1a 39% recovered
CF3
CF3
Ph
O
2 mol% Pd(PPh3)4
2 mol% dippf
R’
+
O
O
O
N
S
N
+
SMe HSC12H25
O
O
SMe
SMe
SMe
MeCN
90 °C, 12 h
SC12H25
S
1a
1.0 equiv
5c 79% (R’ = OMe)
5d 62% (R’ = CO2Et)
5a 66%
5b 82%
1j 59% generated
Scheme 6. Thiolate exchange reactions.
tBuN
Scheme 3. Benzofuran synthesis followed by isocyanide insertion.
P
CF3
SMe
CF3
CF3
isocyanide insertion
then hydrolysis
SMe
Ph
MeS
Tf2O
Zn,
O
SMe
Ar SMe
Pd
P
Ar
ref. [19]
S
S
SMe
Zn SMe
4e
5e 81%
O
P
P
Scheme 4. Benzothiophene synthesis followed by isocyanide insertion.
tBuN
I
Pd
P
Ar Pd P
III
cat. Pd2(dba)3/P(2-furyl)3
(4-anisyl)B(OH)2
Ph
Ar
EtO2C
SMe
Zn
Zn SMe
O
2-thienylCO2Cu
5d
O
4-anisyl
THF, 65 °C
P
6 85%
Ar Pd
P
CNtBu
Scheme 5. Liebeskind-Srogl cross-coupling of thioester 5d.
II
Scheme 7. Proposed reaction mechanism.
To get insights into the role of additives, several mechanistic
experiments were carried out. When benzothiazolyl
trideuteriomethyl sulfide (1a-d) and methyl 5-
With these results in mind, we describe a proposed catalytic
cycle of the isocyanide insertion in Scheme 7. First, oxidative
addition of heteroaryl sulfides 1 to dippf-ligated Pd(0) would
provide arylpalladium thiolate intermediate I. Lewis acidic zinc
salt would activate intermediate I to generate cationic complex II
methylbenzothiazolyl sulfide (1t) were mixed in the presence of
catalytic amounts of Pd(PPh3)4, dippf, and Zn(OAc)2, scrambling
of the sulfur units occurred to yield a statistical mixture of 1a, 1a-
d, 1t, and 1t-d (Scheme 6a). Interestingly, this scrambling was
totally shut down without Zn(OAc)2 even in the presence of the
palladium catalyst. Based on these results, we made two
hypotheses about the role of Zn(OAc)2: (1) promoting oxidative
addition to Pd(0) by weakening the C–S bond of 1, or (2)
promoting isocyanide to insert by weakening the Pd–S bond of
the oxidative adduct. When 1a was treated with dodecanethiol as
an external thiol source, the thiolate exchange happened even in
the absence of Zn(OAc)2 (Scheme 6b).[21] This implies that
oxidative addition would proceed without the aid of Zn(OAc)2.[22]
Therefore, Zn(OAc)2 would serve as a Lewis acid to cleave the
Pd–S bond of the oxidative adduct to generate transient vacant
site on the Pd complex.[23] Notably, the presence or absence of
K3PO4 had negligible effects in the reactions in Scheme 6.
reversibly.
Coordination of tert-butyl isocyanide to II and
successive migratory insertion provide imidoyl palladium
intermediate III. Reaction of III with zinc thiolate species followed
by reductive elimination would afford the corresponding
thioimidate. The thioimidate is supposed to resist undesired
oxidative addition to palladium because of the steric hindrance of
the tBu group, thus this unprecedented insertion being achieved.
In summary, we have developed insertion of isocyanides
into C–S bonds of heteroaryl sulfides by means of catalytic
amounts of palladium complex, Zn(OAc)2, and K3PO4. The
products, thioimidates, could be readily converted to synthetically
useful thioesters through acidic hydrolysis. The usefulness of the
insertion was strengthened by combining with extended
Pummerer chemistry and/or Liebeskind-Srogl cross-coupling.
In order to understand the role of K3PO4, several potassium
salts as well as Na3PO4 were tested instead of K3PO4 (Table S2).
As a result, potassium salts were found to show activity while
Na3PO4 did not. In addition, the yield of this reaction depends on
the ratio of Zn(OAc)2 and K3PO4, not simply on the equivalents
themselves. While the role of potassium bases is still unclear, we
speculate that Zn(OAc)2 and potassium salts compose cluster
structures that have higher activity for isocyanide insertion.[24,25]
Acknowledgements
This work was supported by JSPS KAKENHI Grant Numbers
JP16H01019, JP16H01149, JP16H04109, JP16H06887, as well
as JST ACT-C Grant Number JPMJCR12ZE, Japan. S.O.
acknowledges JSPS Predoctoral Fellowship.
Keywords: thioimidate • thioester • C–S bond activation •
isocyanide • palladium
[1]
Reviews: a) E.-i. Negishi, Handbook of Organopalladium Chemistry for
Organic Synthesis, Wiley-VCH, New York, 2002; b) T. Morimoto, K.
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[14] 2-(Methylsulfanyl)benzothiazoles can be prepared from corresponding 2-
bromoanilines. See the Supporting Information for details.
[15] See Table S2 and S3 in the Supporting Information for more details.
[16] Since attempted hydrolysis of thioimidate 2l provided not only 3l but also
the corresponding tert-butyl amide, the isolated yield of 2l is shown.
[17] Retro-Michael dealkylation of 2-alkoxycarbonyl thioesters: T. Fukuyama,
L. Xu, J. Am. Chem. Soc. 1993, 115, 8449.
[18] Although the reaction of methyl p-tolyl sulfide was tried, no conversion
was observed. 2-Naphthyl methyl sulfide and 2,3,5,6-tetrafluoro-4'-
methyl-4-(methylsulfanyl)biphenyl, which would be more reactive than
methyl p-tolyl sulfide, gave only trace amounts of the products. We infer
that the oxidative addition of the C–S bonds of such aryl sulfides would
be unfavorable compared to that of heteroaryl sulfides. In fact, the
thiolate exchange described in Scheme 6b was not observed when p-
tolyl methyl sulfide was used instead of 1a. In general, oxidative addition
of heteroaryl halides is considered to be more favored than that of phenyl
halides: B. U. W. Maes, S. Verbeeck, T. Verhelst, A. Ekomié, N. von Wolff,
G. Lefèvre, E. A. Mitchell, A. Jutand, Chem. Eur. J. 2015, 21, 7858.
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[21] When the thiolate exchange described in Scheme 6b was conducted in
the presence of 25 mol% of Zn(OAc)2, a 53% yield of 1j was generated
along with 46% recovery of 1a.
[6]
Review: a) V. Hirschbeck, R. H. Gehrtz, I. Fleischer, Chem. Eur. J. 2018,
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[22] To investigate the oxidative addition step, stoichiometric reactions were
conducted with 1a-d, Pd(PPh3)4, and dippf in the presence or absence of
Zn(OAc)2, and analyzed by 2H NMR. In both cases, two signals derived
from 1a-d and the oxidative adduct were observed at δ 2.7 and 1.1 ppm,
respectively. Notably, the intensity ratios of the two signals were
approximately same in both experiments. These results also indicate that
Zn(OAc)2 has a negligible effect for the oxidative addition step. See the
Supporting Information and Figure S1 for more details.
[7]
[8]
H. E. Holmquist, J. E. Carnahan, J. Org. Chem. 1960, 25, 2240.
a) C. M. Crudden, H. Alper, J. Org. Chem. 1995, 60, 5579; b) K.
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[9]
M. Furuya, S. Tsutsuminai, H. Nagasawa, N. Komine, M. Hirano, S.
Komiya, Chem. Commun. 2003, 2046.
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B. U. W. Maes, R. V. A. Orru, Angew. Chem. Int. Ed. 2013, 52, 7084; b)
B. Song, B. Xu, Chem. Soc. Rev. 2017, 46, 1103; c) M. Suginome, Y. Ito,
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T. Bando, T. Matsuura, M. ishikawa, J. Chem. Soc. Chem. Commun.
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reported to be larger than that in [(P–P)Pd(Me)Cl], where P–P is a
bidentate ligand. See: G. P. C. M. Dekker, C. J. Elsevier, K. Vrieze, P. W.
N. M. Van Leeuwen, Organometallics 1992, 11, 1598.
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when heated in refluxing toluene. See: Y. Hayashi, T. Ohshima, Y. Fujii,
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halides and thiols, see reference 6a. Examples: a) H. Cao, L. McNamee,
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10.1002/anie.201802369
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
✂
S. Otsuka, K. Nogi, H. Yorimitsu*
Page No. – Page No.
NtBu
Y
Ar
Z
Y
Ar
Z
cat. Pd/dippf
NtBu
+
SMe
C
C
SMe
Insertion of tert-butyl isocyanide into the C(sp2)–S bonds of heteroaryl sulfides
proceeded catalyzed by a palladium–diphosphine complex. Thioimidates generated
through this reaction could be readily hydrolyzed under acidic conditions to yield the
corresponding thioesters of synthetic use. This insertion is useful because starting
heteroaryl sulfides were readily prepared in conventional ways or through sulfur-
specific extended Pummerer reactions.
This article is protected by copyright. All rights reserved.