Copper-Catalyzed Electrophilic Thiolation of Organozinc Halides by Using N-Thiophthalimides Leading to Polyfunctional Thioethers

Article abstract of DOI:10.1002/chem.201806261

(Hetero)aryl, benzylic, and alkyl zinc halides were thiolated with N-thiophthalimides at 25 °C within 1 h in the presence of 5–10 % Cu(OAc)₂?H₂O to furnish the corresponding polyfunctionalized thioethers in good yields. This electrop

Full text of DOI:10.1002/chem.201806261

A Journal of
Accepted Article
Title: Copper-Catalyzed Electrophilic Thiolation of Organozinc Halides
Using N-Thiophthalimides Leading to Polyfunctional Thioethers
Authors: Simon Graßl, Clémence Hamze, Thaddäus Johannes Koller,
and Paul Knochel
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To be cited as: Chem. Eur. J. 10.1002/chem.201806261
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Copper-Catalyzed Electrophilic Thiolation of Organozinc Halides
Using N-Thiophthalimides Leading to Polyfunctional Thioethers
Simon Graßl, Clémence Hamze, Thaddäus J. Koller and Paul Knochel*
Abstract: (Hetero)aryl, benzylic and alkyl zinc halides were thiolated
with N-thiophthalimides at 25 °C within 1 h in the presence of 5–10%
Cu(OAc)2·H2O to furnish the corresponding polyfunctionalized
thioethers in good yields. This electrophilic thiolation was extended to
the introduction of trifluoromethylthio (SCF3), thiocyanate (SCN) and
selenophenyl (SePh) groups. The utility of this method was shown in
a seven step synthesis of a potent cathepsin D inhibitor in 34% overall
yield.
In preliminary experiments, we have examined the effect of a
transition metal catalyst on the formation of thioether 1a.
Therefore, 4-anisylzinc chloride (2a)[7] was treated with
N-(cyclohexylthio)phthalimide (3a; 25 °C, 1 h). In the absence of
a catalyst, a yield of only 49% of 1a was obtained (Table 1,
entry 1). Catalysis with FeCl2, CrCl2, Fe(acac)3, CoCl2, NiCl2 and
MnCl2 (5%) increased this yield up to 72% (entries 2-7). By testing
various copper salts such as CuBr2, CuBr, CuCl2, Cu(OAc) and
CuCN·2LiCl, we have further increased the yield up to 88%
(entries 8–12). However, CuCl and Cu(OAc)2·H2O were found to
give the best results (93–95% yield, entries 13–14).
Thioethers are very common functional group in bioactive
molecules[1] and the synthesis of the sulphur linkage led to the
development of numerous methodologies.[2] Thus, Cu-catalyzed
nucleophilic thiolations using aryl halides and organic thiols have
been reported.[3] Also, electrophilic thiolations involving
electrophilic sulfur-reagents of type RS-X (X = SR, halogeno,
N-succimidyl and arylsulfonyl) with various organometallics have
found growing interest.[4] In this respect, the use of polyfunctional
organozinc reagents[5] is of special interest, since they are readily
prepared and tolerate a broad range of functional groups like an
ester, a nitrile or an aldehyde.
Table 1. Catalyst screening for the electrophilic thiolation of zinc organometallic
2a.
Yield
[%][a]
Yield
[%][a]
Entry
Catalyst
Entry
Catalyst
1
2
3
4
5
6
7
-
49
54
60
63
64
71
72
8
CuBr2
CuBr
74
79
FeCl2
9
CrCl2
10
11
12
13
14
CuCl2
82
Fe(acac)3
CoCl2
NiCl2
Cu(OAc)
CuCN·2LiCl
CuCl
88
88
93
95[b]
MnCl2
Cu(OAc)2·H2O
[a] GC yield using undecane as internal standard [b] Isolated yields of analytically
pure products
Scheme 1. General preparation of N-thiophthalimides 3 and their reaction with
organozinc reagents 2 to provide thioethers of type 1.
Herein, we wish to report
polyfunctional thioesters of type 1 by the reaction of functionalized
aryl, heteroaryl, alkyl or benzylic organozinc halides 2 with
a convenient preparation of
With this optimized procedure, we have examined the scope of
organozinc reagents 2. Thus, the reaction of electron-rich (2a-e)
as well as electron-poor arylzinc chlorides (2f-g) with
N-thiophthalimide 3a or 3b using 5% Cu(OAc)2·H2O provided the
desired thioethers 1b-h in 86-99% yield (Table 2, entries 1-7).
Moreover, ferrocenylzinc chloride (2h) was coupled with
thiophthalimide 3b, furnishing the ferrocenyl thioether 1i in 90%
yield (entry 8). Also heteroarylzinc halides 2h-k underwent an
electrophilic thiolation giving the thioethers 1j-l in 71-94% yield
(entries 9-11). Furthermore, alkyl and benzylic zinc halides 2l-n
were successfully coupled with N-(phenylthio)phthalimide (3b)
and N-(cyclohexylthio)-phthalimide (3a), furnishing the thioethers
1m-o (entries 12-14). Noteworthy, sensitive functional groups
such as nitriles, esters, aldehydes and ketones were tolerated
(entries 6, 7, 9, 10 and 14). Also, sterically hindered nucleophiles
such as zinc organometallics 2c and 2k gave the desired
thioethers 1d and 1l in 94-99% yield (entry 5 and 11).
N-thiophthalimides
3.
These
N-thiophthalimides
were
conveniently prepared by an optimized literature procedure based
on the methods published by Liebeskind[4g] and Chen[6], involving
the reaction of commercial N-chlorophthalimide 4 with various
organic thiols of type 5 (Scheme 1).
S. Graßl, C. Hamze, T. J. Koller, Prof. Dr. P. Knochel
Ludwig-Maximilians-Universität München
Department Chemie Butenandtstrasse 5–13, Haus F, 81377
München (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
Supporting information for this article is given via a link at the end of
the document.
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Table 2. Thioethers of type 1 via a copper-catalyzed thiolation of organozinc
reagents of type 2 with N-thiophthalimides of type 3.
12
3b
1m: 97%
2l
13
3b
Entry
1
Zinc reagent 2
Pht-SR 3[a]
Product of type 1[b]
1n: 96% (d.r. 71:29)
1o: 98% (d.r. 97:3)
2m
2n
14
3a
2a
2b
3b
3b
1b: 98%
1c: 98%
2
3
Pht = phthalimide; [b] Isolated yields of analytically pure products.
[a]
3a
3b
Next, we have investigated the scope of polyfunctional
thiophthalimides of type 3. We have found that both, alkyl and
(hetero)aryl thiophthalimides gave excellent results. Therefore,
the alkyl thiophthalimides 3a and 3c were coupled with arylzinc
chlorides 2a and 2o affording thioethers 1a and 1p in 71-95%
yield (Table 3, entries 1-2). Also various functionalized aryl- and
heteroaryl thiophthalimides have been prepared according to the
method described above (Scheme 1) and subsequently coupled
to form the corresponding thioether of type 1. Thus, the copper-
catalyzed thiolation of organozinc reagents 2c, 2f, 2p-s and
thiophthalimides 3d-l led to the expected thiolation products 1p-y
in 55-97% yield (entries 3-12). Electron-rich as well as electron-
poor aryl and heteroaryl derivatives can be used for this thiolation.
Furthermore, sensitive functional groups such as esters and
nitriles attached to the N-thiophthalimide were tolerated (entries
8-9). Noteworthy, even highly reactive nitro groups are tolerated
with only slightly reduced yields. Thus, the reaction of
thiophthalimide 3f with organozinc chloride 2o provided thioether
1s in 55% yield (entry 6).
1d: 90%
1e: 86%
2c
2d
4
5
6
7
3b
3b
3b
1f: 99%
1g: 98%
2e
2f
1h: 95%
2g
Table 3: Electrophile scope of electrophilic thioether formation using various
N-thiophthalimides of type 3.
8
3b
1i: 90%
1j: 89%
1k: 71%
2h
2i
9
3b
3b
10
Entry
1
Zinc reagent 2
Pht-SR 3[a]
Product of type 1[b]
2j
11
3b
1l: 94%
2a
3a
1a: 95%
2k
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trifluoromethylthiolated products (6a-d) in 78-91% yield (Scheme
2). Next, we have extended the scope to thiocyanates. As
expected, the reaction of N-thiophthalimide 3n[7] with arylzinc
chlorides of type 2 provided arylthiocyanates 7a-c in 72-93% yield
(Scheme 2). Due to the lower reactivity of these thiophthalimides
(3m-n), 10% Cu(OAc)2·H2O was necessary.
2
2o
3c
3d
1p: 71%
1q: 94%
3
2f
4
2p
3e
3e
3f
1r: 97%
1s: 96%
1t: 55%
5
2q
6
2o
7
Scheme 2. Preparation of SCF3, SCN and SePh substituted aryl and heteroaryl
derivatives via a copper-catalyzed thiolation of arylzinc chlorides.
2c
3g
3h
1u: 89%
1v: 70%
8
Additionally, we have extended this method to the preparation of
selenium compounds. Thus, selenophthalimide (3o) was treated
with 4-chlorophenylzinc chloride (2s) to give selenoether 8 in 83%
yield (Scheme 2). Last, we have applied this methodology to a
short synthesis of the bioactive cathepsin-D inhibitor 9[9] starting
from 4-bromobenzonitrile 10 (Scheme 3). Thus, the conversion of
10 to the corresponding Grignard reagent was achieved with
turbo-Grignard (iPrMgCl·LiCl)[10], leading after thiolation with
elementary sulphur to the thiol 11 in 95% yield.[11] In this
procedure, it was important to remove iPrBr under vacuum after
the Br/Mg-exchange step. Using the above described procedure,
thiol 11 was converted to the corresponding N-thiophthalimide in
2f
9
2r
3i
3j
1w: 90%
1x 94%
10
2s
11
76% yield.
A subsequent copper-catalyzed thiolation with
heteroarylzinc chloride 12[7] afforded the desired thioether 13 in
94% yield. Next, the nitrile functionality was hydrolysed using
acetaldoxime and NiCl2·6H2O to provide an intermediate amide in
91% yield.[12] The corresponding aniline derivative 14 was
obtained via a Hofmann rearrangement (Br2, NaOH) in 63%
yield.[13] Finally, using an iodine/triphenylphosphine-mediated
amidation, the desired target 9 was obtained in 61% yield (97%
based on recovered starting material).[14]
2s
3k
1y: 85%
12
2q
3l
1z: 81%
[a]
Pht = phthalimide; [b] Isolated yields of analytically pure products.
Interestingly, this method was further extended to the introduction
of a trifluoromethylthio (SCF3), a thiocyanate (SCN) as well as an
phenylselenyl (SePh) moiety. SCF3 groups are important
bioisosteres to alter the biological activity of drugs, what entails
the requirement of elaborated methods for their introduction.[8]
Therefore,
commercially
available
N-(trifluoromethylthio)
phthalimide 3m was treated with arylzinc halides of type 2 in the
presence of 10% Cu(OAc)2·H2O to give the corresponding
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Scheme 3. Synthesis of bioactive cathepsin-D inhibitor 9.
Yield based on
recovered starting material.
In summary, we have developed a new preparation of thioethers
(1) from N-thiophthalimides 3 via a Cu(OAc)2·H2O-catalyzed
thiolation of organozinc halides 2. This method has a broad scope,
tolerating various reactive functional groups including aldehydes
and nitro groups. An extension to the introduction of SCF3, SCN
and SePh groups was also achieved. The utility of the method
was shown in a short synthesis of a bioactive cathepsin-D inhibitor
9. Further applications are currently underway in our laboratories.
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Acknowledgements
We thank the Ludwig-Maximilians-Universität München and the
Deutsche Forschungsgemeinschaft (DFG) for financial support.
We thank Albemarle (Germany) for the generous gift of chemicals.
Keywords: electrophilic thiolation • copper-catalysis •
organozinc halide • trifluoromethylthioation • thioether
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Simon Graßl, Clémence Hamze,
Thaddäus J. Koller and Paul Knochel*
Page No. – Page No.
Copper-Catalyzed Electrophilic
Thiolation of Organozinc Halides
Using N-Thiophthalimides Leading to
Polyfunctional Thioethers
Text for Table of Contents
(Hetero)aryl, benzylic and alkyl zinc halides were thiolated with N-thiophthalimides at 25 °C within 1 h in the presence of 5–10%
Cu(OAc)2·H2O to furnish the corresponding polyfunctionalized thioethers in 55-98% yield. This electrophilic thiolation was extended to
the introduction of trifluoromethylthio (SCF3), thiocyanate (SCN) and selenophenyl (SePh) groups. The utility of this method was shown
in the seven step synthesis of a potent cathepsin D inhibitor in 34% overall yield.
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