Cobalt-catalyzed acylation-reactions of (hetero)arylzinc pivalates with thiopyridyl ester derivatives

Article abstract of DOI:10.1039/c9sc01817d

A cobalt-catalyzed acylation reaction of various primary, secondary and tertiary alkyl, benzyl and (hetero)aryl S-pyridyl thioesters with (hetero)arylzinc pivalates is reported. The thioesters were prepared directly from the corresponding carboxylic acids under mild conditions, thus tolerating sensitive functional groups. Acylations of α-chiral S-pyridyl esters proceeded with very high stereoretention leading to optically enriched α-chiral ketones.

Full text of DOI:10.1039/c9sc01817d

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DOI: 10.1039/C9SC01817D
ARTICLE
Cobalt-Catalyzed Acylation-Reactions of (Hetero)Arylzinc Pivalates
with Thiopyridyl Ester Derivatives
a
†
†
†
Ferdinand H. Lutter , Lucie Grokenberger , Maximilian S. Hofmayer , and Paul Knochel*
Received 00th January 20xx,
Accepted 00th January 20xx
A cobalt-catalyzed acylation reaction of various primary, secondary and tertiary alkyl, benzyl and (hetero)aryl S-pyridyl
thioesters with (hetero)aryl zinc pivalates is reported. The thioesters were prepared directly from the corresponding
carboxylic acids under mild conditions, thus tolerating sensitive functional groups. Acylations of α-chiral S-pyridyl esters
proceeded with very high stereoretention leading to optically enriched α-chiral ketones.
DOI: 10.1039/x0xx00000x
Herein, we wish to report a new cobalt-catalyzed acylation
reaction of various saturated and unsaturated thioesters of type
Introduction
R1C(O)SPy (
R2ZnOPiv (
of type . Although thioesters are readily available from the
corresponding acid chlorides and thiols,10 the pyridyl thioesters
were prepared under exceedingly mild and neutral conditions
1
) with aryl- and heteroarylzinc pivalates of type
The carbonyl group is a central functionality in organic
chemistry and the performance of acylation reactions
employing organometallic reagents represents a general access
to various ketones.1 A major drawback of these reactions is the
moderate chemoselectivity or the use of expensive catalysts.1
Acid chlorides are the most common acylation reagents.1-2
However, their preparation requires harsh conditions, thus
lowering the functional group tolerance. In contrast, the use of
thioesters is a valuable alternative since Fukuyama showed in
pioneering work that these acylating reagents react readily with
organozinc halides in the presence of a palladium catalyst.3
Additionally, Seki,4 Rovis,5 Fleischer,6 and others7 showed that
these reactions can be performed using transition metal
catalysts. Recently, we have shown that organozinc pivalates
(RZnOPiv) are an attractive class of zinc organometallics due to
their enhanced air- and moisture stability and their excellent
compatibility with various transition metal-catalyzed
transformations.8 Especially, cobalt-catalyzed reactions have
proven to be advantageous.9
2
), leading to a broad range of polyfunctional ketones
3
1
from the corresponding carboxylic acid of type
Mukaiyama’s method (Scheme 1).11
4 using
Results and discussion
In preliminary experiments, S-(pyridin-2-yl)-cyclohexanecarbo-
thioate (1a) was treated with 4-(methoxyphenyl)zinc pivalate
(2a) under various conditions (Table 1). In the absence of a
catalyst, ketone 3a was obtained in only 9% yield (Table 1,
entry 1). Although palladium and nickel are well-known metal
catalysts for the Fukuyama acylation, the use of cheaper12 and
more abundant catalysts is highly desirable. Whereas, MnCl2,
CrCl2, FeCl2 or CuCl2 gave unsatisfying results (entries 2-5), CoCl2
proved to be an excellent catalyst for this transformation (entry
6). Its catalytic efficiency could be further improved by the
addition of various ligands. After a short screening it became
clear that 4,4'-di-tert-butyl-2,2'-dipyridyl (dtbbpy) gave the best
results leading to the ketone 3a in 88% isolated yield (entry 11).
At this point, we verified that no other metal contaminations
are responsible for this catalysis. Thus, using CoCl2 (99.99%
purity)13 led to 3a in 86% yield (entry 12). Furthermore, a
screening showed that RC(O)SPy thioesters are superior to
thioesters of type RC(O)SEt or RC(O)SPh.14
Scheme 1 Preparation of thiopyridyl esters of type 1 from carboxylic acids 4 and cobalt-
catalyzed acylation with organozinc pivalates 2, affording ketones of type 3. Py = In a typical experiment palmitic acid (4b) was treated with 2,2'-
2-pyridyl.
dipyridyl disulfide (1.1 equiv) and PPh3 (1.5 equiv) in acetonitrile
(0.3 M) under reflux for 3 h. Short purification using flash column
chromatography afforded 1b in 98% yield. The required zinc
pivalate 2b was prepared by treating 1-bromo-3,4-(methylene-
dioxy)benzene (5b) with Mg (1.2 equiv) and anhydrous LiCl
(1.2 equiv) for 2 h at 0 °C leading to the corresponding
arylmagnesium derivative (91% yield).15 Transmetalation with
a.Ludwig-Maximilians-Universität München, Department Chemie
Butenandtstraße 5-13, Haus F, 81377 München (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
† These authors contributed equally to this work.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Zn(OPiv)2 (1.0 equiv) afforded the zinc organometallic 2b in 93%
yield.15 The thioester 1b reacted with 3,4-(methylene-dioxy)-1-
phenylzinc pivalate (2b) in the presence of 10 % CoCl2 and
10% dtbbpy in THF (25 °C, 4 h) furnishing after standard workup
and chromatographic purification the ketone 3b in 90% yield
(Table 2, entry 1).
Table 2 Ketones 3 obtained by the acylation of various alkylthiopyridyl esters 1 with
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(hetero)arylzinc pivalates 2.[a]
DOI: 10.1039/C9SC01817D
Table 1 Optimization of the reaction conditions for the acylation of thioester 1a with
arylzinc pivalate 2a.
Entry
Catalyst
Ligand
Yield of 3a[a]
[%]
1
2
3
4
-
-
-
-
-
9
MnCl2
CrCl2
FeCl2
traces
traces
50
5
6
CuCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
-
-
29
67
[b]
7
PPh3
63
8
TMEDA
neocuproine
bipy[c]
64
9
49
10
11
12
71
90 (88)[e] (87)[f]
86
dtbbpy[d]
dtbbpy[d]
[g]
CoCl2
[a] Reactions were performed on a 0.5 mmol scale. Determined by GC-analysis.
Tetradecane (C14H30) was used as internal standard. [b] 20% of the ligand was used.
[c] 2,2'-Bipyridine. [d] 4,4'-Di-tert-butyl-2,2'-dipyridyl. [e] Isolated yield. [f]
Reaction was performed on a 5 mmol scale. [g] CoCl2 (99.99% purity) was used.
According to this procedure various ketones of type
3 were
prepared. Hence, the heterocyclic indolylzinc pivalate (2c) was
acylated with palmitic S-pyridyl thioate (1b) furnishing ketone
3c in 74% yield (entry 2). Additionally, secondary thioesters
derived from cyclobutane- (4c) and cyclohexanecarboxylic acid
(4a) were employed to this acylation procedure leading to the
corresponding ketones (3d 3g) in 60-95% yield (entries 3-6).
-
Tertiary S-pyridyl thioesters 1d and 1e derived from 1-
adamantanecarboxylic acid (4d) and the lipid regulating drug
gemfibrozil16
(4e) reacted smoothly with various functionalized
arylzinc pivalates affording acylation products (3h-3k) in 61-81%
yield (entries 7-10).
[a] The reactions were performed on a 0.5 mmol scale [b] Isolated yield of the S-
pyridyl thioester prepared from the corresponding carboxylic acid, PySSPy
(1.1 equiv), PPh3 (1.5 equiv), MeCN, reflux, 3 h. [c] Isolated yield. [d] Prepared using
iPrMgCl•LiCl (1.1 equiv), THF, -20 °C, 2 h.
2 | J. Name., 2012, 00, 1-3
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Furthermore, the acylation reaction was extended to aryl- and Also, 2-benzothiophenylzinc pivalate 2l generated via directed
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heteroaryl-S-pyridyl thioesters (Table 3). Thus, (4- metalation of benzothiophene usingDOTIM: 10P.M10g39C/lC•9LSiCCl018a1n7Dd
8d
(ethoxycarbonyl)-phenyl)-zinc pivalate (2k) prepared via I/Mg- subsequent transmetalation with Zn(OPiv)2 underwent a
exchange using iPrMgCl•LiCl followed by transmetalation with cobalt catalyzed acylation reaction with 1f leading to the ketone
8d
Zn(OPiv)2 was readily acylated with S-pyridyl thioester 1f 3m in 68% yield (entry 2). Various substituted aryl thioesters
affording the benzophenone 3l in 71% yield (entry 1).
and ferrocenyl derivatives reacted successfully with
functionalized (hetero)arylzinc pivalates affording the diaryl
ketones 3n-3r in 81-96% yield (entries 3-7). Additionally, 4-
Table 3 Ketones 3 obtained by the acylation of (hetero)aryl-S-pyridyl thioesters 1 with
(hetero)arylzinc pivalates 2.[a]
trifluoro-methoxyphenylzinc pivalate (2o) was acylated using
quinoline thioester 1j furnishing ketone 3s in 68% yield
(entry 8).17
The synthesis of α-chiral ketones is of great interest3, 5, 7c, 7f, 18
but often challenging under basic conditions due to
epimerization. Also, reactions under pH-neutral conditions have
been reported by Liebeskind et al. for the synthesis of highly
enantiopure peptidyl ketones.19
Table 4 Preparation of α-chiral ketones 3 by acylation of thiopyridyl esters 1 with
(hetero)arylzinc pivalates 2.[a]
[a] The reactions were performed on a 0.5 mmol scale and at 0 °C instead of 25 °C.
[b] Isolated yield of the S-pyridyl thioester prepared from the corresponding
carboxylic acid, PySSPy (1.0 equiv), PPh3 (1.0 equiv), MeCN, 0 °C to 25 °C, 16 h.
[c] Isolated yield. [d] Prepared using iPrMgCl•LiCl (1.1 equiv), THF, 0 °C, 2 h.
[a] The reactions were performed on a 0.5 mmol scale [b] Isolated yield of the S-
pyridyl thioester prepared from the corresponding carboxylic acid, PySSPy
(1.1 equiv), PPh3 (1.5 equiv), MeCN, reflux, 3 h [c] Isolated yield [d] Prepared using
iPrMgCl•LiCl (1.1 equiv), THF, -40 °C, 2 h. [e] Prepared using TMPMgCl•LiCl
(1.0 equiv), THF, 0 °C, 3 h. [f] TMEDA was used instead of dtbbpy.
We also tested the applicability of this cobalt-catalyzed
acylation to the synthesis of optically enriched α-chiral ketones.
Using α-chiral S-pyridyl thioesters at 0 °C afforded several α-
chiral ketones with high stereoretention (Table 4). Thus, S-
pyridyl thioester 1k prepared from N-Boc protected (S)-proline
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was treated with arylzinc reagents 2a and 2b leading to the
corresponding α-chiral ketones in 72-82% yield and >99% ee
(entries 1-2).
Conflicts of interest
There are no conflicts to declare.
View Article Online
DOI: 10.1039/C9SC01817D
Furthermore, thioester 1l derived from enantiopure
(S)-ibuprofen reacted smoothly with the functionalized arylzinc
pivalates 2p and 2n in 71-89% yield and 94-97% ee (entries 3-4).
Also, arylzinc pivlalates 2q and 2r bearing an amide or
dimethylamino functionality were acylated using optically pure
Acknowledgements
We thank the DFG for financial support. We also thank
Albemarle (Hoechst, Germany) and BASF SE (Ludwigshafen,
Germany) for the generous gift of chemicals. We also thank
Vanessa Braun, Constantin Nuber, and Arne Stolpmann for the
preparation of starting materials.
S-(pyridin-2-yl)-(S)-2-methylbutanethioate
furnishing
the
α-chiral ketones in 69-84% yield and 95-98% ee (entries 5-6).
To gain insights into the reaction mechanism, radical trapping
experiments were carried out. Thus, to a standard acylation
setup of the developed protocol using S-pyridyl thioester 1a and
Notes and references
organozinc pivalate 2a various amounts of the radical trapping
1.
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agent 2,2,6,6-tetramethylpiperidinyloxyl (TEMPO) were added.
With 10% of the trapping reagent a decrease of the yield by 19%
was observed for the acylation product 3a. However, using
1.5 equiv of TEMPO the product formation is almost completely
suppressed. This may indicate the involvement of radical
intermediates within this acylation reaction.14
2.
8199-8202;
(d)
Handbook
of
Functionalized
The utility of this acylation was demonstrated in the synthesis,
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the anitlipedemic drug fenofibrate20
(
3z) was synthesized
(Scheme 2). Alkylation of 4-iodophenol ( ) with isopropyl
2-bromo-2-methyl-propanoate ( ) affords the corresponding
iodo-aryl ether in 70% yield. was treated with Mg, LiCl and
6
7
3.
4.
5.
6.
7.
8
8
Zn(OPiv)2 generating the arylzinc pivalate 2s in 72% yield.8a
Using the new cobalt-catalyzed acylation procedure,
fenofibrate (3z) was obtained in 65% yield.
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Scheme 2 Synthesis of fenofibrate (3z) using the Co-catalyzed acylation.
Conclusion
In conclusion, we have reported a cobalt-catalyzed acylation
procedure of a variety of functionalized (hetero)aryl zinc
pivalates utilizing primary, secondary and tertiary alkyl, benzyl
and (hetero)aryl S-pyridyl thioesters as mild acylating agents.
These thioesters were readily prepared under neutral
conditions from the corresponding carboxylic acid thus allowing
their synthesis in the presence of various sensitives functional
groups. Several α-chiral ketones were prepared with high
stereoretention (94% to >99% ee). Further investigations are
currently underway in our laboratories.
9.
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Hofmayer, J. M. Hammann, F. H. Lutter and P. Knochel,
ARTICLE
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DOI: 10.1039/C9SC01817D
10.
11.
12.
13.
World market prices: Pd ca. 33938 €/kg and 3594 €/mol,
Co ca 49 €/kg and 3 €/mol; http://www.infomine.com/;
retrieved Dezember 2018.
A new stirring bar and flask was used for the reaction, see:
E. O. Pentsak, D. B. Eremin, E. G. Gordeev, V. P. Ananikov,
ACS Catal., 2019, DOI: 10.1021/acscatal.1029b00294.
For further details, see supporting information.
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17.
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DOI: 10.1039/C9SC01817D
A cobalt-catalyzed acylation reaction of (hetero)aryl zinc pivalates using primary, secondary and tertiary
alkyl, benzyl and (hetero)aryl S-pyridyl thioesters has been developed.
R2 ZnOPiv
PySSPy, PPh3, MeCN
reflux, 3 h or 0 °C, 16 h
CoCl2, dtbbpy
O
O
O
R1
OH
R1
R2
R1
S
N
THF, 0 °C or 25 °C, 4 h
R1: 1o, 2o and 3o alkyl, benzyl, (hetero)aryl
R2: (hetero)aryl
OCF3
OMe
O
iPr
O
F
N
Me
Fe
CN
O
OMe
O
Boc
81% yield
81% yield
89% yield, 97% ee
72% yield, >99% ee