Iron-Catalyzed Acylation of Polyfunctionalized Aryl- and Benzylzinc Halides with Acid Chlorides

Article abstract of DOI:10.1021/acs.orglett.6b01677

FeCl₂ (5 mol %) catalyzes a smooth and convenient acylation of functionalized arylzinc halides at 50 °C (2-4 h) and benzylic zinc chlorides at 25 °C (0.5-4 h) with a variety of acid chlorides leading to polyfunctionalized diaryl and aryl heteroaryl ketones.

Full text of DOI:10.1021/acs.orglett.6b01677

Letter
pubs.acs.org/OrgLett
Iron-Catalyzed Acylation of Polyfunctionalized Aryl- and Benzylzinc
Halides with Acid Chlorides
Andreas D. Benischke, Marcel Leroux, Irina Knoll, and Paul Knochel*
Department of Chemistry, Ludwig-Maximilians-Universitat, Butenandtstrasse 5-13, 81377 Munich, Germany
̈
S
* Supporting Information
ABSTRACT: FeCl2 (5 mol %) catalyzes a smooth and convenient acylation of functionalized arylzinc halides at 50 °C (2−4 h)
and benzylic zinc chlorides at 25 °C (0.5−4 h) with a variety of acid chlorides leading to polyfunctionalized diaryl and aryl
heteroaryl ketones.
Table 1. Screening of Catalysts for the Acylation of Benzylzinc
Chloride (1a) with 4-Chlorobenzoyl Chloride (2a)
rganozinc reagents belong to the most useful organo-
Ometallics for organic synthesis since they show a high
tolerance of functional groups and undergo efficient trans-
metalations to various metallic salts leading to a broad reactivity
pattern.1 The reaction of zinc reagents with acid chlorides is an
important method for preparing a range of polyfunctionalized
ketones.2 Although such acylations proceed without catalysts, the
a
a
yields are usually low due to extensive side reactions.3
A
entry
catalyst
yield (%)
entry
catalyst
yield (%)
b
transmetalation of organozinc reagents to the corresponding
copper reagents using CuCN·2LiCl4 considerably extends the
reaction scope of this acylation procedure and allows the
preparation of various highly functionalized ketones.5 Although
this acylation can be performed in many cases using
substoichiometric amounts of copper catalyst, lower yields
generally result under such conditions. Alternatively, Negishi6
reported a palladium-catalyzed acylation method of organozinc
halides, and Rieke7 described a related nickel-catalyzed acylation
for the preparation of aryl ketones. Recently, Gosmini8 reported
a cobalt-catalyzed acylation of arylzinc bromides. Interestingly,
organozinc reagents can also be acylated with thioesters as shown
by Fukuyama9 or with acyl cyanides.10 Since iron salts are cheap,
environmentally friendly, and of moderate toxicity, their use as
acylation catalysts would be especially attractive.11 Marchese12
1
2
3
4
74
60
65
60
5
6
7
8
FeBr3
85
MnCl2
CrCl2
Fe(acac)2
FeBr2
73
b
82
c
d
Fe(acac)3
FeCl2
90 (70)
a
b
Isolated yields of pure product. FeBr2 and FeBr3 of 98% purity.
FeCl2 of 99.5% purity. FeCl2 of 98% purity.25
c
d
catalyst (Table 1, entry 8) in THF as solvent.16 Additives like 4-
(dimethylamino)pyridine,17 Sc(OTf)3,18 InCl3,19 BF3·OEt2,20
and LaCl3·2LiCl21 did not lead to an improvement.22 In addition,
the testing of various solvent mixtures showed that THF was the
ideal solvent for this acylation reaction since the ketone 3a was
obtained after 0.5 h reaction time in 90% isolated yield.23 To
ensure that FeCl2 is the true catalyst of this acylation, we have
used FeCl2 of high purity (99.5%).24 The coupling experiment
with FeCl2 of lower purity (98%) proceeded somewhat less
cleanly and gave 70% yield of product.
This iron-catalyzed acylation proved to be quite general. Thus,
the reaction of (3-trifluoromethylbenzyl)zinc chloride (1b) with
4-tert-butylbenzoyl chloride (2b) provides within 0.5 h at 25 °C
the desired ketone 3b in 65% yield (Table 2, entry 1). In the
absence of an iron catalyst, the yield leveled at 38% yield.
Similarly, the acylation of 1b with 4-chlorobenzoyl chloride (2a)
gave the ketone 3c in 71% yield (entry 2). Furthermore, (3-
fluorobenzyl)zinc chloride (1c) reacted in the presence of FeCl2
and Furstner13 already demonstrated that iron-catalyzed
̈
reactions of acid chlorides with organomagnesium reagents can
be readily performed. In addition, Cahiez14 showed that
organomanganese reagents prepared from the corresponding
Grignard species undergo acylation reactions with excellent
yields.
Herein, we report an efficient iron-catalyzed acylation of
polyfunctionalized aryl- and benzylzinc halides with acid
chlorides. Thus, benzylzinc chloride (1a, 1.0 equiv), prepared
by the insertion of Mg turnings and ZnCl2, reacts with 4-
chlorobenzoyl chloride (2a, 0.8 equiv) in THF (25 °C, 0.5 h) in
the presence of various transition-metal salts (Table 1).15a This
rapid screening indicated that iron(II) chloride is an excellent
Received: June 10, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01677
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Organic Letters
Letter
Table 2. Iron-Catalyzed Acylations of Benzylic Zinc Reagents (1b−g) with Acid Chlorides (2a−e)
a
b
c
d
0.8 equiv of the acid chloride was used. Isolated yield of pure product. Up to 20% of homocoupling was observed. Isolated yield of pure product
without catalyst.
(5 mol %) with 4-tert-butylbenzoyl chloride (2b) within 0.5 h,
furnishing the expected diaryl ketone (3d) in 88% yield (entry 3).
The acylation of the benzylic zinc chloride (1c) with the
electron-deficient 4-fluorobenzoyl chloride (2c) afforded the bis-
fluorinated ketone 3e in 74% yield (entry 4). Remarkably, the
readily available benzylic zinc reagent 1d15a bearing an ester
moiety underwent an efficient acylation with 4-chlorobenzoyl
chloride (2a) leading to the functionalized diaryl ketone 3f in
50% yield (entry 5).
Additionally, the electron-rich (4-methoxybenzyl)zinc chlor-
ide (1e) reacted with 4-tert-butylbenzoyl chloride (2b) to afford
ketone 3g in 58% yield (entry 6). Interestingly, the acylation of
the sulfur-containing benzylic zinc chloride (1f) with 2-
thiophenecarbonyl chloride (2d) succeeded within 4 h at 25
°C to give the desired aryl heteroaryl ketone (3h) in 60% yield
(entry 7). Finally, the reaction of a secondary benzylzinc reagent
(1g) with selected acid chlorides (2a,d,e) provides the diaryl
ketones 3i−k in 65−79% yield (entries 8−10). In all of these
acylations, less than 20% homocoupling of the benzylic moiety
was observed.
Additionally, we have extended this cross-coupling to arylzinc
chlorides. Compared to benzyliczinc reagents, the carbon−zinc
bond of arylzinc halides has a much lower ionic character and,
therefore, is significantly less reactive. Thus, the direct acylation
of the electron-poor arylzinc halide 4a, conveniently prepared via
an I/Mg exchange using iPrMgCl·LiCl26 followed by trans-
metalation with ZnCl2, proceeds only sluggishly with 4-
chlorobenzoyl chloride (2a) at 50 °C in THF providing the
ketone 5a in 34% yield even after a prolonged reaction time of 12
h. In contrast, when FeCl2 (5 mol %, 99.5% pure) was used, the
acylation with 2a was complete after 4 h reaction time at 50 °C
and the desired ketone 5a was isolated in 62% yield (Table 3,
entry 1).27 Similarly, the arylzinc reagent 4a underwent several
acylations with the functionalized acid chlorides 2b,c,f leading to
the diaryl ketones 5b−d in 65−83% (entries 2−4). Furthermore,
the related arylzinc reagent (4b), bearing an ester moiety in meta
position, reacted rapidly with the acid chlorides 2a,b,h to afford
the ketones 5e−g within 4 h in 60−75% yield (entries 5−7).
Performing such acylations using the ortho-substituted arylzinc
chloride (4c) in combination with the two electron-poor acid
chlorides 4-chlorobenzoyl chloride (2a) and 4-cyanobenzoyl
B
DOI: 10.1021/acs.orglett.6b01677
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Table 3. Iron-Catalyzed Acylations of Arylzinc Reagents (4a−f) with Acid Chlorides (2a−h)
a
b
c
d
0.8 equiv of the acid chloride was used. Isolated yield of pure product. Up to 10% of homocoupling was observed. FeCl2 with a purity of 99.99%
e
was used. Isolated yield of pure product without catalyst.
chloride (2g) proceeded smoothly at 50 °C, yielding the
functionalized diaryl ketones 5h,i in 62−74% yield (entries 8 and
9).
The scope of this acylation procedure proved to be quite
general for a range of other functionalized arylzinc reagents.
Thus, the reaction of (4-(trifluoromethyl)phenyl)zinc chloride
(4d) with acid chlorides bearing electron-donating substituents,
like 4-tert-butylbenzoyl chloride (2b) and 4-methoxybenzoyl
chloride (2e), gave the desired ketones 5j,k in 62−83% yield
(entries 10 and 11). In addition, (4-fluoro-3-methylphenyl)zinc
chloride (4e) underwent efficient acylations with the acid
chlorides 2a,b,e to afford the functionalized diaryl ketones (5l−
n) in 70−79% yield (entries 12−14). Finally, the electron-rich
(4-methoxyphenyl)zinc chloride (4f) reacted with selected acid
C
DOI: 10.1021/acs.orglett.6b01677
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Organic Letters
Letter
(13) Scheiper, B.; Bonnekessel, M.; Krause, H.; Furstner, A. J. Org.
Chem. 2004, 69, 3943.
̈
chlorides bearing a chlorine (2a), a tert-butyl (2b), or a fluorine
substituent (2c) in the para position leading to the ketones 5o−q
within 3 h at 50 °C in 74−82% yield (entries 15−17).
In summary, we have shown that various benzylic zinc and
arylzinc halides react with a broad range of acid chlorides at 25−
50 °C leading to polyfunctionalized diaryl and aryl heteroaryl
ketones within 0.5−4 h. Further extensions of this methodology
are currently underway in our laboratories.28
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little influence on the rate and yield of the acylation as shown by control
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insertion of zinc in the presence of LiCl (see the Supporting
Information).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01677.
Detailed experimental procedures and analytical data
(PDF)
(17) Xu, S.; Held, I.; Kempf, B.; Mayr, H.; Steglich, W.; Zipse, H. Chem.
- Eur. J. 2005, 11, 4751.
(18) (a) Kobayashi, S.; Hachiya, I.; Ishitani, H.; Araki, M. Synlett 1993,
472. (b) Kobayashi, S. Eur. J. Org. Chem. 1999, 15. (c) Quinio, P.;
Kohout, L.; Sustac-Roman, D.; Gaar, J.; Karaghiosoff, K.; Knochel, P.
Synlett 2016, 27, 1715.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: paul.knochel@cup.uni-muenchen.de.
Notes
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Lett. 1996, 37, 7049. (b) Takai, K.; Ikawa, Y. Org. Lett. 2002, 4, 1727.
The authors declare no competing financial interest.
(c) Blumke, T. D.; Chen, Y.-H.; Peng, Z.; Knochel, P. Nat. Chem. 2010,
̈
2, 313. (d) Peng, Z.; Blumke, T. D.; Mayer, P.; Knochel, P. Angew.
̈
ACKNOWLEDGMENTS
■
Chem., Int. Ed. 2010, 49, 8516. (e) Blumke, T. D.; Klatt, T.; Koszinowski,
̈
We thank the SFB 749 (DFG) for financial support. We also
thank Rockwoood Lithium GmbH (Frankfurt) and BASF
(Ludwigshafen) for the generous gift of chemicals.
K.; Knochel, P. Angew. Chem., Int. Ed. 2012, 51, 9926.
(20) (a) Jaric, M.; Haag, B. A.; Unsinn, A.; Karaghiosoff, K.; Knochel,
P. Angew. Chem., Int. Ed. 2010, 49, 5451. (b) Jaric, M.; Haag, B. A.;
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Manolikakes, S. M.; Mollat du Jourdin, X.; Jaric, M.; Bredihhin, A.;
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(22) For an additive screening, see the Supporting Information.
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DOI: 10.1021/acs.orglett.6b01677
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