A unique catalyst effects the rapid room-temperature cross-coupling of organozinc reagents with carboxylic acid fluorides, chlorides, anhydrides, and thioesters

Article abstract of DOI:10.1021/ja044113k

We have identified a catalyst capable of effecting the rapid, room-temperature cross-coupling between acid fluorides and diorganozinc reagents. The use of acid fluorides as electrophilic partners allows this reaction to tolerate epimerizable functionality as well as β leaving groups. The same catalyst is also capable of cross-coupling acid chlorides, acyl cyanides, anhydrides, thioesters, and pyridyl esters. Noteworthy is the ability of the reaction to successfully transfer both groups from the organometalic fragment. Copyright

Full text of DOI:10.1021/ja044113k

Published on Web 11/18/2004
A Unique Catalyst Effects the Rapid Room-Temperature Cross-Coupling of
Organozinc Reagents with Carboxylic Acid Fluorides, Chlorides, Anhydrides,
and Thioesters
Yongda Zhang and Tomislav Rovis*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80526
Received September 27, 2004; E-mail: rovis@lamar.colostate.edu
Table 1. Ni-Catalyzed Coupling of Acyl Fluorides and Ph2Zn
In view of the paramount importance of ketones in the synthesis
of a wide variety of pharmaceutical and material-science target mol-
ecules,1 extensive efforts have been made for efficient synthesis of
this fundamental functionality.2 Transition metal-catalyzed cross-coup-
ling reactions of organometallic reagents with carboxylic acid deriv-
atives present a powerful and convergent approach to ketone syn-
thesis.3 These new approaches have the advantage of avoiding strong-
ly basic and nucleophilic reaction conditions typically associated
with protocols such as the Weinreb amide approach.4 However, the
current state of the art, although enabling in fundamental reaction
design, is typically limited to simple electrophilic partners devoid
of eliminatable groups and epimerizable stereocenters.5 A handful
of exceptions to this generalization have appeared, with Fukuyama’s
thioester cross-coupling being perhaps the most versatile protocol,
although it requires the use of excess nucleophile.6 Herein we report
the rapid cross-coupling of acid fluorides with organozinc reagents
tolerating epimerizable stereocenters and transferring both groups
from zinc in the presence of a versatile catalyst.
We identified acid fluorides as potentially versatile acid deriva-
tives since they are widely used in peptide coupling under conditions
that do not lead to epimerization.7 Acyl fluorides are easily prepared
from carboxylic acids,8 acid anhydrides,9 and acid chlorides9a in
good yields and typically exhibit greater stability toward water and
neutral oxygen nucleophiles than corresponding acid chlorides.7 This
allows for their isolation through organic extraction and flash silica
gel chromatography.
We applied reaction conditions previously developed for anhy-
dride monoalkylation to the coupling reaction of benzoyl fluoride
and Ph2Zn in the presence of Ni(COD)2 and bipy.10-12 The coupling
reaction proceeds smoothly at room temperature with only 0.55
equiv of Ph2Zn, affording 2 in 70% yield after 0.5 h, indicating
that both groups are transferred from zinc.13
a All reactions were conducted in the presence of 10 mol % Ni(COD)2,
12 mol % pyphos, 20 mol % 4-fluorostyrene, and 0.55 equiv of Ph2Zn in
THF for 10-30 min at 23 °C, unless otherwise stated. b Acyl fluorides are
prepared by treatment of acids with DAST or Deoxo-Fluor at 0 °C for 30
min. c Isolated yield. d Reaction was conducted in the presence of 5 mol %
benzoic acid.
% pyphos, and 20 mol % 4-fluorostyrene at room temperature,
afford coupling products between Ph2Zn and a variety of acyl
fluorides in good to excellent yields (Table 1). In most cases, the
reaction proceeds to completion in 10 min. It is worth noting that
the reaction proceeds well albeit much slower with an extremely
bulky acyl fluoride such as 3, providing the ketone in 77% yield.
A range of functionality is tolerated, including thiophene, alkenes,
and acetals. Significantly, â-alkoxides are well tolerated, with
substrates 13 and 15 providing high yield of ketones, entries 7 and
8. Amino acids may be converted into the corresponding ketones
without epimerization, entry 9.17
Treatment of benzoyl fluoride with Me2Zn as a nucleophile using
standard reaction conditions affords the corresponding methyl
ketone in 92% yield (entry 1, Table 2). When Et2Zn is used, no
aldehyde is observed18 and the ethyl ketone may be isolated in 90%
yield.19 An isopropyl group can be transferred without concomitant
isomerization (entry 3). In the case of functionalized organozinc
reagent derived from [(1-ethoxycyclopropyl)oxy]trimethylsilane,20
We have found that the reaction is very sensitive to ligand (eq
1), with pyphos [(2-diphenylphosphinoethyl)pyridine]14 being su-
perior. With this ligand, in situ IR spectroscopy indicates the acyl
fluoride band at 1845 cm-1 disappears in 3 min.15 In the absence
of Ni(COD)2, no product is observed on TLC even after a mixture
of PhCOF, Ph2Zn, pyphos, and 4-fluorostyrene in THF is stirred
overnight at room temperature. Without 4-fluorostyrene, the isolated
yield of benzophenone is only 18% after 16 h, consistent with
previous observations about the beneficial effect of these additives.16
Our optimized reaction conditions, 10 mol % Ni(COD)2, 12 mol
9
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J. AM. CHEM. SOC. 2004, 126, 15964-15965
10.1021/ja044113k CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Alkylzinc Nucleophiles
organozinc reagents. The procedure can be applied to a variety of
acid derivatives, including pyridyl esters and tolerates epimerizable
stereocenters.
Acknowledgment. We thank the National Institute of General
Medical Sciences (GM65407) for support of this research. T.R.
thanks Merck, GlaxoSmithKline, Amgen, and Eli Lilly for support.
entrya
R2Zn
R
yield (%)b
1
2
3
4
Me2Zn
Et2Zn
i-Pr2Zn
Me (19a)
Et (19b)
i-Pr (19c)
92
90
91
95
Supporting Information Available: Experimental procedures and
characterization data of all new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
(EtO2CCH2CH2)2Zn
CH2CH2CO2Et (19d)
a See Table 1. b Isolated yield.
References
the desired coupling product may be isolated in 95% yield without
formation of O-acylation product.21
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One of the current shortcomings of metal-catalyzed ketone syn-
thesis is that epimerizable functionality has not been extensively
illustrated to participate.6a,22 The use of acyl fluorides allows this to
occur. Lactate-derived acyl fluoride 20 undergoes the reaction in good
yield without loss of stereochemical integrity, while 22 also par-
ticipates well with no elimination or epimerization (eqs 2 and 3).15
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In order to render this reaction more practical, we have found
that air-stable Ni(acac)2 may be used as a precatalyst in place of
the air-sensitive Ni(COD)2. As a further testament to the practi-
cality of this protocol, we have conducted this reaction using 1.0 mol
% Ni(acac)2, 1.2 mol % pyphos, and 2.0 mol % 4-fluorostyrene on
a 40 mmol scale to afford 19b in 93% yield after 5 min at 23 °C
(eq 4).23
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(12) We have found that Pd complexes are also capable of cross-coupling acid
fluorides with organozinc halides and organoboronic acids.
(13) THF is the optimal solvent; the use of Et2O, CH2Cl2, and DMA only
afforded the coupling product in 26, 33, and 49% yields, respectively.
(14) Ligand pyphos is easily prepared form 2-vinylpyridine and Ph2PH. See:
Toto, S. D.; Doi, J. T. J. Org. Chem. 1987, 52, 4999.
(15) To ensure that the reaction proceeded to completion, the reaction mixture
was stirred for 10 min before the reaction was quenched with 1 M HCl.
(16) (a) Detailed investigation of the influence of styrene in anhydride cross-
coupling will be reported. Bercot, E. A.; Rovis T. J. Am. Chem. Soc. In
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(17) See Supporting Information for details.
(18) It has been reported that aldehyde is observed in the palladium-catalyzed
coupling reaction of acid chlorides and organozinc compounds. See ref 5b.
(19) Yields in these reactions are much higher than that of Ni(0)-catalyzed
coupling of acyl chloride and Grignard reagents: Malanga, C.; Aronica,
L. A.; Lardicci, L. Tetrahedron Lett. 1995, 36, 9185.
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We have extended this protocol to other acid derivatives. Impress-
ively, acid chlorides, anhydrides, acyl cyanides, thioesters, and even
pyridyl and aryl esters are good reaction partners with this catalyst
(Table 3), providing the coupling product in excellent yields with
slightly longer reaction times.
Table 3. Other Acid Derivatives as Coupling Partners
entrya
RCOX
reaction time
yield (%)b
1
PhCOCl
PhCOCN
PhCOSEt
PhCOOCO2i-Bu
(PhCO)2O
10 min
30 min
2 h
97
93
92
91
95
68c
95
95
50
2
3d
4
1 h
5d
6d
7
30 min
30 min
6 h
10 min
5 h
(PhCO)2O
PhCOO-2-Py
PhCOS-2-Py
PhCOOPh
8
9e
a See Table 1. b Isolated yield. c Technical grade (PhCO)2O (90%) was
used. d Performed with 1.1 equiv of Ph2Zn. e Reaction was conducted at
60 °C.
(21) Nakamura, E.; Kuwajima, I. Tetrahedron Lett. 1986, 27, 83.
(22) (a) Crisp, G. T.; Bubner, T. P. Synth. Commun. 1990, 20, 1665. (b) Cahiez,
G.; Metais, E. Tetrahedron Lett. 1995, 36, 6449.
(23) We observed a significant exotherm under these conditions, which likely
accelerated the coupling reaction.
In summary, an efficient ketone synthesis protocol has been
developed by Ni-catalyzed cross-coupling of acid fluorides and
JA044113K
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J. AM. CHEM. SOC. VOL. 126, NO. 49, 2004 15965