Stoichiometric reactions of acylnickel(II) complexes with electrophiles and the catalytic synthesis of ketones

Article abstract of DOI:10.1021/om5004682

Acylnickel(II) complexes feature prominently in cross-electrophile coupling (XEC) reactions that form ketones, yet their reactivity has not been systematically investigated. We present here our studies on the reactivity of acylnickel(II) complexes with a series of carbon electrophiles. Bromobenzene, α-chloroethylbenzene, bromooctane, and iodooctane were reacted with (dtbbpy)Ni^II(C(O)C₅H₁₁)(Br) (1b) and (dtbbpy)Ni^II(C(O)tolyl)(Br) (1c) to form a variety of organic products. While reactions with bromobenzene formed complex mixtures of ketones, reactions with α-chloroethylbenzene were highly selective for the cross-ketone product. Reactions with iodooctane and bromooctane also produced the cross-ketone product, but in intermediate yield and selectivity. In most cases the presence or absence of a chemical reductant (zinc) had only a small effect on the selectivity of the reaction. The coupling of 1c with iodooctane (60% yield) was translated into a catalytic reaction, the carbonylative coupling of bromoarenes with primary bromoalkanes (six examples, 60% average yield).

Full text of DOI:10.1021/om5004682

Article
pubs.acs.org/Organometallics
Open Access on 07/10/2015
Stoichiometric Reactions of Acylnickel(II) Complexes with
Electrophiles and the Catalytic Synthesis of Ketones
Alexander C. Wotal, Ryan D. Ribson, and Daniel J. Weix*
Department of Chemistry, University of Rochester, Rochester, New York 14627-0216, United States
S
* Supporting Information
ABSTRACT: Acylnickel(II) complexes feature prominently in cross-electrophile
coupling (XEC) reactions that form ketones, yet their reactivity has not been
systematically investigated. We present here our studies on the reactivity of
acylnickel(II) complexes with a series of carbon electrophiles. Bromobenzene, α-
chloroethylbenzene, bromooctane, and iodooctane were reacted with (dtbbpy)-
NiII(C(O)C5H11)(Br) (1b) and (dtbbpy)NiII(C(O)tolyl)(Br) (1c) to form a
variety of organic products. While reactions with bromobenzene formed complex
mixtures of ketones, reactions with α-chloroethylbenzene were highly selective for
the cross-ketone product. Reactions with iodooctane and bromooctane also
produced the cross-ketone product, but in intermediate yield and selectivity. In
most cases the presence or absence of a chemical reductant (zinc) had only a small effect on the selectivity of the reaction. The
coupling of 1c with iodooctane (60% yield) was translated into a catalytic reaction, the carbonylative coupling of bromoarenes
with primary bromoalkanes (six examples, 60% average yield).
electrophile (R2X) to form the ketone product (R1C(O)R2).
Studies of the generation of acylnickel(II) intermediates from
nickel(0) have clearly delineated its formation, but no such
systematic studies on the reactivity of 1 with carbon
electrophiles have been reported.
Despite our recent success in developing and understanding
INTRODUCTION
The ketone is ubiquitous in organic synthesis because it is a
synthetically useful functional group and a common motif in
biologically active molecules. Among the many synthetic
methods known, carbonylative cross-coupling of a carbon
nucleophile with a carbon electrophile is attractive because it is
■
convergent (eq 1).1 A common challenge for all of these
the mechanism of nickel-catalyzed cross-electrophile coupling
of aryl halides with alkyl halides, we foresaw several challenges
for the carbonylative reaction. First, the coupling of two
electrophiles with a third component (CO) results in a large
number of potential products in comparison to two-component
couplings.8 Second, the reactivity of the proposed acylnickel
intermediates is relatively unknown, limiting our ability to
troubleshoot reactions.
We report here our progress toward understanding the
reactivity of acylnickel(II) complexes toward aryl, alkyl, and
benzylic electrophiles and a cross-selective carbonylative
coupling of unactivated primary alkyl bromides with aryl
halides to form aryl alkyl ketones.
carbonylative cross-coupling reactions is the availability and
stability of the carbon nucleophile component, which has led to
the development of alternative methods, such as C−H
activation,1b and milder organometallic reagents.2
An alternative strategy to avoid the challenges of nucleophilic
carbon reagents is the coupling of two different carbon
electrophiles (Figure 1). Cross-electrophile coupling (XEC)
has been much less studied than the cross-coupling of
electrophiles with nucleophiles, but recent reports have
demonstrated the generality of this approach3−6 and have
shed light on the origins of selectivity.7 Two different nickel-
catalyzed XEC approaches to ketones have been developed: the
coupling of acid chlorides with alkyl and benzyl halides4 and the
carbonylative coupling of aryl halides with alkyl halides.6 The
carbonylative coupling approach has only been demonstrated
with electrochemical reduction (Ni/Fe sacrificial anode), and
high yields were only obtained with aryl iodides and benzyl
bromides.6f
BACKGROUND
■
Stoichiometric reactions with Ni(CO)4 with electrophiles to
form ketones are well-known to proceed via intermediate
acylnickel(II) complexes (eq 2),9 but these reactions are not
often used today due to toxicity concerns10 and limited
availability.11,12 Catalytic versions of these stoichiometric
reactions have proven to be difficult to develop.
Special Issue: Catalytic and Organometallic Chemistry of Earth-
Abundant Metals
A common feature of many4d−f,6 of these approaches (A and
B, Figure 1) is the intermediacy of an acylnickel(II)
intermediate (1) that is proposed to react with a carbon
Received: May 2, 2014
© XXXX American Chemical Society
A
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a number of pathways, including intermediate reduction of 1
from nickel(II) to nickel(I).
Acylnickel complexes may be generated by addition of CO to
the corresponding organonickel(II) complex15 or by the
reaction of nickel(0) with an activated ester.16 Phosphine-
ligated acylnickel(II) halide complexes are reported to lose
carbon monoxide over time16 or to reversibly eliminate CO and
exchange it with other nickel complexes.15a Only one study has
reported on the reactivity of an acylnickel(II) species with a
bidentate N−N ligand (bpy).15c All of the reported ketone-
forming XEC reactions call for N−N ligands of this type.4,6
Yamamoto and co-workers explored the reactivity of 1 under
thermolysis (eq 3) and with dioxygen (eq 4),15c but the
Figure 1. Acylnickel(II) intermediates 1 important to both XEC
ketone synthesis methods A and B. Their reactivity with organic
halides (R2X) has not been systematically studied.
stoichiometric reactivity of 1 with organic electrophiles has
never been systematically examined. Amatore and Jutand
generated 1 under electrochemical conditions in their study
on the acylation of benzyl bromides and showed it can easily be
reduced to an acylnickel(I) species but did not study the
reactivity of either species with organic electrophiles.7a
In studies related to the acylation of alkyl halides, Gong
reacted (dmbpy)Ni0 (dmbpy = 4,4′-dimethyl-2,2′-bipyridine)
with a mixture of benzoic anhydride and a secondary alkyl
bromide and reported that only the anhydride was consumed
(Scheme 2).4e No ketone formation was observed from the
The catalytic, carbonylative coupling of two organic halides
has primarily been developed by the group of Troupel. Early
work revealed that Fe(CO)5 was a more convenient and
reliable CO source1,13,14 for these reactions than CO gas
because the reaction was strongly inhibited by the formation of
unreactive (L)Ni0(CO)2 at higher CO concentrations.6a,b
To date, the electrolysis conditions of Troupel are the best
conditions for carbonylative XEC (Scheme 1).6f With 30 mol %
Scheme 2. Stoichiometric Studies on Acylation of RX4e
Scheme 1. Electroreductive Synthesis of Ketones6f
resulting uncharacterized mixture unless a reductant (Zn0) was
added. A similar reaction with a mixture of anhydride and
iodoalkane resulted in partial consumption of both electro-
philes and no ketone formation. From these studies it appeared
that the initial acylnickel(II) (1) had to be reduced to an
acylnickel(I)7a before it could form ketone products from the
reaction with secondary bromoalkanes.
of (bpy)NiBr2, benzyl chlorides could be coupled with aryl
iodides (2 equiv) to form aryl benzyl ketones in 43−88% yield,
but yields were lower with aryl bromides (32−60%) and an
unactivated alkyl iodide, iodooctane (35−42%). Functional
group compatibility was promising, with free phenol and aniline
groups coupling in good yield.
Troupel’s electrochemical mechanistic studies on this process
implicated an acylnickel(II) intermediate, (bpy)Ni(COR1)X
(1), and examined the rate and mechanism of its formation
under catalytically relevant conditions. Further reaction of 1
with another organic halide (R2X) to form ketone (R1COR2)
was not studied, but it was proposed that it could occur through
An improved fundamental understanding of how (L)NiII(C-
(O)R)X (1) reacts with electrophiles would be generally
helpful to developing XEC reactions for ketone synthesis,
especially for an improved method for the carbonylative XEC
of aryl halides with alkyl halides to form aryl alkyl ketones. We
also sought to improve upon the results of Troupel in the
carbonylative coupling of aryl halides with unactivated alkyl
halides (Scheme 1).
B
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a
RESULTS AND DISCUSSION
Table 2. Reaction of (dtbbpy)NiII(COC5H11)Br with RX
■
Stoichiometric Studies. In order to study the key
proposed bond-forming step, we synthesized the dark red
(dtbbpy)NiII(C(O)C5H11)Br (1b) from the reaction of deep
purple (dtbbpy)Ni0(cod)3g (3) with hexanoyl bromide in THF,
in analogy to several literature reports (Table 1).16 The
Table 1. Synthesis of (dtbbpy)NiII(COR1)Br and Selected
a
Characterization Data
yield
c
IR
NMR
(ppm)
UV−vis (cm−1
)
)
b
d
e
f
a
entry [Ni]
(%)
(cm−1
)
(103 M−1 cm−1
Reactions run in a 1/1 THF-d8/DMA mixture using freshly prepared
1b. See the Supporting Information for full experimental details and
tables with all products formed. Yields are uncorrected GC yields of
products formed in >7% yield.
1
2
1b
1c
74
89
1612
1617
3.12 (t)
N/A
20325 (5)
20576 (7)
b
a
b
dtbbpy = 4,4′-di-tert-butyl-2,2′-bipyridine. See the Supporting
c
Information for full characterization data and procedures. 1H NMR
d
yield vs liberated cyclooctadiene; average of two runs. CO
stretches reported that are characteristic of M−C(O)R complexes.15e
is needed before it can react with organic halides, we also ran
reactions with an added reductant, zinc flake.
The reaction of 1b with bromobenzene produced similar
amounts of cross-ketone (4) and symmetric ketone or diketone
products (8 and 9; Table 2, entry 1). The addition of zinc flake
eliminated the symmetric diketone products (8 and 9), but the
reaction remains only marginally selective (entry 2).
e
1H NMR chemical shift and multiplicity for α proton of M−
C(O)CH2R.15c N/A = not applicable. UV−vis absorbances reported
f
as wavenumbers (ε values are given in parentheses).
resulting acylnickel(II) intermediate proved difficult to isolate;
therefore, it was characterized in solution by 1H NMR, IR, and
UV−vis. The yield was determined to be 74% by NMR
(average of two runs).
Hexanoyl complex 1b reacts with α-chloroethylbenzene
rapidly (under 5 min at room temperature) to exclusively form
cross-ketone product 4 (Table 2, entry 3) in a yield that
compares well with those reported for the XEC of acid
chlorides with α-chloroethylbenzene (49−52% for similar
conditions).4c,f The addition of zinc flake did not improve
the reaction yield or selectivity (entry 4), suggesting that
reduction of 1b is not required.
Finally, the reaction of 1b with bromooctane or iodooctane
produced nearly equal amounts of cross-ketone product 4 and
dioctyl ketone 5 (Table 2, entries 5−7). The addition of zinc
flake improved the yield of ketone products (entry 6) but did
not improve the selectivity for cross-ketone over symmetric
ketone significantly (1.4/1 to 1.6/1). XEC of acid chlorides
with alkyl halides is reported to be sensitive to the reductant
and solvent, perhaps explaining the difference between these
modest yields and those reported by Gong4d and ourselves.4c
The reactivity of aroylnickel 1c was examined in the same
manner as for 1b, and the results are shown in Table 3.
Complex 1c was more stable than 1b, but we again prepared it
fresh for each experiment.
The results compared well to those of Yamamoto.15c
Distinctive features were as follows: (1) the Ni−C(O)-
CH2CH2CH2CH3 triplet (3.12 ppm) agrees well with the
3.19 ppm triplet reported for (bpy)NiII(C(O)Et)(Cl); (2) the
IR spectrum revealed a CO stretch at 1612 cm−1, in good
agreement with (bpy)NiII(C(O)Et)(Cl) at 1655 cm−1 and
consistent with other acylnickel complexes (1600−1640
cm−1);15b,d,e (3) the UV−vis spectrum showed a strong
MLCT at 20325 cm−1, in good agreement with Yamamoto’s
report for (bpy)NiII(C(O)Et)(Cl) (19880 cm−1).15c
A similar reaction with 4-methylbenzoyl bromide afforded
(dtbbpy)NiII(C(O)tolyl)Br (1c). This complex was similarly
1
1
characterized in solution by H NMR, IR, and UV−vis. H
NMR analysis clearly showed the formation of a single, new
diamagnetic complex in 89% yield. The IR stretch was in good
agreement with that reported for (dppe)NiII(C(O)Ph)Cl: 1617
vs 1630 cm−1.16b
Reactions of hexanoylnickel 1b with four different organic
halides (bromobenzene, α-chloroethylbenzene, bromooctane,
and iodooctane) were performed, and the results are
summarized in Table 2.17 Because 1b decomposes over about
2 h in solution, we generated it fresh for each experiment in
THF-d8 and then diluted it with DMA to a 1/1 mixture for
reactions with electrophiles. Finally, because it has been
proposed that intermediate reduction of an acylnickel complex
Reaction of 1c with bromobenzene again produced a mixture
of ketone products (Table 3, entry 1). The addition of zinc as a
reductant improved the total yield of all coupled products from
1c (nearly quantitative from 70%) but also resulted in the
formation of significant amounts of noncarbonylated cross-aryl
product 7 (entry 2).
C
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Table 3. Reaction of (dtbbpy)NiII(COC6H4CH3)Br with
RX
Examination of several metal carbonyls (Mn2CO10, W(CO)6,
Mo(CO)6, Cr(CO)6) showed that iron carbonyl was best and
that the reaction could be run in DMA instead of DMPU, but
no significant improvements in yield were forthcoming.
a
The major reaction products were our desired aryl alkyl
ketone, hydrodehalogenated aryl bromide, diaryl ketone, and
noncarbonylated product. We envisioned that both the diaryl
ketone and the aryl alkyl ketone product could arise from the
aroyl nickel (1) formed by CO insertion into the aryl−nickel
bond of 17 (Scheme 3). Aroylnickel(II) complexes are well-
Scheme 3. Proposed Source of Aryl Side Products
a
Reactions were run in a 1/1 mixture of THF-d8/DMA using freshly
prepared 1c. See the Supporting Information for full experimental
b
known to decompose into diaryl ketones by disproportionation
upon heating.15,16 The noncarbonylated product presumably
arose when not enough CO was available in solution, allowing
for the formation of 18.7b
details and tables with all products formed. Yields are uncorrected
c
GC yields of products formed in >7% yield. 76% 1H NMR yield after
workup and filtration through silica gel.
The reaction of aroylnickel 1c with α-chloroethylbenzene
was again rapid and clean, affording a 94% GC yield of the
cross-ketone product 10 (Table 3, entry 3). In this case, we
filtered the product mixture and obtained a 76% NMR yield of
the cross-ketone product. There are no reports of a catalytic
version of this reaction, but Gong reported that benzyl bromide
and methallyl chloride couple with benzoyl chloride in high
yield (70 and 76%).4d This result suggests that, as long as the
aroyl activated ester reacts with nickel(0) first, such a cross-
coupling will be high-yielding. Again, the addition of a
reductant (zinc flake) did not improve the yield or selectivity
(entry 4).
The reaction of iodooctane with aroylnickel 1c formed cross-
ketone in 60% yield along with some dioctyl ketone 11 (Table
3, entry 5). If zinc flake was added, the amount of dioctyl
ketone increased significantly (entry 6), suggesting decarbon-
ylation of 1c, loss of the tolyl group, and coupling with
iodooctane. Dioctyl ketone is not a major side product in the
carbonylative coupling of aryl bromides with alkyl bromides,
but the isolated yields of cross-ketone 10 are similar between
the two methods (vide infra; Table 4, entry 17). Here, the
addition of zinc increased the rate of the reaction (entry 6) but
not the selectivity.
A comparison of the reaction of hexanoylnickel 1b with
bromobenzene (Table 2, entries 1 and 2) and the reaction of
aroylnickel 1c with iodooctane (Table 3, entries 5 and 6)
strongly suggests that the carbonylative coupling of aryl halides
with alkyl halides will work best if the aryl halide reacts first
with the nickel catalyst. Our recent work on the reactivity of
(dtbbpy)Ni0(cod) demonstrated that aryl halides do react more
quickly than alkyl halides under similar conditions.7b
Catalytic Studies. We started our catalytic studies by
adding carbon monoxide sources to our published conditions
for the coupling of aryl bromides with alkyl bromides.3d Initial
results with 20 mol % of Fe(CO)5 were modest (26% yield).
Consistent with these hypotheses, the addition of more alkyl
bromide (2.25 equiv from 1 equiv) resulted in less diaryl
ketone, although little effect was observed above 2.25 equiv
(Table 4, entries 1−4). Increasing the amount of iron carbonyl
eliminated noncarbonylated products, but too much iron
carbonyl diminished yields (Table 4, entry 3 vs entries 5−7).
The addition of iodide was essential for reactivity. A reaction
with no NaI gave no ketone product (Table 4, entry 8), but
substitution of NaI with LiI and KI provided results similar to
those for NaI (Table 4, entry 3 vs entries 9 and 10). Lowering
the catalyst loading from 7 to 5 mol % resulted in a 14% lower
yield (entry 11). A reaction run without added reductant
produced a small amount of 22. In this case, the Fe(CO)5 likely
served as the reductant (entry 15). Finally, 6/1 and 1/1
mixtures of DMA to THF formed products in 76% and 52%
yields, respectively, but a 1/2 mixture did not consume most of
the starting material (entries 16−18).
The highest yields were obtained when water was strictly
excluded. For example, if starting materials were left on the
bench for extended periods of time, the yield of product would
drop (up to 20% difference in yield). Reactions also worked
best when the mixtures were heated immediately after
assembly. Stirring a reaction mixture at room temperature for
30 min before heating to 60 °C diminished the yield by about
10%.
In order to examine the scope of this reaction, several aryl
bromides were coupled with primary alkyl bromides (Table 5).
Yields were similar to those for the optimized reaction, but the
coupling of an aryl bromide containing an electron-withdrawing
group, −CF3, resulted in a lower yield (Table 5, entries 1 and
5), due to competitive formation of both diaryl ketone and
biaryl.18 Aryl chlorides were not reactive (entry 2), and both
protected alcohols and fluorinated substrates were also well
tolerated (entries 4−6). Although α-chloroethylbenzene
formed high yields of ketone product from reactions with
D
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a
a
Table 4. Optimization and Controls
Table 5. Scope of Reaction with Aryl-X
entry
notes
X
Y
22
20
21
1
2
3
4
0.35
0.35
0.35
0.35
0.40
0.45
0.50
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
2.50
2.25
2.0
69
5
6
4
6
72 (60)
56
50
51
42
32
0
7
8
1.5
9
15
8
b
5
2.0
7
c
6
2.0
3
5
c
7
d
2.0
3
4
8
no NaI
2.0
0
0
9
LiI for NaI
2.0
49
48
42
0
7
7
10
11
KI for NaI
2.0
4
8
5 mol % catalyst
no dtbbpy
2.0
6
9
e
12
2.25
2.0
0
2
ef
,
13
14
15
16
17
18
no Ni or Zn
no Ni
0
0
1
eg
,
2.0
<1
25
76
52
<1
<1
<1
7
0
cg
,
no Zn
2.25
2.25
2.25
2.25
4
6/1 DMA/THF
1/1 DMA/THF
1/2 DMA/THF
0
7
3
eg
,
0
1
a
Reactions were run on a 0.75 mmol scale in 3 mL of DMA. Yields are
uncorrected GC yields vs dodecane. The yield in parentheses is an
b
c
isolated yield of purified product. PhBr (8%) remained. PhBr (27%−
47%) remained. Starting materials were unchanged after 40 h, except
d
e
for a 13% yield of hydrodehalogenated 19. PhBr (75%) remained.
f
g
Alkyl-Br 19 not consumed. Dialkyl ketone (12−23%) was formed.
acylnickel complexes (Tables 2 and 3), the catalytic reactions
were plagued by rapid dimerization of this reactive substrate.
a
Reactions were performed on a 0.75 mmol scale on the benchtop in 3
b
c
mL of DMA. Isolated yield of purified product. Product contains an
CONCLUSIONS
additional 3% of benzophenone.
■
In conclusion, our studies on acylnickel complexes have
revealed differential reactivity with respect to electrophiles.
Both aroyl- and alkanoylnickel complexes react with secondary
benzylic chlorides to form product without added reductant,
but the aroylnickel complex reacts with alkyl iodides to produce
more cross-ketone than the alkanoylnickel complex. Neither
complex reacts with bromobenzene to selectively produce
cross-ketone product. The addition of an external reductant
(zinc flake) did not improve the selectivity of reactions with
alkyl or benzyl halides but did improve the rate in one case,
suggesting that reduction of acylnickel(II) to acylnickel(I)4d−f
is not a necessary step in XEC ketone synthesis reactions and
that zinc might facilitate a radical initiation step.7 Gong
reported a reductant effect more dramatic than the effect we
observed, but under significantly different conditions. Finally,
the observed reactivity of 1c with alkyl halides can be translated
into the first carbonylative cross-coupling of bromoarenes with
bromoalkanes. Further studies on the reactivity of acylnickel
complexes and translation to new reactions is ongoing.
or synthesized according to the literature procedures.20,21 Zinc flake
(−325 mesh; Alfa) was used as received. Anhydrous N,N-
dimethylacetamide (DMA; Aldrich) was stored over activated 4 Å
molecular sieves. DMA used for stoichiometric reactions was
sequentially dried over 4 Å MS, degassed, and then vacuum-
transferred. The water content was routinely measured using Karl
Fischer titration (Metrohm) and was less than 70 ppm. THF-d8 was
purchased from Cambridge Isotopes, dried sequentially over MS 4 Å,
degassed, and then vacuum-transferred. Hexanoyl bromide and p-
toluoyl bromide were synthesized using the literature procedures. 1-
Iodooctane (Aldrich), 1-bromooctane (Aldrich), bromobenzene, and
ethyl 4-bromobutanoate (Aldrich) were filtered through a dry,
activated, basic alumina pad (1.5 cm) under nitrogen until they were
colorless before use.
1H and 13C NMR spectra were acquired on 500 or 400 MHz
(proton) Bruker NMR instruments, and data analysis was performed
using the iNMR software package (version 5.3.5, http://www.inmr.
net). NMR chemical shifts are reported in ppm and referenced to the
residual solvent peak as an internal standard (for CDCl3 δ 7.260 ppm
(1H), δ 77.160 ppm (13C); for THF-d8 δ 1.720, 3.573 ppm (1H)).
GC analyses were performed on an Agilent 7890A GC instrument
equipped with dual DB-5 columns (20 m × 180 μm × 0.18 μm) and
dual FID detectors and with hydrogen as the carrier gas. The analysis
method used in all cases was a 1 μL injection of sample, an injection
temperature of 300 °C, and a 100:1 split ratio; the initial inlet pressure
was 20.3 psi but was varied as the column flow was held constant at 1.8
EXPERIMENTAL SECTION
■
Materials and Methods. NiCl2(1,2-dimethoxyethane)
(NiCl2(dme)) was purchased from Strem or synthesized according
to the literature procedure.19 Ni(cod)2 was purchased from Strem.
4,4′-Di-tert-butyl-2,2′-bipyridine (dtbbpy) was purchased from Aldrich
E
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mL/min for the duration of the run. The initial oven temperature of
50 °C was held for 0.46 min, followed by a temperature ramp up to
300 °C at 65 °C/min; finally the temperature was held at 300 °C for
0.69 min. The total run time was ∼5 min. The FID temperature was
325 °C. Dodecane (Aldrich) was used as an internal standard for GC
analysis of catalytic reactions. Mesitylene (Aldrich) was used as an
internal standard for GC analysis of stoichiometric reactions. GC
analysis of reaction mixtures was accomplished by removal of a 25 μL
aliquot with a 100 μL gastight syringe which was quenched with 50 μL
of 1 M aqueous NaHSO4, diluted with ethyl ether or TBME (1 mL),
and filtered through a short silica pad (2 cm) in a pipet packed with
glass wool. The filtrate was analyzed by GC.
quenched with diethyl ether (1 mL) and aqueous NaHSO4 (1 M, 0.5
μL), and the resulting mixture was filtered through a pad of silica gel
1
before being analyzed by GC, GC/MS, and/or H NMR. See the
Supporting Information for tables of all products produced in these
reactions. Attempts to visualize the nickel products of these reactions
were unsuccessful, and in some cases precipitation of unknown
products occurred.
General Procedure for Aryl Bromides. A flame-dried 10 mL
round-bottom flask (14/20 joint) containing a Teflon-coated magnetic
stir bar was charged with NiCl2(dme) (11.5 mg, 0.053 mmol), 4,4′-di-
tert-butyl-2,2′-bipyridine (14.5 mg, 0.054 mmol), anhydrous NaI (28.1
mg, 0.1875 mmol), and zinc flake (98.0 mg, 2 equiv). The round-
bottom flask was then fitted with a septum (14/20) and sealed tightly
with a double strand of 20 gauge copper wire. The round-bottom flask
was purged with nitrogen (1 min), and 2 mL of anhydrous DMA (<70
ppm of H2O by KF titration) was added by syringe. The resulting
mixture was stirred for 1 h at room temperature (∼21 °C) until the
supernatant had turned dark gray. Alkyl bromide (1.69 mmol, 2.25
equiv), a solution of aryl halide (0.75 mmol in 1 mL of anhydrous
DMA), and Fe(CO)5 (35 μL, 52 mg, 0.27 mmol) were added
sequentially by syringe. The reaction mixture was stirred (1000 rpm)
at 60 °C (oil bath) until judged complete by GC analysis (less than 1%
aryl bromide remaining, 17−36 h). The resulting mixture was filtered
through a 1 cm silica gel pad and the pad rinsed with diethyl ether
(∼100 mL). The collected organic layer was then washed with 60 mL
of water, and the aqueous layer was extracted with diethyl ether (3 ×
15 mL). The combined organic extracts were dried over MgSO4,
filtered, and concentrated in vacuo. The resulting residue was purified
by flash chromatography (SiO2) to yield the desired ketone products.
Ethyl 5-(Phenyl)-5-oxopentanoate (22) [73172-56-2].25 The
general procedure was followed with bromobenzene (80 μL, 0.75
mmol) and ethyl 4-bromobutyrate (240 μL, 1.69 mmol). The reaction
was judged complete after 18 h. Following chromatography (1/10
ethyl acetate/hexanes, Rf = 0.25, UV and p-anisaldehyde visualization),
the product was isolated as a light yellow oil (103.6 mg, 63% yield). 1H
NMR (400 MHz; CDCl3): δ 7.97−7.95 (m, 2H), 7.55 (tt, J = 7.4, 1.6
Hz, 1H), 7.47−7.43 (m, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.05 (t, J = 7.2
Hz, 2H), 2.43 (t, J = 7.2 Hz, 2H), 2.07 (quintet, J = 7.2 Hz, 2H), 1.25
(t, J = 7.1 Hz, 3H). 13C NMR (101 MHz; CDCl3): δ 199.6, 173.4,
136.9, 133.2, 128.7, 128.2, 60.5, 37.6, 33.5, 19.5, 14.4. IR (cm−1): 1728
(s, CO, ester), 1682 (s, CO, aryl ketone). EIMS (70 eV): m/z
220 (M+).
Thin-layer chromatography was performed on EMD Chemicals
TLC silica gel 60 F254 plates. Visualization was accomplished with p-
anisaldehyde stain after inspection under UV light. Flash chromatog-
raphy was performed using EMD silica gel 60, particle size 0.040−
0.063 mm, using standard flash techniques. Some compounds were
purified using a Combiflash Rf 200 (Teledyne Isco) with Redisep Rf
Gold normal-phase silica columns.
4,4′-Di-tert-butyl-2,2′-bipyridine (dtbbpy). 1H NMR (400
MHz; THF-d8): δ 8.56 (s, 2H), 8.51 (d, J = 5.1 Hz, 2H), 7.31 (d, J
= 5.1 Hz, 2H), 1.37 (s, 18 H).
1
Ni(cod)2. H NMR (400 MHz; THF-d8): δ 4.30 (br s, 4H), 2.11
(br s, 8H).
1,5-Cyclooctadiene (cod). 1H NMR (400 MHz; THF-d8): δ 5.49
(s, 4H), 2.32 (s, 8H).
(dtbbpy)Ni0(cod) (2). In a nitrogen-filled glovebox, an oven-dried
1 dram vial was charged with Ni(cod)2 (10.0 mg, 0.0364 mmol), 4,4′-
di-tert-butyl-2,2′-bipyridine (9.8 mg, 0.036 mmol), and dry, degassed
THF-d8 (0.75 mL). The resulting mixture was swirled by hand to give
a deep purple solution. The mixture was then quantitatively transferred
(2 × 0.125 mL of THF-d8 wash) to a screw-capped NMR tube with a
PTFE-coated septum and sealed. The NMR tube was shaken until the
mixture was homogeneous and was allowed to sit overnight at 22 °C
(room temperature). The solution of (dtbbpy)Ni0(cod) and free cod
was characterized by 1H NMR, paramagnetic 1H NMR, and 13C NMR.
Data for the complex matched those in our previous literature
report.7b
(dtbbpy)NiII(C(O)R)Br. The NMR tube was returned to the
glovebox, and a carboxylic acid bromide (0.0382 mmol, 1.05 equiv)
was added. The color immediately changed to deep red in both cases,
and the resulting mixture was characterized by 1H NMR, paramagnetic
1H NMR, IR, and UV−vis spectroscopy.22
Ethyl 5-(4-Chlorophenyl)-5-oxopentanoate (23) [54029-03-7].26
The general procedure was followed using 4-chlorobromobenzene
(143.6 mg, 0.75 mmol) and ethyl 4-bromobutyrate (240 μL, 1.68
mmol). The reaction was judged complete after 17 h. Following
chromatography (6/1 hexanes/ethyl acetate, Rf = 0.42, stained purple
with p-anisaldehyde stain), the product was isolated as a white
crystalline solid (118.3 mg, 62%). Mp: 52−55 °C (lit.26 mp 34−36
°C). 1H NMR (500 MHz; CDCl3): δ 7.90 (d, J = 8.6 Hz, 2H), 7.43 (d,
J = 8.5 Hz, 2H), 4.14 (q, J = 7.1 Hz, 2H), 3.02 (t, J = 7.2 Hz, 2H), 2.43
(t, J = 7.1 Hz, 2H), 2.09−2.03 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H). 13C
NMR (126 MHz; CDCl3): δ 198.4, 173.3, 139.7, 135.3, 129.6, 129.1,
60.6, 37.6, 33.4, 19.5, 14.4. IR (cm−1): 1724 (s, CO, ester), 1686 (s,
CO, aryl ketone). EIMS (70 eV): m/z 254 (M+).
(dtbbpy)Ni(C(O)C5H11)(Br) (1b). The general procedure was
followed with hexanoyl bromide23 (6.8 mg, 0.038 mmol). The yield
1
was determined by H NMR: 72% (vs mesitylene, average of two
1
runs), 74% (vs cyclooctadiene, average of two runs). H NMR (400
MHz; THF-d8): δ 9.09 (d, J = 4.1 Hz, 1H), 8.11 (m, 3H), 7.53−7.49
(m, 2H), 3.12 (t, J = 7.3 Hz, 2H), 1.64 (dt, J = 13.0, 6.3 Hz, 2H), 1.38
(s, 18H), 1.29−1.25 (m, 10H), 0.84 (t, J = 6.7 Hz, 3H). IR (cm−1):
1612 (CO). UV−vis (THF) 1/λ (ε): 20325 cm−1 (5 × 103).
(dtbbpy)Ni(C(O)C6H4Me)(Br) (1c). The general procedure was
followed using 4-methylbenzoyl bromide24 (7.6 mg, 0.038 mmol). The
yield was determined by 1H NMR: 95% (vs mesitylene, average of two
runs), 89% (vs cyclooctadiene, average of two runs). The product
mixture contained 7 mol % of toluoyl bromide, as evidenced by the
1
Ethyl 5-(3,5-Dimethoxyphenyl)-5-oxopentanoate (24) [898758-
62-8]. The general procedure was followed using 1-bromo-3,5-
dimethoxybenzene (162.8 mg, 0.75 mmol) and ethyl 4-bromobutyrate
(240 μL, 1.68 mmol). The reaction was judged complete after 36 h.
Following chromatography (23% ethyl acetate in hexanes, Rf = 0.40,
stained purple with p-anisaldehyde stain), the product was isolated as a
characteristic doublets at 7.95 and 7.37 ppm. H NMR (400 MHz;
THF-d8): δ 9.14 (d, J = 5.7 Hz, 1H), 8.37 (d, J = 8.0 Hz, 2H), 8.17 (d,
J = 7.3 Hz, 2H), 7.74 (d, J = 6.0 Hz, 1H), 7.58 (d, J = 5.3 Hz, 1H),
7.29 (d, J = 4.3 Hz, 1H), 7.12 (d, J = 7.8 Hz, 2H), 2.32 (s, 3H), 1.41
(s, 9H), 1.34 (s, 9H). IR (cm−1): 1617 (CO). UV−vis (THF) 1/λ
(ε): 20576 cm−1 (7 × 103).
Reactivity Studies (Tables 2 and 3). The NMR tube was
returned to the glovebox, and dry, degassed DMA (1 mL, <16 ppm of
H2O by KF titration) was added to the red solution, resulting in a
small change to dark red-orange. The appropriate electrophile (0.291
mmol, 8 equiv) was added, and the NMR tube was again sealed,
removed from the glovebox, and heated to 60 °C (oil bath). The
reaction was judged complete when the vivid red-orange color of the
nickel acyl halide complex had disappeared. The resulting reaction was
1
light pink amorphous solid (130.8 mg, 62%). Mp: 40.5−45 °C. H
NMR (400 MHz; CDCl3): δ 7.09 (d, J = 2.3 Hz, 2H), 6.64 (t, J = 2.2
Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.83 (s, 6H), 3.00 (t, J = 7.2 Hz,
2H), 2.42 (t, J = 7.2 Hz, 2H), 2.05 (quintet, J = 7.2 Hz, 2H), 1.25 (t, J
= 7.1 Hz, 3H). 13C NMR (101 MHz; CDCl3): δ 198.5, 172.8, 160.5,
138.5, 105.8, 105.3, 60.6, 55.8, 38.0, 33.8, 20.0, 14.7. IR (cm−1): 1728
(s, CO, ester), 1670 (s, CO, aryl ketone). EIMS (70 eV): m/z
280 (M+).
F
dx.doi.org/10.1021/om5004682 | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Ethyl 5-(2-Methoxy-5-fluorophenyl)-5-oxopentanoate (25)
[951889-85-3]. The general procedure was followed using 2-bromo-
5-fluoroanisole (97 μL, 0.75 mmol) and ethyl 4-bromobutyrate (240
μL, 1.68 mmol). The reaction was judged complete after 22 h.
Following chromatography (8/1 hexanes/ethyl acetate, Rf = 0.20,
stained purple with p-anisaldehyde stain), the product was isolated as a
(University of Rochester) for experimental assistance with
Table 4.
REFERENCES
■
(1) Reviews: (a) Colquhoun, H. M.; Thompson, D. J.; Twigg, M. V.
Carbonylation, Direct Synthesis of Carbonyl Compounds; Plenum Press:
New York, 1991. (b) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Soc.
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(2) Knochel, P. Handbook of Functionalized Organometallics:
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1
white amorphous solid (132.1 mg, 62%). Mp: 30−33 °C. H NMR
(400 MHz; CDCl3): δ 7.40 (dd, J = 7.1, 2.6 Hz, 1H), 7.14 (ddd, J =
7.2, 5.9, 2.6 Hz, 1H), 6.90 (dd, J = 7.3, 3.2 Hz, 1H), 4.12 (q, J = 5.7
Hz, 2H), 3.87 (s, 3H), 3.02 (t, J = 5.7 Hz, 2H), 2.37 (t, J = 5.9 Hz,
2H), 2.00 (quintet, J = 5.8 Hz, 2H), 1.23 (t, J = 5.7 Hz, 3H). 13C NMR
(126 MHz; CDCl3): δ 200.3, 173.3, 156.9 (d, J = 240 Hz), 154.9 (d, J
= 2.3 Hz), 129.2 (d, J = 5.7 Hz), 119.7 (d, J = 23.6 Hz), 116.4 (d, J =
23.8 Hz), 113.1 (d, J = 7.1 Hz), 60.3, 56.2, 42.7, 33.6, 19.6, 14.3. 19F
NMR (376 MHz; CDCl3): δ −60.66. IR (cm−1): 1728 (s, CO,
ester), 1674 (s, CO, aryl ketone). EIMS (70 eV): m/z 268 (M+).
Ethyl 5-(4-Trifluoromethylphenyl)-5-oxopentanoate (26)
[898777-81-6].27 The general procedure was followed using 4-
bromobenzotrifluoride (105 μL, 0.75 mmol) and ethyl 4-bromobuty-
rate (240 μL, 1.68 mmol). The reaction was judged complete after 24
h. Following chromatography (15% ethyl acetate in hexanes, Rf = 0.40,
stained purple with p-anisaldehyde stain), the product was isolated as a
(3) For C(sp2)−C(sp3) bond formation: (a) Everson, D. A.;
Shrestha, R.; Weix, D. J. J. Am. Chem. Soc. 2010, 132, 920−921.
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(c) Anka-Lufford, L. L.; Prinsell, M. R.; Weix, D. J. J. Org. Chem. 2012,
77, 9989−10000. (d) Everson, D. A.; Jones, B. A.; Weix, D. J. J. Am.
Chem. Soc. 2012, 134, 6146−6159. (e) Wang, S.; Qian, Q.; Gong, H.
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Wang, Y.-W. Chem. Eur. J. 2012, 18, 6039−6048. (g) Biswas, S.; Weix,
D. J. J. Am. Chem. Soc. 2013, 135, 16192−16197. (h) Buonomo, J. A.;
Everson, D. A.; Weix, D. J. Synthesis 2013, 45, 3099−3102. (i) Everson,
D. A.; George, D. T.; Weix, D. J.; Buergler, J. F.; Wood, J. L. Org.
Synth. 2013, 90, 200−214. (j) Zhao, Y.; Weix, D. J. J. Am. Chem. Soc.
2014, 136, 48−51.
1
white amorphous solid (102.9 mg, 48%). Mp: 29−32.5 °C. H NMR
(500 MHz; CDCl3): δ 8.07 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.1 Hz,
2H), 4.14 (q, J = 7.1 Hz, 2H), 3.08 (t, J = 7.1 Hz, 2H), 2.44 (t, J = 7.1
Hz, 2H), 2.08 (quintet, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 4H). 13C
NMR (126 MHz; CDCl3): δ 198.5, 173.3, 139.5, 134.5 (q, J = 32.7
Hz), 128.5, 125.8 (q, J = 3.7 Hz), 123.7 (q, J = 273 Hz), 60.6, 37.9,
33.3, 19.3, 14.3. 19F NMR (376 MHz; CDCl3): δ −0.38. IR (cm−1):
1728 (s, CO, ester), 1674 (s, CO, aryl ketone). EIMS (70 eV):
m/z 288 (M+).
(4) (a) Marzouk, H.; Rollin, Y.; Folest, J. C.; Ned
J. J. Organomet. Chem. 1989, 369, C47−C50. (b) Amatore, C.; Jutand,
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́ ́ ́
elec, J. Y.; Perichon,
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(c) Wotal, A. C.; Weix, D. J. Org. Lett. 2012, 14, 1476−1479. (d) Wu,
F.; Lu, W.; Qian, Q.; Ren, Q.; Gong, H. Org. Lett. 2012, 14, 3044−
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1-Phenyl-4-(tert-butyldimethylsilyloxy)-1-butanone (27)
[143878-47-1]. The general procedure was followed using bromo-
benzene (80 μL, 0.75 mmol) and 3-(tert-butyldimethylsilyloxy)-1-
bromopropane (427 mg, 1.68 mmol). The reaction was judged
complete after 18 h. Following chromatography (4% diethyl ether in
pentane, Rf = 0.22, stained yellow with p-anisaldehyde stain), the
product was isolated with 3% benzophenone impurity as a clear,
(5) Other disconnections include the following. Conjugate addition:
(a) Shrestha, R.; Weix, D. J. Org. Lett. 2011, 13, 2766−2769.
(b) Millan, A.; Martin-Lasanta, A.; Miguel, D.; Cienfuegos, L. A. d.;
Cuerva, J. M. Chem. Commun. 2011, 47, 10470−10472. (c) Shrestha,
R.; Dorn, S. C. M.; Weix, D. J. J. Am. Chem. Soc. 2013, 135, 751−762.
Cross-Wurtz coupling: (d) Yu, X.; Yang, T.; Wang, S.; Xu, H.; Gong,
H. Org. Lett. 2011, 13, 2138−2141. (e) Xu, H.; Zhao, C.; Qian, Q.;
Deng, W.; Gong, H. Chem. Sci. 2013, 4, 4022−4029. Coupling of RX
with CO2: (f) Troupel, M.; Rollin, Y.; Perichon, J.; Fauvarque, J. F.
Nouv. J. Chim. 1981, 5, 621−625. (g) Fauvarque, J. F.; Chevrot, C.;
1
colorless oil (135.7 mg, 65%). H NMR (500 MHz; CDCl3): δ 7.96
(d, J = 7.7 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H),
3.70 (t, J = 6.0 Hz, 2H), 3.05 (t, J = 7.2 Hz, 2H), 1.95 (quintet, J = 6.7
Hz, 2H), 0.88 (s, 9H), 0.03 (s, 6H). 13C NMR (126 MHz; CDCl3): δ
200.4, 137.3, 133.0, 128.7, 128.2, 62.4, 35.0, 27.6, 26.1, 18.5, −5.2. IR
(cm−1): 1686 (CO aryl ketone). EIMS (70 eV): m/z 221 (M+ − t-
Bu).
Jutand, A.; Franco̧ is, M.; Perichon, J. J. Organomet. Chem. 1984, 264,
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ASSOCIATED CONTENT
■
S
* Supporting Information
(6) (a) Ocafrain, M.; Devaud, M.; Troupel, M.; Perichon, J. J. Chem.
Tables S1 and S2, giving the full product distribution for Tables
2 and 3, respectively, pictures of the the reaction of 1c with
electrophiles, and figures giving NMR spectra for 1b,c, 3, and
22−27. This material is available free of charge via the Internet
at http://pubs.acs.org.
Soc., Chem. Commun. 1995, 2331−2332. (b) Dolhem, E.; Oca
Nedelec, J. Y.; Troupel, M. Tetrahedron 1997, 53, 17089−17096.
(c) Ocafrain, M.; Dolhem, E.; Nedelec, J.; Troupel, M. J. Organomet.
Chem. 1998, 571, 37−42. (d) Troupel, M.; Ocafrain, M.; Dolhem, E.;
Folest, J.-C.; Barhdadi, R. Can. J. Chem. Eng. 1998, 76, 1013−1019.
(e) Ocafrain, M.; Devaud, M.; Nedelec, J. Y.; Troupel, M. J.
̧ frain, M.;
́
́
̧
̧
̧
́
Organomet. Chem. 1998, 560, 103−107. (f) Dolhem, E.; Barhdadi,
R.; Folest, J.; Nedelec, J.; Troupel, M. Tetrahedron 2001, 57, 525−529.
AUTHOR INFORMATION
■
́
(7) (a) Amatore, C.; Jutand, A.; Perichon, J.; Rollin, Y. Monatsh.
Corresponding Author
Chem. 2000, 131, 1293−1304. (b) Biswas, S.; Weix, D. J. J. Am. Chem.
Soc. 2013, 135, 16192−16197.
*E-mail for D.J.W.: daniel.weix@rochester.edu.
Notes
(8) Potential coupling products: three dicarbonyls (R1(CO)2R1,
R2(CO)2R1, R2(CO)2R2), three ketone products (R1C(O)R1, R1(CO)
R2, R2(CO)R2), three non-carbonylated products (R1R1, R1R2, R2R2).
Other side products: one β-hydride elimination product (olefin from
R2X), two hydrodehalogenation products (R1H, R2H), two carboxylic
acids (R1CO2H, R2CO2H).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NIH (R01 GM097243).
A.C.W. thanks the University of Rochester for a Weisburger
Fellowship. R.D.R. was an NSF REU summer student at the
University of Rochester (CHE-1156340). D.J.W. is an Alfred P.
Sloan Research Fellow. We are grateful to Jill Caputo
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871. (d) Hirota, Y.; Ryang, M.; Tsutsumi, S. Tetrahedron Lett. 1971,
G
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(17) Complete tables of all products formed in Tables 2 and 3 can be
found in the Supporting Information.
(18) Aryl bromides with stronger electron-withdrawing groups
provided still lower yields of cross-coupled ketone under these
conditions. Expansion of the synthetic utility of this coupling
chemistry is ongoing.
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(22) Attempts to obtain clean 13C NMR spectra were unsuccessful.
(23) Bernady, K. F.; Floyd, M. B.; Poletto, J. F.; Schaub, R. E.; Weiss,
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H
dx.doi.org/10.1021/om5004682 | Organometallics XXXX, XXX, XXX−XXX