From Alkyl Halides to Ketones: Nickel-Catalyzed Reductive Carbonylation Utilizing Ethyl Chloroformate as the Carbonyl Source

Article abstract of DOI:10.1002/anie.201903330

Ketones are an important class of molecules in synthetic and medicinal chemistry. Rapid and modular synthesis of ketones remains in high demand. Described here is a nickel-catalyzed three-component reductive carbonylation method for the synthesis of dialkyl ketones. A wide range of both symmetric and asymmetric dialkyl ketones can be accessed from alkyl halides and a safe CO source, ethyl chloroformate. The approach offers complementary substrate scope to existing carbonylation methods while avoiding the use of either toxic CO or metal carbonyl reagents.

Full text of DOI:10.1002/anie.201903330

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Accepted Article
Title: From Alkyl Halides to Ketones: Nickel-Catalyzed Reductive
Carbonylation Utilizing Ethyl Chloroformate as a Carbonyl Source
Authors: Renyi Shi and Xile Hu
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From Alkyl Halides to Ketones: Nickel-Catalyzed Reductive
Carbonylation Utilizing Ethyl Chloroformate as a Carbonyl Source
Renyi Shi[a] and Xile Hu*[a]
Abstract: Ketones are an important class of molecules in synthetic
and medicinal chemistry. Rapid and modular synthesis of ketones
remains in high demand. Here we describe a nickel-catalyzed three-
component reductive carbonylation method for the synthesis of dialkyl
ketones. A wide range of both symmetric and asymmetric dialkyl
ketones can be accessed from alkyl halides and a safe CO source,
ethyl chloroformate. Our approach offers complementary substrate
scope to existing carbonylation methods while avoiding the use of
toxic CO or metal carbonyl reagents.
Ketone is an recurring moiety in numerous natural products,
pharmaceutical molecules (Figure 1a) and materials.[1] Ketones
are also ubiquitous synthetic intermediates in chemical synthesis.
The synthesis of ketone is a cornerstone of modern organic
chemistry. Classic methods are based on transformations of pre-
existing functional groups, for example, oxidation of alcohols and
conversion of carboxylic acid derivatives.[1-2] Transition-metal-
catalyzed carbonylative cross-coupling is an attractive alternative
because a diverse set of ketones can be rapidly assembled from
smaller building blocks (Figure 1b).[3] Nevertheless, carbonylative
cross-coupling suffers from several limitations: (i) the
methodology works well for the synthesis of aryl ketones, but not
alkyl ketones. Like in conventional cross-coupling,[4] the reactions
of alkyl electrophiles in carbonylative cross-coupling is
problematic due to β-H elimination. (ii) the carbonyl sources are
mostly CO gas or metal carbonyl complexes, which are toxic and
can be inconvenient to handle, although a few practical CO
surrogates have been developed to mitigate this issue.[5] To
address the first limitation, Ni-catalyzed reductive cross-coupling
of alkyl halides with carboxylic acid derivatives has recently been
developed to give dialkyl ketones (Figure 1b).[6] However, these
Figure 1. (a) Examples of bio-active ketones. (b) Previous cross-coupling type
carbonylation methods. (c) Ni-catalyzed reductive carbonylation described in
this work.
reactions require carboxylic acid derivatives as reagents and are
not well suited for the synthesis of symmetric dialkyl ketones.
Here we describe
a three-component, reductive coupling
The three-component coupling of (3-iodopropyl)benzene
(1a), iodocyclohexane (2a), and ClCOOEt was used as the test
reaction (Table 1). After optimization (Figure S1-S8, SI), the
optimized conditions were: NiBr2·Diglyme (10 mol%) as pre-
catalyst, bipyridine (15 mol%) as ligand, Zn (4 equiv) as reductant,
1:2:2 ratio of (3-iodopropyl)benzene to iodocyclohexane to
ClCOOEt, TMSCl (50 mol%) as activator of Zn, and THF/DMA
(3/1; 2.0 mL) as solvent, and 40 oC as the reaction temperature.
The desired product, 1-cyclohexyl-4-phenylbutan-1-one (3a), was
obtained in 75% yield after 1h (entry 1, Table 1). Compound 4a
and 4c, the symmetric dialkyl ketones, were formed in 10% and
59% (relative to 1a), respectively. Here 2a was used in excess (2
equiv) to favor a high yield of asymmetric dialkyl ketone. If 1 equiv
of 2a was used, then the yields of 3a, 4a, and 4c were 49%, 23%,
18%, respectively (entry 2, Table 1). If 1a was used in excess (2
equiv), the yields of 3a, 4a, and 4c (relative to 2a) were 62%, 62%,
12%, respectively (entry 3, Table 1). There was no reaction
without the nickel pre-catalyst (entry 4, Table 1). The yield was
69% with 10 mol% NiCl2·dme as the pre-catalyst (entry 5, Table
approach that complements the above-mentioned methods and
overcome their limitations. Using Ni catalysis, we are able to
prepare a wide range of both symmetric and asymmetric dialkyl
ketones from two molecules of alkyl halides and ethyl
chloroformate (ClCOOEt),[7] a safe and easy to handle CO source
(Figure 1c).
[a]
R. Shi, Prof. X. Hu
Laboratory of Inorganic Synthesis and Catalysis, Institute of
Chemical Sciences and Engineering, École polytechnique fédérale
de Lausanne (EPFL), ISIC-LSCI
BCH 3305,Lausanne 1015 (Switzerland)
E-mail: xile.hu@epfl.ch
Homepage: http://lsci.epfl.ch
Supporting information for this article is given via a link at the end of
the document.
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Table 2 Nickel-catalyzed reductive carbonylative cross-coupling
1). The reaction did not occur without Zn or Bipy (entries 6-7,
Table 1). Without ClCOOEt, no carbonylative coupling but only
alkyl-alkyl coupling products were detected (entry 8, Table 1).
Without TMSCl the yield was only 10% (entry 9, Table 1). With
THF or DMA as the sole solvent, the yield decreased greatly
(entries 10-11, Table 1). Replacing Zn with Mn led to 14% yield
(entry 12, Table 1). When the reaction was conducted at room
temperature the yield was 70% (entry 13, Table 1).
Table 1. Summary of the effects of reaction parameters and conditions on
the reaction efficiency[a]
Entry
Variation
from
Yield of
3a (%)
Yield of
4a (%)
Yield of
4c (%)
standard conditions[b]
1
2
3
4
5
None
75
49
62
0
10
23
62
0
59
18
12
0
1a/2a = 1/1
1a/2a = 2/1
No NiBr2·diglyme
10 mol% NiCl2 · dme
69
6
61
instead of NiBr2
diglyme
·
6
No Zn
0
0
0
0
2
1
0
0
0
8
5
7
No Bipy
0
8
No ClCOOEt
No TMSCl
0
9
10
4
10
2.0 mL THF instead of
THF/DMA
11
2.0 mL DMA instead
of THF/DMA
31
2
37
[a] The reaction was carried out with 1 (0.2 mmol), 2 (2 equiv), NiBr2·diglyme
(10 mol%), Bipy (15 mol%), ClCOOEt (2 eq.), TMSCl (50 mol%), Zn (4 eq.),
THF (1.5 mL) and DMA (0.5 mL), 1 hour, at 40 oC. Yield is that of the isolated
product.
12
13
Mn instead of Zn
14
70
3
6
8
Room
temperature
65
instead of 40 oC
[a] Yields determined by GC using n-dodecane as an internal standard.[b]
The optimized reaction conditions were 1a (0.2 mmol), 2a (2 equiv), NiBr2·
diglyme (10 mol%), Bipy (15 mol%), ClCOOEt (2 eq.), TMSCl (50 mol%), Zn
(4 eq.) THF 1.5 mL and DMA (0.5 mL), 1 hour, 40 oC.
tolerated (3p, 3q and 3r), offering opportunities for subsequent
functionalization. Substrates containing a heterocycle group such
as pyrrole and indole were coupled in moderate yields (3s and 3t).
When a substrate containing two iodo groups, 1, 6-diiodohexane,
was used, the double carbonylation product, 1, 8-
dicyclohexyloctane-1, 8-dione (3u), was obtained in 42% yield.
This protocol was suitable for the derivatization of a natural
product, dihydrocholesterol, offering 3v in 70% yield. Functional
groups such as –COOH, -OH and N-Boc were unfortunately not
tolerated. Benzyl chlorides were also suitable substrates (3v-3ab).
Both electron-withdrawing groups such as F, Cl, CF3 (3w, 3x and
3y) and electron donating groups such as OCF3, OPh, and OMe
(3z, 3aa and 3ab) were tolerated as a substituent in the aryl ring
of the benzyl chlorides. When two different secondary alkyl
iodides, i.e., cyclopentyl and cyclohexyl iodide, were used, the
asymmetric dialkyl ketone was formed in 40% yield while a
The optimized conditions in table 1 were employed to
synthesize a wide range of asymmetric dialkyl ketones (Table 2).
Various secondary (cyclic and acyclic) and primary alkyl iodides
could be coupled (3a-3h). Even a tertiary alkyl iodide was a viable
coupling partner (3i), albeit in a low yield of 30%. The scope of
primary alkyl iodides was explored using iodocyclohexane as a
second partner (3j-3u). Alkyl groups containing ester, ether,
cyano and amide groups were well tolerated (3k, 3l, 3m and 3n).
The carbonylative reductive coupling yield was only 33% for a
thioether-containing substrate (3o), and some non-carbonylative
C-C reductive coupling products were also formed (Figure S9, SI).
The coordination of S to the Ni catalyst might be responsible for
significant byproduct formation. Chloro and bromo groups were
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significant amount of symmetric dialkyl ketone byproducts were
also formed (Figure S10, SI). When an aryl iodide or bromide was
used as substrate, the desired asymmetric ketone was obtained
in a low yield while many side products originated from C-C cross-
coupling and homo-coupling were also formed (Figure S11, SI).
By using only one alkyl halide as coupling partner, the above
method can be adapted for the synthesize of symmetric di-alkyl
ketones (Table 3), which is less accessible using previous
reported Ni-catalyzed reductive coupling of alkyl halides with
carboxylic acid derivatives.[6a-f] Both primary and secondary alkyl
halides could be used (4a-4d). Various functional groups such as
chloro (4e), ether (4f), thioether (4g), amide (4h) and cyano (4i)
were well tolerated. Heterocyclic functional groups such as pyrole
(4j) and indole (4k) were also tolerated. Aryl-Cl and aryl-Br groups
survived the reaction (4l and 4m), which opened a possibility for
subsequent coupling. 1, 5-bis(3-methoxyphenyl)pentan-3-one
(4n), an important intermediate for the synthesis of chiral spiro-
To illustrate its utility, the present carbonylation method was
applied for the synthesis of Nabumetone, a non-steroidal anti-
inflammatory drug.[9] The corresponding alkyl iodide reaction
partner, 2-(2-iodoethyl)-6-methoxynaphthalene, was prepared
from 2-bromo-6-methoxynaphthalene in one-pot and 89% yield.
Carbonylation following the protocol in Table 2 gave Nabumetone
in 54% yield (Scheme 1). Moreover, the same protocol furnished
two other alkyl derivatives in high yields (Scheme 1)
Scheme 1. Application of the carbonylation method in the synthesis of
Nabumtone and its analogues
scaffolds,[8]
was
produced
from
1-(2-iodoethyl)-3-
The mechanism of this coupling is subject to a dedicated
future study. Consistent with carbonylative coupling, a Ni carbonyl
species should be a key intermediate. This intermediate is likely
generated by first oxidative addition of ClCOOEt to a low-valent
Ni center followed by decarbonylation, as proposed in an earlier
report.[7] When hexadecyl chloroformate was used as a CO
source, the carbonylative coupling also worked, and dihexadecyl
carbonate was obtained as a byproduct (eq. 1, Figure 2). This
result was consistent with Ni-mediated decarbonylation from
hexadecyl chloroformate, which generated an alkyl alkoxide that
was trapped by hexadecyl chloroformate. When the reaction was
conducted using CO instead of ClCOOEt, the yield of 3a was only
17% (Figure S12, SI). When of Ni(bipy)(CO)2 (bipy = bipyridine)
was used as the catalyst, the yield of 3a was only 34% under
standard conditions (Figure S13, SI). These results indicate that
in-situ release of CO from ClCOOEt is advantageous probably by
avoiding the formation of less active Ni-CO species. The
activation of alkyl halide typically leads to radical intermediates.
To confirm this, we conducted coupling reactions using radical-
clock substrates (Figure 2). The coupling of 6-iodohex-1-ene led
methoxybenzene in 76% yield. Various benzyl chlorides, with
either electron-withdrawing or electron-donating substituents,
were also suitable substrates (4o to 4w). Again benzyl chlorides
with aryl-Cl and aryl-Br groups were selectively coupled (4r and
4s).
Table 3. Nickel-catalyzed reductive carbonylative homo-coupling
to
both
1-cyclopentylhex-5-en-2-one
and
1,
3-
dicyclopentylpropan-2-one, with a ratio of 1:2 (eq. 2). The
coupling of 6-iodohex-1-ene and (3-iodopropoxy)benzene gave a
product that contains a cyclopentyl ring in 36% yield (eq. 3). The
coupling
of
(iodomethyl)cyclopropane
and
(3-
iodopropoxy)benzene gave 40% of 1-phenoxyoct-7-en-4-one in
which the cyclopropyl ring was opened (eq. 4). These results
confirmed the involvement of alkyl radicals in the coupling
reactions.
[a] The reaction was carried out with alkyl iodides or benzyl chlorides (0.4
mmol), NiBr2·diglyme (5 mol%), Bipy (7.5 mol%), ClCOOEt (1 eq.), TMSCl (25
mol%), Zn (2 eq.), THF (1.5 mL) and DMA (0.5 mL), 2 hours at 40 oC. Yield is
that of the isolated product.
Figure 2. Mechanistic probes.
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The three-component coupling is selective for carbonylative
cross-coupling of two different alkyl halides over carbonylative
homo-coupling of the same alkyl halides (entries 1-3, Table 1).
This selectivity is surprising because selective reductive cross-
coupling was typically achieved using two different types of
electrophiles, e.g., one alkyl halide and one aryl halide.[6d-f] Gong
and co-workers reported examples of selective reductive cross-
coupling of two alkyl halides, where the selectivity was partially
achieved by using 3 equiv. of one alkyl halide.[10] In the present
case, selectivity towards asymmetric dialkyl ketone was observed
even when the two alkyl halides were in equal amount (entry 2,
Table 1). To compare the reactivity of different alkyl halides, the
reaction profiles of three reactions were monitored: the
carbonylative cross-coupling reaction of 1a and 2a as in entry 2,
Table 1 and the carbonylative homo-coupling reactions of 1a or
2a alone (Figure S14-16, SI). Under identical conditions, the
primary alkyl iodide 1a reacted slightly faster than the secondary
alkyl iodide 2a. The rate of formation followed the following order:
3a > 4a > 4c. These observations might be explained by two
different activation processes of alkyl halides, one favoring
primary alkyl halide and one favoring secondary alkyl halides.
activation of an alkyl halide by the Ni0 CO species (IV) and the
subsequent CO insertion to give XII should be faster than the
activation of the second alkyl halide by an NiI species (e.g., IX). In
the former process, a primary alkyl halide might be more active
than a secondary alkyl halide due to sterics. In the later process,
a secondary alkyl halide might be more active than a primary alkyl
halide due to thermodynamics. The net result is the selectivity
towards an asymmetric dialkyl ketone product. Alternatively, the
insertion of CO into a secondary alkyl group is faster than the
analogous insertion into a primary alkyl group. The resulting acyl
species (VII) reacts faster with a primary alkyl radical than with a
secondary alkyl radical, which leads to the selectivity towards an
asymmetric dialkyl ketone product.
In conclusion, we have developed a nickel-catalyzed
reductive carbonylation method to synthesize a wide range of
both symmetric and asymmetric dialkyl ketones from readily
available alkyl halides and a safe CO source, ethyl chloroformate.
These carbonylation reactions occur under mild reaction
conditions and have broad scope and high functional group
tolerance. The method provides a valuable complement to
existing approaches in the synthesis of ketones, which are
ubiquitous synthetic intermediates and bio-active compounds.
Acknowledgements
This work is supported by the Swiss National Science Foundation.
Keywords: ketone synthesis • reductive coupling • nickel
catalysis • carbonylation •alkyl halides
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[3]
Figure 3. Proposed mechanism.
According to the above results and considerations, we
propose a tentative mechanism (Figure 3). The Ni catalyst
precursor is reduced to NiI and Nio species by Zn. Oxidative
addition of ClCOOEt to Ni0 affords a NiII species II, which
undergoes decarbonylation to give a NiII carbonyl species III.
Reduction of III by Zn gives a Ni0 carbonyl species IV. Activation
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radical, which can be trapped by VII to give a NiIII alkyl acyl
species VIII. Reductive elimination from the latter furnishes the
ketone product and regenerates a NiI species IX. Because we
observe little if any non-carbonylative alkyl-alkyl coupling, the
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Renyi Shi, Xile Hu*
Nickel-catalyzed three-component
coupling of alkyl halides and ethyl
chloroformate can be used to prepare
a wide range of unsymmetrical and
symmetrical dialkyl ketones under
mild conditions
Page No. – Page No.
From Alkyl Halides to Ketones: Nickel-
Catalyzed Reductive Carbonylation
Utilizing Ethyl Chloroformate a as
Carbonyl Source
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