Ester Formation via Nickel-Catalyzed Reductive Coupling of Alkyl Halides with Chloroformates

Article abstract of DOI:10.1021/acs.orglett.6b03158

The synthesis of alkyl esters from readily available alkyl halides and chloroformates was achieved for the first time using a mild Ni-catalyzed reductive coupling protocol. Unactivated primary and secondary alkyl iodides as well as glycosyl, benzyl, and aminomethyl halides were successfully employed to yield products in moderate to excellent yields with high functional group tolerance.

Full text of DOI:10.1021/acs.orglett.6b03158

Letter
pubs.acs.org/OrgLett
Ester Formation via Nickel-Catalyzed Reductive Coupling of Alkyl
Halides with Chloroformates
Min Zheng,† Weichao Xue,† Teng Xue,† and Hegui Gong*,†,‡
†Center for Supramolecular Chemistry and Catalysis and Department of Chemistry, Shanghai University, 99 Shang-Da Road,
Shanghai 200444, China
‡Shanghai Key Lab of Chemical Assessment and Sustainability, Tongji University, 1239 Siping Road, Shanghai 200092, China
S
* Supporting Information
ABSTRACT: The synthesis of alkyl esters from readily
available alkyl halides and chloroformates was achieved for
the first time using a mild Ni-catalyzed reductive coupling
protocol. Unactivated primary and secondary alkyl iodides as
well as glycosyl, benzyl, and aminomethyl halides were
successfully employed to yield products in moderate to
excellent yields with high functional group tolerance.
lkyl acid esters are important structural motifs commonly
found in bioactive natural products, pharmaceuticals,
envisioned that direct coupling of alkyl halides with readily
accessible chloroformates would be an efficient strategy to
access the ester functional group. However, toward this end, the
development of analogous conditions for ester synthesis proved
to be more challenging. In fact, the complexities of these
carboacylation transformations has been evidenced by their
mechanistic distinctions. While a radical-chain process is
involved in reductive ketone formation, insertion of CO2 or
isocyanates to an alkyl-NiI species is proposed for the
production of acids and amides.13f,15,16
At the outset of this research, we examined the coupling
between 4-iodo-1-tosylpiperidine (1) (limiting reagent) and
methyl chloroformate. Initial attempts implementing previous
methods used for the acylation of alkyl halides with acid
derivatives provided the ester in only trace amounts.13d−g We
were pleased to find that a combination of Ni(COD)2/3a/Zn
with TBAI as an additive in DMA/THF (7:3 v/v) was optimal.
Under these conditions, the ester product (2a) was obtained in
82% yield (Table 1, entry 1), wherein commercially available
isopropyl chloroformate proved to be a superior coupling
partner (see 2b−d in Figure 2). Upon removal of TBAI, the
yield diminished slightly (entry 2). Hence TBAI may facilitate
removal of the salts on the zinc surface or assist the
homogeneity of the reaction mixture. Without Ni(COD)2, no
product was detected (entry 3). Other solvents and nickel
sources (Table S1)17 as well as ligands (3b−d and 4−8, Figure
1; entries 4−12) and temperatures (entries 13 and 14) failed to
improve the yield. Importantly, no product was observed
without ligand 3a (entry 15), and the use of 1.5 equiv of
chloroformate resulted in 65% yield (entry 16). Finally, no
reactions occurred when alkyl bromides were used, regardless
of whether Kl or NaI was added.
A
materials, and biofuels.1 In addition to the textbook
esterification of acid derivatives with alcohols, their preparation
can be achieved through additions of alkyl-M (M = Mg, Zn, Li,
etc.) to chloroformates or CO gas (M = In, Hg).2−6 These
reactions often require palladium catalysts, although a
stoichiometric amount of CuBr2 can promote the reaction of
alkyl-Mg with chloroformates (Scheme 1).3 Harsh alkyl
Scheme 1. Transition-Metal-Catalyzed Ester Formation via
Carbonylation and Coupling Strategies
nucleophiles appear to be inevitable for most cases. On the
other hand, Pd- and Pt-catalyzed carbonylation of alkyl iodides
under a CO atmosphere (usually high pressure) exemplifies a
different protocol for ester formation that avoids prepreparation
of organometallic reagents.7−9 With the promotion of photo-
irradiation, inexpensive metals (e.g., Cu, Mn, Co) can also
catalyze such a process.10,11 Herein we report the efficient
construction of alkyl acid esters under mild, Ni-catalyzed
reductive coupling conditions from both primary and secondary
alkyl halides. The practicality of this method is manifested in
the synthesis of α-C-glycosyl and amino esters.
In line with the recent progress in Ni-catalyzed reductive
ketone, acid, and amide synthesis via the coupling of alkyl
halides with acid derivatives, CO2, and isocyanates,12−16 we
Received: October 21, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03158
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Table 1. Optimization of the Formation of 2
a
b
entry
variation from the standard conditions
yield (%)
c
1
2
none
82
TBAI (0%)
74
d
3
without Ni(COD)2
3b instead of 3a
3c instead of 3a
3d instead of 3a
4 instead of 3a
5a instead of 3a
5b instead of 3a
6 instead of 3a
7 instead of 3a
8 instead of 3a
40 °C
ND
4
trace
61
5
6
60
7
78
8
70
9
10
d
10
11
12
13
14
15
16
ND
78
63
82
82
0 °C
without 3a
d
ND
1.5 equiv of ClC(O)OiPr
65
a
Reaction conditions: 1 (0.15 mmol), chloroformate (2 equiv), Ni (10
mol %), ligand (10 mol %), TBAI (50 mol %), Zn (3 equiv), DMA/
b
THF (7:3 v/v, 1 mL). NMR yields using 2,5-dimethylfuran as the
c
d
internal reference. Isolated yield. Not detected by 1H NMR analysis.
Figure 2. Scope of alkyl iodides. (a) Reaction conditions: as in Table
1, entry 1. (b) Isolated yields. (c) NMR yield using 2,5-dimethylfuran
as the internal reference. (d) 3 equiv of chloroformate was used. (e) 4
equiv of chloroformate was used. (f) Without TBAI.
Figure 1. Structures of ligands.
Next, we examined the scope of alkyl iodides using the
optimized conditions (Table 1, entry 1). The results are
summarized in Figure 2. Both cyclic and open-chain secondary
alkyl iodides were compatible, furnishing esters 9−22 in good
to excellent yields. The sterically more hindered 6-iodounde-
cane afforded 16 in 70% yield. Primary alkyl iodides were also
suited for this coupling protocol, as manifested in 23−26.
Furthermore, the mild reaction conditions tolerated a wide
range of functional groups, including furyl, thienyl, and
tosylamide.
The practicality of the ester-forming strategy was further
manifested in the synthesis of C1-glycosyl esters (Figure 3).
Moderate α-selectivity was shown for acetyl-protected gluco-
side 27 and galactoside 28. Despite the propensity for benzylic
substrates to undergo homocoupling, the use of activated 1-
chloro-2,3-dihydro-1H-indene derivatives generated esters 29−
31 in good yields. Installation of the ester functional group to
phthamidyl-protected α-chloromethanamine was able to
generate glycine methyl ester 32, albeit in low yield. However,
to the best of our knowledge, this is the first example of the
synthesis of an α-amino acid using the reductive coupling
protocol. Starting from their α-precursors, β-amino esters 33−
37 were readily formed in good to excellent yields, wherein the
iodo substrates were obtained from the ester precursor by
Figure 3. Coupling of activated alkyl halides and synthesis of β-amino
acids. (a) Reaction conditions: as in Table 1, entry 1. (b) Isolated
yields. (c) Glycosyl bromide was used. (d) 5a was used as the ligand.
(e) Benzyl chloride was used.
reduction and iodination. Finally, 38 was achieved as a racemic
mixture in good yield from its racemic iodo precursor.
In accord with previous mechanistic studies, the radical
nature of this method was verified by the synthesis of racemic
ester 38 from its (R)-iodo precursor (87% ee) and by the ring-
opening esterification of (iodomethyl)cyclopropane to yield
isopropylpent-4-enoate in 30% yield.17 Moreover, when N-
hydroxyphthalimide ester 39 was subjected to the optimized
reaction conditions, the transesterification product 40 was
B
DOI: 10.1021/acs.orglett.6b03158
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Letter
obtained in 40% yield, thus signifying the participation of alkyl
radical via a possible NiI-mediated decarboxylative process (eq
1).18,19 Although this result is indirectly related to alkyl iodides,
both cases may accommodate an analogous mechanism.
major product (eq 3). Under the catalytic conditions, the good
coupling yield of 2a (70%; Table 1, entry 8) may arise from
slow formation of complex II-a due to low concentrations of
(5a)Ni0, wherein decomposition of complex II-a may become
less favored. As a result, complex II may have a long enough
lifetime to trap escaped alkyl radical via a radical-chain process
leading to iPrOC(O)−(Ln)NiIII−alkyl (III) (Scheme 2).22 The
radical escape−rebound process is also supported by the
experiments of esterification of 6-iodo-1-hexene under different
Ni loadings.23
The results shown in eq 3 also indicated that oxidative
addition of 2 equiv of chloroformate to Ni0, resulting in
complex II, is much more favored than that of 1 equiv of alkyl
iodide leading to alkyl−(Ln)NiII−I species. However, stepwise
reactions of (5a)Ni(COD) with n-octyl iodide followed by
addition of chloroformate with or without Zn disclosed that the
presence of Zn enabled a low ratio of product 43 to n-octyl
dimerization product 42 (eq 4). Therefore, reduction of the
Additional mechanistic studies excluded the possibility of an
in situ Negishi mechanism. Exposure of alkylzinc reagent 41 to
iPrOC(O)Cl under catalytic Ni conditions (eq 2) resulted in
ester 26 in low yields both with and without Zn.17
We then questioned whether the present ester formation
event complies with a radical-chain mechanism analogous to
the reductive ketone synthesis (Scheme 2). Interestingly, the
Scheme 2. A Proposed Radical-Chain Catalytic Cycle
alkyl-NiII precursor to give an alkyl−(Ln)NiI species that further
reacts with chloroformate to produce the ester, although less
likely, cannot be excluded at this time.24,25
In summary, we have demonstrated that alkyl esters are
readily accessible through reductive cross-electrophile coupling
of alkyl iodides with isopropyl chloroformate under mild Ni-
catalyzed conditions. This method tolerates a broad range of
functional groups and displays an excellent substrate scope with
application in the synthesis of amino esters and C1-glycosyl
esters. The expansion of this method to new substrates and
further mechanistic studies are currently underway.
key intermediate Bipy−Ni(Cl)−C(O)iPr (I) engaged in the
radical-chain process for ketone synthesis was stable in DMF
(Figure 4),13f whereas Bipy−Ni(Cl)−C(O)OiPr (II-a) and its
analogs (II-b and II-c) arising from oxidative addition of
chloroformate to Ni0 decomposes instantly (Figure 4).20,21
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03158.
Detailed experimental procedures and characterization of
new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*hegui_gong@shu.edu.cn
ORCID
Figure 4. Stability of the proposed acyl intermediates in Ni-catalyzed
ketone- and ester-forming methods.
Hegui Gong: 0000-0001-6534-5569
Notes
Treatment of 1 with iPrOC(O)Cl in the presence of 1 equiv
of Ni(COD)2/5a but without Zn did not afford 2a, and 1 was
majorly recovered (eq 3), which may indicate that complex II-a
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the National Natural Science
Foundation of China (21372151 and 21572127), the Shanghai
Municipal Education Commission for the Peak Discipline
Construction (N.13-A302-15-L02), and the Shanghai Science
and Technology Commission (14DZ2261100). We thank Dr.
Hongmei Deng (Shanghai University) for use of the NMR
facility, Mr. James Brewster (UTexas Austin) for proofreading
formed but decomposed fast. With Zn, 2a was obtained in 27%
yield, wherein hydrodeiodination of 1 was observed as the
C
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Wang, J.; Pan, C.-M.; Gianatassio, R.; Schmidt, M. A.; Eastgate, M. D.;
Baran, P. S. J. Am. Chem. Soc. 2016, 138, 2174.
(20) The Bipy−Ni(Cl)−C(O)OEt complex resulting from the
reaction of Bipy−Ni(COD) with ethyl chloroformate was found to
be thermally stable in the solid state. See: Seidel, W.; Raupach, L. Z. Z.
Chem. 1988, 28, 414.
the manuscript, and Mr. Qingchen Zhang (Shanghai
University) for preparation of the substrates.
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