Continuous-flow synthesis of monoarylated acetaldehydes using aryldiazonium salts

Article abstract of DOI:10.1021/ja305660a

Anilines and ethyl vinyl ether can be used as precursors for a process that is the synthetic equivalent of the α-arylation of acetaldehyde enolate. The reaction manifests a high level of functional group compatibility, allowing the ready preparation of a number of synthetically valuable compounds.

Full text of DOI:10.1021/ja305660a

Communication
pubs.acs.org/JACS
Continuous-Flow Synthesis of Monoarylated Acetaldehydes Using
Aryldiazonium Salts
Natalia Chernyak and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S
* Supporting Information
hydrolysis sequence (eq 2). The relatively high reaction rates of
ABSTRACT: Anilines and ethyl vinyl ether can be used
as precursors for a process that is the synthetic equivalent
of the α-arylation of acetaldehyde enolate. The reaction
manifests a high level of functional group compatibility,
allowing the ready preparation of a number of synthetically
valuable compounds.
addition of aryl radicals to unsaturated bonds allow these
reactions to proceed rapidly and with high functional group
compatibility under nonbasic reaction conditions at low
temperatures. In addition, a wide range of commercially
available anilines, along with several methods reported for
their diazotization, render these compounds particularly
attractive alternatives to aryl halides as the aryl group donor
sources. However, despite these perceived advantages, the
application of the Meerwein arylation reaction to the synthesis
ransition-metal-catalyzed α-arylation of carbonyl com-
Tpounds and their equivalents has seen increased use over
the past 15 years.1,2 Extensive research in this field has resulted
in the development of a variety of direct metal-catalyzed
enolate arylation methods for aldehydes,2a−d ketones,2l,i,j
acetate esters,2e,g,h and amides.2l In addition, efficient
enantioselective arylation reactions of carbonyl compounds
have been demonstrated.3 Yet, despite the significant progress
in this field, the selective arylation of simple acetaldehyde still
remains a challenge. This problem arises from the intrinsic
sensitivity of acetaldehyde and its arylation products toward the
typically basic reaction conditions as well as the tendency of the
initially formed products to undergo further arylation (eq
1).2a−d
of arylacetaldehydes remains largely underdeveloped.5
A
significant drawback of this arylation methodology is the
generation of highly reactive, thermo- and shock-sensitive
aryldiazonium salts. These issues raise significant safety
concerns and impose very stringent procedures and regulations
on the use of these materials in large-scale reactions.6 It has
previously been demonstrated that continuous-flow manufac-
turing can provide a solution for the efficient and safe handling
of highly reactive intermediates on a variable scale.7 In this
communication, we report a method for the synthesis of
monoarylacetaldehydes 3 via a ferrocene-catalyzed Meerwein
arylation reaction of ethyl vinyl ether with aryldiazonium
chlorides 2 generated in situ from anilines 1 using a continuous
flow technique (Scheme 1).
Scheme 1. Meerwein Arylation Reaction Approach toward
Monoarylacetaldehydes
One of the major prerequisites for an efficient flow process is
the homogeneity of the reaction conditions. Thus, small-scale
batch optimizations were initially performed to establish
suitably homogeneous Meerwein arylation conditions.8 Accord-
ingly, p-chlorophenyl diazonium salt intermediates 2a were
generated in situ with acid and sodium nitrite and subsequently
allowed to react with a 10-fold excess of ethyl vinyl ether in the
presence of either copper or iron salts (Table 1). The use of p-
chlorophenyl diazonium chloride in the presence of CuCl as
either a catalyst (entry 1) or a promoter (entry 2) resulted in
rapid decomposition of the aryldiazonium salt, furnishing
Radical processes often can provide a feasible alternative to
metal-catalyzed anionic reactions. Among these, the Meerwein
arylation represents an attractive, synthetically equivalent
method to access α-arylated carbonyl compounds (eq 2).4
This process employs aryldiazonium salts as effective sources of
reactive aryl radicals. One of the versions of this reaction
proceeds via the addition of an aryl radical across the double
bond of an enol derivative to produce an alkyl radical
intermediate. The latter is converted into the corresponding
arylated carbonyl compound upon a single-electron oxidation/
Received: June 18, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja305660a | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Continuous-Flow Setup for the Diazotization/
Arylation Sequence12
b
c
entry
catalyst [mol %]
HX
solvent/H2O
yield (%)
1
2
CuCl [5]
HCl
MeCN/H2O
MeCN/H2O
MeCN/H2O
DMSO/H2O
DMSO/H2O
acetone/H2O
acetone/H2O
DMSO/H2O
acetone/H2O
MeCN/H2O
32
52
60
71
43
32
65
63
80
79
CuCl [100]
HCl
3
CuCl [100]
H2SO4
H2SO4
HCl
4
FeSO4·7H2O [10]
FeSO4·7H2O [10]
FeSO4·7H2O [10]
Cp2Fe [10]
5
6
HCl
7
H2SO4
H2SO4
HCl
8
Cp2Fe [10]
9
Cp2Fe [10]
10
Cp2Fe [10]
HCl
a
Optimization of the reaction conditions was conducted on a 60 μmol
b
scale. See the Supporting Information for details. 3:1 solvent/water
mixture. Determined by GC analysis versus a calibrated internal
c
With the optimized conditions in hand, the scope of this
transformation with various anilines was investigated using the
continuous-flow setup outlined in Scheme 2 (Table 2). Most of
the anilines examined underwent efficient diazotization in 0.6−
3 min in the first reactor followed by a facile Meerwein
arylation reaction in 8.5 min in the second reactor. We found
that a wide range of anilines possessing both strongly electron-
withdrawing substituents and mildly electron-donating groups
underwent the Meerwein arylation quite efficiently (entries
3a−x). Notably, with this method, a number of monoaryl-
acetaldehydes possessing a variety of functional groups (F, Cl,
Br, I, CN, NO2, CF3, OCF3, and CO2t-Bu) were obtained in
good to high yields. In addition, we found that polyhalogenated
anilines could efficiently serve as aryl group donors, furnishing
the corresponding aldehydes as useful building blocks
possessing multiple sites for further modular functionalizations
of the benzene ring (entries 3d−g, 3o, and 3s−u). These
polyhalogenated derivatives would be challenging to access via
the existing transition-metal-catalyzed methodologies. Further-
more, o-nitroaniline derivatives also reacted readily to provide
o-nitro-substituted arylacetaldehydes 3p−r, which are impor-
tant precursors for the synthesis of indole derivatives. Finally,
heterocyclic amines, such as 3-aminopyridines, could success-
fully be employed in this reaction to access the corresponding
heteroarylated acetaldehydes 3v−x in good yields (Table 2).
A plausible mechanism for this process is depicted in Scheme
3.13 A single-electron reduction of the aryldiazonium salt
intermediate with the ferrocene catalyst produces the
corresponding aryl radical 4 and ferrocenium cation. Next,
radical arylation of ethyl vinyl ether leads to alkyl radical
intermediate 5. A single-electron oxidation of the latter with
ferrocenium ion affords acylium cation intermediate 6 and
regenerates the ferrocene catalyst. Finally, hydrolysis of 6
provides arylacetaldehyde product 3 (Scheme 3).
standard.
moderate yields of the aldehyde product 3a. Switching to an
aryldiazonium salt possessing the less nucleophilic hydrosulfate
counterion led only to a moderate improvement in the reaction
yield (entry 3). Interestingly, the use of aryldiazonium
hydrosulfate in the presence of stoichiometric amounts of a
water-soluble FeSO4·7H2O promoter in a mixture of dimethyl
sulfoxide (DMSO) and H2O provided 3a in good yield. The
identity of the diazonium salt counterion was crucial, as
switching to the more reactive diazonium chloride resulted in
decreased product yields (entries 5 and 6).
Encouraged by these results with iron salts, we next chose to
explore the use of ferrocene (Cp2Fe), which is soluble in most
organic solvents, as a catalyst for this transformation.9 We
found that both in situ-generated diazonium chloride and
hydrosulfate salts reacted well in the presence of 10 mol %
ferrocene. When the solvent was changed to an acetone/water
mixture, the desired product 3a was obtained in 80% yield
(Table 1, entry 9). Similar results were achieved by using an
acetonitrile/water mixture as the solvent (entry 10). Notably,
the ferrocene-catalyzed Meerwein arylation reaction occurred
rapidly, with full conversions achieved in 8.5−10 min in all
cases.
Next, we focused on translating these promising batch results
into a continuous-flow process.10 The flow setup for the
diazotization/arylation sequence was assembled as shown in
Scheme 2. Diazotization of aniline 1a was carried out at 0 °C in
the first reactor (R1 in Scheme 2) for 2.5 min by mixing an
acidic solution of 1a (syringe 1) with a stream of sodium nitrite
solution (syringe 2). The resultant solution of aryldiazonium
chloride 2a (Scheme 2) was then mixed with a stream of a
solution of ethyl vinyl ether (10 equiv) in acetone from syringe
3. Finally, a solution of ferrocene from syringe 4 was introduced
into the system, and the reaction mixture was then allowed to
flow through the second reactor (R2 in Scheme 2) at 0 °C, after
which it was collected in a precooled (0 °C) flask under an
inert atmosphere. Following aqueous workup and purification,
the corresponding arylacetaldehyde product 3a was obtained in
71% isolated yield.11
Considering the high synthetic value of arylacetaldehydes, we
decided to demonstrate the utility of the crude monoarylacet-
aldehyde products obtained using our continuous-flow method
by using them to synthesize several important molecules
(Scheme 4). β-Phenethylamines represent an important class of
compounds possessing a wide range of pharmaceutically
important properties. Accordingly, reductive amination of
crude 3 with p-anisidine in the presence of NaBH(OAc)3
B
dx.doi.org/10.1021/ja305660a | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 2. Continuous-Flow Synthesis of
Monoarylacetaldehydes
Scheme 3. Plausible Catalytic Cycle for Meerwein Arylation
Reaction
a
Scheme 4. Further Transformations of Arylacetaldehydes 3
Obtained via the Continuous-Flow Method15
building blocks for organic synthesis and medicinal chemistry.
We envisioned that polyhalogenated aldehydes 3f, 3g, 3s, and
3u (Table 2) could serve as suitable precursors for their
synthesis. Thus, a Cu2O-catalyzed amination/condensation of
these crude polyhalogenated aldehydes furnished the corre-
sponding indole derivatives 5f, 5g, 5s, and 5u in good overall
yields. Finally, a Cu(I)-catalyzed cyclization of o-bromoaryl-
acetaldehydes 3f, 3g, and 3u under basic reaction conditions
afforded the corresponding 4,6-dichloro- (6f), 4-chloro-6-
fluoro- (6g), and 4-bromo-6-methyl-substituted (6u) benzofur-
ans in good yields via a three-step sequence starting from the
corresponding anilines 1 (Scheme 4).14
a
Isolated yields (averages of two runs) are shown. See the Supporting
b
Information for details. Isolated as the corresponding alcohol after
In summary, we have demonstrated an efficient continuous-
flow process for the synthesis of monoarylated acetaldehydes
featuring the Meerwein arylation reaction as a synthetic
equivalent of the direct α-arylation of acetaldehyde enolate.
Notably, the mild reaction conditions of this process,
particularly the absence of base, allow for high functional
group tolerance and enable the ready preparation of an array of
reduction of the crude reaction mixture with NaBH4.
provided easy access to N-PMP-protected β-phenethylamine
derivatives 4k and 4s in good yields (Scheme 4; PMP = p-
methoxyphenyl). Next, we explored the possibility of synthesiz-
ing polyhalogenated heterocycles, which could be valuable
C
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Journal of the American Chemical Society
Communication
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
sbuchwal@mit.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge Novartis International AG for funding. The
Varian 300 MHz and Bruker 400 MHz NMR spectrometers
used in this work were supported by grants from the National
Science Foundation (CHE-9808061 and DBI-9729592) and
the National Institutes of Health (1S10RR13886-01), respec-
tively. We thank Dr. Meredeth A. McGowan for help with the
preparation of this manuscript.
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