One-Pot Synthesis of Deuterated Aldehydes from Arylmethyl Halides

Article abstract of DOI:10.1021/acs.orglett.8b00016

A facile, one-pot approach for synthesizing deuterated aldehydes from arylmethyl halides was developed using D₂O as the deuterium source. The efficient process is realized by a sequence of formation, H/D exchange, and oxidation of pyridinium salt intermediates. The mild and air-compatible reaction conditions enable efficient synthesis of diverse deuterated aldehydes with high deuterium incorporation.

Full text of DOI:10.1021/acs.orglett.8b00016

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
One-Pot Synthesis of Deuterated Aldehydes from Arylmethyl Halides
Xiangmin Li,†,§ Shanchao Wu,‡,§ Shuqiang Chen,‡,§ Zengwei Lai,† Hai-Bin Luo,*,†
and Chunquan Sheng*,‡
†School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China
‡School of Pharmacy, Second Military Medical University, Shanghai 200433, China
S
* Supporting Information
ABSTRACT: A facile, one-pot approach for synthesizing
deuterated aldehydes from arylmethyl halides was developed
using D2O as the deuterium source. The efficient process is
realized by a sequence of formation, H/D exchange, and
oxidation of pyridinium salt intermediates. The mild and air-
compatible reaction conditions enable efficient synthesis of
diverse deuterated aldehydes with high deuterium incorporation.
he importance of aldehydes is well demonstrated by their
irreplaceable roles in numerous transformations.1 Deu-
Scheme 1. Conversions of Arylmethyl Halides to Aldehydes
T
terated aldehydes and their derivatives have a variety of
practical applications, such as metabolic pathway probing2 and
reaction mechanism study.3 Although synthesis of aldehydes
has been extensively investigated, efficient synthesis of 1-
deuterioaldehydes is still highly challenging. A number of
efforts have been devoted to expand the approaches of
deuterated aldehydes synthesis.4−11 Traditional access to
deuterioaldehydes mainly includes deuteride reduction of
corresponding ester followed by oxidation,4 Rosenmund
reduction of acid chlorides with D2 gas,5 H/D exchange of
dithiol protected aldehydes,6 reduction of dihydro-1,3-oxa-
zines,7 and hydrolysis of benzal-bispyridinium dibromide.8
However, most of these methods require cumbersome
multistep procedures,6−8 costly deuterated reagents,4 or harsh
conditions.6,7 More recently, new synthetic approaches have
been developed for deuterioaldehydes, such as treatment of
tertiary amides with Cp2ZrDCl,9 decarboxylation of α-
oxocarboxylic acids,10 and ruthenium-, rhodium-, or iridium-
catalyzed H/D exchange.11 Despite these impressive studies,
significant synthetic challenges remain to be tackled. In
particular, high temperature,10,11 limited substrate scope,9 low
reagent availability,9,10 and poor deuterium incorporation11 of
current approaches limited their practical applications. Herein,
a novel one-pot process was designed for convenient and
economical synthesis of deuterated aldehydes from readily
available arylmethyl halides under mild conditions (Scheme 1,
eq 3).
aldehyde was detected, and most substrates converted to 2-
naphthalenemethanol (Scheme S1). Therefore, we envisioned
that the arylmethyl halides should be first stabilized to prevent
the formation of alcohol and accelerate the H/D exchange on
the benzyl position before further oxidation to an aldehyde.
Pyridinium salts formed by condensation of arylmethyl
halides and pyridine can be oxidized to aldehydes by
nitrosobenzene, which is known as Krohnke oxidation (Scheme
̈
1, eqs 2).13 However, this transformation was rarely used due to
the cumbersome multistep operation. With an aim of
developing an efficient method for 1-deuterioaldehyde syn-
thesis, we proposed that pyridinium salts could serve as the
stabilized intermediates of arylmethyl halides (Scheme 2). In
the serach for a feasible synthesis, widely used pyridine was
chosen as the auxiliary reagent and readily available p-
nitrosodimethyl aniline as the oxidant.
Arylmethyl halides are important synthetic intermediates that
are used for various transformations.12 Considering the active
nature and wide availability of arylmethyl halides, we
investigated their potential to be efficiently converted into
deuterated aldehydes. To probe the feasibility, we initiated the
study by the reaction of 2-naphthylmethyl bromide (1a) using
K2CO3 (2 equiv) as a base and D2O as the deuterium source.
DMSO was used as both oxidant and solvent, and the mixture
was heated to 80 °C for 8 h. However, only a trace amount of
To validate the feasibility, we tested the reaction of 2-
naphthylmethyl bromide (1a) in the presence of pyridine (I, 2
equiv), D2O, and K2CO3 (4 equiv) in DMSO (Table 1). The
mixture was stirred at room temperature for 10 h before p-
Received: January 3, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00016
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Scope of the Deuterated Aldehyde Synthesis with
Table 1. Optimization of the Reaction Conditions
Arylmethyl Bromides Standard*
b
c
pyridine
derivative
yield
(%)
deuteration
(%)
entry
solvent, base
1
I
DMSO, K2CO3
MeCN, K2CO3
dioxane, K2CO3
DMF, K2CO3
41
trace
28
65
d
2
I
ND
3
I
12
62
4
I
39
5
I
DMSO, Na2CO3
DMSO, Cs2CO3
DMSO, K3PO4
DMSO, K3PO4
DMSO, K3PO4
DMSO, K3PO4
DMSO, K3PO4
DMSO, K3PO4
DMSO, K3PO4
DMSO, K3PO4
DMSO, K3PO4
41
<10
d
6
I
trace
48
ND
7
I
85
<10
82
8
II
III
IV
V
VI
III
III
III
<10
67
9
10
11
12
22
44
d
trace
trace
72
ND
d
ND
e
13
92
95
98
ef
,
g
14
15
90 (88)
h
g
88
a
Standard reaction conditions: a mixture of 1a (0.5 mmol), pyridine
derivative (1 mmol), solvent (3 mL), D2O (0.5 mL), and base (2
mmol) was stirred at room temperature for 10 h before p-
nitrosodimethyl aniline (1 mmol) was added. The resulting mixture
was stirred for 4 h before being acidified with 3 N HCl (see the SI for
*
Reaction conditions: a mixture of DMSO (3 mL), D2O (1 mL), 1
b
c
details). Yields based on 1H NMR. Deuterium incorporation
(0.5 mmol), 4-picoline (2 mmol), and K3PO4 (2 mmol) was stirred at
room temperature for 10 h before p-nitrosodimethyl aniline (1 mmol)
was added. After being stirred for 4 h, the mixture was acidified with 3
d
e
determined by 1H NMR. Not determined. 1 mL of D2O was
f
g
used. 2 mmol of 4-picoline was used. Yield of the isolated product.
0.25 mmol of 1a was used.
a
b
h
N HCl (see the SI for details). Yields are for the isolated product. D
c
in brackets represents deuteration, as determined by 1H NMR. Step 1
d
was conducted at 50 °C. 0.25 mmol of substrate 1q was used.
donating (II, V) or -withdrawing groups (VI) had negative
effects on the reaction (entries 8, 11−12). When a double
amount of D2O was used, the deuterium incorporation was
improved to 92% (entry 13). A further increase of the amount
of 4-picoline (III) to 4 equiv achieved the optimal result (entry
14). A higher deuterium incorporation (98%) could be
obtained by reducing the amount of 1a to 0.25 mmol (entry
15).
With the optimized reaction conditions in hand (Table 1,
entry 14), we first probed the scope of the one-pot process
using arylmethyl bromides as substrates. The results revealed
that the protocol was suitable for the synthesis of structurally
diverse deuterated aldehydes (Scheme 2). A broad range of
substituted arylmethyl bromides were tested and were
compatible with the process. Electron-deficient substrates
(1a−ah) reacted smoothly to give the corresponding products
(2a−h) in moderate to good yields (56−88%) and excellent
deuterations (94−97%). Bromobenzyls with electron-donating
groups (1j−l) also worked well, although a higher temperature
(50 °C) was required for the formation of pyridinium salts. It
was found that higher temperature promoted the formation of
pyridinium salts and accelerated the H/D exchange process.
Moreover, fluorine-containing and disubstituted bromobenzyls
(1i,l,m) also reacted to obtain the corresponding deuterated
aldehydes (2i,l,m) in moderate yields. Significantly, the 1-
deuterioaldehyde synthesis method could be employed to
nitrosodimethyl aniline (1 mmol) was added. The resulting
mixture was stirred for a further 4 h and then acidified with 3 N
HCl. To our delight, the expected product 2-naphthaldehyde
(2a) was obtained in 41% yield and 65% deuteration (entry 1).
Encouraged by the result, we attempted to optimize the
reaction conditions to improve the yields and deuterium
incorporations. Under the same reaction conditions, solvent
screening indicated that the use of DMSO gave the best results
both in yield and deuterium incorporation (entry 1), and DMF
achieved a similar performance (entry 4), whereas 1,4-dioxane
and CH3CN led to poor results (entries 2 and 3). It was found
that the bases were important for the process (entries 1, 5−7).
K3PO4 with a little higher basicity favors the process (48% yield
and 85% deuteration, entry 7). Na2CO3 offered the same yield
to K2CO3 but much lower deuterium incorporation (entry 5).
Only a trace amount of product was found with Cs2CO3 (entry
6). Consequently, DMSO and K3PO4 were chosen as the best
solvent and base for further investigation of different pyridines
to seek the optimal reaction conditions. Substituents of
pyridines had a great effect on the reaction (entries 7−12).
For instance, 4-picoline (III) gave the best results (67% yield
and 82% deuteration, entry 9), while 2-picoline (IV) offered a
much lower yield and deuterium incorporation, presumably due
to steric reasons. Furthermore, pyridines with strong electron-
B
DOI: 10.1021/acs.orglett.8b00016
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
transform various pharmaceutically relevant heterocyclic
arylmethyl bromides, such as those containing benzothiophene
and pyridine rings, into the corresponding aldehydes 2n−p in
excellent yields (91−95%) and excellent deuterium incorpo-
ration (>93%). Bis(bromomethyl) binaphthalene 1q also
served as an effective substrate in this reaction, affording the
corresponding aldehyde 2q in good yield and excellent
deuteration. However, aliphatic bromide substrates failed to
form the pyridinium salt and the corresponding aldehydes
cannot be obtained.
Scheme 4. Deuterated Cinnamaldehyde Synthesis from
Cinnamyl Halides
cinnamyl halides were used. To the best of our knowledge,
these reactions are the first examples of the formylation of
deuterated cinnamaldehydes without applying deuterium-
containing reductants.14
Finally, to highlight the practical nature of this new synthetic
approach, a large-scale (10 mmol) reactions using pitavastatin
(a cholesterol lowering drug) intermediate 1p was performed
(Scheme 5). We found that the new methodology is compatible
The scope of the transformation with respect to the
arylmethyl chlorides was also explored under the optimized
reaction conditions (Scheme 3). A series of structurally diverse
Scheme 3. Scope of the Deuterated Aldehyde Synthesis with
Arylmethyl Chlorides*
Scheme 5. Gram-Scale Synthesis of Aldehyde-Deuterated
Pitavastatin Intermediate 2p
with gram-scale application. Under the standard conditions,
aldehyde-deuterated pitavastatin intermediate 2p was obtained
in 89% isolated yield and 94% isotope purity (see the SI for
details).
Similar to the Krohnke oxidation (Scheme 1, eqs 2),13
plausible reaction mechanism is proposed for the one-pot
synthesis of deuterated aldehyde from arylmethyl halides
(Scheme 6). Condensation of arylmethyl halide (1, 3) and 4-
a
̈
*
a
Scheme 6. Proposed Mechanism for One-Pot Synthesis of
Deuterated Aldehydes
Reaction conditions: see Scheme 2 and the SI. Yields are for the
b
isolated product. D in brackets represent deuteration, as determined
by H NMR.
1
of arylmethyl chlorides were found to undergo the highly
efficient one-pot process to form the corresponding 1-
deuterioaldehyde products in high yields and excellent
deuterium incorporations. The process tolerated a variety of
functionalities, including naphthyl (product 4a), cyano
(product 4b), halides (products 4c−e) and vinyl (product
4f). Electron-donating groups on benzyl chloride resulted in
slightly decreased yields (product 4g,h). Similarly, the reaction
can be applied to generate deuterated aldehydes from
arylmethyl chlorides containing pharmaceutically relevant
hetereoaromatic moieties, such as thiazole (product 4i),
pyridines (products 4j and 4k), and oxazole (product 4l).
Similar to the aliphatic bromide substrates, the aliphatic
chloride substrates also failed to form the pyridinium salt and
the corresponding aldehydes.
picoline (III) produces pyridinium salt 7. Then the benzyl
hydrogens are exchanged to deuterium in the presence of D2O
and K3PO4 to give deuterated pyridinium salt 8. Oxidation of
intermediate 8 by p-nitrosodimethyl aniline affords 9. Finally,
acidification of 9 gives corresponding deuterated aldehyde. To
support the proposed mechanism, we synthesized and isolated
pyridinium salt 7a (Ar = 2-naphthalene) by mixing 4-picoline
Furthermore, the protocol was used to transform cinnamyl
halides (5a-5b) into deuterated cinnamaldehydes (6a-6b) in
good yields and excellent deuterations (Scheme 4). Notably,
only the trans products 6a and 6b were formed, when trans
C
DOI: 10.1021/acs.orglett.8b00016
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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The process was realized by formation, H/D exchange, and
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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.8b00016.
Experimental details and analytical data PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: shengcq@smmu.edu.cn.
*E-mail: luohb77@mail.sysu.edu.cn.
ORCID
(13) Krohnke, F. Angew. Chem. 1963, 75, 317.
̈
(14) (a) Fujihara, T.; Cong, C.; Iwai, T.; Terao, J.; Tsuji, Y. Synlett
2012, 23, 2389. (b) Shi, Y.; Jung, B.; Torker, S.; Hoveyda, A. H. J. Am.
Chem. Soc. 2015, 137, 8948.
Hai-Bin Luo: 0000-0002-2163-0509
Chunquan Sheng: 0000-0001-9489-804X
Author Contributions
§X.L., S.W., and S.C. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Grant No. 21702238 to X.L. and
81725020 to C.-q.S.) and the Science and Technology
Commission of Shanghai Municipality (Grant No.
17XD1404700 to C.-q.S.).
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D
DOI: 10.1021/acs.orglett.8b00016
Org. Lett. XXXX, XXX, XXX−XXX