N-Heterocyclic Carbene Catalyzed Deuteration of Aldehydes in D 2 O

Article abstract of DOI:10.1055/s-0040-1707993

An N-heterocyclic carbene (NHC)-catalyzed direct deuteration of aldehydes in a mixed solvent of deuterium oxide (D ₂ O) and cyclopentyl methyl ether was established. The present deuteration is possibly initiated by the formation of a Breslow intermediate from the aldehyde and the NHC, with subsequent trapping by D ₂ O providing the monodeuterated aldehyde.

Full text of DOI:10.1055/s-0040-1707993

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–D
letter
A
en
Y. Sawama et al.
Letter
Synlett
N-Heterocyclic Carbene Catalyzed Deuteration of Aldehydes in
D2O
Yoshinari Sawama*
Yuya Miki
0
0
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0-0
0
0
2-
9
9
2
3-2
4
1
2
–
Cl
N
N
Hironao Sajiki*
(IMes·HCl)
Na2CO3
CHO
CDO
Ar
Ar
Laboratory of Organic Chemistry, Gifu Pharmaceutical
University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
sawama@gifu-pu.ac.jp
D2O, CPME
argon, 120 °C
sajiki@gifu-pu.ac.jp
IMes
H
O
OH
R
N
R
N
Ar
D
OD
Ar
D
N
N
R
R
Breslow intermediate
• Organocatalytic one-pot deuteration of aldehydes
• Ar groups include naphthyl, pyrrolyl, indolyl, etc.
• 14 examples, up to 99% yield (>99% D)
Received: 02.12.2019
Accepted after revision: 08.01.2020
Published online: 03.03.2020
the aldehydes-d1. There have been recent reports of plati-
num-group-metal-catalyzed syntheses of derivatives of al-
dehydes-d1 from aryl halides5 or benzoic acids6 by using
D2O as the least expensive source of deuterium among the
various labeling agents that are available. Although the di-
rect deuteration of aromatic aldehyde can be accomplished
by using a homogeneous Ir catalyst under atmospheric D2
gas7 or a Ru catalyst in D2O,8 the deuteration efficiencies are
low to moderate and concomitant deuteration of the aro-
matic moiety cannot be suppressed. We have investigated
platinum-group-metal-catalyzed polydeuterations of vari-
ous compounds,2b,c,9 as well as organocatalyzed deuterium
labeling of alkynes10a,b or nitromethane.10c Furthermore, an
N-heterocyclic carbene (NHC)-catalyzed direct deuteration
of aromatic aldehydes to aldehydes-d1 has recently been
studied in our laboratory (Scheme 1). NHC is known to re-
act with aldehydes 1 to give the corresponding Breslow in-
termediates A, which couple with another molecule of alde-
hyde 1 to give a benzoin product.11 If the Breslow interme-
diate A could be trapped by D2O, the corresponding
monodeuterated aldehyde 1-d1 would be reliably obtained
without deuteration of the aromatic ring of 1. Unfortunate-
ly, an NHC-catalyzed deuteration of aldehydes by D2O in-
volving a similar concept to our present results was pub-
lished in October 2019.12
DOI: 10.1055/s-0040-1707993; Art ID: st-2010-u0643-l
Abstract An N-heterocyclic carbene (NHC)-catalyzed direct deutera-
tion of aldehydes in a mixed solvent of deuterium oxide (D2O) and cy-
clopentyl methyl ether was established. The present deuteration is pos-
sibly initiated by the formation of a Breslow intermediate from the
aldehyde and the NHC, with subsequent trapping by D2O providing the
monodeuterated aldehyde.
Key words deuteration, aldehydes, N-heterocyclic carbenes, organo-
catalysis
Deuterium (2H, D) is a stable isotope of hydrogen (1H),
and deuterium-labeled compounds are widely used in vari-
ous scientific fields related to microanalysis, elucidation of
organic reaction mechanisms, heavy drugs, and isotopic
contrast, among others.1 Consequently, many direct ap-
proaches have been developed for the synthesis of deuteri-
um-labeled materials from mother substrates.2 Because al-
dehydes are useful precursors as electrophiles that can be
transformed into various functional groups, deuterium-
labeled aldehydes (aldehydes-d1) can serve as valuable syn-
thons for syntheses of deuterium-labeled target molecules.
In conventional methods, aldehydes-d1 are constructed by a
stepwise process, such as the reduction of esters to deuteri-
um-labeled alcohols by using an expensive deuteride
source such as LiAlD4, and subsequent oxidation to give the
aldehyde-d1.3 Alternatively, an umpolung reaction via cy-
anohydrin intermediates derived from aldehydes can also
be used to prepare aldehydes-d1.4 Treatment of the cyano-
hydrin intermediates with a strong base such as BuLi and
subsequent quenching by with D2O gives a monodeuterated
cyanohydrin intermediates that can be hydrolyzed to form
4-Methoxybenzaldehyde (1a: 0.2 mmol) was treated
with D2O (1 mL) in the presence of 1,3-dimesitylimidazoli-
um chloride (IMes·HCl; 3, 20 mol%) and Na2CO3 at 120 °C for
six hours to give the desired monodeuterated aldehyde 1a-
d1 in 74% yield with 84% D content; this was accompanied
by the formation of 15% of the benzoin derivative 2a-d1 (Ta-
ble 1, entry 1). Whereas the use N,N-dimethylacetamide
(DMA), N,N-dimethylformamide (DMF), or 1,4-dioxane as a
cosolvent suppressed both the desired deuteration and the
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B
Y. Sawama et al.
Letter
Synlett
Table 1 Effects of the Cosolvent, Temperature, and Catalyst Loading
R
R
N
N
O
O
, base
IMes·HCl (20 mol%)
Ar
D
Ar
H
D2O
CHO
Na2CO3 (20 mol%)
CDO
R
R
1
1-d1
N
N
R
R
D2O (1 mL), cosolvent (0.2 mL)
120 °C, time (h)
N
N
MeO
MeO
+
1a
(0.2 mmol)
1a-d1
base
H
OMe
+
O
OH
HO
D
R
N
R
N
N
N
Ar
D
OD
–
Ar
Cl
IMes·HCl (3)
D
N
O
N
MeO
R
R
2a-d1
A
Scheme 1 The concept of direct deuteration of aldehydes by using an
N-heterocyclic carbene
Entry
Cosolvent
Time (h) Yield (%)
D content
of 1a-d1 (%)
a
1a-d1
2a-d1
1
2
̶
6
6
6
6
6
6
6
2
2
2
3
74
100
95
15
84
7
benzoin condensation (entries 2–4), tetrahydrofuran (THF),
toluene, and cyclopentyl methyl ether (CPME) were effi-
cient cosolvents, giving 1a-d1 in moderate yields with
quantitative D content (entries 5–7). CPME was chosen as
the preferred solvent because of its excellent stability
against oxidation (peroxide formation), which makes it
suitable for use in process chemistry.13 The deuteration was
completed within two hours when CPME was used as the
cosolvent (entry 8). Deuterations at lower temperatures
(80 °C or 25 °C) hardly proceeded (entries 9 and 10). When
the catalyst loading was reduced from 20 mol% to 10 mol%,
1a-d1 was obtained in moderate yield with quantitative D
content (entry 11).
DMA
trace
trace
trace
49
3
DMF
10
4
1,4-dioxane
THF
91
47
5
45
>99
>99
>99
>99
14
6
toluene
CPME
CPME
CPME
CPME
CPME
50
50
7
50
50
8
60
40
9b
10c
11d
91
7
100
0
0
59 (58)e 41 (38)e
>99
a A 100% yield of the benzoin product 2a-d1 means that 0.1 mmol of 2a-d1
was obtained. Therefore, a 50% yield indicates the isolation of 0.05 mmol of
During the deuteration of 1a, the benzoin byproduct 2a-
d1 was also deuterated quantitatively. The unlabeled benzo-
in derivative 2a was also directly deuterated in the presence
of IMes and D2O with generation of the deuterated aldehyde
1a-d1, as shown in Scheme 2 (eq. 1). These results indicated
that the present reaction is an equilibrium that depends on
the substrate (see also Table 3 below). Additionally, the deu-
teration of 2a effectively proceeded in basic D2O to give 2a-
d1 in nearly quantitative yield and D content through a
base-catalyzed keto–enol tautomerism (Scheme 2, eq. 2).
2a-d1.
b At 80 ℃.
c At 25 ℃.
d IMes·HCl (10 mol%) was used.
e Isolated yield.
reactive as NHC precursors (entries 3, 4, and 6–9). As a re-
sult of our screening of various catalysts, IMes was chosen
as the optimal organocatalyst for the direct deuteration of
aldehydes (entry 1).
We then examined the scope of the reaction with re-
spect to the aldehyde (Table 3).14,15 2,4-Dimethoxybenzal-
dehyde (1b), 2,6-dimethoxybenzaldehyde (1c), and 4-me-
thoxy-1-naphthaldehyde (1d) were efficiently deuterated
in excellent yields and with excellent D contents (Table 3,
entries 1–3). The deuteration of unsubstituted 1-naphthal-
dehyde (1e) and 4-(benzyloxy)benzaldehyde (1f) gave
moderate yields of the corresponding quantitatively deuter-
ated aldehydes 1e-d1 and 1f-d1, together with benzoin by-
products (entries 4 and 5). 1-Benzyl-1H-indole-3-carbalde-
hyde (1g) and pyrrole-2-carbaldehyde (1h) were also effi-
ciently deuterated (entries 6 and 7), whereas 1-benzyl-1H-
pyrrole-2-carbaldehyde (1i) gave the deuterated derivative
in moderate yield and D content (entry 8). 4-Bromobenz-
aldehyde (1j), 2-bromobenzaldehyde (1k), 3-methoxybenz-
aldehyde (1l), and 2-methoxybenzaldehyde (1m) gave the
corresponding products with high D contents but in low to
moderate yields (entries 9–12). 4-(Dimethylamino)benz-
aldehyde (1n) was also moderately deuterated (entry 13).
Although deuteration efficiencies and yields were strongly
HO
Ar
H
IMes·HCl (10 mol%)
Na2CO3 (20 mol%)
HO
Ar
D
>99%
O
Ar
Ar
>99%
+
(eq. 1)
D2O (1 mL), CPME (0.2 mL)
120 °C, 3 h
Ar
D
O
O
2a
(0.2 mmol)
2a-d1: 45%
1a-d1: 47%
Ar = 4-MeOC6H4
HO
Ar
H
97%
D
HO
Ar
Ar
Na2CO3 (20 mol%)
Ar
(eq. 2)
D2O (1 mL), CPME (0.2 mL)
120 °C, 3 h
O
2a
O
2a-d1: 100%
(0.2 mmol)
Ar = 4-MeOC6H4
Scheme 2
Next, we examined the effects of various catalysts
(Table 2).1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene
(IPr) and 1,3-bis(diphenylmethyl)imidazol-2-ylidene, de-
rived from catalysts 4 and 7, respectively, were also effec-
tive in providing 1a-d1 in moderate yields and with high D
contents (Table 2, entries 2 and 7), whereas other imidaz-
olium salts 5, 6 and 8 and thiazolium salts 9–11 were less
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

C
Y. Sawama et al.
Letter
Synlett
Table 2 Effects of Various Catalysts
Table 3 Scope of Substrates
catalyst (10 mol%)
IMes·HCl (10 mol%)
CHO
Na2CO3 (20 mol%)
CDO
N
N
Na2CO3 (20 mol%)
CHO
CDO
Cl–
D2O (1 mL), CPME (0.2 mL)
120 °C, 3 h
Ar
Ar
D2O (1 mL), CPME (0.2 mL)
MeO
MeO
MeO
1
1–d1
1a
(0.2 mmol)
1a-d1
HO
120 °C, time
(0.2 mmol)
3; IMes·HCl
OMe
D
Entry
1
Product
Time
Yield (%)
99
D content of
aldehyde (%)
O
2a-d1
OMe
catalyst
CDO
Ar =
2,4,6-Me3C6H2 (3; IMes·HCl)
2,6-(i-Pr)2C6H3 (4; IPr·HCl)
2-HOC6H4 (5)
4-HOC6H4 (6)
N
N
3 h
3 h
90
Ar
Ar
+
MeO
Cl–
1b-d1
OMe
Bn
N+
Me
Ph
Ph
Ph
Ph
N
N
Cl–
N
N
–
+
+
Cl–
CDO
OMe
1c-d1
S
BF4
HO
H2N
2
3
91
98
>99
94
8
9
7
H2N
N
N
N
N
N+
S
Me
Me
N+
Cl–
CDO
O
P
Cl–
O
S
P
O
O
HO
HO
11
OH
OH
3 h
10
MeO
1d-d1
Entry
Catalyst
Yield (%)
D content of 1a-d1 (%)
CDO
1a-d1
2a-d1
4
5
3 h
3 h
68
>99
>99
1
2
3
4
5
6
7
8
9
3
4
59
41
95
99
46
97
87
97
99
41
47
̶
>99
78
0
1e-d1
1f-d1
5
CDO
6
̶
0
51 (60)a
BnO
7
50
̶
>99
0
8
Bn
9
̶
11
2
N
D
10
11
̶
6
24 h
70
91b
CDO
1g-d2
̶
4
H
N
influenced by the electronic and steric properties of the
substrate, detailed tendencies in the direct deuteration re-
main unclear.
CDO
1h-d1
Bn
7
8
3 h
86
79
19
52
>99
65
In conclusion, we have established a method for the di-
rect deuteration of aldehydes by using an NHC catalyst in a
mixed solvent of D2O and CPME. The present method is reli-
able for the monodeuteration of aldehydes. D2O is the least
expensive deuterium source, and CPME is a process-
chemistry-friendly solvent. In comparison with the results
reported in a recent publication,12 the range of substrates
that we examined was somewhat different, and the deuter-
ation of the benzoin byproduct was also accomplished. Our
alternative method is also useful for the construction of
deuterated target materials by using the resulting mono-
deuterated aldehydes.
N
CDO
24 h
1i-d1
CDO
9
5 min
>99
90
Br
1j-d1
Br
CDO
10
5 min
1k-d1
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

D
Y. Sawama et al.
Letter
Synlett
Table 3 (continued)
(5) (a) Ibrahim, M. Y. S.; Denmark, S. E. Angew. Chem. Int. Ed. 2018,
57, 10362. (b) Li, X.; Wu, S.; Chen, S.; Lai, Z.; Luo, H.-B.; Sheng, C.
Org. Lett. 2018, 20, 1712.
(6) Zhang, M.; Yuan, X.-A.; Zhu, C.; Xie, J. Angew. Chem. Int. Ed.
2019, 58, 312.
(7) Kerr, W. J.; Reid, M.; Tuttle, T. Angew. Chem. Int. Ed. 2017, 56,
7808.
(8) Isbrandt, E. S.; Vandavasi, J. K.; Zhang, W.; Jamshidi, M. P.;
Newman, S. G. Synlett 2017, 28, 2851.
(9) (a) Park, K.; Matsuda, T.; Yamada, T.; Monguchi, Y.; Sawama, Y.;
Doi, N.; Sasai, Y.; Kondo, S.; Sawama, Y.; Sajiki, H. Adv. Synth.
Catal. 2018, 360, 2303. (b) Sawama, Y.; Nakano, A.; Matsuda, T.;
Kawajiri, T.; Yamada, T.; Sajiki, H. Org. Process Res. Dev. 2019, 23,
648.
(10) (a) Yabe, Y.; Sawama, Y.; Monguchi, Y.; Sajiki, H. Chem. Eur. J.
2013, 19, 484. (b) Yamada, T.; Park, K.; Monguchi, Y.; Sawama,
Y.; Sajiki, H. RSC Adv. 2015, 5, 92954. (c) Yamada, T.; Kuwata, M.;
Takakura, R.; Monguchi, Y.; Sajiki, H.; Sawama, Y. Adv. Synth.
Catal. 2018, 360, 637.
Entry
Product
Time
3 h
Yield (%)
D content of
aldehyde (%)
MeO
CDO
11
21
55
81
>99
>99
57
1l-d1
OMe
CDO
12
13
3 h
1m-d1
1n-d1
CDO
24 h
Me2N
a Isolated yield.
b There was 37% incorporation of deuterium at the 2-position of 1g.
(11) (a) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719. (b) Menon, R. S.;
Biju, A. T.; Nair, V. Beilstein J. Org. Chem. 2016, 12, 444.
(12) Geng, H.; Chen, X.; Gui, J.; Zhang, Y.; Shen, Z.; Qian, P.; Chen, J.;
Zhang, S.; Wang, W. Nat. Catal. 2019, 2, 1071.
Supporting Information
(13) For the physical and toxicological properties of CPME, see:
(a) Watanabe, K.; Yamagiwa, N.; Torisawa, Y. Org. Process Res.
Dev. 2007, 11, 251. (b) Antonucci, V.; Coleman, J.; Ferry, J. B.;
Johnson, N.; Mathe, M.; Scott, J. P.; Xu, J. Org. Process Res. Dev.
2011, 15, 939. (c) Watanabe, K. Molecules 2013, 18, 3183.
(14) Monodeuterated Aldehydes 1a-d1 to 1n-d1; General Proce-
dure
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707993.
S
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References and Notes
(1) (a) Pirali, T.; Serafini, M.; Cargnin, S.; Genazzani, A. A. J. Med.
Chem. 2019, 62, 5276. (b) Atzrodt, J.; Derdau, V.; Kerr, W. J.;
Reid, M. Angew. Chem. Int. Ed. 2018, 57, 1758. (c) Atzrodt, J.;
Derdau, V.; Fey, T.; Zimmermann, J. Angew. Chem. Int. Ed. 2007,
46, 7744. (d) Herbert, J. M. J. Labelled Compd. Radiopharm. 2010,
53, 658.
(2) (a) Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid, M. Angew. Chem. Int.
Ed. 2018, 57, 3022. (b) Sawama, Y.; Monguchi, Y.; Sajiki, H.
Synlett 2012, 23, 959; and references cited therein. (c) Sawama,
Y.; Park, K.; Yamada, T.; Sajiki, H. Chem. Pharm. Bull. 2018, 66,
21; and references cited therein.
(3) (a) Adcock, H. V.; Chatzopoulou, E.; Davies, P. W. Angew. Chem.
Int. Ed. 2015, 54, 15525. (b) Olsen, E. P. K.; Singh, T.; Harris, P.;
Andersson, P. G.; Madsen, R. J. Am. Chem. Soc. 2015, 137, 834.
(c) Ge, J.-J.; Yao, C.-Z.; Wang, M.-M.; Zheng, H.-X.; Kang, Y.-B.; Li,
Y. Org. Lett. 2016, 18, 228.
(4) (a) Curley, R. W. Jr.; Panigot, M. J.; Hansen, A. P.; Fesik, S. W.
J. Biomol. NMR 1994, 4, 335. (b) Ramalingam, K.; Nanjappan, P.;
Kalvin, D. M.; Woodard, R. W. Tetrahedron 1988, 44, 5597.
An 18 mL test tube was charged with the appropriate aldehyde
(0.2 mmol), IMes·HCl (6.8 mg, 0.02 mmol), Na2CO3 (4.2 mg, 0.04
mmol), CPME (0.2 mL), and D2O (1.0 mL). The tube was then
sealed with a septum and the gas inside the tube was immedi-
ately replaced with Ar. The mixture was then heated at 120 °C
for the appropriate time (Table 3), then extracted with EtOAc.
The organic layers were dried (MgSO4) and concentrated in
vacuo. If necessary, the residue was purified by column chroma-
tography (silica gel).
4-Methoxybenzaldehyde-d1 (1a-d1): Yield: 15.8 mg (58%; 99%
D incorporation). 1H NMR (400 MHz, CDCl3):  = 9.88 (s, 0.01 H),
7.84 (d, J = 8.2 Hz, 2 H), 7.00 (d, J = 8.2 Hz, 2 H), 3.89 (s, 3 H). 2H
NMR (77 MHz, CHCl3):  = 9.91 (br s).
(15) Because of the volatility of the aldehyde products, yields were
determined by 1H NMR with CH2Br2 as an internal standard,
unless otherwise noted.
Thieme. All rights reserved. Synlett 2020, 31, A–D