Visible-light-mediated deuteration of aldehydes with D2O via polarity-matched reversible hydrogen atom transfer

Article abstract of DOI:10.1016/j.tet.2021.131946

Hydrogen/deuterium exchange at the formyl groups of aldehydes is the most direct way to synthesize deuterated aldehydes, which are of interest for labeling studies and drug discovery. Herein, we report a mild, general protocol for visible-light-mediated m

Full text of DOI:10.1016/j.tet.2021.131946

Tetrahedron 82 (2021) 131946
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Visible-light-mediated deuteration of aldehydes with D2O via
polarity-matched reversible hydrogen atom transfer
Jian-Yang Dong a, Wen-Tao Xu a, Fu-Yang Yue a, Hong-Jian Song a, Yu-Xiu Liu a,
, b, *
Qing-Min Wang a
a State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin,
300071, China
b Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, 300071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Hydrogen/deuterium exchange at the formyl groups of aldehydes is the most direct way to synthesize
deuterated aldehydes, which are of interest for labeling studies and drug discovery. Herein, we report a
mild, general protocol for visible-light-mediated metal-free deuteration of aldehydes in D2O with syn-
ergistic photoredox and thiol catalysis. The protocol is highly efficient, has a broad substrate scope, and
shows excellent functional group tolerance and selectivity, all of which make it suitable for generating
libraries of deuterated compounds. The efficient deuteration was attributed to a photoredox-catalyzed
polarity-matched reversible hydrogen atom transfer reaction between the aldehydes and the thiol.
© 2021 Elsevier Ltd. All rights reserved.
Received 16 December 2020
Received in revised form
8 January 2021
Accepted 11 January 2021
Available online 15 January 2021
Keywords:
Aldehydes
Deuteration
Hydrogen atom transfer
Photoredox catalysis
Synergistic catalysis
Thiol catalysis
1. Introduction
with LiAlD4 and subsequent oxidation [20e22], by reactions of
amides with deuterated Schwartz’s reagent [23], by Pd/Rh-
Deuterium-labeled compounds are of importance for drug dis-
covery [1,2]; investigation of reaction mechanisms [3]; analysis of
drug absorption, distribution, metabolism, and excretion [4e6];
nuclear magnetic resonance spectroscopy [7]; and mass spec-
trometry [8,9]. In addition, there has recently been a surge in ap-
plications for approval of deuterated pharmaceutical agents by the
US Food and Drug Administration. The first deuterated drug, deu-
tetrabenazine (Austedo), was approved by the FDA in 2017 [10], and
many deuterated drug candidates are emerging [1,2]. Therefore,
convenient, selective catalytic methods for generating deuterated
building blocks are urgently needed [11e18].
cocatalyzed reductive carbonylation reactions of aryl halides [24],
and by deoxygenative deuteration of carboxylic acids (Scheme 1A)
[25]. However, the ideal method for preparing deuterated alde-
hydes would be direct hydrogen isotope exchange (HIE), which
would eliminate the need for functional group manipulation. In
fact, the research groups of Tuttle and Newman independently
reported Ir- and Ru-catalyzed HIE reactions of benzaldehydes
(Scheme 1A) [26,27]. However, the chemoselectivity is difficult to
control (deuteration of the aryl rings is observed), and the deute-
rium incorporation is unsatisfactory (14e84%). Recently, the groups
of Wang and Yan developed catalytic HIE processes promoted by N-
heterocyclic carbenes (Scheme 1A) [28,29]. Mechanistically, these
HIE transformations proceed via ionic reaction pathways.
We envisioned that HIE could instead be accomplished by
photoredox catalysis, which has recently emerged as a method for
achieving organic transformations via radical processes [30e32]. In
fact, we recently pioneered a general strategy for deuteration of
aldehydes by D2O with mediation by a synergistic combination of
light-driven, tetra-n-butylammonium decatungstateefacilitated
hydrogen atom transfer (HAT) and thiol catalysis (Scheme 1B)
Deuterated aldehydes are of particular interest because alde-
hydes can serve as building blocks for quick access to a wide array
of biologically important molecules [19]. Traditionally, deuterated
aldehydes are produced by reduction of the corresponding esters
* Corresponding author. State Key Laboratory of Elemento-Organic Chemistry,
Research Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin, 300071, China.
E-mail address: wangqm@nankai.edu.cn (Q.-M. Wang).
https://doi.org/10.1016/j.tet.2021.131946
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

J.-Y. Dong, W.-T. Xu, F.-Y. Yue et al.
Tetrahedron 82 (2021) 131946
Scheme 2. Plausible mechanism.
of 4CzIPN (2) generates excited-state species 3 (E1/2 (*4CzIPN/
4CzIPNꢀ.) ¼ þ1.35 V vs. SCE in MeCN) [39], which is reductively
Scheme 1. Strategies for the synthesis of formyl-deuterated aldehydes.
quenched by triisopropylsilanethiol (5a, Eox ¼ þ0.28 V vs. SCE in
1/2
MeCN) via single electron transfer to give reduced species 4 and
thiyl radical 6a after deprotonation by Na2CO3 [40]. The presence of
a catalytic amount of base presumably facilitates deprotonation to
generate thiyl radical 6a. Radical 6a, which is electrophilic, then
undergoes a polarity-matched HAT reaction involving abstraction
of the formyl hydrogen atom of 2-naphthaldehyde (1a), generating
reactive nucleophilic formyl radical 7a. At the same time, thiol
catalyst 5a undergoes an exchange reaction with the excess D2O to
give deuterated thiol 8a, which serves as the deuterium source.
Radical 7a abstracts a deuterium atom from 8a to generate
deuterated aldehyde 9a and thiyl radical 6a. The similarity of the
BDEs of the C(¼O)H bond of the aldehyde (94 kcal molꢀ1) and the
SeH bond of 5a (88 kcal molꢀ1) make the HAT reaction between the
aldehyde and the thiol reversible (1a to 7a to 9a) [34e36]. More-
over, the strength of the CꢀD bond can be expected to facilitate
CꢀD bond formation. Single electron reduction of thiyl radical 6a
[33]. In these previously reported reactions, the gap between the
bond dissociation energies (BDEs) of the C(¼O)H bonds of the al-
dehydes (94 kcal molꢀ1
)
and the SeH bond of 2,4,6-
triisopropylbenzenethiol (80 kcal molꢀ1) drives HAT from the
thiol catalyst to the nucleophilic acyl radical to form a deuterated
aldehyde irreversibly. However, this strategy is unsuitable for the
preparation of ortho-substituted deuterated aldehydes owing to
the selectivity of the decatungstate for abstraction of sterically
accessible CeH bonds. In addition, the reaction requires high-
energy UVA (390 nm) irradiation, a toxic metal (tungsten), and a
long reaction long time (4 days); and the deuterium incorporation
is mainly 88e95%. Recently, two similar works were reported by
Wang and Wu groups respectively [34,35].
Therefore, we set about developing a protocol for visible-light-
mediated HIE reactions of aldehydes that affords 100% deutera-
tion incorporation and does not require a metal or high-energy UV
light. In addition, we wanted the new HIE protocol to be suitable for
generating ortho-substituted deuterated aldehydes. To accomplish
our aims, we would need to achieve visible-light-mediated
reversible HAT between the aldehyde substrate and the thiol; in
addition, we would have to overcome the challenge posed by the
fact that the control of reversibility enables direct abstraction of the
formyl hydrogen by a thiol radical, which produces an acyl radical
that participates in a HAT reaction with the thiol catalyst [36,37].
We recognized that the choice of a suitable thiol catalyst, that is,
one with a BDE close to that of the C(¼O)H bonds, would be key to
the success of our strategy. Moreover, we expected that the polarity
matching effect and the greater strength of the CꢀD bond relative
to the CeH bond (the BDEs are 341.4 and 338 kJ/mol, respectively)
would facilitate CꢀD bond formation [38]. With these consider-
ations in mind, we have developed a protocol for visible-light-
mediated metal-free HIE reactions of aldehydes with D2O with
synergistic thiol and photoredox catalysis (Scheme 1C).
(Ered
¼ ꢀ0.82 V vs. SCE in MeCN) by reduced species 4 (E1/
1/2
2(4CzIPN/4CzIPNꢀ.) ¼ ꢀ1.21 V vs. SCE in MeCN) regenerates pho-
tocatalyst 2 and deuterated thiol 8a after protonation by D2O [39].
To test this mechanistic hypothesis, we began by exploring
deuteration reactions of 2-naphthaldehyde (1a) under various
conditions (Table 1). First, several thiol catalysts were screened in
the presence of 4CzIPN (5 mol %) as the HAT photocatalyst and
Na2CO3 as the base in 1:1 (v/v) ethyl acetate/D2O under irradiation
with a blue LEDs. To our delight, 2-naphthaldehyde (9a) with 93%
deuterium incorporation was obtained when triisopropylsilane-
thiol (5a, 40 mol %) was used as the thiol catalyst (entry 1). Under
the same conditions, other thiols gave considerably lower deute-
rium incorporation percentages (entries 2e4). This result may have
been due to the fact that the gap between the BDE of the C(¼O)H
bond of the aldehyde (94 kcal molꢀ1) and the BDEs of the SeH
bonds of 5be5d (80e86 kcal molꢀ1) prevented direct abstraction
of the formyl hydrogen by the thiol radical. The use of N-methyl-2-
pyrrolidinone, dichloromethane, or chloroform as the cosolvent
instead of ethyl acetate also resulted in lower deuterium incorpo-
ration (entries 5e7). Reducing the amount of either thiol 5a or
Na2CO3 slightly decreased the deuterium incorporation percentage
(entries 8 and 9). Control experiments showed that the reaction
failed to proceed in the absence of the photocatalyst, light, the thiol
catalyst, or Na2CO3 (entries 10e13).
2. Results and discussion
We hypothesized that visible-light-mediated deuteration of al-
dehydes might proceed via the mechanism shown in Scheme 2 for
2-naphthaldehyde (1a). In this mechanism, initial photoexcitation
2

J.-Y. Dong, W.-T. Xu, F.-Y. Yue et al.
Tetrahedron 82 (2021) 131946
Table 1
were also tolerated under our deuteration conditions; 9r and 9s
were obtained with 99% deuterium incorporation. In addition, the
reaction was amenable to scale up; when it was carried out on a 8-
mmol scale, 9j was isolated in 83% yield with no decrease in
deuterium incorporation.
Optimization of conditions for photoredox catalytic deuteration of aldehydesa.
Aliphatic aldehydes are also of interest because they constitute
an even greater proportion of known eCHO compounds. Gratify-
ingly, aliphatic aldehydes were suitable substrates for our protocol,
affording the deuterated products 9tꢀ9v in 74e85% yields and
99e100% deuterium incorporation. Notably, no products of CO
dissociation were observed, and deuterium was not incorporated at
entry
deviation from standard conditions
Deuteration (%)b
1
2
3
4
5
6
7
8
none
93
45
26
19
8
46
38
70
86
18
7
5b instead of 5a
5c instead of 5a
5d instead of 5a
NMP instead of EA
DCM instead of EA
CHCl3 instead of EA
20 mol % of 5a
20 mol% of Na2CO3
no 4CzIPN
other acidic CeH positions, particularly at enolizable
However, in our previously reported method, deuteration also
takes place at the -positions of formyl [33]. In addition, reaction of
a-positions.
a
adapalene, an antiacne drug, afforded deuterated aldehyde 9w with
high deuterium incorporation. These reactions confirm the poten-
tial utility of our protocol for late-stage modification of pharma-
ceutical intermediates and for generating libraries of deuterated
compounds.
9
10
11
12
13
no light
no 5a
no Na2CO3
13
24
Having explored the substrate scope and utility of the reaction,
we carried out some experiments in support of the proposed
mechanism shown in Scheme 2. When the radical scavenger
TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was present in the
reaction mixture, deuterium incorporation decreased markedly (to
2%), and radical-trapping product 2,2,6,6-tetramethyl-1-(((triiso-
propylsilyl)thio)oxy)piperidine (10) was observed by mass spec-
trometry (Scheme 3A). When 2,6-di-tert-butyl-4-methylphenol
was used as the radical scavenger, 2,6-di-tert-butyl-4-
methylphenyl 2-naphthoate (11) was observed by mass spec-
trometry (Scheme 3B). When 1,1-diphenylethylene was the radical
scavenger, radical-trapping products 1-(naphthalen-2-yl)-3,3-
diphenylprop-2-en-1-one (12) and ((2,2-diphenylvinyl)thio)triiso-
propylsilane (13) were observed by mass spectrometry (Scheme
3C). 1,2-di(naphthalen-2-yl)ethane-1,2-dione (14) was observed
by mass spectrometry after reaction (Scheme 3D). These results
suggest that thiol radical 6a and acyl radical 7a were generated.
Furthermore, light on/off experiments indicated that the reaction
stopped completely in the absence of light but began again when
irradiation was recommenced (Figure S12). This result indicates
that light was essential for the transformation and that any chain-
propagation process was short-lived.
a
Reaction conditions, unless otherwise noted: 2-naphthaldehyde (1a, 0.3 mmol),
photocatalyst 4CzIPN (0.015 mmol), thiol 5a (0.12 mmol), Na2CO3 (0.12 mmol), and
1:1 (v/v) EA/D2O (3.0 mL) under Ar atmosphere.
b
Deuterium incorporation was determined by integration of the residual formyl
proton in the 1H NMR spectrum of the product. EA ¼ ethyl acetate, NMP ¼ N-
methyl-2-pyrrolidinone.
Having optimized the protocol, we explored the substrate scope.
These experiments revealed the protocol to be a mild, general
approach for the synthesis of a wide array of deuterated aldehydes
in good yields (up to 93%) and with uniformly high levels of
deuterium incorporation (90e100%, Table 2). Deuterated 2-
naphthaldehyde 9a was isolated in 88% yield after purification by
column chromatography, indicating that decomposition and side-
product formation were minimal. Benzaldehydes bearing sub-
stituents with various electronic and steric properties afforded
deuterated products 9be9q. We were particularly interested in
halogenated substrates because halogenated molecules account for
approximately 50% of the market-leading drugs, owing to their
lower susceptibility to oxidation by cytochrome P450 [41].
Furthermore, they offer a valuable platform for generating molec-
ular complexity by means of cross-coupling reactions [42,43].
Surprisingly, we found that fluoro-, chloro-, bromo-, and iodo-
substituted benzaldehydes gave the corresponding products
(9be9e) with higher deuterium incorporation (90e96%) than our
previously reported method. Notably, benzaldehydes with elec-
tronically neutral functional groups, such as t-butyl and methyl,
worked well under the optimal conditions, giving moderate to high
yields and up to 99% deuterium incorporation (9fe9i). Moreover,
electron-rich aldehydes were also suitable, giving the desired
products (9je9n) with 98e99% deuterium incorporation. Intrigu-
ingly, relatively sensitive yet versatile functional groups, a boronic
ester (9o) and a OH group (9p) tolerated the deuteration conditions
well. As mentioned above, our previously reported method was
unsuitable for ortho-substituted aldehydes [33]. In contrast, this
new HIE method afforded ortho-substituted deuterated aldehyde
9q with excellent deuterium incorporation. Because hetero-
aromatic moieties are present in the scaffolds of many pharma-
ceutical compounds, we were pleased to find that N-heterocycles
3. Conclusion
In conclusion, we have developed a protocol for visible-light-
mediated HIE reactions that directly convert readily accessible al-
dehydes to their 1-deutero counterparts in D2O with synergistic
visible-light photoredox catalysis and thiol catalysis. Unlike estab-
lished photoredox catalytic HIE reactions, this protocol is suitable
for ortho-substituted aldehydes, and deuterium incorporation is
higher. We anticipate that this protocol will facilitate access to a
wide range of deuterated compounds, which are highly valuable in
the fields of biological, medicinal, and organic chemistry [44].
4. Experimental section
4.1. General experimental information
1H and 13C Nuclear Magnetic Resonance (NMR) spectra were
recorded on Bruker Avance 400 Ultrashield NMR spectrometers.
Chemical shifts (d) were given in parts per million (ppm) and were
measured downfield from internal tetramethylsilane. HRMS were
made by means of ESI/EI-FTMS. The melting points were deter-
mined on an X-4 microscope melting point apparatus and are un-
corrected. Conversion was monitored by thin layer chromatography
3

J.-Y. Dong, W.-T. Xu, F.-Y. Yue et al.
Tetrahedron 82 (2021) 131946
Table 2
Exploration of substrate scopea.
(TLC). Flash column chromatography was performed over silica gel
(100e200 mesh). Blue LED (36 W, lmax ¼ 470 nm) purchased from
JIADENG (LS) was used for blue light irradiation. A fan attached to
the apparatus was used to maintain the reaction temperature at
room temperature, the internal temperature is 30 ꢁC. The photo-
catalyst 4CzIPN was synthesized according to literature report [45].
The spectral data of the photocatalyst is consistent with the liter-
ature data. The other photocatalysts (Eosin Y, Ir[dF(CF3)
ppy]2(dtbbpy)PF6, Ir(dtbbpy)(ppy)2PF6, [Ru(bpy)3]Cl2$6H2O, and
Ru(bpy)3(PF6)2 are commercially available.
4.2. General procedure for the formyl-selective deuteration of
aldehydes
To a 10 mL glass vial was added 4CzIPN (11.8 mg, 0.015 mmol,
5 mol %), aldehyde (0.3 mmol, 1.0 equiv), thiol 5a (22.8 mg,
0.12 mmol, 40 mol %), Na2CO3 (12.7 mg, 0.12 mmol, 40 mol %), and
EA/D2O (1:1, v/v; 3.0 mL). The reaction mixture was degassed by
bubbling with Ar for 15 s with an outlet needle and the vial was
sealed with PTFE cap. The mixture was then stirred rapidly and
Scheme 3. Experiments in support of the proposed mechanism.
4

J.-Y. Dong, W.-T. Xu, F.-Y. Yue et al.
Tetrahedron 82 (2021) 131946
irradiated with a 36 W Blue LED (approximately 2 cm away from
the light source) at room temperature for 36 h. The reaction
mixture was diluted with 10 mL of aqueous 1 M NaHCO3 solution,
and extracted with DCM (3 ꢂ 20 mL). The combined organic ex-
tracts were washed with brine (40 mL), dried over Na2SO4, and
concentrated in vacuo. Purification of the crude product by flash
chromatography on silica gel using the indicated solvent system
afforded the desired product.
99%.
1H NMR (400 MHz, CDCl3)
7.15 (t, J ¼ 8.8 Hz, 1H), 2.35 (d, J ¼ 2.0 Hz, 3H).
d
9.93 (s, 0.01H), 7.80e7.69 (m, 2H),
4.2.9. 3,5-di-tert-butylbenzaldehyde-formyl-d1 (9i)
According to the general procedure. Colorless oil (47.3 mg, 72%).
Rf 0.40 (Petroleum ether/EtOAc, 40/1). D incorporation by 1H
NMR: 99%. 1H NMR (400 MHz, CDCl3)
d
10.01 (s, 0.01H), 7.77e7.69
(m, 2H), 7.26 (s,1H),1.37 (s,18H). 13C NMR (100 MHz, CDCl3)
152.0,
129.1, 124.3, 35.1, 31.5. HRMS (EI-FTMS) m/z: [M]þ. Calcd for
15H21DO 219.1733; Found 219.1726.
d
4.2.1. 2-naphthaldehyde-formyl-d1 (9a)
According to the general procedure. The spectral Data is consis-
tent with the literature data [33]. White solid (41.4 mg, 88%). Mp:
86e87 ꢁC. Rf 0.40 (Petroleum ether/EtOAc, 40/1). D incorporation
C
4.2.10. tert-butyl (3-formylphenyl)carbamate-formyl-d1 (9j)
According to the general procedure. The spectral Data is consis-
tent with the literature data [33]. White solid (60.6 mg, 91%). Mp:
88e89 ꢁC. Rf 0.40 (Petroleum ether/EtOAc,10/1). D incorporation by
by 1H NMR: 93%. 1H NMR (400 MHz, CDCl3)
d 10.16 (s, 0.07H), 8.33
(s,1H), 8.11e7.82 (m, 4H), 7.76e7.46 (m, 2H). HRMS (ESI-FTMS) m/z:
[M þ H]þ Calcd for C11H8DO 158.0711; Found 158.0712.
1H NMR: 99%. 1H NMR (400 MHz, CDCl3)
d 9.98 (s,0.01H), 7.94 (s,
4.2.2. 4-fluorobenzaldehyde-formyl-d1 (9b)
1H), 7.64 (d, J ¼ 7.6 Hz, 1H), 7.56 (d, J ¼ 7.6 Hz, 1H), 7.45 (t, J ¼ 7.6 Hz,
According to the general procedure. The spectral Data is consis-
tent with the literature data [33]. Colorless oil (27.4 mg, 73%). Rf
0.40 (Petroleum ether/EtOAc, 40/1). D incorporation by 1H NMR:
96%.
1H), 6.78 (s, 1H), 1.53 (s, 9H).
4.2.11. 4-(methylthio)benzaldehyde-formyl-d1 (9k)
According to the general procedure. The spectral Data is consis-
tent with the literature data [25]. Colorless oil (34.9 mg, 76%). Rf
0.40 (Petroleum ether/EtOAc, 10/1). D incorporation by 1H NMR:
1H NMR (400 MHz, CDCl3)
d 9.97 (s, 0.04H), 7.99e7.87 (m, 2H),
7.26e7.15 (m, 2H).
99%. 1H NMR (400 MHz, CDCl3)
2H), 7.32 (d, J ¼ 8.0 Hz, 2H), 2.53 (s, 3H).
d
9.92 (s, 0.01H), 7.77 (d, J ¼ 8.0 Hz,
4.2.3. 4-chlorobenzaldehyde-formyl-d1 (9c)
According to the general procedure. The spectral Data is consis-
tent with the literature data [33]. White solid (34.3 mg, 81%). Mp:
44e45 ꢁC. Rf 0.40 (Petroleum ether/EtOAc, 40/1). D incorporation
4.2.12. 4-(dimethylamino)benzaldehyde-formyl-d1 (9l)
According to the general procedure. The spectral Data is consis-
tent with the literature data [25]. White solid (43.5 mg, 93%). Mp:
67e69 ꢁC. Rf 0.40 (Petroleum ether/EtOAc,10/1). D incorporation by
by 1H NMR: 95%. 1H NMR (400 MHz, CDCl3)
d 9.99 (s, 0.05H), 7.84
(d, J ¼ 8.4 Hz, 2H), 7.52 (d, J ¼ 8.4 Hz, 2H).
1H NMR: 98%. 1H NMR (400 MHz, CDCl3)
d 9.73 (s, 0.02H), 7.73 (d,
4.2.4. 4-bromobenzaldehyde-formyl-d1 (9d)
J ¼ 8.8 Hz, 2H), 6.68 (d, J ¼ 8.8 Hz, 2H), 3.09e3.02 (m, 0.18H).
According to the general procedure. The spectral Data is consis-
tent with the literature data [33]. White solid (34.4 mg, 62%). Mp:
76e77 ꢁC. Rf 0.40 (Petroleum ether/EtOAc, 40/1). D incorporation by
4.2.13. benzo[d] [1,3]dioxole-5-carbaldehyde-formyl-d1 (9m)
According to the general procedure. The spectral Data is consis-
tent with the literature data [25]. Colorless oil (33.5 mg, 74%). Rf
0.40 (Petroleum ether/EtOAc, 20/1). D incorporation by 1H NMR:
1H NMR: 95%. 1H NMR (400 MHz, CDCl3)
d 9.98 (s, 0.05H), 7.76 (d,
J ¼ 8.4 Hz, 2H), 7.69 (d, J ¼ 8.4 Hz, 2H).
99%. 1H NMR (400 MHz, CDCl3)
1H), 7.34 (s, 1H), 6.94 (d, J ¼ 8.0 Hz, 1H), 6.13e6.01 (m, 1.66H).
d
9.81 (s, 0.01H), 7.42 (d, J ¼ 8.0 Hz,
4.2.5. 4-iodobenzaldehyde-formyl-d1 (9e)
According to the general procedure. The spectral Data is consis-
tent with the literature data [33]. White solid (58.0 mg, 83%). Mp:
98e99 ꢁC. Rf 0.40 (Petroleum ether/EtOAc, 40/1). D incorporation
4.2.14. 2,3-dihydrobenzo[b] [1,4]dioxine-6-carbaldehyde-formyl-d1
(9n)
by 1H NMR: 90%. 1H NMR (400 MHz, CDCl3)
d
9.98 (s, 0.1H), 7.94 (d,
According to the general procedure. The spectral Data is consis-
tent with the literature data [28]. Yellow solid (45.0 mg, 91%). Mp:
44e45 ꢁC. Rf 0.40 (Petroleum ether/EtOAc, 20/1). D incorporation
J ¼ 8.4 Hz, 2H), 7.62 (d, J ¼ 8.4 Hz, 2H).
4.2.6. 4-(tert-butyl)benzaldehyde-formyl-d1 (9f)
by 1H NMR: 99%. 1H NMR (400 MHz, CDCl3)
d 9.82 (s, 0.01H), 7.40
According to the general procedure. The spectral Data is consis-
tent with the literature data [33]. Colorless oil (43.5 mg, 89%). Rf
0.50 (Petroleum ether/EtOAc, 40/1). D incorporation by 1H NMR:
(dd, J ¼ 4.4, 2.4 Hz, 2H), 6.98 (d, J ¼ 8.8 Hz, 1H), 4.36e4.32 (m, 2H),
4.31e4.27 (m, 2H).
99%. 1H NMR (400 MHz, CDCl3)
d
9.98 (s, 0.01H), 7.82 (d, J ¼ 8.0 Hz,
4.2.15. 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
benzaldehyde-formyl-d1 (9o)
2H), 7.55 (d, J ¼ 8.0 Hz, 2H), 1.36 (s, 9H).
According to the general procedure. The spectral Data is consis-
tent with the literature data [33]. Colorless oil (55.2 mg, 79%). Rf
0.40 (Petroleum ether/EtOAc, 20/1). D incorporation by 1H NMR:
4.2.7. 3,4-dimethylbenzaldehyde-formyl-d1 (9g)
According to the general procedure. The spectral Data is consis-
tent with the literature data [33]. Colorless oil (30.4 mg, 75%). Rf
0.40 (Petroleum ether/EtOAc, 40/1). D incorporation by 1H NMR:
99%.
98%. 1H NMR (400 MHz, CDCl3)
d 10.05 (s, 0.02H), 8.31 (s, 1H), 8.06
(d, J ¼ 7.2 Hz, 1H), 8.03e7.95 (m, 1H), 7.53 (t, J ¼ 7.6 Hz, 1H), 1.37 (s,
12H).
1H NMR (400 MHz, CDCl3)
d 9.93 (s, 0.01H), 7.80e7.52 (m, 2H),
7.28 (d, J ¼ 7.6 Hz, 1H), 2.46e2.19 (m, 6H).
4.2.16. 2,6-di-tert-butyl-4-hydroxybenzaldehyde-formyl-d1 (9p)
According to the general procedure. White solid (62.7 mg, 89%).
Mp: 136e137 ꢁC. Rf 0.40 (Petroleum ether/EtOAc, 20/1). D incor-
4.2.8. 4-fluoro-3-methylbenzaldehyde-formyl-d1 (9h)
According to the general procedure. The spectral Data is consis-
tent with the literature data [33]. Colorless oil (32.9 mg, 79%). Rf
0.40 (Petroleum ether/EtOAc, 40/1). D incorporation by 1H NMR:
poration by 1H NMR: 90%. 1H NMR (400 MHz, CDCl3)
d
9.86 (s,
0.1H), 7.74 (s, 2H), 5.88 (s, 1H), 1.48 (s, 18H). 13C NMR (100 MHz,
CDCl3)
191.8 (t, J ¼ 26.5 Hz), 159.7, 136.6, 128.7 (t, J ¼ 3.5 Hz), 127.7,
d
5

J.-Y. Dong, W.-T. Xu, F.-Y. Yue et al.
Tetrahedron 82 (2021) 131946
34.4, 30.1. HRMS (EI-FTMS) m/z: [M]þ. Calcd for C15H21DO2
235.1683; Found 235.1675.
1H), 7.61 (d, J ¼ 2.4 Hz, 1H), 7.55 (dd, J ¼ 8.4, 2.4 Hz, 1H), 7.00 (d,
J ¼ 8.4 Hz, 1H), 3.90 (s, 3H), 2.18 (s, 6H), 2.11 (s, 3H), 1.80 (s, 6H).
4.2.17. 2,6-dichlorobenzaldehyde-formyl-d1 (9q)
4.3. Gram-scale reaction
According to the general procedure. White solid (25.7 mg,49%).
Mp: 54e55 ꢁC. Rf 0.40 (Petroleum ether/EtOAc, 40/1). D incorpo-
To an oven dried Schlenk tube was added 4CzIPN (316 mg,
0.4 mmol, 5 mol %), tert-butyl (3-formylphenyl)carbamate 1j
(8 mmol, 1.0 equiv), thiol 5a (0.61 g, 3.2 mmol, 40 mol %), Na2CO3
(339 mg, 3.2 mmol, 40 mol %), and EA/D2O (1:1, v/v; 80 mL). The
tube was evacuated and backfilled with Ar (this process was
repeated three times). The mixture was then stirred rapidly and
irradiated with two 36 W blue LEDs (approximately 2 cm away
from the light source) at room temperature for 48 h. The reaction
mixture was diluted with 100 mL of aqueous 1 M NaHCO3 solution,
and extracted with DCM (3 ꢂ 50 mL). The combined organic ex-
tracts were washed with brine (150 mL), dried over Na2SO4, and
concentrated in vacuo. Purification of the crude product by flash
chromatography on silica
ration by 1H NMR: 99%. 1H NMR (400 MHz, CDCl3)
d
10.50 (s,
0.01H), 7.40 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 136.9, 133.6, 129.8.
HRMS (EI-FTMS) m/z: [M ꢀ D]þ. Calcd for C7H3Cl2O 172.9555;
Found 172.9555.
4.2.18. 1-tosyl-1H-indole-5-carbaldehyde-formyl-d1 (9r)
According to the general procedure. The spectral Data is consis-
tent with the literature data [33]. White solid (63.9 mg, 71%). Mp:
120e121 ꢁC. Rf 0.40 (Petroleum ether/EtOAc, 5/1). D incorporation
by 1H NMR: 99%. 1H NMR (400 MHz, CDCl3)
d 10.03 (s, 0.01H), 8.11
(d, J ¼ 8.4 Hz, 1H), 8.07 (s, 1H), 7.86 (dd, J ¼ 8.4, 1.2 Hz, 1H), 7.79 (d,
J ¼ 8.4 Hz, 2H), 7.68 (d, J ¼ 3.6 Hz, 1H), 7.26 (d, J ¼ 8.0 Hz, 2H), 6.78
(d, J ¼ 3.6 Hz, 1H), 2.35 (s, 3H).
gel using the indicated solvent system afforded the desired
product 9j in 83% yield (1.474 g) and 99% D incorporation.
4.2.19. 9-ethyl-9H-carbazole-3-carbaldehyde-formyl-d1 (9s)
According to the general procedure. The spectral Data is consis-
tent with the literature data [28]. White solid (58.5 mg, 87%). Mp:
84e85 ꢁC. Rf 0.40 (Petroleum ether/EtOAc, 5/1). D incorporation by
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
1H NMR: 99%. 1H NMR (400 MHz, CDCl3)
d 10.04 (s, 0.01H), 8.53 (d,
J ¼ 3.6 Hz, 1H), 8.15e8.05 (m, 1H), 8.00e7.91 (m, 1H), 7.50 (t,
J ¼ 7.6 Hz, 1H), 7.39 (dd, J ¼ 9.2, 5.6 Hz, 2H), 7.29 (t, J ¼ 7.6 Hz, 1H),
4.41e4.22 (m, 2H), 1.49e1.35 (m, 3H).
Acknowledgements
4.2.20. 3-(benzo[d] [1,3]dioxol-5-yl)-2-methylpropanal-formyl-d1
(9t)
We are grateful to the National Natural Science Foundation of
China (22077071, 21772102) and the Tianjin Research Innovation
Project for Postgraduate Students (2019YJSB085) for generous
financial support for our programs.
According to the general procedure. The spectral Data is consis-
tent with the literature data [33]. Colorless oil (42.8 mg, 74%). Rf
0.40 (Petroleum ether/EtOAc, 20/1). D incorporation by 1H NMR:
99%. 1H NMR (400 MHz, CDCl3)
d
9.70 (d, J ¼ 1.6 Hz, 0.01H), 6.73 (d,
Appendix A. Supplementary data
J ¼ 8.0 Hz, 1H), 6.66 (d, J ¼ 1.6 Hz, 1H), 6.61 (dd, J ¼ 8.0, 1.6 Hz, 1H),
5.93 (s,1.72H), 3.00 (dd, J ¼ 13.6, 5.6 Hz,1H), 2.67e2.47 (m, 2H),1.08
(d, J ¼ 6.8 Hz, 3H).
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.131946.
4.2.21. 3-(benzo[d] [1,3]dioxol-5-yl)-2,2-dimethylpropanal-formyl-
d1 (9u)
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