Reductive Deuteration of Nitriles Using D2O as a Deuterium Source

Article abstract of DOI:10.1021/acs.joc.9b02056

The first single electron transfer reductive deuteration of nitriles using D₂O as a deuterium source has been developed for the synthesis of valuable α,α-dideuterio amines. A mild reductant (SmI₂) was employed as the electron donor w

Full text of DOI:10.1021/acs.joc.9b02056

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Article
Reductive Deuteration of Nitriles using D2O as Deuterium Source
Yuxuan Ding, Shihui Luo, Chaoqun Weng, and Jie An
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02056 • Publication Date (Web): 14 Oct 2019
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The Journal of Organic Chemistry
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Yuxuan Ding‡, Shihui Luo‡, Chaoqun Weng and Jie An*
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College of Science, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, China
Supporting Information Placeholder
ABSTRACT: The first single electron transfer reductive deuteration of nitriles using D
for the synthesis of valuable α,α-dideuterio amines. A mild reductant SmI was employed as the electron donor with Et
additive. This reaction is amenable to both aromatic and aliphatic nitriles, and features high deuterium incorporation, excellent re-
gioselectivity and good functional group tolerance. The synthetic utility of this protocol was demonstrated by the synthesis of a
series of important deuterium labelled building blocks for medicinal chemistry and agrochemistry applications.
2
O as deuterium source has been developed
N as the
2
3
general strategies for the synthesis of deuterium labelled com-
pounds. Traditionally, α-deuterio amines are synthesized by
the reductive deuteration reactions mediated by expensive and
pyrophoric metal deuterides, such as LiAlD and NaBD .
4 4
As was exemplified in the Sanofi’s synthesis of AVE5638-d ,
2
this classic method often failed to give satisfactory results.
Therefore, direct hydrogen isotope exchange process has been
extensively investigated in recent years. The most important
advances include an Ir-photoredox-catalyzed α-selective deu-
teration reaction of tertiary amines reported by MacMillan , a
Ru-catalysed α,β-deuteration of tertiary amines developed by
Beller , and another Ru-catalysed stereoretentive α-selective
deuteration of α-chiral primary amines reported by
Szymczak . Nevertheless, unsatisfactory deuterium incorpora-
tion and/or moderate regioselectivity were still regarded as the
inherent limitations associated with most of the current H/D
exchange processes. In addition, the use of toxic and difficult
to remove heavy metal, such as Ir and Ru, might also be a
concern in the context of drug synthesis.
The past decade has witnessed the renaissance of deuterated
3
c,5
1
medicines. Since 2014, more than 7 billion dollars have been
1
a
invested in the acquisitions and licensing deals in this field.
3
c
In 2017, the FDA’s approval of the first deuterated drug, deu-
tetrabenazine, as a new chemical entity represented a mile-
6
2
stone in the development of deuterated medicines. Given the
unique properties of deuterium, precise deuteration of drugs
provides an attractive tool to modify pharmacokinetic proper-
6
c
1
a-1c
ties, reduce toxicity and increase bioactivity.
Rigorous
6d
selection of the deuterium labelled position is crucial for the
development of a successful deuterated drug. One of the most
well-known drug metabolic pathways that can be markedly
effected by deuterium incorporation is the oxidative transfor-
6
e
1
a
mation catalysed by amine oxidases. As the cleavage of the
α-C–H bond is critical in the oxidation process, selective α-
deuteration of the amine moiety in drugs is of high research
3
interest. The recently discovered drug candidates of this type,
3
b
3c
Scheme 2. Strategies for the Synthesis of α,α-Dideuterio
Amines
2
such as SD-1077 (Teva) and AVE5638-d (Sanofi) , clearly
demonstrated superior metabolic stabilities compared with
their parent nondeuterated compounds (Scheme 1).
Scheme 1. Examples of Recent Developed α-Deuterated
Amine-Containing Drugs
Adding to their promising applications in pharmaceutical
industry, α-deuterated amines are also valuable biological
1
b
probes for life science , and important LC-MS standards for
4
food safety-risk analysis. However, the synthesis of α-
deuterated amines is far from straightforward. Reductive deu-
teration and direct hydrogen isotope exchange are two most
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Our previous studies have demonstrated single electron
Page 2 of 8
equiv) at rt, and the resulting mixtures were stirred for 15 min
b
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transfer (SET) reductive deuteration as an attractive emerging
strategy to afford high deuterium incorporations and good
regioselectivities, while avoiding the problems associated with
under an inert atmosphere. Determined by H NMR.
7
metal deuteride reductions. In the SET reductive deuteration
We started our investigation by optimizing the reaction
strategy, the reductant and the deuterium donor are provided
by two different reagents. Therefore, the tedious preparation
of deuterated reductants is not necessary, and cheap reagents,
such as D O or deuterated alcohols, can be used as the deuter-
2
ium sources.
conditions using an aromatic nitrile 1a as the model compound
(
Table 1). In SmI
commonly used as a proton donor and as a ligand to Sm(II).
Therefore, SmI –D O system was first tested in the reductive
2
mediated SET reactions, water has been
2
2
deuteration of 1a (entry 1, Table 1). However, no product was
detected under these conditions and >95% of 1a was recov-
ered. To further increase the reduction potential of the reagent
system, a series of Lewis bases was screened as additives (en-
tries 2-5, Table 1). All of the tested primary, secondary and
tertiary amines were effective in increasing the reactivity of
Based on the SET reductive deuteration strategy, we have
recently developed a practical method for converting nitriles
0
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0
7
a
1
to α,α-dideuterio amines using Na/EtOD-d . In general, this
method afforded high deuterium incorporation and good regi-
oselectivity. However, undesired partial deuterium labeling at
the β-position of amines and moderate deuterium incorpora-
tions were observed (Scheme 2A). Furthermore, in the reduc-
tive deuteration of aromatic nitriles, complex by-products
2
SmI . However, the yield and deuterium incorporation were
dramatically influenced by the nature of the Lewis base. The
highest yield and deuterium incorporation were obtained using
triethylamine (entry 5, Table 1). The reduction of nitriles to
primary amines is a four electron transfer process, while de-
creasing the amount of SmI from 6 to 4 equiv resulted in 48%
2
yield of 2a (entry 6, Table 1). Then, we attempted to further
1
were formed under Na/EtOD-d conditions. These limitations
motivated us to investigate new reagents for the SET reductive
deuteration process of nitriles.
8
Kagan’s reagent (samarium diiodide) has attracted our in-
terest as an alternative electron donor for the reductive deuter-
ation of nitriles because it is milder and more selective com-
improve the deuterium incorporation by changing the amount
of Et
incorporation of 2a was obtained, when 12 equiv of Et
8 equiv of D O were used (entry 10, Table 1). However,
3
N or D
2
O (entries 7-9, Table 1). Improved deuterium
pared with sodium and can well-tolerate D
2
O as the deuterium
3
N and
9
donor. D
2
O is the most ideal deuterium donor for a SET re-
1
2
ductive deuteration process, as it is the source of all the deu-
terated organic compounds. The above features have made
these conditions only afforded a moderate yield of 62% (entry
10, Table). To balance to yield and deuterium incorporation,
SmI
2
a promising reagent for introducing deuterium into med-
mediated reductive
the conditions using 6.0 equiv of SmI
2 2
and 36 equiv of D O
icines and other target molecules. SmI
2
and Et N were used as the optimal conditions in the study. Of
3
deuteration was pioneered by Szostak et al. In 2014, they re-
ported a reductive deuteration of carboxylic acids for the syn-
note, changing the addition order of reagents resulted in lower
yields and deuterium incorporations.
Next, the optimal conditions (entry 5, Table 1) were applied
to the reductive deuteration of different classes of nitriles.
Both aromatic nitriles (Scheme 3A) and aliphatic nitriles
10
thesis of α,α-dideuterio alcohols. However, the vast potential
for SmI
plored. In this study, we aim to develop the first SmI
ed SET reductive deuteration of nitriles using D O as the deu-
terium donor which proceeds via imidoyl radicals (Scheme
B).
2
mediated SET reductive deuterations remains unex-
2
mediat-
2
(Scheme 3B) were converted to corresponding α,α-dideuterio
1
1
amines with excellent deuterium incorporations and high
yields. High deuterium incorporations suggested high aptitude
of the imidoyl radical intermediate to undergo reduction to the
anion. Of note, very few examples of the SET reduction of
aromatic nitriles to amines have been reported previously.
This reaction is amenable to aromatic nitriles with electroni-
cally diverse substituents, which provides a practical method
for the synthesis of α,α-dideuterio benzylamines and signifi-
cantly complements the sodium-mediated reductive deuter-
ation of nitriles. Importantly, primary, secondary and tertiary
aliphatic nitriles were readily reduced (Scheme 3B). Fluoride
(1a, 1h, 1i) did not interfere with the reaction conditions.
Chloride 1j was also tolerated, but <20% of by-product was
formed via the reductive dechlorination. Sensitive functional
groups such as OMe (1l, 1m and 1w), SMe (1k), and acetal
2
Table 1. Optimization Studies in the SmI
ductive Deuterations of Nitriles
2
-Mediated Re-
a
entry
SmI
equiv)
2
amine (equiv)
-
D
2
O
yield
(%)
2
[D ]
(%)
b
b
(
(equiv)
1
2
3
4
5
6
7
8
9
6.0
6.0
6.0
6.0
6.0
4.0
6.0
6.0
6.0
6.0
36
0
-
n-BuNH
DIPA (36)
EtN(Me) (36)
2
(36)
36
64
67
53
81
48
72
60
65
62
27
71
41
96
91
96
96
96
97
36
(
1n and 1x), were stable under the reaction conditions. In ad-
dition, this method was amenable to heterocyclic substrates
1o, 1p, 1z, 1aa and 1ab), which markedly expands the syn-
2
36
Et
Et
Et
Et
Et
Et
3
3
3
3
3
3
N (36)
36
(
N (36)
N (24)
N (12)
N (12)
N (12)
36
thetic application for the preparation of bioactive molecules,
and the by-products derived from dearomatization were not
observed in any of those reactions. In all the tested examples,
C–CN homolysis, transimination or β-deuteration was not
detected. However, moderate yields were observed if the de-
rived amine (2b) is soluble in water. When lower deuterium
incorporations were obtained as was the case with some sub-
36
36
72
1
0
18
aConditions: 1a (0.20 mmol, 1.0 equiv) in THF was added to
the solution of SmI in THF (0.10 M, 8.0-12 mL), followed by
amine (0-7.2 mmol, 0-36 equiv) and D O (3.60-14.4 mmol, 18-72
strates, reaction conditions with less Et
3 2
N and D O (entry 10,
2
Table 1) were used to increase deuterium incorporations.
2
2
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The Journal of Organic Chemistry
Primary amines are present in a vast number of bioactive
used as precursors (Scheme 3C).12 The target molecules in-
clude medicines (Lacosamide, Benznidazole, Flupirtine, Do-
lutegravir, Berberine chloride), veterinary medicines (Yohim-
bine), hormones (Meletonin), insecticides (Tebufenpyrad),
fungicides (Pencycuron), and other bioactive compounds (Ty-
ramine, Dopamine and Serotonin) (Scheme 3C). So far, none
of those bioactive compounds (Scheme 3C) has been used as
their deuterated analogues. This new method is a useful tool
for the development of new deuterated drugs and other valua-
ble deuterated amines, and its further applications will be in-
1
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9
compounds and constitute key building blocks in the chemical
industry. Thus, the synthetic utility of this new method was
exemplified in the synthesis of a series of deuterium labelled
building blocks and deuterium labelled neurotransmitters,
2 2
including tryptamine-d (2aa) and phenethylamine-d (2y).
Excellent deuterium incorporations at the α-position of these
amines were obtained. With the synthesized α,α-dideuterio
amines in hand, a number of deuterium labelled medicines and
agrochemicals can be synthesized according to the reported
synthetic routes where the parent nondeuterated amines were
vestigated in future studies.
1
1
1
1
1
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1
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0
a
Scheme 3. Scope of the Reductive Deuteration of Nitriles, and the Application of the Synthesized α,α-dideuterio amines
aConditions: 1a (0.20 mmol, 1.0 equiv) in THF was added to a solution of SmI
6.0 equiv) and D O (7.2 mmol, 36.0 equiv) at rt, and the resulting mixtures were stirred for 15 min under an inert atmosphere; isolated as
HCl salts; percentage of exchanged protons is determined by H NMR or HRMS and indicated in square brackets. 1a (0.20 mmol, 1.0
in THF (0.10 M, 12 mL), followed by amine (7.2 mmol,
2
3
2
1
b
equiv) in THF was added to a solution of SmI
2
in THF (0.10 M, 12 mL), followed by amine (2.4 mmol, 12.0 equiv) and D
2
O (3.6 mmol,
18.0 equiv) at rt, and the resulting mixtures were stirred for 15 min under an inert atmosphere.
3
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Page 4 of 8
In conclusion, the first general SET reductive deuteration of
both aromatic and aliphatic nitriles has been developed for the
synthesis of valuable α,α-dideuterio amines. Crucially, benign
treated with a 3.0 M solution of HCl in cyclopentylmethyl
ether and filtered. The solid was then washed with diethyl
ether and dried under vacuum to give the pure product. Per-
1
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9
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1
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1
reagent D
2
O was employed as the deuterium donor. This mild
centage of exchanged protons are determined by H NMR or
reagent system shows excellent functional group tolerance.
High yields and excellent deuterium incorporations were ob-
tained with a broad range of nitriles, which supersede the re-
ductive deuterations mediated by pyrophoric metal deuterides
HRMS and indicated in square brackets. General procedure B:
to a solution of samarium (II) iodide (0.10 M in THF; 12 mL,
1.2 mmol, 6.0 equiv), a solution of nitrile (0.20 mmol) in THF
(2.0 mL) was added, followed by Et
12 equiv) and D O (72 mg, 3.6 mmol, 18 equiv) under Ar at
room temperature and stirred vigorously. After 15 min, excess
SmI was oxidized by bubbling air through the reaction mix-
ture. The reaction mixture was diluted with CH Cl (10 mL)
and NaOH (10 mL, 1.0 M, aq). The aqueous layer was ex-
tracted with CH Cl (3 × 10 mL). Organic layers were com-
bined, washed with Na (2 × 20 mL, sat, aq.), dried over
MgSO , filtered and concentrated. The crude product was
3
N (0.33 mL, 2.4 mmol,
or Na/EtOD-d
1
. Given that the selective α-deuteration of
2
amines is critical for the development of new deuterated
drugs, this new method has been further applied in the synthe-
sis of many key deuterated intermediates for the preparation of
deuterated drugs and important bio-active compounds. The
2
0
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9
0
2
2
potential of SmI
2
-mediated SET reductive deuterations will be
2
2
the subject of our future studies.
2 2 3
S O
4
treated with a 3.0 M solution of HCl in cyclopentylmethyl
ether and filtered. The solid was then washed with diethyl
ether and dried under vacuum to give the pure product. Per-
General Information. Glassware was dried in an oven
overnight before use. Thin layer chromatography was carried
out on SIL G/UV254 silica-aluminum plates and plates were
1
centage of exchanged protons are determined by H NMR or
HRMS and indicated in square brackets.
4
visualized using ultra-violet light (254 nm) and KMnO solu-
-amine Hydrochloride11 (2a,
4-Fluorophenyl)methan-d
2
(
tion. For flash column chromatography, silica gel 60, 35-70
μm was used. NMR data was collected at 300 MHz. Data was
manipulated directly from the spectrometer or via a networked
PC with appropriate software. All samples were analyzed in
Scheme 3). According to the general procedure A, the reaction
of 4-fluorobenzonitrile (24 mg, 0.20 mmol), samarium (II)
iodide (0.10 M in THF; 12 mL, 1.2 mmol), triethylamine (1.0
mL, 7.2 mmol) and D
mg of 2a in 81% yield as a white solid. H NMR (300 MHz,
DMSO-d ) δ 8.45 (br, 3H), 7.57 (m, 2H), 7.25 (m, 2H);
C{ H} NMR (75 MHz, DMSO-d ) δ 162.1 (d, J = 244.5 Hz),
31.4 (d, J = 8.4 Hz), 130.3 (d, J = 3.1 Hz), 115.3 (d, J = 21.5
2
O (0.13 mL, 7.2 mmol) afforded 26.5
DMSO-d
6
unless otherwise stated. Reference values for resid-
1
1
ual solvent were taken as δ = 2.50 (DMSO-d
= 39.5 (DMSO-d
6
) for H NMR; δ
6
) for C NMR. Multiplicities for coupled
1
3
6
1
3
1
6
signals were designated using the following abbreviations: s =
singlet, d = doublet, t = triplet, q = quartet, quin = quintet, br =
broad signal, and are given in Hz.
1
Hz), 41.1 (m).
Phenylmethanamine-1,1-d
Hydrochloride14
2
-amine
(2b,
All compounds used in this study have been described in
the literature or are commercially available. All solvents and
reagents were used as supplied. Samarium (II) iodide (0.10 M
Scheme 3). According to the general procedure A, the reaction
of benzonitrile (21 mg, 0.20 mmol), samarium (II) iodide
(0.10 M in THF; 12 mL, 1.2 mmol), triethylamine (1.0 mL,
13
in THF) was prepared by standard methods.
7.2 mmol) and D
2b in 62% yield as a white solid. H NMR (300 MHz, DMSO-
2
O (0.13 mL, 7.2 mmol) afforded 18.1 mg of
Optimization Studies (Table 1). To a solution of samarium
II) iodide (0.10 M in THF; 8.0 mL-12 mL, 0.80 mmol-1.2
mmol, 4.0 equiv-6.0 equiv ), a solution of nitrile (0.20 mmol,
1.0 equiv) in THF (2.0 mL) was added, followed by amine (0
1
(
d
6
3
) δ 8.57 (br, 3H), 7.57–7.46 (m, 2H), 7.44–7.33 (m, 3H);
1
1
C{ H} NMR (75 MHz, DMSO-d
6
) δ 133.9, 128.9, 128.5,
-amine Hydrochloride15 (2c, Scheme 3).
2
1
28.3, 41.7 (m).
mmol-7.2 mmol, 0-36 equiv) and D
.60 mmol-14.4 mmol, 18 equiv-72 equiv) under Ar at room
temperature and stirred vigorously. After 15 min, excess SmI
was oxidized by bubbling air through the reaction mixture.
The reaction mixture was diluted with CH Cl (10 mL) and
NaOH (10 mL, 1.0 M, aq). The aqueous layer was extracted
with CH Cl (3 × 10 mL), organic layers were combined,
washed with Na (2 × 20 mL, sat, aq.) dried over MgSO
filtered and concentrated. Then the sample was analyzed by H
NMR (CDCl , 300 MHz) to obtain the deuterium incorpora-
2
O (72.0 mg-576.8 mg,
m-Tolylmethan-d
3
According to the general procedure A, the reaction of 3-
methylbenzonitrile (23 mg, 0.20 mmol), samarium (II) iodide
2
(0.10 M in THF; 12 mL, 1.2 mmol), triethylamine (1.0 mL,
2
2
7
2
d
.2 mmol) and D
c in 80% yield as a white solid. H NMR (300 MHz, DMSO-
) δ 8.50 (br, 3H), 7.33–7.27 (m, 3H), 7.19 (m, 1H), 2.31 (s,
2
O (0.13 mL, 7.2 mmol) afforded 25.5 mg of
1
2
2
6
2
S
2
O
3
4
,
1
3
1
1
6
3H); C{ H} NMR (75 MHz, DMSO-d ) δ 137.7, 133.9,
1
29.5, 128.9, 128.4, 126.0, 41.7 (m), 20.9.
3
(3,5-Dimethylphenyl)methan-d
2
-amine Hydrochloride15 (2d,
tion and yield using internal standard (1,1,2,2-tetrachlorethan)
and comparison with corresponding samples.
General Procedure for the Reductive Deuteration of Ni-
Scheme 3). According to the general procedure A, the reaction
of 3,5-dimethylbenzonitrile (26 mg, 0.20 mmol), samarium
(
(
2
II) iodide (0.10 M in THF; 12 mL, 1.2 mmol), trimethylamine
1.0 mL, 7.2 mmol) and D O (0.13 mL, 7.2 mmol) afforded
8.8 mg of 2d in 83% yield as a white solid. H NMR (300
triles by SmI
of samarium (II) iodide (0.10 M in THF; 12 mL, 1.2 mmol,
.0 equiv), a solution of nitrile (0.20 mmol, 1.0 equiv) in THF
2.0 mL) was added, followed by Et N (1.0 mL, 7.2 mmol, 36
O (0.13 mL, 7.2 mmol, 36 equiv) under Ar at
2
–Et
3
N–D
2
O. General procedure A: to a solution
2
1
6
(
6
MHz, DMSO-d ) δ 8.49 (br, 3H), 7.10 (s, 2H), 7.00 (s, 1H),
3
1
3
1
2
.26 (s, 6H); C{ H} NMR (75 MHz, DMSO-d
133.8, 129.6, 126.6, 41.6 (m), 20.8.
(2,6-Dimethylphenyl)methan-d
-amine Hydrochloride16 (2e,
6
) δ 137.6,
equiv) and D
2
room temperature and stirred vigorously. After 15 min, excess
SmI was oxidized by bubbling air through the reaction mix-
ture. The reaction mixture was diluted with CH Cl (10 mL)
and NaOH (10 mL, 1.0 M, aq). The aqueous layer was ex-
tracted with CH Cl (3 × 10 mL). Organic layers were com-
bined, washed with Na (2 × 20 mL, sat, aq.), dried over
MgSO , filtered and concentrated. The crude product was
2
2
Scheme 3). According to the general procedure A, the reaction
of 2,6-dimethylbenzonitrile (26 mg, 0.20 mmol), samarium
2
2
(
(
2
II) iodide (0.10 M in THF; 12 mL, 1.2 mmol), trimethylamine
1.0 mL, 7.2 mmol) and D O (0.13 mL, 7.2 mmol) afforded
8.5 mg of 2e in 82% yield as a white solid. H NMR (300
2
2
2
2 2 3
S O
1
4
4
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The Journal of Organic Chemistry
6
) δ 8.44 (br, 3H), 7.17 (m, 1H), 7.07 (m, 2H), (300 MHz, DMSO-d ) δ 8.55 (br, 3H), 7.45 (m, 2H), 7.28 (m,
MHz, DMSO-d
6
3
1
1
13
1
1
2
3
4
5
6
7
8
9
2.40 (s, 6H); C{ H} NMR (75 MHz, DMSO-d
) δ 138.0,
6
2H), 2.47 (s, 3H); C{ H} NMR (75 MHz, DMSO-d ) δ
6
130.7, 128.7, 128.2, 35.7 (m), 19.4.
138.6, 130.4, 129.7, 125.8, 41.3 (m), 14.6.
1
7
14
(4-Isopropylphenyl)methan-d
2
-amine Hydrochloride (2f,
(4-Methoxyphenyl)methan-d
2
-amine Hydrochloride
(2l,
Scheme 3). According to the general procedure A, the reaction
of 4-isopropylbenzonitrile (29 mg, 0.20 mmol), samarium (II)
iodide (0.10 M in THF; 12 mL, 1.2 mmol), triethylamine (1.0
Scheme 3). According to the general procedure B, the reaction
of 4-methoxybenzonitrile (27 mg, 0.20 mmol), samarium (II)
iodide (0.10 M in THF; 12 mL, 1.2 mmol), triethylamine (0.33
mL, 7.2 mmol) and D
mg of 2f in 98% yield as a white solid. H NMR (300 MHz,
DMSO-d ) δ 8.44 (br, 3H), 7.42 (m, 2H), 7.27 (m, 2H), 2.89
m, 1H), 1.19 (d, J = 6.9 Hz, 6H); 13C{ H} NMR (75 MHz,
DMSO-d ) δ 148.7, 131.4, 129.0, 126.4, 41.3 (m), 33.2, 23.8.
(4-(tert-Butyl)phenyl)methan-d
2
O (0.13 mL, 7.2 mmol) afforded 36.8
mL, 2.4 mmol) and D
of 2l in 71% yield as a white solid. H NMR (300 MHz,
DMSO-d ) δ 8.46 (br, 3H), 7.43 (m, 2H), 6.95 (m, 2H), 3.75
2
O (72 mg, 3.6 mmol) afforded 24.9 mg
1
1
6
6
13
1
1
(
6
(s, 3H); C{ H} NMR (75 MHz, DMSO-d ) δ 159.3, 130.5,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
125.9, 113.9, 55.2, 41.2 (m).
1
8
(2-Methoxyphenyl)methan-d
2
-amine Hydrochloride17 (2m,
2
-amine Hydrochloride (2g,
Scheme 3). According to the general procedure A, the reaction
of 4-tert-butylbenzonitrile (32 mg, 0.20 mmol), samarium (II)
iodide (0.10 M in THF; 12 mL, 1.2 mmol), triethylamine (1.0
Scheme 3). According to the general procedure A, the reaction
of 2-methoxybenzonitrile (27 mg, 0.20 mmol), samarium (II)
iodide (0.10 M in THF; 12 mL, 1.2 mmol), trimethylamine
mL, 7.2 mmol) and D
mg of 2g in 98% yield as a white solid. H NMR (300 MHz,
DMSO-d ) δ 8.52 (br, 3H), 7.47–7.38 (m, 4H), 1.27 (s, 9H);
2
O (0.13 mL, 7.2 mmol) afforded 39.5
(1.0 mL, 7.2 mmol) and D
21.8 mg of 2m in 62% yield as a white solid. H NMR (300
MHz, DMSO-d ) δ 8.39 (br, 3H), 7.44–7.34 (m, 2H), 7.06 (m,
1H), 6.97 (m, 1H), 3.82 (s, 3H); C{ H} NMR (75 MHz,
2
O (0.13 mL, 7.2 mmol) afforded
1
1
6
6
1
3
1
13
1
6
C{ H} NMR (75 MHz, DMSO-d ) δ 150.9, 131.0, 128.7,
1
25.2, 41.3 (m), 34.3, 31.0.
6
DMSO-d ) δ 157.1, 130.2, 130.1, 121.6, 120.2, 110.8, 55.5,
(4-(tert-Butyl)phenyl)methan-d
2
-amine Hydrochloride18 (2g,
37.1 (m).
Scheme 3). According to the general procedure A, the reaction
of 4-tert-butylbenzonitrile (159 mg, 1.00 mmol), samarium
(II) iodide (0.10 M in THF; 60.0 mL, 6.00 mmol), triethyla-
Benzo[d][1,3]dioxol-5-ylmethan-d
2
-amine18 (2n, Scheme 3).
To a solution of samarium (II) iodide (0.10 M in THF; 12 mL,
1.2 mmol), a solution of benzo[d][1,3]dioxole-5-carbonitrile
(29 mg, 0.20 mmol) in THF (2.0 mL) was added, followed by
mine (5.0 mL, 36 mmol) and D
2
O (0.65 mL, 36 mmol) afford-
1
ed 193.5 mg of 2g in 96% yield as a white solid. H NMR and
trimethylamine (1.0 mL, 7.2 mmol) and D
mmol) under Ar at room temperature and stirred vigorously.
After 15 min, excess SmI was oxidized by bubbling air
through the reaction mixture. The reaction mixture was diluted
with CH Cl (10 mL) and NaOH (10 mL, 1.0 M, aq). The
aqueous layer was extracted with CH Cl (3 × 10 mL). Organ-
ic layers were combined, washed with Na (2 × 20 mL,
sat, aq.), dried over MgSO , filtered and concentrated. The
2
O (0.13 mL, 7.2
1
3
1
C{ H} NMR data were same as previously descripted.
1
9
(3-Fluorophenyl)methan-d
2
-amine Hydrochloride
(2h,
2
Scheme 3). According to the general procedure B, the reaction
of 3-fluorobenzonitrile (24 mg, 0.20 mmol), samarium (II)
iodide (0.10 M in THF; 12 mL, 1.2 mmol), trimethylamine
2
2
2
2
(
2
0.33 mL, 2.4 mmol) and D
1.3 mg of 2h in 65% yield as a white solid. H NMR (300
2
O (72 mg, 3.6 mmol) afforded
2 2 3
S O
1
4
MHz, DMSO-d
1H); C{ H} NMR (75 MHz, DMSO-d
6
) δ 8.63 (br, 3H), 7.51–7.33 (m, 3H), 7.21 (m,
) δ 161.9 (d, J =
243.6 Hz), 136.7 (d, J = 7.8 Hz), 130.6 (d, J = 8.3 Hz), 125.1
d, J = 2.6 Hz), 115.8 (d, J = 22.2 Hz), 115.2 (d, J = 20.9 Hz),
1.1 (m).
2,4-Difluorophenyl)methanamine-d
crude product was purified by flash chromatography (silica,
1
3
1
6
20-100% EtOAc/hexane), afforded 16.8 mg of 2n in 55%
1
yield as a colorless oil. H NMR (300 MHz, DMSO-d
6
) δ 6.98
(
4
(s, 1H), 6.88–6.79 (m, 2H), 5.98 (s, 2H), 4.26 (br, 2H);
1
3
1
C{ H} NMR (75 MHz, DMSO-d
120.8, 108.2, 107.9, 100.7, 43.3 (m).
(1H-indol-5-yl)methan-d -amine
6
) δ 147.1, 146.1, 134.5,
(
2
-amine
Hydrochlo-
2
0
Hydrochloride17
ride (2i, Scheme 3). According to the general procedure A,
the reaction of 2,4-difluorobenzonitrile (28 mg, 0.20 mmol),
samarium (II) iodide (0.10 M; 12 mL, 1.2 mmol), triethyla-
2
(2o,
Scheme 3). According to the general procedure A, the reaction
of 5-cyanoindole (28 mg, 0.20 mmol), samarium (II) iodide
(0.10 M in THF; 12 mL, 1.2 mmol), triethylamine (1.0 mL,
mine (1.0 mL, 7.2 mmol) and D
forded 22.5 mg of 2i in 62% yield as a white solid. H NMR
300 MHz, DMSO-d ) δ 8.53 (br, 3H), 7.68 (m, 1H), 7.35 (m,
1H), 7.18 (m, 1H); HRMS (ESI-TOF) m/z M calcd for
N 146.0745, found C N 146.0742.
4-Chlorophenyl)methanamine-d
-amine Hydrochloride14
2j, Scheme 3). According to the general procedure A, the
2
O (0.13 mL, 7.2 mmol) af-
1
7.2 mmol) and D
2o in 84% yield as a white solid. H NMR (300 MHz, DMSO-
) δ 11.32 (br, 1H), 7.64 (m, 1H), 7.41 (m, 1H), 7.37 (m, 1H),
2
O (0.13 mL, 7.2 mmol) afforded 31.0 mg of
1
(
6
+
d
6
1
3
1
C
H
7 6
D
2
F
2
H
7 6
D
2
F
2
7.20 (dd, J = 8.4, 1.5 Hz, 1H), 6.42 (m, 1H); C{ H} NMR
(75 MHz, DMSO-d ) δ 135.6, 127.5, 126.1, 124.7, 121.9,
120.7, 111.4, 101.0, 42.7 (m).
(1H-indol-6-yl)methan-d -amine (2p,
(
2
6
(
reaction of 4-chlorobenzonitrile (28 mg, 0.20 mmol), samari-
um (II) iodide (0.10 M; 12 mL, 1.2 mmol), triethylamine (1.0
2
Hydrochloride21
Scheme 3). According to the general procedure A, the reaction
of 6-cyanoindole (28 mg, 0.20 mmol), samarium (II) iodide
(0.10 M in THF; 12 mL, 1.2 mmol), trimethylamine (1.0 mL,
mL, 7.2 mmol) and D
2
O (0.13 mL, 7.2 mmol) afforded 26.7
mg of 2j in 74% yield as a white solid. Phenylmethanamine-
1
1
7
,1-d
2% yield. H NMR (300 MHz, DMSO-d
.58–7.45 (m, 4H); HRMS (ESI-TOF) m/z M calcd for
ClN 144.0544, found C ClN 144.0542.
(4-(Methylthio)phenyl)methan-d -amine
Hydrochloride14
2
-amine hydrochloride was formed as the by-product in
7.2 mmol) and D
2p in 72% yield as a white solid. H NMR (300 MHz, DMSO-
) δ 11.26 (br, 1H), 7.51 (m, 1H), 7.47 (m, 1H), 7.34 (m, 1H),
2
O (0.13 mL, 7.2 mmol) afforded 26.6 mg of
1
1
6
) δ 8.54 (br, 3H),
+
d
6
1
3
1
C
H
7 7
D
2
H
7 7
D
2
7.05 (dd, J = 8.1, 1.5 Hz, 1H), 6.41 (m, 1H); C{ H} NMR
(75 MHz, DMSO-d ) δ 135.7, 127.6, 126.3, 126.2, 120.0,
119.9, 112.3, 100.9, 42.3 (m).
4-Phenylbutan-1,1-d
-1-amine Hydrochloride7a (2q, Scheme
2
6
(2k, Scheme 3). According to the general procedure A, the
reaction of 4-(methylthio)benzonitrile (30 mg, 0.20 mmol),
samarium (II) iodide (0.10 M in THF; 12 mL, 1.2 mmol), tri-
2
3). According to the general procedure B, the reaction of 4-
phenylbutanenitrile (29 mg, 0.20 mmol), samarium (II) iodide
(0.10 M in THF; 12 mL, 1.2 mmol), triethylamine (0.33 mL,
ethylamine (1.0 mL, 7.2 mmol) and D
afforded 28.8 mg of 2k in 75% yield as a white solid. H NMR
2
O (0.13 mL, 7.2 mmol)
1
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The Journal of Organic Chemistry
Page 6 of 8
2
.4 mmol) and D
2q in 94% yield as a white solid. H NMR (300 MHz, DMSO-
) δ 8.11 (br, 3H), 7.32–7.24 (m, 2H), 7.21–7.14 (m, 3H),
2
O (72 mg, 3.6 mmol) afforded 35.3 mg of
2-(Benzo[d][1,3]dioxol-5-yl)ethan-1,1-d
2
-1-amine22
(2x,
1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 3). To a solution of samarium (II) iodide (0.10 M in
THF; 12 mL, 1.2 mmol), a solution of 2-(benzo[d][1,3]dioxol-
5-yl)acetonitrile (32 mg, 0.20 mmol) in THF (2.0 mL) was
added, followed by trimethylamine (1.0 mL, 7.2 mmol) and
d
6
1
3
1
2.57 (t, J = 6.8 Hz, 2H), 1.62–1.57 (m, 4H); C{ H} NMR (75
MHz, DMSO-d ) δ 141.7, 128.3, 128.2, 125.7, 38.1 (m), 34.6,
7.7, 26.4.
-Phenylpropan-1,1-d
Hydrochloride14
6
2
D
2
O (0.13 mL, 7.2 mmol) under Ar at room temperature and
stirred vigorously. After 15 min, excess SmI was oxidized by
bubbling air through the reaction mixture. The reaction mix-
ture was diluted with CH Cl (10 mL) and NaOH (10 mL, 1.0
M, aq). The aqueous layer was extracted with CH Cl (3 × 10
mL). Organic layers were combined, washed with Na (2
× 20 mL, sat, aq.), dried over MgSO , filtered and concentrat-
2
2
-1-amine
(2r,
2
Scheme 3). According to the general procedure A, the reaction
of 2-phenylpropanenitrile (26 mg, 0.20 mmol), samarium (II)
iodide (0.10 M in THF; 12 mL, 1.2 mmol), trimethylamine
2
2
2
2
(1.0 mL, 7.2 mmol) and D
2
O (0.13 mL, 7.2 mmol) afforded
5.4 mg of 2r in 73% yield as a white solid. H NMR (300
2 2 3
S O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
4
MHz, DMSO-d
6
) δ 7.38–7.22 (m, 5H), 3.04 (q, J = 7.0 Hz,
ed. The crude product was purified by flash chromatography
1
3
1
1H), 1.25 (d, J = 7.0 Hz, 3H); C{ H} NMR (75 MHz,
DMSO-d ) δ 143.1, 128.6, 127.1, 126.8, 44.5 (m), 37.4, 19.2.
Cycloheptylmethanamine-d
According to the general procedure A, the reaction of cyclo-
heptanecarbonitrile (25 mg, 0.20 mmol), samarium (II) iodide
(silica, 20-100% EtOAc/hexane), afforded 27.8 mg of 2x in
1
6
83% yield as a colorless oil. H NMR (300 MHz, DMSO-d
6
) δ
7
a
2
Hydrochloride (2s, Scheme 3).
6.85–6.80 (m, 2H), 6.67 (m, 1H), 5.96 (s, 2H), 5.50 (br, 2H),
1
3
1
2.70 (s, 2H); C{ H} NMR (75 MHz, DMSO-d
6
) δ 147.3,
145.7, 132.2, 121.6, 109.0, 108.2, 100.7, 40.7 (m), 34.8.
2-Phenylethan-1,1-d -1-amine Hydrochloride (2y, Scheme
2
3). According to the general procedure A, the reaction of 2-
phenylacetonitrile (23 mg, 0.20 mmol), samarium (II) iodide
(0.10 M in THF; 12 mL, 1.2 mmol), trimethylamine (1.0 mL,
1
4
(0.10 M in THF; 12 mL, 1.2 mmol), trimethylamine (1.0 mL,
7
2
d
.2 mmol) and D
s in 77% yield as a white solid. H NMR (300 MHz, DMSO-
) δ 8.03 (br, 3H), 1.82–1.28 (m, 11H), 1.16 (m, 2H);
2
O (0.13 mL, 7.2 mmol) afforded 25.5 mg of
1
6
13
1
C{ H} NMR (75 MHz, DMSO-d
27.8, 25.4.
((3r,5r,7r)-Adamantan-1-yl)methan-d
6
) δ 44.0 (m), 36.8, 31.0,
7.2 mmol) and D
2y in 89% yield as a white solid. H NMR (300 MHz, DMSO-
6
d ) δ 8.22 (br, 3H), 7.37–7.28 (m, 2H), 7.28–7.20 (m, 3H),
2
O (0.13 mL, 7.2 mmol) afforded 28.4 mg of
1
2
-amine Hydrochlo-
7
a
+
ride (2t, Scheme 3). According to the general procedure B,
the reaction of 1-adamantanecarbonitrile (32 mg, 0.20 mmol),
samarium (II) iodide (0.10 M in THF; 12 mL, 1.2 mmol), tri-
2.90 (s, 2H); HRMS (ESI-TOF) m/z M calcd for C
124.1090, found C N 124.1089.
2-(Benzo[b]thiophen-3-yl)ethan-1,1-d
8 10 2
H D N
8
10 2
H D
2
-1-amine Hydrochlo-
1
4
methylamine (0.33 mL, 2.4 mmol) and D
2
O (72 mg, 3.6
ride (2z, Scheme 3). According to the general procedure A,
the reaction of 2-(benzo[b]thiophen-3-yl)acetonitrile (34.6 mg,
0.20 mmol), samarium (II) iodide (0.10 M in THF; 12 mL, 1.2
mmol) afforded 40.0 mg of 2t in 98% yield as a white solid.
1
6
H NMR (300 MHz, DMSO-d ) δ 8.01 (br, 3H), 1.95 (m, 3H),
13
1
1
4
.95–1.51 (m, 12H); C{ H} NMR (75 MHz, DMSO-d
6
) δ
mmol), trimethylamine (1.0 mL, 7.2 mmol) and D
2
O (0.13 mL,
9.2 (m), 38.8, 36.1, 31.4, 27.3.
7.2 mmol) afforded 26.8 mg of 2z in 62% yield as a white
Hydrochloride7a
(2u,
solid. H NMR (300 MHz, DMSO-d
1
3
-Butoxypropan-1,1-d
2
-1-amine
6
) δ 7.99 (m, 1H), 7.91
Scheme 3). According to the general procedure A, the reaction
of 3-butoxypropanenitrile (25 mg, 0.20 mmol), samarium (II)
iodide (0.10 M in THF; 12 mL, 1.2 mmol), trimethylamine
(m, 1H), 7.59 (s, 1H), 7.46-7.35 (m, 2H), 3.18 (s, 2H);
1
3
1
6
C{ H} NMR (75 MHz, DMSO-d ) δ 139.7, 138.3, 131.6,
124.4, 124.1, 123.8, 122.9, 121.5, 37.7 (m), 25.7. Percentage
of exchanged protons are determined by HRMS.
2
(1.0 mL, 7.2 mmol) and D O (0.13 mL, 7.2 mmol) afforded
1
Hydrochloride7a
3
2.2 mg of 2u in 95% yield as a white solid. H NMR (300
2-(1H-indol-3-yl)ethan-1,1-d
2
-1-amine
MHz, DMSO-d
6
) δ 8.20 (br, 3H), 3.39 (m, 2H), 3.32 (t, J = 6.4
(2aa, Scheme 3). According to the general procedure A, the
reaction of 3-indoleacetonitrile (31 mg, 0.20 mmol), samarium
(II) iodide (0.10 M in THF; 12 mL, 1.2 mmol), trimethylamine
Hz, 2H), 1.78 (t, J = 5.9 Hz, 2H), 1.44 (p, J = 6.4 Hz, 2H),
1
3
1
1
.27 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H); C{ H} NMR (75
MHz, DMSO-d ) δ 69.7, 66.9, 36.0 (m), 31.2, 27.0, 18.8, 13.7.
-(4-Methoxyphenyl)ethan-1,1-d
2v, Scheme 3). According to the general procedure A, the
6
(1.0 mL, 7.2 mmol) and D
37.0 mg of 2aa in 93% yield as a white solid. H NMR (300
MHz, DMSO-d ) δ 11.04 (br, 1H), 8.13 (br, 3H), 7.56 (m,
2
O (0.13 mL, 7.2 mmol) afforded
7a
1
2
2
-1-amine Hydrochloride
(
6
reaction of (4-methoxyphenyl)acetonitrile (29 mg, 0.20
mmol), samarium (II) iodide (0.10 M in THF; 12 mL, 1.2
mmol), trimethylamine (1.0 mL, 7.2 mmol) and D
1H), 7.36 (m, 1H), 7.23 (d, J = 2.1 Hz, 1H), 7.08 (m, 1H), 6.99
(m, 1H), 3.01 (s, 2H); HRMS (ESI-TOF) m/z M calcd for
+
2
O (0.13 mL,
C
10
H
11
D
2
N
2
163.1199, found C10
H
11
D
2
N
2
163.1198.
-1-amine Hydro-
7
.2 mmol) afforded 30.7 mg of 2v in 81% yield as a white
2-(5-Methoxy-1H-indol-3-yl)ethan-1,1-d
2
1
23
solid. H NMR (300 MHz, DMSO-d
6
) δ 8.20 (br, 3H), 7.17
chloride (2ab, Scheme 3). According to the general proce-
dure A, the reaction of 2-(5-methoxy-1H-indol-3-
yl)acetonitrile (37 mg, 0.20 mmol), samarium (II) iodide (0.10
M in THF; 12 mL, 1.2 mmol), triethylamine (1.0 mL, 7.2
m, 2H), 6.88 (m, 2H), 3.72 (s, 3H), 2.82 (s, 2H); 13C{ H}
1
(
6
NMR (75 MHz, DMSO-d ) δ 158.0, 129.6, 129.2, 114.0, 55.0,
3
1.9 (m), 31.8.
-(3,4-Dimethoxyphenyl)ethan-1,1-d
2
2
-1-amine Hydrochlo-
mmol) and D
2
O (0.13 mL, 7.2 mmol) afforded 29.7 mg of 2ab
7a
1
ride (2w, Scheme 3). According to the general procedure A,
the reaction of (3,4-dimethoxyphenyl)acetonitrile (35 mg, 0.20
mmol), samarium (II) iodide (0.10 M in THF; 12 mL, 1.2
mmol), trimethylamine (1.0 mL, 7.2 mmol) and D
7.2 mmol) afforded 43.1 mg of 2w in 98% yield as a white
in 65% yield as a white solid. H NMR (300 MHz, DMSO-d )
6
δ 10.85 (br, 1H), 7.25 (d, J = 8.7 Hz, 1H), 7.18 (d, J = 1.9 Hz,
1H), 7.09 (d, J = 2.2 Hz, 1H), 6.73 (dd, J = 8.7, 2.2 Hz, 1H),
3.77 (s, 3H), 2.97 (s, 2H); HRMS (ESI-QFT) m/z: M calcd
+
2
O (0.13 mL,
13 2 2 13 2 2
for C11H D N O 193.1310, found C11H D N O 193.1310.
1
solid. H NMR (300 MHz, DMSO-d
6
6
) δ 8.14 (br, 3H), 6.91–
.85 (m, 2H), 6.75 (dd, J = 8.1, 2.0 Hz, 1H), 3.74 (s, 3H), 3.71
+
(s, 3H), 2.81 (s, 2H); HRMS (ESI-TOF) m/z M calcd for
C
H
10 14
D
2
NO 184.1301, found C10 NO 184.1300.
2
H
14
D
2
2
The Supporting Information is available free of charge on the
1
13
ACS Publications website. H and C NMR spectra (PDF).
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The Journal of Organic Chemistry
examples, see: (c) Loh, Y. Y.; Nagao, K.; Hoover, A. J.; Hesk, D.;
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*E-mail: jie_an@cau.edu.cn.
Yuxuan Ding: 0000-0002-4201-2689
Shihui Luo: 0000-0002-5661-4082
Jie An: 0000-0002-1521-009X
Chiral Amines with D
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‡
These authors contributed equally.
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We thank National Key Research and Development Plan of China
2017YFD0200504), National Natural Science Foundation of
China (No. 21602248), the Natural Science Foundation of Beijing
Municipality (No. 2192026) and Tianjin Haiyi Tech. Ltd. for
financial support and Ms Lingxin Kong for the design of cover
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