Dehalogenative Deuteration of Unactivated Alkyl Halides Using D2O as the Deuterium Source

Article abstract of DOI:10.1021/acs.joc.9b02026

The general dehalogenation of alkyl halides with zinc using D₂O or H₂O as a deuterium or hydrogen donor has been developed. The method provides an efficient and economic protocol for deuterium-labeled derivatives with a wide substrate scope under mild reaction conditions. Mechanistic studies indicated that a radical process is involved for the formation of organozinc intermediates. The facile hydrolysis of the organozinc intermediates provides the driving force for this transformation.

Full text of DOI:10.1021/acs.joc.9b02026

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Article
Dehalogenative Deuteration of Unactivated Alkyl
halides Using D2O as the Deuterium Source
Aiyou Xia, Xin Xie, Xiaoping Hu, Wei Xu, and Yuanhong Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02026 • Publication Date (Web): 30 Sep 2019
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Dehalogenative Deuteration of Unactivated Alkyl halides Using D O as the
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Deuterium Source
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Aiyou Xia, Xin Xie, Xiaoping Hu, Wei Xu and Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of
Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, People’s
Republic of China
Fax: (+86) 21-64166128, E-mail: yhliu@sioc.ac.cn
Zn/D O (H O)
2
2
Ralkyl
X
Ralkyl ZnX
Ralkyl D/H
o
CH CN, rt-80 C
3
X = Br, I, Cl
up to >99% yield, 97% D
organozinc serves as transient intermediate in the presence of water
simple procedure
wide scope
high efficiency
Tin-and metal hydride free
Abstract: The general dehalogenation of alkyl halides with zinc using D O or H O as a
2
2
deuterium or hydrogen donor has been developed. The method provides an efficient and
economic protocol for deuterium-labeled derivatives with wide substrate scope under mild
reaction conditions. Mechanistic studies indicated that a radical process is involved for the
formation of organozinc intermediates. The facile hydrolysis of the organozinc
intermediates provides the driving force for this transformation.
INTRODUCTION
Recently, great attention has been paid to the deuteration of organic compounds due to
the rapidly-growing interests in the development of deuterated drug molecules. Based on
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the kinetic isotopic effect, C-D bonds are stronger than the corresponding C-H bonds
toward oxidative metabolism, thus introducing the deuterium into the specific sites of the
drugs may improve absorption, distribution, metabolism and excretion properties (ADME)
of the drug candidates, such as slowing the drug metabolism and reducing the toxic
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metabolites etc. A first deuterated drug of Austedo (Deutetrabenazine) for the treatment of
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a
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chorea associated with Huntington’s disease was approved in 2017 (Figure 1) .
D
CD3
O
O
D
S
F3C
Cl
N
N
O
O
NH
O
H
O
CD3
N
O
O
H
Austedo (Deutetrabenazine)
Efavirenz
DRX-065
Figure 1. Representative Bioactive Deuterated Molecules
Deuteration reactions have also found wide applications in organic chemistry,
organometallic chemistry, spectroscopy, mechanistic investigations of organic and
3
bio-organic reactions, and the production of optical fibers etc. Among various methods in
this field, deuterodehalogenation of alkyl halides would be one of the most important
3
strategies for the construction of C(sp )-D bonds, since the halide substrates are widely
available or can be readily prepared from the easily-accessible alcohols. The method also
enables the deuteration to occur at the well-defined positions. Despite much progress in
deuteration of the aryl halides, the reactions employing alkyl halides as the substrates still
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remain as a formidable task. Traditionally, these transformations have been performed
through deuteration of the organometallic regents such as Grignard or organolithium
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reagents, reduction with metal deuteride, transition-metal-mediated reduction reactions,
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or radical reductive dehalogenation with AIBN(or Et B)/Bu SnD. However, these
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methods suffer from low functional-group tolerance, or involve the use of hazardous
radical initiators (e.g., AIBN), highly toxic Bu SnD as the deuterium donor, and generating
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the tin halides byproducts which are difficult to be separated from the desired products.
Recently, dehalogenation process in the presence of D O as the deuterium donor
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emerges as one of the most promising methods since it is economic and environmentally
benign. In this context, Wood et al. reported an excellent R B/H O-mediated
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hydrodehalogenation of xanthates or alkyl iodides, in which the deuterated alkyl
derivatives could be produced using D O from xanthates. Renaud re-investigated the above
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reactions and disclosed that the thiol is acting as a highly active co-catalyst (Scheme 1).10
However, these transformations are limited to alkyl iodides, and have never been applied
to alkyl bromides due to the competitive deuteration of the in situ-generated ethyl radical.
More recently, Loh et al reported an interesting deuteration of halogenated compounds
using porous CdSe nanosheets as the catalyst under irradiation conditions in a mixed
11
solvent of CH CN/D O, in which primary alkyl iodides were deuterated smoothly. In this
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paper, we describe a general and attractive method for deuterodehalogenation of
unactivated alkyl bromides as well as iodides using D O mediated by inexpensive zinc. It
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is realized that alkylzinc is possibly formed as an intermediate in the presence of water.
Organozinc is highly sensitive to moisture and air, usually moisture free reaction media
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and inert conditions are required for their preparation. Alkylzinc reagents could be
prepared by oxidative insertion of zinc metal into alkyl halides. However, the method has
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been limited to the activated halides such as allyl halides and alkyl iodides . Due to the
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low reactivity of the alkyl bromides or chlorides, the preparation of organozinc compounds
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derived from these compounds usually require highly reactive Rieke-zinc or activators
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such as 1,2-dibromoethane/Me SiCl/alkali iodide, I or LiCl in dry solvents. It was
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noted that although dehalogenation by Zn in HOAc/H O (with special substrates) or in
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saturated aqueous ammonium chloride and THF (with limited scope), or under aqueous
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micellar catalysis using a designer surfactant, TMEDA and Zn, have been reported, our
method demonstrates that dehalogenation can occur in the presence of D O or water
2
without adding any activators.21,22
Scheme 1. Deuterodehalogenation in the presence of D O
2
a) Radical deuteration (2018, Renaud et al.)
3
1
equiv Et B, 3 equiv D O
3 2
mol% n-C H SH, dry air
1
2 25
Ralkyl
I
Ralkyl
D
benzene, rt
limited to alkyl iodides
b) Reductive dehalogenation (this work)
simple procedure
wide scope
Zn/D O (H O)
2
2
Ralkyl
X
Ralkyl D/H
o
CH CN, rt-80 C
3
high efficiency
X = Br or I
applicable to alkyl bromides
Tin-and metal hydride free
or activated RCl
RESULTS AND DISCUSSION
During our study on Ni/Zn-catalyzed reactions of alkyl halides, we occasionally found
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that alkyl halides could be reduced efficiently by Zn in the presence of water and various
Lewis acid such as Sc(OTf) , In(OTf) , Zn(OTf) , etc. To our surprise, dehalogenation also
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proceeded efficiently even in the absence of a Lewis acid. The results prompted us to make
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a deep evaluation of Zn/H O-mediated dehalogenation, especially, to investigate the
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feasibility of synthesizing the deuterated products using D O.
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Initially, the deuterodehalogenation of a secondary alkyl bromide 1a was investigated.
We were pleased to find that the desired reaction took place smoothly to afford 2a-D in
o
9
8% yield with 92% D-incorporation at 80 C in CH CN in the presence of 2.0 equiv zinc
3
power (99.9% metals basis, -100 mesh) and 3.0 equiv D O (Table 1, entry 1). In the
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absence of zinc, no reaction was observed (entry 2). In the absence of D O, a 12% yield of
2
non-deuterated 2a-H (1-tosylpiperidine) was obtained (entry 3). In this case, the hydrogen
source comes from trace water contained in the solvent. To our delight, the method could
also be successfully applied to hydrodehalogenation using H O (entry 4). These results are
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quite remarkable, since they represent one of the most simple, inexpensive and promising
protocols for dehalogenation reactions. The reaction proceeded more efficiently in polar
solvents (entries 5-8). Addition of even one equiv of D O could also afford 2a-D in
2
excellent yield, albeit with lower D-incorporation (entry 9). The use of two or more than
two equiv of D O gave the products in both high yields and high D-incorporation (entry
2
10). Excellent yield was also achieved using 1.5 equiv Zn (entry 12). Other reducing
agents such as Mg, Al and Mn were not effective (entry 14). The purity of zinc was found
to influence the D-incorporation or product yield (entries 15-16).
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Table 1. Optimization of the reaction conditionsa
Br
D
N
2.0 equiv Zn (powder)
3.0 equiv D O
2
o
CH CN, 80 C, 10 h
3
N
0
1
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Ts
Ts
2a-D
standard conditions
1a
Entry
Deviation from standard conditions
none
Yield (%)
D-inc. (%)
92
1
2
98
no Zn
- (97)
- (84)
-c
-
-
b
3
no D O
2
4
5
6
7
8
9
H O instead of D O
-
2
2
THF instead of CH CN
96
88
82
62
79
81
90-91
90
91
86
-
3
dioxane instead of CH CN
96
3
toluene instead of CH CN
12 (86)
42 (51)
98
3
n-hexane instead of CH CN
3
1.0 equiv D O
2
1
0
1
2.0, 4.0 or 5.0 equiv D O
97->99
82 (16)
98
2
1
1.0 equiv Zn
12 1.5 equiv Zn
o
1
3
4
50 C
69 (28)
-(>97)
1
Mg, Al, or Mn were used instead of Zn
Zn (99% pure, 325 mesh) was used
Zn (>95% pure) was used
15
99
31
81
78
16
aThe yields of 2a-D were determined by 1H NMR using 1,3,5-
trimethoxybenzene as an internal standard. The D-incorporation was
1
determined by H NMR. The yields of 1a are shown in parentheses. Unless
b
noted, zinc power (99.9% metals basis, -100 mesh) was used. 12% of 2a-H (1-
c
tosylpiperidine) was formed. 98% of 2a-H was formed.
We next focused our attention on the substrate scope. The efficiency of this
dehalogenation system was examined using both of the D O and H O (Scheme 2). The
2
2
reactivity of the secondary alkyl halides was first investigated. In most cases, high yields
and high levels of D-incorporation (up to 97%) of the desired products were achieved.
Cyclic substrates bearing a fused benzene ring or with a large-sized ring afforded
deuterated 2b-2d in 88-97% yields. When 2-bromoadamantane was employed, only
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moderate yield of 2e was obtained, probably due to the steric hindrance. Linear substrates
bearing an OBn, aryl, keto or amino functional group were well compatible (2f-2j). It was
noted that in the case of 2j, deuteration also occurred at the ortho- and para-position to
nitrogen of the N-phenyl ring, which might be promoted by a Lewis acid produced in the
reaction mixture.23,24 The reaction system was also highly chemoselective for substrate
bearing an aryl and alkyl bromide moieties, in which the bromide on the aryl ring remained
intact (2k). The method can be used for the late-stage functionalization of medicinally
relevant compounds. For example, deuteration of the enantiomerically pure 1l and 1m
derived from natural products proceeded efficiently (2l, 2m). It should be noted that
racemization occurred during the process. The results indicated that a radical species might
be involved in the reaction.
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Next, the scope of activated secondary alkyl bromides was investigated. For branched
benzyl bromide 1n, the reaction could be performed at the room temperature (2n). In this
case, 10.0 equiv D O was required in order to achieve high D-incorporation (90%). The
2
substrates bearing various functional groups at the -position of the halide such as keto,
ester, carbomyl and even free carboxyl groups were well tolerated (2o-2s). Among these
examples, reduction of optically pure (+)-camphor bromide with D O led to the formation
2
of a mixture of diastereoisomers of 2o-D, emphasizing again the presence of a radical
species. Notably, the deuterated γ-butyrolactone could be easily prepared with 97%
D-incorporation (2q-D), which might be used for the preparation of deuterated polymers
via ring-opening polymerization.25 Substituted urea (bromisoval) was transformed into
2
r-D in an excellent yield, however, with a lower D-incorporation (41%) after stirring for
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47 h. To our delight, the reaction rate was greatly accelerated by increasing the amount of
D O to 10 equiv (18 h) with improved D-incorporation. We envisioned that an adequate
2
amount of water might improve the solubility of the urea-tethered substrate and the product,
which possibly formed a salt under the basic conditions. Especially, when carboxylic acid
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s was employed, the reaction proceeded efficiently at the room temperature (2s-D). The
1H NMR examination of the crude reaction mixture showed that the proton of the COOH
moiety was also deuterated. Possibly, acid substrate could speed up the rate of the
hydrolysis step involving the protonation of the in-situ-formed organozinc species. It was
noted that 2s-H could be formed without addition of water. Activated alkyl chlorides such
as -chloro ketone could also be dehalogenated (2t).
This methodology was well extended to secondary alkyl iodides. As expected,
compared to the alkyl bromides, significant difference in reactivity was observed in
reduction of the alkyl iodides, since the reactions took place rapidly at the room
temperature (2g and 2a). In the latter case, the product yield and D-incorporation were
1
0
comparable with that obtained using Et B/cat.dodecanethiol/D O. Thus our method
3
2
provides a cheap, convenient and practical alternative to deuterated hydrocarbons.
Scheme 2. Dehalogenation of alkyl halidesa
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2
.0 equiv Zn
3.0 equiv D2O or H2O
Ralkyl-X
or 3
Ralkyl-D or Ralkyl-H
CH3CN, 25 - 80 o
C
1
2-D
or 4-D
2-H
4-H
X = Br, I, Cl
For unactivated secondary alkyl bromides
D
D
D
D
D
Bn
Ts
N
D
D
O
MeO
OMe
1
1
1
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0
80 oC, 2 h
80 oC, 4 h
0 oC, 4 h
80 oC, 41 h
80 oC, 8 h
80 oC, 8 h
8
0 oC, 6 h
a-D, 97% (92%)
8
c
2
2b-D, 92% , 82% (90%)
2c-D, 97% (90%)
2c-H, 95%
2d-D, 88% (95%)
2e-D, 53% (94%)
2e-H, 44%
2f-D, 91% (89%)
2f-H, 89%
2g-D, 90% (82%)
2g-H, 97%
c
c
2a-H, 93%
2b-H, 87% , 76%
2
d-H, 96% , 84%
b
Gram scale : 95% (92%)
75%
Br
O
D
D
D
D
O
D
H
Ph
Ph
N
Ph
D
H
H
H
H
D
Me
D
6
8%
O
H
H
D
H
8
0 oC, 4 h
80 oC, 10 h
80 oC, 40 h
80 oC, 8 h
80 oC, 36 h
80 oC, 30 h
2
h-D, >99% (93%)
2i-D, 72% (85%)
2i-H, 75%
2j-D, 63% (82%)
2j-H, 70%
2k-D, 99% (92%)
2k-H, 99%
2l-D, 91% (89%), dr = 1:9.2
2l-H, 95%
2m-D, 99% (92%), dr = 1:2.4
2m-H, 97%
2h-H, >99%
For activated secondary alkyl bromides
For activated secondary
alkyl chloride
D
D
O
O
D
O
O
O
D
D
Bn
N
H
NH2
Ph
D
O
HOOC
O
D
O
O
25 oC, 6 h
80 o
C
80 o
80 oC, 7 h
80 o
C
25 oC, 3.5 h
80 oC, 8 h
C
d
2q-D , 88% (97%) 2r-D, 47 h, 91% (41%)
d
d
2
n-D , 48% (90%) 2o-D, 22 h, 54% (77%) 2p-D, 22 h, 99% (95%)
2
2
s-D , 91% (86%)
2t-D, 83% (91%)
2t-H, 83%
d
2r-D , 18 h, 91% (66%)
s-H, 98%f
2
n-H, 62%
dr = 1:8.4
o-H, 11 h, 69%
2p-H, 11 h, 99%
2q-H, 90%
e
2
2r-H , 9 h, 94%
For secondary alkyl iodides
D
For unactivated primary alkyl bromides
O
D
Ph
Cl
Bn
Ts
N
D
N
O
D
Ph
D
CN
D
D
MeO
O
2
5 oC, 2 h
25 oC, 2 h
80 oC, 26 h
80 oC, 8 h
80 oC, 12 h
80 oC, 48 h
80 oC, 52 h
d
c
2
g-D, 88% (82%)
2a-D , 94% (88%)
2a-H, 94%
4a-D, 85% (93%)
4a-H, 85%
4b-D, 99% (92%)
4b-H, 99%
4c-D, 67% (89%)
4c-H, 62%
4d-D, 86% , 23%( 92%) 4e-D, 85% (97%)
c
2g-H, 94%
4d-H, 79% , 38%
4e-H, 90%
For activated primary alkyl bromide
For unactivated primary alkyl iodide
For activated primary
alkyl chloride
For aryl iodide
D
For aryl bromide
D
D
O
D
D
D
O
nOct
OH
MeO
OMe
O
0 oC, 6 h
25 oC, 4 h
25 oC, 12 h
80 oC, 4 h
80 oC, 24 hg
100 oC, 10 he,i
5b, 0%
8
4
4
d
d
c,d
f-D, 89% (75%)
f-H, 89%
4g-D , 60% (74%)
4g-H, 66%
4h-D , 92% (93%)
4i-D, 82% (90%)
4i-H, 82%
5a-D, 95%, 69% (89%)
c,h
4h-H, 93%
5a-H, 92%, 70%
a
Isolated yields. Deuterium incorporation is shown in parentheses. 1.5 equiv Zn was used. c1H NMR yields. d10 equiv D2O was used. e10 equiv H2O was used. Without
addition of water. Aryl iodide was used as the substrate. h20 equiv H2O was used. Aryl bromide was used as the substrate.
b
f
g
i
We next examined the scope of the primary alkyl halides. Functionalized alkyl
bromides bearing benzyloxy, cyano and amide groups were all compatible (4a-4c). No
further reduction of the cyano and amide groups were observed. 1-Bromodecane appeared
o
to be reduced more slowly at 80 C, leading to 4d-D in 86% yield after 48 h. The results
suggested that the rate of the C-Br bond cleavage process could be facilitated by the
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presence of various functional groups. The system was also chemoselective for alkyl
halides bearing two different halogen atoms such as Cl and Br, in which Cl remained
unaltered (4e). Activated alkyl bromides were dehalogenated smoothly (4f-4g). Besides,
primary alkyl iodide could be reduced at the room temperature (4h). Activated alkyl
chloride could also be dehalogenated successfully (4i). The reaction is operationally simple
and easily scalable, for example, gram-scale reaction of 1a in the presence of 1.5 equiv Zn
afforded 2a without significant change of the yield and D-incorporation. The reactivity of
aryl halides were also examined. To our delight, aryl iodide was also dehalogenated
smoothly, however, aryl bromide failed to give the desired product (5a, 5b).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
It is worth to note that for α-functionalized alkyl halides, when PhCO H was used
2
instead of H O, the reaction temperature could be decreased to room temperature, and
2
there was no evident difference on the product yields. Typical results are shown in Scheme
3
. PhCO H should also play a role in accelerating the hydrolysis of the organozinc
2
intermediates.
Scheme 3. Dehalogenation of alkyl halides in the presence of PhCO Ha
2
2.0 equiv Zn
1.0 equiv PhCOOH
Ralkyl-Br
Ralkyl-H
o
CH CN, 25 C
3
1
2 or 4
O
O
H
O
H
O
O
H
O
Ph
Bn
O
H
H
O
OH
2w-H, 3.5 h, >99% 2p-H, 3.5 h, 99% 2q-H, 6 h, 90%b 4j-H, 2 h, 96%
4f-H, 2.5 h, 83%
a
b
Isolated yields. NMR yield.
1
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To gain a mechanistic insight into this reaction, various control experiments were
performed (Scheme 4). A radical scavenger such as galvinoxyl effectively inhibited the
reaction (Scheme 4, eq 1). α-Bromocyclopropane 1x was chosen to be used as a radical
clock, and the resulting ring-opening product 2x-a was formed in 47% yield (eq 2). Both of
the cyclized product 2y-a via 5-exo-trig ring closure and uncyclized 2y were observed in
the reaction of alkene 1y with Zn (eq 3). The above results strongly support the presence of
a radical species, which are also consistent to the studies by Rieke et al. on the reaction of
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
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
highly active Zn* (prepared by lithium naphthalenide reduction of ZnCl ) with organic
2
bromides.14a A tertiary alkyl bromide 6 reacted with zinc rapidly at room temperature,
however, the desired product 7a was obtained in only 27% yield, along with several
byproducts (eq 4). The results show that the rate of halide reduction is competitive with
other reaction pathways. The formation of hydroperoxide 7a-b indicates that a tertiary
radical is generated, which might be generated through the reaction of alkylzinc
intermediate with O2.14a,26,27 A kinetic isotope effect (KIE) was measured by employing an
equimolar mixture of H O and D O, which revealed a primary kinetic isotope effect of the
2
2
2
8
reaction (eq 5). Parallel experiments gave the similar results (k /k = 3.2). The results
H
D
imply that the cleavage of the O-H/D bond is likely involved in the rate-determining step
of the process.
Scheme 4. Mechanistic Studies
1
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2
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5
5
6
Reaction inhibition
2
.0 equiv galvinoxyl
Br
H
3.0 equiv H O
2
2.0 equiv Zn
+
1a
(1)
o
CH CN, 80 C, 10 h
3
N
N
8
4% recovered
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
Ts
Ts
1a
2a-H, 14%
Ring-opening experiment
3
2
.0 equiv H O
.0 equiv Zn
2
Br
H
(2)
(3)
+
Ph
o
Ph
Ph
CH CN, 80 C, 52 h
3
1x
NMR yields: 2x, 32%
2x-a, 47% (Z:E = 1:6.8)
Ring-closure experiment
3
2
.0 equiv H O
.0 equiv Zn
Br
2
Ts
+
+
N
o
N
CH3CN, 100 C, 12 h
N
N
H
Ts
Ts
Ts
1
y
2y, 21%
2y-a, 17%
2y-b, 61%
OH
Reaction of tertiary alkyl bromide
+
Ar
+
Ar
3
2
.0 equiv H O
.0 equiv Zn
2
Br
7a, 27%
7a-a, 24%
(4)
o
CH CN, 25 C, 3.5 h
OOH
3
6
MeO
+ alkenes (10%)
Ar
Ar = 4-OMeC H
6
4
7
a-b, 14%
Kinetic isotope effect
1
1
2
.5 equiv H O
.5 equiv D O
.0 equiv Zn
Br
2
D
N
2
k /k = 80/20 = 4.0
(5)
H
D
o
CH CN, 80 C, 10 h
N
3
Ts
Ts
2a-D, 97% NMR yield, 20% D
1a
Based on the above results and literature reports, we suggested that the reaction
proceeds via the formation of an organozinc intermediate followed by deuteration or
protonation (Scheme 5). Radical clock experiments and the stereochemical outcome of the
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reaction support that the generation of organozinc takes place through a two single-electron
transfer (SET) steps.14a Generally, organozinc is believe to be highly sensitive to moisture
and air. It may be hard to understand that organozinc could be generated in water without
any activators shown in the reaction mechanism. We suggest here that the intermediate of
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
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5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
1
2
3
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7
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9
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0
RZnBr tends to be easily protonated by H O. After organozinc species is formed,
2
protonation will occur in the presence of water, which shifts the equilibrium completely to
the right-hand side. Thus one of the driving force for this transformation is the facile
protonation of organozinc intermediates to deliver an alkane product. It is also possible that
after the protonation reaction, the soluble organic products and zinc salts are removed from
the zinc surface by the solvent, thus making the zinc surface clean enough for the further
reaction.17,29
Scheme 5. Possible Reaction Mechanism
ET
ET
R Br + Zn
R Br + Zn+
R
+ ZnBr
RZnBr
H O
2
R H + Zn(OH)Br
CONCLUSION
In summary, we have developed a general dehalogenation of alkyl halides with zinc
using D O or H O as the deuterium or hydrogen sources under mild reaction conditions.
2
2
The results of mechanistic studies are consistent with a radical process for the formation of
organozinc intermediates, and KIE experiments support that the cleavage of the O-H/D
1
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6
bond might be involved in the rate-determining step of the process. The facile hydrolysis
of the organozinc intermediates provides the driving force for this transformation.
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EXPERIMENTAL SECTION
General Methods. Unless noted, all reactions were carried out using sealable tubes under
an argon atmosphere or a dry box technique under a nitrogen atmosphere. Tetrahydrofuran
and toluene were distilled from sodium and benzophenone. 1,4-Dioxane and n-hexane was
distilled from sodium. D O (99.9 atom% D) were purchased from Sigma-Aldrich.
2
Deionized water was used. Zinc powder (99.9% metals basis, -100 mesh) was purchased
from Alfa Aesar. Zinc powder (99%, -325 mesh) was purchased from Adamas. Zinc
(>95%) was purchased from Lingfeng. All zinc used in this study was activated by
treatment with 1 M HCl aqueous solution, filtered and washed thoroughly with water,
acetone and diethyl ether and dried under vacuum. Unless otherwise noted, all other
reagents and starting materials were purchased from commercial sources. H, and 13C
NMR spectra were recorded at room temperature in CDCl or d -DMSO (containing
1
3
6
2
0.03% TMS) solutions on Varian or Agilent XL-400 MHz spectrometer. H NMR spectra
were recorded at room temperature in CH Cl or CDCl solutions on Agilent XL-600 MHz
2
2
3
1
spectrometer. H NMR spectra was recorded with tetramethylsilane (0.00 ppm) or solvent
residual peak (CDCl : 7.26 ppm; d -DMSO: 2.50 ppm) as internal reference; Unless
3
6
1
13
otherwise noted, the deuterium incorporation was determined by H NMR spectra. C
NMR spectra was recorded with CDCl (77.00 ppm) or d -DMSO (39.52 ppm) as internal
3
6
reference. High-resolution mass spectra was performed on a mass spectrometer with a TOF
1
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analyzer.
Synthesis of alkyl halides.
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
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0
1
2
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5
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2
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4
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0
Alkyl halides were synthesized according to the published methods.30 For the
characterization of the new substrates, see the following:
Synthesis of 2-bromo-2,3-dihydro-1H-indene (1b). A flame-dried flask equipped with a
stirring bar were charged with 2-indanol (1.34 g, 10 mmol) and CBr (3.61 g, 10.9 mmol)
4
under argon. Anhydrous CH Cl (50 mL) was added and the mixture was placed in an ice
2
2
bath. PPh (2.89 g, 11 mmol) in CH Cl (10 mL) was added dropwise at 0 °C. The reaction
3
2
2
mixture was warmed up to room temperature and then stirred for 8 h. After the starting
material was completely consumed, the mixture was quenched with saturated NaHCO3
solution, extracted with CH Cl and dried over anhydrous Na SO . The solvent was
2
2
2
4
evaporated under the reduced pressure and the residue was purified by column
chromatography on silica gel (eluent: petroleum ether) to afford 1b in 77% yield (1.51 g)
1
as a colourless oil. H NMR (400 MHz, CDCl ) δ 7.26-7.19 (m, 4H), 4.78-4.73 (m, 1H),
3
1
3
1
3.50 (dd, J = 16.8 Hz, 6.4 Hz, 2H), 3.33 (dd, J = 16.8 Hz, 4 Hz, 2H); C{ H} NMR (100
MHz, CDCl ) δ 140.5, 126.9, 124.5, 49.6, 44.6. IR (neat): 3024, 2956, 2877, 2822, 1481,
3
1
461, 1416, 1309, 1271, 1225, 1158, 1023, 968, 908, 808, 795, 740. HRMS (EI-TOF)
+
calcd for C H Br [M] : 195.9888, found 195.9884.
9
9
Synthesis of 2-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene (1c). To a solution of
-methoxy-3,4-dihydronaphthalen-2(1H)-one s-1c (3.52 g, 20 mmol) in MeOH (100 mL)
5
1
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5
6
was added NaBH (907.9 mg, 24 mmol) by four portions in 15 min at room temperature
4
under air. The mixture was stirred at room temperature for 2 h. After the starting material
was completely consumed, the mixture was quenched with saturated NH Cl solution,
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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6
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8
9
0
extracted with CH Cl and dried over anhydrous Na SO . The solvent was evaporated
2
2
2
4
under the reduced pressure and the residue was used for the next step without purification.
A flame-dried flask equipped with a stirring bar were charged with the crude product
above and CBr (7.23 g, 21.8 mmol) under argon. Anhydrous CH Cl (80 mL) was added
4
2
2
and the mixture was placed in an ice bath. PPh (5.77 g, 22 mmol) in CH Cl (20 mL) was
3
2
2
added dropwise at 0 °C. The reaction mixture was warmed up to room temperature and
then stirred for 10 h. After the starting material was completely consumed, the mixture was
quenched with saturated NaHCO solution, extracted with CH Cl and dried over
3
2
2
anhydrous Na SO . The solvent was evaporated under the reduced pressure and the residue
2
4
was purified by column chromatography on silica gel (eluent: petroleum ether to petroleum
o
ether: CH Cl = 15:1) to afford 1c (1.76 g, 36% for 2 steps) as a white solid. Mp 68-70 C.
2
2
1
H NMR (400 MHz, CDCl ) δ 7.11 (t, J = 8.0 Hz, 1H), 6.67 (dd, J = 13.2 Hz, 8.0 Hz, 2H),
3
4.53-4.47 (m, 1H), 3.81 (s, 3H), 3.38 (dd, J = 16.4 Hz, 4.8 Hz, 1H), 3.22 (dd, J = 17.2 Hz,
.0 Hz, 1H), 2.96-2.89 (m, 1H), 2.75-2.67 (m, 1H), 2.38-2.31 (m, 1H), 2.23-2.14 (m, 1H);
8
13
1
C{ H} NMR (100 MHz, CDCl ) δ 157.1, 135.3, 126.5, 123.4, 120.8, 107.4, 55.2, 48.7,
3
40.1, 32.8, 22.5. IR (neat): 2948, 2835, 1584, 1466, 1436, 1253, 1214, 1168, 1089, 1073,
+
1
054, 850, 775, 724, 707, 677. HRMS (EI-TOF) calcd for C H OBr [M] : 240.0150,
1
1
13
found 240.0157.
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Synthesis of bromocyclododecane (1d). Cyclododecanol (3.69 g, 20.0 mmol) was heated
o
and melted at 100 C (oil bath) under air. PBr (0.94 mL, 10.0 mmol) was then added
3
dropwise to the solution and the mixture was stirred for 2 h. After the starting material was
completely consumed, the mixture was poured into cold water, extracted with CH Cl ,
1
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2
2
washed with saturated NaHCO solution and dried over anhydrous Na SO . The solvent
3
2
4
was evaporated under the reduced pressure and the residue was purified by column
chromatography on silica gel (eluent: pentane) to afford 1d in 35% isolated yield (1.74 g)
1
as a colourless oil. H NMR (400 MHz, CDCl ) δ 4.29-4.22 (m, 1H), 2.09-2.00 (m, 2H),
3
1
3
1
1.93-1.84 (m, 2H), 1.56-1.34 (m, 18H); C{ H} NMR (100 MHz, CDCl ) δ 54.0, 34.6,
3
2
3.64, 23.62, 23.4, 22.7. IR (neat): 2928, 2862, 2850, 1468, 1444, 1345, 1244, 1206, 1183,
+
782, 750, 719, 699. HRMS (EI-TOF) calcd for C H Br [M] : 246.0983, found 246.0981.
1
2
23
Synthesis of ((3-bromobutoxy)methyl)benzene (1f). Benzyl bromide (1.78 mL, 15
mmol), DIPEA (2.64 mL, 16 mmol) and 4-hydroxybutan-2-one (881.1 mg, 10 mmol) were
o
charged in a reaction vessel under argon. The mixture was heated at 150 C (oil bath) for 2
h. After the starting material was completely consumed, the mixture was quenched with
aqueous HCl (1 M) solution, extracted with ethyl acetate, and dried over anhydrous
Na SO . The solvent was evaporated under the reduced pressure and the residue was
2
4
purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate =
1
0:1 to 5:1) to afford a yellow oil (1.30 g), which was directly used for the next step.
To a solution of the crude product above (891.2 mg, 5 mmol) in EtOH (10 mL) was
added NaBH (227.0 mg, 6 mmol) by four portions in 15 min at room temperature under
4
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air. The mixture was stirred at room temperature for 1 h. After the starting material was
completely consumed, the mixture was quenched with saturated ammonium chloride
solution, extracted with CH Cl , dried over anhydrous Na SO . The solvent was
2
2
2
4
0
1
2
3
4
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6
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1
2
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evaporated under the reduced pressure and the residue was directly used for the next step.
A flame-dried flask equipped with a stirring bar were charged with the crude product
above and CBr (1.81 g, 5.45 mmol) under air. Anhydrous CH Cl (25 mL) was added and
4
2
2
the mixture was placed in an ice bath. PPh (1.44 g, 5.5 mmol) in CH Cl (15 mL) was
3
2
2
added dropwise at 0 °C. The reaction mixture was warmed up to room temperature and
then stirred for 5.5 h. After the starting material was completely consumed, the mixture
was quenched with saturated NaHCO solution, extracted with CH Cl and dried over
3
2
2
anhydrous Na SO . The solvent was evaporated under the reduced pressure and the residue
2
4
was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl
1
acetate = 40:1) to afford 1f (981.5 mg, 81% for 2 steps) as a yellow oil. H NMR (400
MHz, CDCl ) δ 7.37-7.24 (m, 5H), 4.51 (t, J = 13.2 Hz, 2H), 4.39-4.31 (m, 1H), 3.63 (t, J
3
1
3
1
=
6.0 Hz, 2H), 2.11-2.01 (m, 2H), 1.73 (d, J = 6.8 Hz, 3H); C{ H} NMR (100 MHz,
CDCl ) δ 138.2, 128.4, 127.63, 127.61, 73.1, 68.1, 48.3, 41.0, 26.6. IR (neat): 3030, 2861,
3
1
496, 1453, 1359, 1240, 1186, 1113, 1093, 1057, 1028, 812, 734, 696. HRMS (EI-TOF)
+
calcd for C H OBr [M] : 242.0306, found 242.0311.
1
1
15
Synthesis of (2-bromopropane-1,3-diyl)dibenzene (1h). To
a
solution of
1,3-diphenylpropan-2-one (2.10 g, 10 mmol) in EtOH (20 mL) was added NaBH (454.0
4
mg, 12 mmol) by four portions in 15 min at room temperature under air. The mixture was
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stirred at room temperature for 1 h. After the starting material was completely consumed,
the mixture was quenched with saturated NH Cl solution, extracted with CH Cl , dried
4
2
2
over anhydrous Na SO . The solvent was evaporated under the reduced pressure and the
2
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
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3
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4
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5
5
5
5
5
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0
1
2
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4
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8
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1
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0
1
2
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8
9
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1
2
3
4
5
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7
8
9
0
1
2
3
4
5
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7
8
9
0
residue was purified by column chromatography on silica gel (eluent: petroleum ether:
ethyl acetate = 3:1) to afford a yellow oil, which was directly used for the next step.
A flame-dried flask equipped with a stirring bar were charged with the crude product
above and CBr (3.61 g, 10.9 mmol) under argon. Anhydrous CH Cl (50 mL) was added
4
2
2
and the mixture was placed in an ice bath. PPh (2.89 g, 11 mmol) in CH Cl (10 mL) was
3
2
2
added dropwise at 0 °C. The reaction mixture was warmed up to room temperature and
then stirred for 24 h. After the starting material was completely consumed, the mixture was
quenched with saturated NaHCO solution, extracted with CH Cl and dried over
3
2
2
anhydrous Na SO . The solvent was evaporated under the reduced pressure and the residue
2
4
was purified by column chromatography on silica gel (eluent: petroleum ether to petroleum
ether: ethyl acetate = 20:1) to afford 1h (788.5 mg, 29% for 2 steps) as a light yellow oil.
1
H NMR (400 MHz, CDCl ) δ 7.33-7.19 (m, 10H), 4.40-4.33 (m, 1H), 3.22 (dd, J = 14.0
3
1
3
1
Hz, 5.6 Hz, 2H), 3.14 (dd, J = 14.4 Hz, 8.4 Hz, 2H); C{ H} NMR (100 MHz, CDCl ) δ
3
1
38.4, 129.1, 128.4, 126.8, 57.1, 44.9. IR (neat): 3060, 3028, 1602, 1496, 1453, 1155,
+
1
078, 1029, 928, 742, 696. HRMS (EI-TOF) calcd for C H Br [M] : 274.0357, found
1
5
15
274.0356.
i
Synthesis of 3-bromo-1-phenylpentan-1-one (1i). To a solution of Pr NH (3.10 mL, 22
2
mmol) in THF (50 mL) was added dropwise n-BuLi (12.5 mL, 1.6 M in hexane, 20 mmol)
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6
o
at -78 C under argon. After stirring for 0.5 h, acetophenone (2.34 mL, 20 mmol) was then
added to the mixture. The mixture was stirred for 0.5 h and propionaldehyde (2.86 mL, 40
o
mmol) was then added dropwise to the mixture. The mixture was stirred at -78 C for 2 h.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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After the starting material was completely consumed, the mixture was quenched with
saturated NH Cl solution, extracted with ethyl acetate, and dried over anhydrous Na SO .
4
2
4
The solvent was evaporated under the reduced pressure and the residue was purified by
column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 8:1 to 5:1) to
afford 3-hydroxy-1-phenylpentan-1-one (s-1i) in 71% isolated yield (2.52 g) as a light
1
yellow oil. H NMR (400 MHz, CDCl ) δ 7.97-7.94 (m, 2H), 7.60-7.55 (m, 1H), 7.48-7.44
3
(
m, 2H), 4.16-4.12 (m, 1H), 3.37 (d, J = 3.2 Hz, 1H), 3.17 (dd, J = 17.6 Hz, 2.8 Hz, 1H),
1
3
1
3.04 (dd, J = 17.6, 8.8 Hz, 1H), 1.67-1.55 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H); C{ H} NMR
(
100 MHz, CDCl ) δ 200.9, 136.7, 133.4, 128.6, 128.0, 69.0, 44.5, 29.3, 9.9. The
3
spectroscopic data is in agreement with that previously reported.31
To a solution of s-1i (1.78 g, 10 mmol) in CHCl (30 mL) was added dropwise PBr
3
3
o
(
0.47 mL, 5 mmol) at 0 C under air. The mixture was warmed to room temperature and
stirred for 20 h. After the starting material was completely consumed, the mixture was
quenched with water, extracted with ethyl acetate, washed with saturated NaHCO solution
3
and dried over anhydrous Na SO . The solvent was evaporated under the reduced pressure
2
4
and the residue was purified by column chromatography on silica gel (eluent: petroleum
1
ether: ethyl acetate = 5:1) to afford 1i in 78% isolated yield (1.88 g) as a yellow oil. H
NMR (400 MHz, CDCl ) δ 7.97-7.95 (m, 2H), 7.61-7.57 (m, 1H), 7.50-7.46 (m, 2H),
3
4
.61-4.54 (m, 1H), 3.73 (dd, J = 17.2 Hz, 7.6 Hz, 1H), 3.41 (dd, J = 17.2 Hz, 6.0 Hz, 1H),
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2.05-1.83 (m, 2H), 1.10 (t, J = 7.2 Hz, 3H); C{ H} NMR (100 MHz, CDCl ) δ 196.8,
3
1
1
36.5, 133.4, 128.7, 128.1, 51.7, 47.3, 32.0, 12.1. IR (neat): 2963, 2934, 2871, 1685, 1595,
578, 1449, 1373, 1293, 1269, 1208, 1182, 1158, 1001, 978, 915, 783, 753, 689, 658.
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
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
HRMS (EI-TOF) calcd for C H BrO [M+H] : 241.0223, found 241.0224.
1
1
14
Synthesis of N-(3-bromopentyl)-N-methylaniline (1j). To a solution of N-methylaniline
(
2.17 ml, 20 mmol) in H O (20 mL) was added dropwise ethyl vinyl ketone (2.52 g, 30
2
o
mmol) at room temperature under air. The mixture was stirred at 70 C (oil bath) for 18 h.
After the starting material was completely consumed, the mixture was extracted with ethyl
acetate, washed with brine and dried over anhydrous Na SO . The solvent was evaporated
2
4
under the reduced pressure and the residue was purified by column chromatography on
silica gel (eluent: petroleum ether: ethyl acetate = 8:1) to afford the crude product, which
was directly used for the next step.
To a solution of the crude product above in EtOH (40 mL) was added NaBH (908 mg,
4
2
4 mmol) at room temperature under air. The mixture was stirred at room temperature for
3 h. After the starting material was completely consumed, the mixture was quenched with
saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous
Na SO . The solvent was evaporated under the reduced pressure and the residue was
2
4
purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate =
8
:1 to 5:1) to afford 1-(methyl(phenyl)amino)pentan-3-ol (s-1j) in 83% overall yield for
1
two steps (3.21 g) as a light yellow oil. H NMR (400 MHz, CDCl ) δ 7.25-7.21 (m, 2H),
3
6
.80-6.78 (m, 2H), 6.75-6.71 (m, 1H), 3.66-3.60 (m, 1H), 3.48-3.41 (m, 2H), 2.90 (s, 3H),
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2.20 (bs, 1H), 1.76-1.71 (m, 1H), 1.66-1.62 (m, 1H), 1.52-1.47 (m, 2H), 0.94 (t, J = 7.6 Hz,
1
3
1
3
3
H); C{ H} NMR (100 MHz, CDCl ) δ 149.8, 129.1, 117.0, 113.3, 72.1, 50.7, 38.5, 33.3,
3
0.7, 9.8. IR (neat): 3382, 2961, 2932, 2875, 1598, 1505, 1464, 1370, 1225, 1192, 1119,
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
+
1074, 1034, 990, 931, 864, 746, 691. HRMS (ESI-TOF) calcd for C H NO [M+H] :
1
2
20
1
94.1539, found 194.1546.
To a solution of s-1j (966.0 mg, 5 mmol) in CHCl (20 mL) was added dropwise PBr
3
3
o
(
235.0 μL, 2.5 mmol) at 0 C under air. The mixture was warmed to room temperature and
stirred for 18 h. After the starting material was completely consumed, the mixture was
quenched with water, extracted with ethyl acetate, washed with saturated NaHCO solution,
3
brine and dried over anhydrous Na SO . The solvent was evaporated under the reduced
2
4
pressure and the residue was purified by column chromatography on silica gel (eluent:
petroleum ether: ethyl acetate = 10:1) to afford 1j in 65% isolated yield (833.0 mg) as a
1
light yellow oil. H NMR (400 MHz, CDCl ) δ 7.26-7.22 (m, 2H), 6.74-6.68 (m, 3H),
3
4.02-3.98 (m, 1H), 3.65-3.58 (m, 1H), 3.50-3.43 (m, 1H), 2.95 (s, 3H), 2.12-1.99 (m, 2H),
1
3
1
1
.91-1.83 (m, 2H), 1.05 (t, J = 7.2 Hz, 3H). C{ H} NMR (100 MHz, CDCl ) δ 149.0,
3
129.2, 116.3, 112.2, 57.8, 51.0, 38.6, 35.5, 32.6, 12.0. IR (neat): 2966, 1598, 1505, 1452,
1
434, 1368, 1276, 1210, 1117, 1034, 990, 802, 746, 691. HRMS (ESI-TOF) calcd for
+
C H BrN [M+H] : 256.0695, found 256.0702.
1
2
19
Synthesis of 1-bromo-4-((3-bromobutoxy)methyl)benzene (1k). 4-Bromobenzyl
bromide (2.50 g, 10 mmol), 4-hydroxybutan-2-one (1.32 g, 15 mmol) and DIPEA (3.64
mL, 22 mmol) were charged in a reaction vessel under argon. The mixture was heated at
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150 C (oil bath) for 7 h. After the starting material was completely consumed, the mixture
was quenched with aqueous HCl (1 M) solution, extracted with ethyl acetate, and dried
over anhydrous Na SO . The solvent was evaporated under the reduced pressure and the
2
4
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
residue was purified by column chromatography on silica gel (eluent: petroleum ether:
ethyl acetate = 10:1 to 2:1) to afford 4-((4-bromobenzyl)oxy)butan-2-one as a yellow oil,
which was directly used for the next step.
To a solution of the crude product above in EtOH (20 mL) was added NaBH (454.0
4
mg, 12 mmol) by four portions in 15 min at room temperature under air. The mixture was
stirred at room temperature for 5 h. After the starting material was completely consumed,
the mixture was quenched with saturated NH Cl solution, extracted with CH Cl and dried
4
2
2
over anhydrous Na SO . The solvent was evaporated under the reduced pressure and the
2
4
residue was purified by column chromatography on silica gel (eluent: petroleum ether:
ethyl acetate = 5:1 to 2:1) to afford 4-((4-bromobenzyl)oxy)butan-2-ol as a yellow oil,
which was directly used for the next step.
To a solution of the crude product above in DCM (50 mL) was added CBr (3.61 g,
4
10.9 mmol) at room temperature under air. PPh (2.89 g, 11 mmol) in CH Cl (30 mL) was
3
2
2
o
then added to the mixture at 0 C. The mixture was warmed to room temperature and
stirred for 16 h. After the starting material was consumed, the mixture was quenched with
saturated NaHCO solution, extracted with CH Cl and dried over anhydrous Na SO . The
3
2
2
2
4
solvent was evaporated under the reduced pressure and the residue was purified by column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 50:1 to 20:1) to
1
afford 1k (1.42 g, 44% for 3 steps) as a yellow oil. H NMR (400 MHz, CDCl ) δ 7.47 (d, J
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2
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2
2
2
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= 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 4.46 (s, 2H), 4.37-4.29 (m, 1H), 3.66-3.60 (m, 2H),
1
3
1
2
1
.13-1.98 (m, 2H), 1.73 (d, J = 6.8 Hz, 3H); C{ H} NMR (100 MHz, CDCl ) δ 137.2,
3
31.5, 129.2, 121.4, 72.4, 68.3, 48.1, 40.9, 26.6. IR (neat): 2862, 1593, 1487, 1443, 1396,
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
1378, 1357, 1239, 1186, 1089, 1070, 1011, 801. HRMS (EI-TOF) calcd for C H Br O
1
1
14
2
+
[
M] : 319.9406, found 319.9406.
Synthesis of (3S,5S,8R,9S,10S,13S,14S)-3-bromo-10,13-dimethylhexadecahydro-
7H-cyclopenta[a]phenanthren-17-one (1l). A flame-dried flask equipped with a stirring
1
bar were charged with androsterone (1.45 g, 5 mmol) and CBr (2.49 g, 7.5 mmol) under
4
argon. Anhydrous CH Cl (50 mL) was added and the mixture was placed in an ice bath.
2
2
PPh (1.97 g, 7.5 mmol) in CH Cl (10 mL) was added dropwise at 0 °C. The reaction
3
2
2
mixture was warmed up to room temperature and then stirred for 12 h. After the starting
material was completely consumed, the mixture was quenched with saturated NaHCO3
solution, extracted with CH Cl and dried over anhydrous Na SO . The solvent was
2
2
2
4
evaporated under the reduced pressure and the residue was purified by column
chromatography on silica gel (eluent: petroleum ether to petroleum ether: ethyl acetate =
o
1
2
0:1) to afford 1l in 42% isolated yield (733.4 mg) as a white solid. Mp 165-167 C. H
NMR (400 MHz, CDCl ) δ 4.06-4.00 (m, 1H), 2.44 (dd, J = 18.8 Hz, 8.8 Hz, 1H),
3
1
3
1
2.17-0.93 (m, 20H), 0.88 (s, 3H), 0.86 (s, 3H), 0.73-0.71 (m, 1H); C{ H} NMR (100
MHz, CDCl ) δ 221.1, 54.2, 52.1, 51.3, 47.9, 47.7, 40.4, 39.6, 35.7, 35.4, 34.8, 34.0, 31.4,
3
30.7, 28.0, 21.7, 20.2, 13.7, 12.2. IR (neat): 2915, 2846, 1737, 1453, 1389, 1273, 1159,
+
1
151, 1053, 1011, 800, 699. HRMS (EI-TOF) calcd for C H OBr [M] : 352.1402, found
1
9
29
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352.1400.
Synthesis of 2-bromo-2-cyclopropyl-1-phenylethan-1-one (1w). To a solution of
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PhMgBr (10.7 mL, 3M in Et O, 32.1 mmol) was added dropwise cyclopropylacetonitrile
2
(2.0 g, 24.7 mmol) in Et O (30 mL) at 0 °C under argon. The mixture was stirred for 2 h at
2
0 °C and then warmed to room temperature. After stirring for 9 h at room temperature,
THF (30 mL) and aqueous HCl (1 M) solution (30 mL) were added dropwise to the
mixture at 0 °C sequentially. The reaction mixture was warmed up to room temperature
and then stirred for 12 h. After the starting material was completely consumed, the mixture
was extracted with ethyl acetate and dried over anhydrous Na SO . The solvent was
2
4
evaporated under the reduced pressure and the residue was purified by column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 40:1 to 20:1) to
afford a yellow oil, which was directly used for the next step.
To a solution of the crude product above and TsOH·H O (939.7 mg, 4.94 mmol) in
2
CH Cl (150 mL) was added dropwise NBS (5.72 g, 32.11 mmol) under air. The reaction
2
2
mixture was refluxed for 8 h. After the starting material was completely consumed, the
mixture was quenched with saturated NaHCO solution, extracted with CH Cl and dried
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over anhydrous Na SO . The solvent was evaporated under the reduced pressure and the
2
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residue was purified by column chromatography on silica gel (eluent: petroleum ether:
1
CH Cl = 5:1) to afford 1w in 65% isolated yield (3.81 g) as a yellow oil. H NMR (400
2
2
MHz, CDCl ) δ 8.01-7.99 (m, 2H), 7.61-7.57 (m, 1H), 7.50-7.46 (m, 2H), 4.48 (d, J = 10.0
3
1
3
1
Hz, 1H), 1.89-1.80 (m, 1H), 0.96-0.88 (m, 2H), 0.62-0.41 (m, 2H); C{ H} NMR (100
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MHz, CDCl ) δ 192.4, 134.1, 133.6, 128.8, 128.7, 53.9, 14.6, 9.4, 6.5. IR (neat): 3084,
3
3
063, 3003, 1683, 1596, 1448, 1293, 1233, 1004, 942, 910, 833, 811, 781, 715, 685, 656.
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HRMS (EI-TOF) calcd for C H OBr [M] : 237.9993, found 237.9991.
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General procedure for optimization studies.
In nitrogen-filled glove box, zinc powder (26.2 mg, 0.4 mmol),
-bromo-1-tosylpiperidine 1a (63.6 mg, 0.2 mmol), CH CN or other solvents (1 mL) were
a
4
3
added sequentially to a 4 mL screw-cap vial. The vial cap was then securely fitted and
taken outside the glove box. D O (10.9 μL, 0.6 mmol) or H O (10.8μL, 0.6 mmol) was
2
2
o
added to the vial and the reaction mixture was stirred at 80 C (oil bath) for 10 h. After the
starting material was completely consumed, the mixture was filtered through a pad of silica
gel and washed with CH Cl . The solvent was evaporated under the reduced pressure and
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2
the residue was dissolved in CDCl . The NMR yields and deuterium incorporation were
3
determined by 1H NMR analysis of the crude mixture (for NMR yields,
1
,3,5-trimethoxybenzene (33.6 mg, 0.2 mmol) was used as an internal standard). For the
results, see Table 1.
Zinc-mediated dehalogenation reactions.
Typical procedure for dehalogenation of alkyl halides in the presence of D O. To a
2
sealable tube were added zinc powder (65.4 mg, 1.0 mmol), 4-bromo-1-tosylpiperidine 1a
(159.1 mg, 0.5 mmol), CH CN (2.5 mL) and D O (27.1 μL, 1.5 mmol) under argon (If the
3
2
alkyl bromide is a liquid, it is added after CH CN). The tube was sealed and immersed into
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an oil bath preheated at 80 C. After stirring for 6 h, the mixture was cooled down to room
temperature. Then the reaction mixture was filtered through a short silica gel column and
washed with dichloromethane. The solvent was evaporated under the reduced pressure and
the residue was purified by column chromatography on silica gel (eluent: petroleum ether:
ethyl acetate = 10:1) to afforded 2a-D in 97% yield (116.1 mg) with 92% deuterium
incorporation as a white solid.
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1
-Tosylpiperidine-4-d (2a-D). Mp 98-100 C. H NMR (400 MHz, CDCl ) δ 7.64 (d, J =
3
8
.0 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 2.97 (t, J = 5.2 Hz, 4H), 2.43 (s, 3H), 1.65-1.61 (m,
1
3
1
4H), 1.44-1.36 (m, 1.08H); C{ H} NMR (100 MHz, CDCl ) δ 143.2, 132.9, 129.4, 127.5,
3
4
6.8, 24.9, 23.3 (C-H), 22.9 (t, J = 19.4 Hz, C-D), 21.4. IR (neat): 2922, 2825, 1450, 1353,
1345, 1334, 1327, 1305, 1290, 1164, 1092, 1051, 1018, 930, 813, 800, 722, 705. HRMS
+
(
ESI-TOF) calcd for C H DNO S [M+H] : 241.1116, found 241.1117.
1
2
17
2
2,3-Dihydro-1H-indene-2-d (2b-D). Zinc powder (65.4 mg, 1.0 mmol), CH CN (2.5 mL),
3
2
-bromo-2,3-dihydro-1H-indene 1b (98.5 mg, 0.5 mmol) and D O (27.1 μL, 1.5 mmol)
2
o
were stirred at 80 C for 2 h. With 1,3,5-trimethoxybenzene (84.1 mg, 0.5 mmol) as
internal standard, the NMR yield was 92%. The crude product was purified by column
chromatography on silica gel (eluent: petroleum ether) to afford 2b-D in 82% isolated yield
1
(48.9 mg) with 90% deuterium incorporation as a colourless oil. H NMR (400 MHz,
CDCl ) δ 7.24-7.21 (m, 2H), 7.14-7.11 (m, 2H), 2.90 (d, J = 7.2 Hz, 4H), 2.09-2.00 (m,
3
1
3
1
1.10H); C{ H} NMR (100 MHz, CDCl ) δ 144.1, 125.9, 124.3, 32.7, 25.3 (C-H), 25.0 (t,
3
J = 20.2 Hz, C-D). IR (neat): 3020, 2939, 2845, 1482, 1458, 1305, 1025, 740. HRMS
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(EI-TOF) calcd for C H D [M] : 119.0845, found 119.0839.
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-Methoxy-1,2,3,4-tetrahydronaphthalene-2-d (2c-D). Zinc powder (65.4 mg, 1.0 mmol),
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2-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene 1c (120.6 mg, 0.5 mmol), CH CN (2.5
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o
mL) and D O (27.1 μL, 1.5 mmol) were stirred at 80 C for 4 h. The crude product was
2
purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate =
5
0:1) to afford 2c-D in 97% isolated yield (79.1 mg) with 90% deuterium incorporation as
1
a colourless oil. H NMR (400 MHz, CDCl ) δ 7.06 (t, J = 8.0 Hz, 1H), 6.69 (d, J = 7.6 Hz,
3
1H), 6.64 (d, J = 8.0 Hz, 1H), 3.80 (s, 3H), 2.74 (d, J = 5.6 Hz, 2H), 2.64 (t, J = 6.4 Hz,
1
3
1
2
H), 1.80-1.71 (m, 3.10H); C{ H} NMR (100 MHz, CDCl ) δ 157.3, 138.4, 125.8, 125.6,
3
121.3, 106.6, 55.1, 29.5, 23.0, 22.7, 22.8 (C-H), 22.4 (t, J = 19.3 Hz, C-D). IR (neat): 2920,
2
835, 1584, 1467, 1437, 1337, 1253, 1224, 1093, 1074, 791, 780, 758, 708, 668. HRMS
+
(
EI-TOF) calcd for C H DO [M] : 163.1107, found 163.1109.
1
1
13
Cyclododecane-d (2d-D). Zinc powder (65.4 mg, 1.0 mmol), CH CN (2.5 mL),
3
bromocyclododecane 1d (123.6 mg, 0.5 mmol) and D O (27.1 μL, 1.5 mmol) were stirred
2
o
at 80 C for 4 h. The crude product was purified by column chromatography on silica gel
(
eluent: petroleum ether) to afford 2d-D in 88% isolated yield (74.6 mg) with 95%
o
1
deuterium incorporation (determined by GC-MS) as a white solid. Mp 58-60 C. H NMR
1
3
1
(
400 MHz, CDCl ) δ 1.34 (s, 23H); C{ H} NMR (100 MHz, CDCl ) δ 23.7, 23.6, 23.6,
3
3
23.2 (t, J = 18.9 Hz, C-D). IR (neat): 2926, 2901, 2860, 2847, 1470, 1439, 716, 700.
+
HRMS (EI-TOF) calcd for C H D [M] : 169.1941, found 169.1949.
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(
1r,3r,5r,7r)-Adamantane-2-d (2e-D). Zinc powder (65.4 mg, 1.0 mmol),
2
-bromoadamantane 1e (107.6 mg, 0.5 mmol), CH CN (2.5 mL) and D O (27.1 μL, 1.5
3 2
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mmol) were stirred at 80 C for 41 h. The crude product was purified by column
chromatography on silica gel (eluent: pentane) to afford 2e-D in 53% isolated yield (36.6
o
1
mg) with 94% deuterium incorporation as a white solid. Mp 124-126 C. H NMR (400
1
3
1
MHz, CDCl ) δ 1.87 (s, 4H), 1.75 (s, 11.06H); C{ H} NMR (100 MHz, CDCl ) δ 37.73,
3
3
3
7.72, 37.3 (t, J = 19.0 Hz, C-D), 28.3, 28.2. IR (neat): 2896, 2847, 1448, 1352, 1100, 797.
+
HRMS (EI-TOF) calcd for C H D [M] : 137.1315, found 137.1318.
1
0
15
((Butoxy-3-d)methyl)benzene (2f-D). Zinc powder (65.4 mg, 1.0 mmol), CH CN (2.5
3
mL), ((3-bromobutoxy)methyl)benzene 1f (121.6 mg, 0.5 mmol) and D O (27.1 μL, 1.5
2
o
mmol) were stirred at 80 C for 8 h. The crude product was purified by column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 40:1) to afford 2f-D
1
in 91% isolated yield (75.6 mg) with 89% deuterium incorporation as a colourless oil. H
NMR (400 MHz, CDCl ) δ 7.33-7.25 (m, 5H), 4.49 (s, 2H), 3.46 (t, J = 6.8 Hz, 2H),
3
1
3
1
1
.62-1.56 (m, 2H), 1.40-1.34 (m, 1.11H), 0.91 (d, J = 7.2 Hz, 3H); C{ H} NMR (100
MHz, CDCl ) δ 138.6, 128.3, 127.5, 127.4, 72.8, 70.1, 31.7, 19.3 (C-H), 18.9 (t, J = 19.3
3
Hz, C-D), 13.8. IR (neat): 2957, 2929, 2855, 1496, 1454, 1363, 1098, 1028, 733, 696.
+
HRMS (EI-TOF) calcd for C H DO [M] : 165.1264, found 165.1267.
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1
15
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-(Butyl-3-d)-4-methoxybenzene (2g-D). Zinc powder (65.4 mg, 1.0 mmol), CH CN (2.5
3
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