Pentafluorophenyl Esters: Highly Chemoselective Ketyl Precursors for the Synthesis of α,α-Dideuterio Alcohols Using SmI2 and D2O as a Deuterium Source

Article abstract of DOI:10.1021/acs.orglett.9b04383

We report the first highly chemoselective synthesis of α,α-dideuterio alcohols with exquisite incorporation of deuterium (>98% [D₂]) using pentafluorophenyl esters as ketyl radical precursors, SmI₂ as a mild reducing agent, and D

Full text of DOI:10.1021/acs.orglett.9b04383

pubs.acs.org/OrgLett
Letter
Pentafluorophenyl Esters: Highly Chemoselective Ketyl Precursors
for the Synthesis of α,α-Dideuterio Alcohols Using SmI2 and D2O as a
Deuterium Source
Hengzhao Li,# Yuxia Hou,# Chengwei Liu, Zemin Lai, Lei Ning, Roman Szostak, Michal Szostak,*
and Jie An*
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ABSTRACT: We report the first highly chemoselective synthesis
of α,α-dideuterio alcohols with exquisite incorporation of
deuterium (>98% [D2]) using pentafluorophenyl esters as ketyl
radical precursors, SmI2 as a mild reducing agent, and D2O as the
deuterium source. This system tolerates a variety of functional
groups, offering rapid entry to valuable α,α-dideuterated alcohol
building blocks. More generally, this report introduces penta-
fluorophenyl esters as the most reactive O-ketyl precursors reported to date.
euterium-labeled compounds find wide applications in
D
diverse fields of science,1 including pharmaceutical
development,1a−d materials science,1e,f analytical standardiza-
tion techniques1b and toxicology studies.1b In principle, two
general methods for deuterium incorporation have been
developed: (1) small molecule synthesis2 and (2) direct
hydrogen-isotope-exchange.3 The recent surge of interest in
the synthesis of deuterated molecules has been bolstered by the
U.S. Food and Drug Administration approval of the first [D]-
containing drug, deutetrabenzine, which is a novel VMAT2
inhibitor for the treatment of cholera associated with
Huntington’s disease.1d
In this vein, we have described the synthesis of deuterated
alcohols and amines using single-electron-transfer (SET)
reagents.2a−g These methods offer the unique advantage of
introducing deuterium by exploiting open-shell pathways via
well-defined ketyl−metal complexes with high affinity for protic
additives, which, in turn, enables the convenient use of D2O or
deuterated alcohols as the source of deuterium.
From the industrial standpoint, it is critical that high degrees
of deuterium incorporation (>95% [D]) are achieved under
mild, functional-group-tolerant, and user-friendly reaction
conditions.2 Typically, direct hydrogen-isotope-exchange meth-
ods do not allow for the exquisite degree of deuterium
incorporation.3a,b Traditional reductive deuteration of esters
mediated by expensive and pyrophoric LiAlD4 affords α,α-
dideuterio alcohols in high deuterium incorporations (Figure
1A).2j However, this strategy suffers from low functional group
tolerance and limited scope. SET methods are more practical
and routinely give high degrees of deuterium incorporation;2a−g
however, these methods still fall short of the industrial standards.
In continuation of our studies, we recently questioned
whether the use of activated esters might provide a mild route
Figure 1. Reductive deuteration of esters: (a) traditional method, (b)
previous studies, and (c) this work, using pentafluorophenyl (pfp)
esters as the most reactive precursors to O-ketyl radicals.
to deuterated molecules by the chemoselective generation of
ketyl radicals.4 Herein, we report the first highly chemoselective
synthesis of α,α-dideuterio alcohols with an exquisite incorpo-
ration of deuterium (>98% [D2]), using pentafluorophenyl
esters as ketyl radical precursors and SmI2 as a mild source of
single electrons. There are two notable features of our findings:
Received: December 6, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04383
© XXXX American Chemical Society
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A

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(1) the method represents the most efficient and functional-
group tolerant synthesis of valuable α,α-dideuterated alcohol
building blocks by a SET mechanism; and (2) more broadly, this
report introduces pentafluorophenyl esters as the most reactive
O-ketyl progenitors reported to date (see Figure 1). We
anticipate that the synthesis of α,α-dideuterio alcohols and the
capacity to selectively form ketyl radicals from readily available
and bench-stable pentafluorophenyl esters will be of broad
interest in various areas of SET reactions.5,6
without changes in yield (Table 2, entries 1−4). However, when
the amount of D2O decreased below 75 equiv, a steady decrease
in the reaction yield was observed (Table 2, entries 5 and 6). The
reductive deuteration of 1a is a four-electron transfer process.
The amount of SmI2 could be decreased from 6 equiv to 5 equiv
without detrimental effect on the yield (Table 2, entries 4 and 7).
Shortening the reaction time from 15 min to 5 min or 30 s
resulted in yields of 90% or 70%, respectively, which indicated
that the half-life of this reaction is <30 s and the reaction
required ∼5 min to complete.
Our studies commenced with the examination of various
activated esters in the reduction using mild SmI2−D2O and
SmI2−MeOD-d4 reagents (Table 1). We were delighted to find
Next, the scope of this transformation was investigated using
the optimal conditions (Table 2, entry 7). As shown in Scheme
1, a remarkably broad range of aliphatic and aromatic
pentafluorophenyl esters could be converted to the correspond-
ing α,α-dideuterio alcohols in high yields and with excellent
deuterium incorporation (Scheme 1). For the first time, >98%
D2 incorporation was obtained with each tested example by any
SET process. Perhaps most notably, this method accommodates
an array of functional groups that are sensitive to other electron
transfer conditions, including chlorides (2y and 2o), bromides
(2j), iodides (2k), nitrile groups (2l), multiple fluorine
substitutions (2f and 2i), sulfonyl groups (2m), and alkynes
(2q). Other functional groups such as methoxy (2b), thiomethyl
(2c), phenolic hydroxyl (2e), sulfonamide (2x), and alkenes
(2w) are also stable under the reaction conditions. Interestingly,
conjugated alkenes, such as in perfluorophenyl (E)-3-(4-
methoxyphenyl)acrylate (1u) can be fully reduced to give
alcohols 2u with exquisite deuterium incorporation in the
sequential SET processes. Finally, it is important to note that a
gram scale reaction (2a, see Scheme 1) also resulted in >98% D2
incorporation. Of note, many of the products in Scheme 1 would
not be accessible using metal deuterides or Na/EtOD-d1.
To further demonstrate the synthetic utility of this reaction,
we examined deuterations of pentafluorophenyl esters derived
from pharmaceuticals (aspirin and probenecid) and fatty acids
(oleic acid) (Scheme 1B). Pleasingly, >98% deuterium
incorporation was obtained in each case (2v, 2w, and 2x),
highlighting the potential of this protocol to introduce
deuterium in medicinal chemistry and dietary supplements.
We further demonstrated the synthesis of important deuterium-
labeled building blocks (2y and 2z) for the synthesis of
deuterated drugs (Scheme 1C).7
Furthermore, as extremely useful building blocks, α,α-
dideuterio alcohols can be converted to numerous deuterium
labeled derivatives via well-established methods.8 We have
demonstrated that high deuterium incorporation content was
well-preserved after oxidative (Dess−Martin oxidation),8 basic
(NaH deprotonation),9 and acidic (Denton−Appel reaction)10
reaction conditions (Scheme 1D), leading to useful deuterium-
labeled aldehyde (3), ether (4), and halide (5) products with
>98% D-incorporations.
Most remarkably, pentafluorophenyl esters can be selectively
reduced in the presence of phenolic esters (2v) or alkyl esters
(2r and 2s), attesting to the outstanding chemoselectivity profile
of the pfp group (see Schemes 1A and 1B). To further
investigate the chemoselectivity of this reaction, we conducted
competition experiments between pentafluorophenyl ester (1d)
and representative carbonyl compounds (Scheme 1E). Remark-
able selectivity versus carboxylic acid, ethyl ester, amide, and
lactone substrates were observed, further highlighting the utility
of pentafluorophenyl esters as the most reactive O-ketyl
precursors discovered to date.
a
Table 1. Optimization Studies of the Leaving Group
b
entry
R
R′OD
R′OD (equiv) SmI2 (equiv) yield (%)
1
2
3
4
5
6
7
8
OPh
OPh
SEt
D2O
CD3OD
D2O
CD3OD
D2O
CD3OD
D2O
200
500
200
500
200
500
200
500
6
6
6
6
6
6
6
6
20
<5
65
SEt
10
OEt
OEt
Opfp
Opfp
<5
<5
>95
<5
CD3OD
a
Conditions: 1 in tetrahydrofuran (THF) was added to a solution of
SmI2 in THF, followed by R'OD at room temperature (rt), and the
b
1
resulting mixtures were stirred under Ar. Determined by H NMR.
that the model pentafluorophenyl ester (pfp = C6F5) showed far
superior reactivity to the analogous OPh, SEt, and OEt
derivatives, while the SmI2−D2O system was more reactive
than SmI2−MeOD-d4. Further optimization studies demon-
strated that the yield of 2a is influenced by the amount of both
SmI2 and D2O, whereas it is noteworthy that high deuterium
incorporation was uniformly obtained under different reaction
conditions (see Table 2). When 6 equiv of SmI2 was used, the
amount of D2O could be decreased from 200 equiv to 75 equiv
Table 2. Optimization of the Reductive Deuteration of
a
Pentafluorophenyl Esters, Using SmI2−D2O
b
b
entry SmI2 (equiv) D2O (equiv) time (min) yield (%) [D2] (%)
1
2
3
4
5
6
7
8
9
6.0
6.0
6.0
6.0
6.0
6.0
5.0
4.0
5.0
5.0
200
150
100
75
50
25
75
75
75
75
15
15
15
15
15
15
15
15
>98
>98
>98
>98
85
45
>98
75
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
5.0
0.50
90
70
10
a
Conditions: 1a in THF was added to the solution of SmI2 in THF,
followed by D2O at rt, and the resulting mixtures were stirred under
b
1
Ar. Determined by H NMR.
B
https://dx.doi.org/10.1021/acs.orglett.9b04383
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Scheme 1. Reductive Deuteration of Pentafluorophenyl Esters Using SmI2−D2O, Applications, Derivatization, and Competition
a
Studies
a
Conditions: 1 (0.20 mmol, 1.0 equiv) in THF was added to the solution of SmI2 in THF (5.0 equiv), followed by D2O (75 equiv) at rt, and the
b
resulting mixtures were stirred for 15 min under Ar. Isolated yields. SmI2 (7.0 equiv) and D2O (105 equiv) were used.
Intrigued by the superb chemoselectivity of the reaction, we
performed DFT calculations to probe the facility of ester
reduction (B3LYP/6-311++G(d,p)) (Figure 2). The computa-
tional method reported by Nicewicz was employed to determine
C
https://dx.doi.org/10.1021/acs.orglett.9b04383
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Letter
Jie An − China Agricultural University, Beijing, China;
orcid.org/0000-0002-1521-009X; Email: jie_an@
cau.edu.cn
Other Authors
Hengzhao Li − China Agricultural University, Beijing,
China
Yuxia Hou − China Agricultural University, Beijing, China
Chengwei Liu − Rutgers University, Newark, New Jersey;
orcid.org/0000-0003-1297-7188
Zemin Lai − China Agricultural University, Beijing, China
Lei Ning − China Agricultural University, Beijing, China
Roman Szostak − Wroclaw University, Wroclaw, Poland
Figure 2. Redox potentials of O-ketyl precursors. Note that MeCO2pfp
derived from unactivated alkyl precursor is characterized by a lower
redox potential (E1/2 = −1.82 V) than PhCO2Me derived from activated
benzoic acid (E1/2 = −2.12 V). See the Supporting Information (SI) for
details.
electrochemical potentials.11 To our delight, we found that the
reduction potential of a model pfp acetate, MeCO2-pfp, (E1/2
=
Complete contact information is available at:
−1.82 V vs SCE in CH3CN) is dramatically lower than that of
methyl acetate, MeCO2-Me (E1/2 = −3.06 V vs SCE in CH3CN)
and phenyl acetate, MeCO2-Ph (E1/2 = −2.75 V vs SCE in
CH3CN), in agreement with the strong activating effect of the
pfp group and the selectivity studies. Furthermore, the
calculations suggest that the attachment of the pfp group to
simple unactivated alkyl carboxylic acids has a comparable effect
to using activated benzoic acids (PhCO2-pfp, E1/2 = −1.79 V vs
SCE in CH3CN; PhCO2-Me, E1/2 = −2.12 V vs SCE in CH3CN;
PhCO2−Ph, E1/2 = −1.96 V vs SCE in CH3CN). This is much
lower than that of a model six-membered lactone (tetrahydro-
2H-pyran-2-one, E1/2 = −2.86 V vs SCE in CH3CN)the most
reactive O-ketyl precursor to date2,4and in the range of simple
ketones (PhCOMe, E1/2 = −1.93 V vs SCE in CH3CN).
In summary, the first highly chemoselective synthesis of α,α-
dideuterio alcohols resulting in exquisite levels of deuterium
incorporation (typically >98% [D2]) has been developed under
SET conditions using pentafluorophenyl esters as the most
reactive O-ketyl precursors reported to date. A mild electron
donor SmI2 and a benign deuterium source D2O were employed
as reagents. This method is distinguished by its remarkable
functional group tolerance, including even iodides, alkyl and
phenolic esters, and lactones being tolerated. Furthermore, this
protocol has been applied to the synthesis of key deuterated
intermediates for the preparation of deuterated drugs.
Derivatization studies demonstrated full preservation of the
deuterium content under various conditions. The high reactivity
of pentafluorophenyl ester as the O-ketyl precursor has been
demonstrated experimentally and further established by
determination of redox potentials. We anticipate that the high
capacity of pentafluorophenyl esters to serve as O-ketyl
precursors will be of interest in various areas of electron
transfer. Further applications in SET reactions will be the subject
of our future work.
https://pubs.acs.org/10.1021/acs.orglett.9b04383
Author Contributions
#These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank National Key R&D Plan (No. 2017YFD0201900),
NSFC (No. 21602248), Natural Science Foundation of Beijing
Municipality (No. 2192026), and Tianjin Haiyi Tech, Ltd., for
financial support. M.S. gratefully acknowledges Rutgers
University and the NSF (CAREER CHE-1650766). We thank
the Wroclaw Center for Networking and Supercomputing
(Grant No. WCSS159).
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04383.
Experimental details, characterization data, and computa-
tional details (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Michal Szostak − Rutgers University, Newark, New Jersey;
orcid.org/0000-0002-9650-9690;
Email: michal.szostak@rutgers.edu
D
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