Water Compatible Hypophosphites- d2 Reagents: Deuteration Reaction via Deutero-deiodination in Aqueous Solution

Article abstract of DOI:10.1021/acs.orglett.0c00001

Contrary to conventional deuteration approaches which typically entail deuterated solvents and/or moisture exclusion, an unprecedented deutero-deiodination reaction attainable in aqueous (H₂O) solution is presented herein. By utilizing the stability of inorganic deuterated calcium/sodium hypophosphites against wayward H/D isotopic exchange within pH 2.5-11.7, these shelf-stable, nontoxic, cost-effective, and environmentally benign deuteration reagents mediate deuteration of a broad range alkyl and aryl iodides with ample isotopic incorporation in aqueous (H₂O) solution.

Full text of DOI:10.1021/acs.orglett.0c00001

pubs.acs.org/OrgLett
Letter
Water Compatible Hypophosphites‑d2 Reagents: Deuteration
Reaction via Deutero-deiodination in Aqueous Solution
Zejin Song, Jing Zeng, Ting Li, Xiang Zhao, Jing Fang, Lingkui Meng, and Qian Wan*
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ABSTRACT: Contrary to conventional deuteration approaches
which typically entail deuterated solvents and/or moisture
exclusion, an unprecedented deutero-deiodination reaction attain-
able in aqueous (H2O) solution is presented herein. By utilizing
the stability of inorganic deuterated calcium/sodium hypophos-
phites against wayward H/D isotopic exchange within pH 2.5−
11.7, these shelf-stable, nontoxic, cost-effective, and environ-
mentally benign deuteration reagents mediate deuteration of a
broad range alkyl and aryl iodides with ample isotopic incorporation in aqueous (H2O) solution.
euterium (2H or D) as a rare but stable and
nonradioactive isotope of hydrogen was first isolated
Scheme 1. Various Deuteration Reagents in Deuteration
Reactions
D
by Harold Urey in 1932,1 and mainly exists in the form of
deuterium oxide (D2O). Notwithstanding the minute natural
abundance of 0.0156%,2 deuteration has served as a paramount
research tool in metabolic studies,3 microanalysis,4 spectro-
metric simplification, and mechanistic investigation of organic
reactions.5 In a clinical setting, deuterium embedment has
proved prolific to improve the absorption, distribution,
metabolism, and excretion (ADME) properties of drug
candidates while retaining the biological potencies.6 Since
the introduction of deuterium to medicinal chemistry in 1961,7
the decades long pursuit has eventually witnessed the approval
of the first deuterated drug (Austedo) in 2017, which could
also signify a new era of deuterated drugs.
In chemistry laboratories, this versatility of deuterium-
labeled compounds has driven the development of valuable
methods for their access.8 A suite of deuteration reagents,
including NaBD4,9 LiAlD4,10 DCOONa,11 n-Bu3SnD,12
deuterated silanes,13 deuterated alcohols,14 deuterated
acids,15 deuterated acetones,8k and D2 gas, etc.,8a,h have been
reliable deuterium sources for various highly efficient labeling
reactions (Scheme 1a). However, limitations such as some
reagents are unstable, flammable,9,10 toxic,12 water insoluble,12
or noneconomical8a,h given large excess is often encountered.
As the most abundant and thus ideal deuterium source,
2
application of deuterium oxide (D2O) for direct H atom
transfer (HAT) in deuterium-labeling reactions is stymied by
the high bond dissociation free energy (BDE) of D2O.16
MacMillian,17 Renaud,18 Studer,19 Xie,20 Wu,21a and Wang21b
et al. have auspiciously enabled these deuterium transfer
processes with the aid of various thiols as the HAT catalysts
(Scheme 1b) in high efficiency; the isotopic incorporation
ratio is nevertheless liably affected by the facile contamination
of 1H2O in deuterium oxide, substrates, cosolvent, or fortuitous
Received: January 1, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00001
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
exposure to humid environment. “Anhydrous” deuterium oxide
(of high quality, high purity, and low H-incorporation) is
therefore used in large excess or even as solvent. Considering
the water-sensitivity (LiAlD4) and insolubility (n-Bu3SnD) of
conventional deuteration reagents, as well as the fast H−D
exchange between the reagents (deuterated alcohol, acid, D2O,
acetone, D2, etc.), together with other issues, enlisting H2O as
solvent in deuteration protocols seems counterintuitive
although H2O is considered to be the most ideal solvent
regarding environmental and economical concerns.22 Thus,
finding a novel water-tolerable deuteration protocol that is
robust, efficient, safe, low cost, and operationally simple
became a highly appealing task to us.
Scheme 2. pH Dependent H−D Exchange Studies of
a
Deuterated Hypophosphite
En route toward large scale preparation of deoxy sugars,23
we were intrigued to discover that calcium hypophosphite
(Ca(H2PO2)2) used to mediate reductive hydro-deiodination
reaction in water delivered identical deiodination efficency
without deuteration when the same reaction was performed in
D2O or H2O. This conspicuously ruled out an intermediate
H−D exchange step. Galvanized by this observation,
−
deuterated hypophosphite salts (D2PO2 ) could be the idea;
reducing reagents for clean halogen-D exchange reaction in an
aqueous system as conceived. Oshima24 and Oba25 have
independently introduced deuterated hypophosphites as
deuteration reagents in deutero-dehalogenation reactions
with D2O as the reaction solvent or cosolvent (Scheme
1c).26 In Oshima’s work, the in situ generation of D3PO2 via
isotopic exchange of NaH2PO2 in DCl/D2O for one-pot
radical deiodination−deuteration reaction necessitates strict
exclusion of H2O in the reaction system. Additionally, the
radical pathway renders the efficiency of the D-incorporation
level due to the potential H-donation ability of the solvent such
as dioxane. The more recent work of Oba et al. reported a
palladium-catalyzed reductive deuteration in D2O using D3PO2
as a deuterium source under alkaline conditions. As D2
generated from D3PO2 and D2O under the palladium-catalyzed
conditions was the actual deuterium source, the presence of
H2O might significantly attenuate the deuteration efficiency
due to cogeneration of H2 or HD.8a,27
a
H-decoupling 31P NMR spectra, 243 MHz. Ca(D2PO2)2 (0.12 mol/
L), spectra were recorded after H/D exchange for 24 h, pH was
measured by pH meter (for details, see the Supporting Information
(SI)).
water-soluble methyl 6-iodoglucoside 1b as a model reaction
(Table 1). The radical reductive deutero-deiodination reaction
proceeded smoothly in H2O to afford 2b with 98% D-
incorporation by employment of 0.8 equiv of Ca(D2PO2)2 as
the reductant, 0.2 equiv of 2,2′-Azobis(2-methyl-propiona-
Table 1. Deutero-dehalogenation Reaction with Deuterated
Hypophosphite in H2O
We then considered the stability of a proposed deuterating
−
reagent (D2PO2 ) under ambient or even aqueous conditions.
Prototropic tautomerization in phosphinylidene compounds
underlies the preparation of D3PO2 from aqueous H3PO2 and a
large amount of D2O via H−D exchange (Scheme 2a).28 This
process causes the deuteration level of D3PO2 to be extremely
sensitive to humidity (note: H3PO2 is highly hydroscopic). To
our favor, the H−D exchange often occurs under strong acidic
conditions. Moreover, Montchamp et al. suggested an
extremely slow prototropic tautomerization rate of NaH2PO2
compared to H3PO2.28a On the basis of these reports, we
surmised that the H−D exchange of hypophosphite should be
highly pH dependent which could be leveraged to preserve the
stability of deuterated hypophosphite salts in a certain pH
range. To verify this hypothesis, we first examined the H−D
exchange rate of Ca(D2PO2)2 (99% D-inc.) in aqueous
solutions with different pH values (Scheme 2b−d). Pleasingly,
rapid H−D exchange was observed under strong acidic and
alkaline conditions, but was virtually absent at pH 2.5−11.7,
which cohered with our hypothesis. This also implied that
these deuterated hypophosphite salts should augur well for the
conceived deutero-deiodination reaction in H2O (Scheme 2d).
On the basis of our hypothesis and preliminary observations,
we commenced to realize the titled reaction with reduction of
yield
a
entry
1
1
reagents (equiv)
(D-inc.)
c
1b
1c
1c
1a
1a
Ca(D2PO2)2/AIBA/NaHCO3 (0.8/0.2/2.0)
Ca(D2PO2)2/AIBA/NaHCO3 (0.8/0.2/2.0)
Ca(D2PO2)2/AIBA/NaHCO3 (1.2/0.2/2.0)
Ca(D2PO2)2/AIBA/Na2CO3 (4.0/0.3/5.0)
NaD2PO2·H2O/AIBA/NaHCO3
(4.0/0.3/2.5)
93% (98%)
82% (99%)
92% (99%)
91% (94%)
94% (97%)
b
d
2
3
b
4
5
e
6
1a
10% Pd/C/Ca(D2PO2)2/Na2CO3
(1.5%/2.0/4.0)
N.R.
e
7
1a′ 10% Pd/C/Ca(D2PO2)2/Na2CO3
61% (46%)
(1.5%/2.0/4.0)
a
1
Isolated yield; deuterium incorporation level was determined by H
b
c
NMR. t-BuOH was used as cosolvent (t-BuOH/H2O 1:1). Yield
d
e
obtained after acylation. Yield determined by 1H NMR. 50 °C; 5 h.
AIBA = 2,2′-Azobis(2-methyl-propionamide) dihydrochloride.
B
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a
Scheme 3. Substrate Scope
a
b
1
Isolated yield, and the deuterium incorporation level was determined by H NMR. For detailed reaction conditions, see the SI. Condition A:
Ca(D2PO2)2/NaHCO3/AIBA (0.8/2.0/0.2) in H2O, 80 °C, yield was obtained after acylation. Condition B: Ca(D2PO2)2/NaHCO3/AIBA (1.2/
2.0/0.2) in t-BuOH/H2O (v/v = 1:1), 80 °C. Condition C: NaD2PO2·H2O/NaHCO3/AIBA (4.0/2.5/0.3), in H2O, 80 °C. Unless otherwise
specified, the equivalents of reagents were based on each iodine.
mide) dihydro-chloride (AIBA) as the radical initiator, and 2.0
equiv of NaHCO3 as the base (entry 1). Extension of these
conditions to peracetylated iodoglucoside 1c was unsuccessful
due to the poor water solubility of 1c. To accommodate water-
insoluble substrates, cosolvent should be used, but the
potential H-donation ability of an organic solvent such as
dioxane, THF, acetonitrile, and methanol led to the use of
corresponding deuterated solvents. In contrast to these
traditional examples,24,29 t-BuOH was introduced as a
cosolvent in a 1:1 ratio to avoid the undesirable proton
abstraction. Upon this modification, the yield was improved to
82% with 99% D-incorporation (entry 2). The reaction yield
could be further enhanced to 92% with an increased amount of
Ca(D2PO2)2 to 1.2 equiv (entry 3). Encouraged by these
successes, the viability of aryl iodides in the present conditions
was then investigated. The efficiency of the current deuteration
reaction diminished altogether when the above optimized
conditions were applied to 4-iodobenzoic acid 1a. Switching to
Na2CO3 and 4.0 equiv of Ca(D2PO2)2 in the reaction system
aided to deliver 2a in satisfactory yield and D-incorporation
level (entry 4). Interestingly, the alternative NaD2PO2·H2O
delivered a better D-incorporation level in 2a. In this case, 2.5
equiv of NaHCO3 were sufficient to maintain the high
efficiency (2a, entry 5). Drawing on Oba’s conditions, Pd/C
was attempted as catalyst in place of the radical initiator AIBA,
which was found incompatible with the current deiodination−
deuteration protocol (entry 6). When applied to 1a′ with
chloride substitution, dechlorination occurred as expected to
furnish 2a in moderate yield, but with a poor D-incorporation
level (entry 7) due to the existence of H2O. These results
indicated the high efficiency of this deutero-dehalogenation
reaction was ensured by the radical pathway. It is worth noting
that both Ca(D2PO2)2 and NaD2PO2·H2O are cheap and
shelf-stable and could be easily prepared on large scales (the
raw material cost for Ca(D2PO2)2 is around 3.5 $/g and for
NaD2PO2·H2O is around 2.7 $/g; for details, see the SI).
With the optimized conditions in hand, we next examined
the substrate scope (Scheme 3). All surveyed substrates,
including primary and secondary alkyl iodides (2d−2o) as well
as aryl iodides (2p−2z) underwent deutero-deiodination in
good yields with an excellent D-incorporation level under
respective optimal conditions. Acyl groups such as acetyl (2f,
2g), benzoyl (2k), and lactone (2o) were left unscathed due to
the weak basicity of the reaction conditions. Reactions with
1,6-anhydosugar (2j) and glycal (2l) provided corresponding
deuterated products perfectly. Reactive hydrogen atoms
susceptible to H−D exchange with other deuteration reagents
remained innate under the current conditions leading to
deuterated products with high reaction efficiencies (2d−2e, 2l,
2o, 2p−2zd). Both electron-donating and -withdrawing aryl
substituents posed negligible effects on deuteration efficiency
except a longer reaction time was required of aryl iodides
containing electron-donating groups (2s, 2t, 2z). The bromo
and chloro substituents (2u−2x) located in substrates
C
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remained unaffected, which displayed the chemoselectivity of
current method and authorized downstream functionalization.
In polyiodides (2i, 2zc, 2zd) with more than one reaction
center, multideuteration took place smoothly with a high
incorporation level at all sites. Lastly, the utility of this
methodology was evidenced on gram scale, as both an
aromatic (1a) and alkyl substrate (1c) were successfully
transformed to respective deuterated analogues with excellent
D-incorporation levels and isolation yields.
Subsequently, with reference to our previous mechanistic
studies on the hypophosphite-mediated deiodination reac-
tions,23 the plausible radical chain mechanism for this
deuteration reaction was outlined in Scheme 4. The radical
The inertness of these deuterated hypophosphite salts against
H/D isotopic exchange allows radical dehalogenative deutera-
tion reaction to be performed in water, which is in stark
contrast to stringent moisture exclusion required in most
conventional deuteration reactions. A wide range of alkyl and
aryl iodides showed excellent compatibility with this cost-
effective and environmental-benign deuterium labeling proto-
col. The inclusion of water-insoluble alkyl iodides was made
viable using t-BuOH as cosolvent. To the best our knowledge,
this is the first example of deuteration−halogen exchange
reactions in H2O.
ASSOCIATED CONTENT
■
sı
* Supporting Information
Scheme 4. Postulated Mechanism
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00001.
Detailed experimental procedures, characterization, and
1
copies of H and 13C NMR spectra of new compounds
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
Qian Wan − Hubei Key Laboratory of Natural Medicinal
Chemistry and Resource Evaluation, School of Pharmacy,
Huazhong University of Science and Technology, Wuhan, Hubei
430030, P. R. of China; orcid.org/0000-0001-9243-8939;
Email: wanqian@hust.edu.cn
Authors
Zejin Song − Hubei Key Laboratory of Natural Medicinal
Chemistry and Resource Evaluation, School of Pharmacy,
Huazhong University of Science and Technology, Wuhan,
Hubei 430030, P. R. of China
Jing Zeng − Hubei Key Laboratory of Natural Medicinal
Chemistry and Resource Evaluation, School of Pharmacy,
Huazhong University of Science and Technology, Wuhan,
Hubei 430030, P. R. of China; orcid.org/0000-0001-
9116-9861
Ting Li − Hubei Key Laboratory of Natural Medicinal
Chemistry and Resource Evaluation, School of Pharmacy,
Huazhong University of Science and Technology, Wuhan,
Hubei 430030, P. R. of China
Xiang Zhao − Hubei Key Laboratory of Natural Medicinal
Chemistry and Resource Evaluation, School of Pharmacy,
Huazhong University of Science and Technology, Wuhan,
Hubei 430030, P. R. of China
Jing Fang − Hubei Key Laboratory of Natural Medicinal
Chemistry and Resource Evaluation, School of Pharmacy,
Huazhong University of Science and Technology, Wuhan,
Hubei 430030, P. R. of China
initiator first abstracts a deuterium atom from deuterated
hypophosphite to produce a phosphorus centered radical I (eq
1). The radical chain is propagated by abstraction of an iodine
atom from an iodide (1) by radical I, yielding carbon centered
radical II and iodo-phosphosrous anion III (eq 2). Hydrolysis
of intermediate III occurs facilely to give a monodeuterated
phosphorus anion (IV), observable by 31P NMR (for details,
see SI). Upon deuterium atom abstraction of radical II by
deuterated hypophosphite as a radical chain carrier, the
formation of deuterated product 2 is accompanied by
regeneration of phosphorus centered radical I (eq 3).
Moreover, a small amount of phosphate was observed by 31P
NMR, indicated that the in situ generated deuterated phosphite
(IV) partially served as the D-donor. Two factors could be
attributed to the high deuteration efficiency: first, the weakly
basic environment inhibits H−D exchange between the
deuterated hypophosphite and H2O; second, the high BDEs
of nondeuterated solvent (H2O and t-BuOH) deter the
undesirable proton abstraction.
Lingkui Meng − Hubei Key Laboratory of Natural Medicinal
Chemistry and Resource Evaluation, School of Pharmacy,
Huazhong University of Science and Technology, Wuhan,
Hubei 430030, P. R. of China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00001
In summary, described herein is a novel deuteration reaction
adopting deuterated hypophosphite salts as shelf-stable,
effective, nontoxic, and easily accessible deuterium sources.
Notes
The authors declare no competing financial interest.
D
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ACKNOWLEDGMENTS
■
The financial support from National Natural Science
Foundation of China (21877043, 21702068, 21672077,
21761132014), Wuhan Creative Talent Development Fund,
Fundamental Research Funds for the Central Universities
(2019kfyXKJC080, 2019JYCXJJ046, 2017KFYXJJ150) is
greatly appreciated. We also thank the Analytical and Testing
Center of HUST for NMR tests.
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