Deoxygenative Deuteration of Carboxylic Acids with D2O

Article abstract of DOI:10.1002/anie.201811522

We report a general, practical, and scalable means of preparing deuterated aldehydes from aromatic and aliphatic carboxylic acids with D₂O as an inexpensive deuterium source. The use of Ph₃P as an O-atom transfer reagent can facilitate the deoxygenation of aromatic acids, while Ph₂POEt is a better O-atom transfer reagent for aliphatic acids. The highly precise deoxygenation of complex carboxylic acids makes this protocol promising for late-stage deoxygenative deuteration of natural product derivatives and pharmaceutical compounds.

Full text of DOI:10.1002/anie.201811522

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Accepted Article
Title: Deoxygenative Deuteration of Carboxylic Acids with D2O
Authors: Jin Xie
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201811522
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10.1002/anie.201811522
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Deoxygenative Deuteration of Carboxylic Acids with D2O
Muliang Zhang, Xiang-Ai Yuan, Chengjian Zhu and Jin Xie*
Abstract: We report a general, practical and scalable means of
preparing deuterated aldehydes from aromatic and aliphatic
carboxylic acids with D2O as an inexpensive deuterium source. The
use of Ph3P as an O-atom transfer reagent can facilitate the
deoxygenation of aromatic acids while Ph2POEt is a better O-atom
transfer reagent for aliphatic acids. Highly precise deoxygenation of
complex carboxylic acids allows this protocol promising for late-stage
deoxygenative deuteration of natural product derivatives and
pharmaceutical chemicals.
Aromatic aldehydes are very useful building blocks in organic
synthesis.[8] The development of a highly efficient protocol to
construct aromatic aldehydes deuterated at the formyl position
should enhance the library of deuterated lead compounds.
Several methodologies that access deuterated aromatic
aldehydes have been reported. Representative strategies include
Pd/Rh co-catalyzed reductive carbonylation of arylhalides
(Scheme 1Aa),[9] Ru- and Ir-catalyzed hydrogen isotope
exchange (HIE) (Scheme 1Ab)[10] and careful reduction of
carboxylic acid derivatives with deuterated reductants[11]
(Schemes 1Ac and 1Ad). Given the importance of deuterated
aromatic aldehydes, a convenient and step-economical synthetic
approach is still highly desired. Moreover, late-stage introduction
of deuterium into structurally complex aldehydes remains a
challenge in organic synthesis.
Deuteration labeling technique has long been regarded as an
important tool in analysis of drug metabolism[1] and investigation
of reaction mechanism[2] as well as nuclear magnetic resonance
spectroscopy[3] and mass spectrometry[4]. Incorporation of
deuterium atom can dramatically enhance the metabolism and
pharmacokinetic properties of parent drugs and drug
candidates.[5] In 2017, FDA permission for the entry to market of
the first deuterated drug, deutetrabenazine,[6] has significantly
Very recently, our group achieved the first direct synthesis of
ketones from abundant aromatic acids and alkenes in aqueous
solution by phosphoranyl radical-assisted deoxygenation enabled
by visible-light photoredox catalysis.[12] We questioned if the
generation of acyl radicals from aromatic acids has the potential
to produce deuterated aldehydes with D2O. However, the strong
bond dissociation energy (BDE) of D-O-D bonds (BDE = 118 kcal
mol-1) prohibits a direct deuterium atom transfer (HAT) from
D2O.[13] Very recently, radical deuteration with D2O was
successfully reported by MacMillan[14a] and by Renaud[14b] using a
HAT catalyst to bridge the energy gap. Our experience in
synergistic thiol catalysis and photoredox catalysis[15] suggested
that the thermodynamic property of thiols was an important factor
in the success of such reactions. The use of a suitable thiol
catalyst may be able to tune the equilibrium with D2O as well as
the HAT rate and possibly furnish deuterated aldehydes. With
these considerations in mind, we herein report a general and
practical radical deoxygenative deuteration of carboxylic acids
with D2O enabled by synergistic thiol catalysis, photoredox
catalysis and phosphoranyl radical chemistry (Scheme 1B).
A synergistic mechanism for direct deoxygenative deuteration
of carboxylic acids is proposed in Scheme 2. Density functional
theory (DFT) calculations indicate that the pKa of thiols (2a-d)
ranges from 10-16, and the proton of a thiol catalyst can exchange
with excessive D2O (pKa = 32)[16] to furnish a D-labeled thiol (4),
which serves as the source of deuterium. The photoexcited
*Ir(dF(CF3)ppy)2(dtbbpy)]PF6 [1/2Ered (*IrIII/IrII) = + 1.21 V vs SCE;
τ = 2.3 μs][17] is a strong oxidant, which can achieve single electron
oxidation of triphenylphosphine (1/2Ered = + 0.98 V vs SCE)[18] to
generate a triphenylphosphine radical cation (7). This radical
cation reacts with carboxylate ion to form an intermediate (8),
which can proceed by -scission[19] to produce triphenylphosphine
oxides and a reactive acyl radical (9) as a result of the strong
affinity between phosphine and oxygen atom. The DFT
calculations also demonstrate that although the S-H bond in thiols
(2a-d) varies significantly, the BDE for C-H of an aldehyde (94
kcal mol-1) is still much higher than that of the S-H bond of these
thiols (2a-d) (80-88 kcal mol-1). The BDE gap between C-H and
S-H bonds would be an important driving force for HAT processes
(4 → 5 and 9 → 3). In this context, the nucleophilic acyl radical
(9)[20] can readily undergo a HAT from the thiol (4) to form
motivated the development
of deuteration synthetic
methodology,[7] and will certainly accelerate the discovery and
development of deuterium-labeled drugs.
Scheme 1. Summary of previous and current work.
M. Zhang, Prof. Dr. C. Zhu, Prof. Dr. J. Xie,
State Key Laboratory of Coordination Chemistry, Jiangsu Key
Laboratory of Advanced Organic Materials, School of Chemistry and
Chemical Engineering, Nanjing University, Nanjing 210023, China
Email: xie@nju.edu.cn
Homepage: http://hysz.nju.edu.cn/xie
Prof. Dr. X.-A. Yuan
School of Chemistry and Chemical Engineering, Qufu Normal
University, Qufu 273165, China
Prof. Dr. C. Zhu
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry
Shanghai 200032, China
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201811522
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deuterated aldehydes, a reaction which is controlled by a polarity
matching effect.[21] The generated electrophilic thiyl radical (5)
subsequently accepts one electron from reducing Ir(II)-species to
complete the photoredox cycle and the generated thiol anion (6)
attracts one deuteron from D2O to restart the thiol catalysis.
Table 1: Optimization of the reaction conditions
Entry
Variation of standard conditions
none
Yield[a]
86%
12%
nd
D-Inc.[b]
96%
95%
nd
1
2
3
4
5
6
7
8
9
Ph2POEt instead of Ph3P
P(OEt)3 instead of Ph3P
no Ph3P
nd
nd
2a instead of 2c
65%
38%
20%
80%
nd
95%
96%
94%
92%
nd
2b instead of 2c
2d instead of 2c
Ir(dF(Me)ppy)2(dtbbpy)]PF6
no light or no photocatalyst
Standard conditions: 1a (0.2 mmol), Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (1 mol %), 2c
(15 mol %), Ph3P (1.1 equiv), K2HPO4 (1.0 equiv) and DCM-D2O (2 mL, v/v =
1:1), 5 W blue LEDs, 36 h. [a] Isolated yield. [b] Determined by 1H NMR. nd =
not detected.
With the optimized conditions in hand, we investigated the
scope of carboxylic acids in this transformation (Scheme 3). In
general,
the
developed
phosphoranyl
radical-assisted
deoxygenation potentially could overcome the limitation of redox-
potential of carboxylic acids and thus in principle, a wide variety
of aromatic carboxylic acids should be competent substrates. A
diverse range of electron-donating- (-Ph, t-Bu, -NMe2, -BnO, -
SMe and -NBoc), and electron-withdrawing- (-COOMe, -COMe
and -pyridinyl) functional groups on the ortho-, meta- and para-
position of phenyl rings are entirely compatible. Such substrates
uniformly deliver the desired deuterated aryl aldehydes (3a-r) in
moderate to good (up to 92%) yields with high D-incorporation
(92-97% D) exclusively at the formyl position. Both 1-naphthoic
acids and 2-naphthoic acids are efficient substrates (3o, 3p). The
reactive terminal alkene and alkyne units remain intact (3s, 3t).
Intriguingly, several relatively sensitive yet versatile functional
groups, such as a free hydroxyl (3u), or amino group (3x),
halogen (3i and 3j), boronic esters (3v, 3w), aldehyde (3z) and
ketone (3n), tolerate the deoxygenative deuteration conditions
well, and this should support promising broad-ranging
applications in synthetic and medicinal chemistry. In addition, the
reaction can be scaled up conveniently and the product 3x was
obtained in 76% yield with high D-incorporation when the reaction
was carried out on an 8 mmol scale. The robustness of the
reaction is illustrated by the precise synthesis of mono-deuterated
meta-phthalaldehyde derivatives (3z). The quinoline- and indole-
heteroaromatic acids (3aa, 3bb) undergo this deoxygenative
deuteration smoothly. In addition to aromatic acids, aliphatic
Scheme 2. Mechanistic proposal.
Our investigation began with optimization of the deoxygenative
deuteration of 4-phenylbenzoic acid with D2O (Table 1). The
optimized reaction conditions include of
1
mol% of
Ir[dF(CF3)ppy]2(dtbbpy)PF6 as the photocatalyst, 15 mol% of
2,4,6-triisopropylbenzenethiol (2d) as the HAT catalyst, 1.1 equiv
Ph3P as an oxygen-atom transfer reagent and DCM/D2O (1:1, v/v)
as solvent (Entry 1). The desired deuterated product (3a) was
obtained in 86% yield with 96% D-incorporation using
commercially inexpensive D2O as an ideal deuterium source. The
use of other relative electron-poor trivalent phosphorus
compounds, such as Ph2POEt and P(OEt)3 led to decreased
reaction yields (Entries 2 and 3), suggesting that the choice of O-
transfer reagent was crucial for the success of the reaction
(Entries 2-4). When other thiols were employed under the same
conditions, the reaction yields significantly decreased, although
the D-incorporation remained at a high level (Entries 5-7). The use
of
a
lower
oxidation
potential
photocatalyst,
Ir(dF(Me)ppy)2(dtbbpy)]PF6 [1/2Ered (*IrIII/IrII) = + 0.97 V vs SCE; τ
= 1.2 μs][22] resulted in a slightly declined yield and D-
incorporation (Entry 8). Control experiments demonstrated that
the deoxygenative deuteration reaction could not occur in the
absence of either light or photocatalyst (Entry 9).
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10.1002/anie.201811522
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COMMUNICATION
Scheme 3. Reaction scope: see Supporting Information (SI) for detailed reaction conditions. The yields are isolated yields after column chromatography on SiO2
and D-content was determined by 1H NMR. [a] Proton/deuterium exchange ratio of acidic protons with D2O.
carboxylic acids are also good substrates and afford deuterated
aliphatic aldehydes (3cc-ff) with moderate yields and D-
incorporation under modified reaction conditions.[23] In such
cases, the combination of Ir(dF(Me)ppy)2(dtbbpy)]PF6 as
photocatalyst and Ph2POEt as an O-atom transfer reagent is a
key factor for control of deoxygenation as opposed to the well-
studied decarboxylation.[24]
This excellent functional group tolerance enables potential
application of the reaction in synthesis of complex deuterated
aldehydes by late-stage functionalization of biologically active
natural products, pharmaceuticals, and agrochemicals (Scheme
3, lower part). Deoxygenative deuteration of pharmaceuticals
such as hiestrone (3gg), telmisartan (3hh) and adapalene (3ii)
were successfully achieved in 67-92% yields with 95-97% D-
incorporation. For complex carboxylic acids containing a tertiary
amine motif, for example repaglinide, besides the expected
deoxygenative deuteration, visible-light-induced HIE was
observed at -C(sp3)-H of tertiary amines (3jj).[14a] The derivatives
of
diacetone-D-glucose
(3kk),
epiandrosterone
(3ll),
pregnenolone (3mm) and L-menthol (3nn) could achieve radical
deuteration in 64-89% yields and high D-incorporation (up to 99%
D), exclusively at the formyl position. These examples indicate
that this protocol represents a practical late-stage modification in
synthetic medicinal chemistry.
The versatility of aldehydes in organic transformations allows a
practical strategy to access an enhanced library of deuterated
compounds (Scheme 4). For example, the deuterium-labeled
aldehydes obtained in this way are easily elaborated through
Horner-Wadsworth-Emmons olefination and reductive amination
to deliver -deuterated, -unsaturated esters (10) and highly
valuable deuterated amines[7a] (11). The reaction of
aminobenzaldehydes with D-labeled aldehydes provides an
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10.1002/anie.201811522
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COMMUNICATION
efficient route to D-labeled nitrogen-containing heterocycle
compounds, such as quinazolines (12) and quinolines (13).
Acknowledgements
We gratefully acknowledge National Natural Science Foundation
of China (21702098, 21672099, 21732003 and 21703118), the
Fundamental Research Funds for the Central Universities (No.
020514380158, 020514380131), Shandong Provincial Natural
Science Foundation (No. ZR2017MB038), “1000-Youth Talents
Plan” and start-up funds from Nanjing University for financial
support. M. Zhang was supported by Nanjing University
Innovation and Creative Program for PhD candidate (NO.
CXCY17-19).
Keywords: carboxylic acids • aldehydes • deuteration •
deoxygenation • synergistic catalysis
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Layout 2:
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Muliang Zhang, Xiang-Ai Yuan,
Chengjian Zhu and Jin Xie*
Page No. – Page No.
Deoxygenative Deuteration of
Carboxylic Acids with D2O
Drink of Water: A general, practical and scalable means of preparing deuterated
aldehydes from aromatic and aliphatic carboxylic acids has been achieved with D2O
as an inexpensive deuterium source enabled by synergistic photoredox catalysis,
thiol catalysis and phosphoranyl radical chemistry.
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