Mesoionic Carbene (MIC)-Catalyzed H/D Exchange at Formyl Groups

Full text of DOI:10.1016/j.chempr.2019.08.011

Article
Mesoionic Carbene (MIC)-Catalyzed H/D
Exchange at Formyl Groups
Wei Liu, Liang-Liang Zhao,
Mohand Melaimi, ..., Jean
Bouffard, Guy Bertrand, Xiaoyu
Yan
bouffard@ewha.ac.kr (J.B.)
gbertrand@ucsd.edu (G.B.)
yanxy@ruc.edu.cn (X.Y.)
HIGHLIGHTS
A metal-free catalyzed H/D
exchange at formyl groups is
described
The formation of Breslow
intermediates is reversible with
1,2,3-triazolylidenes (MICs)
Interrupted benzoin condensation
in deuterated methanol
Broad scope of applications for
aldehydes and even aldimines
The formation of Breslow intermediates in the reaction of 1,2,3-triazolylidenes
(mesoionic carbenes) with aldehydes is reversible. The benzoin condensation is
inhibited in deuterated methanol, allowing for H/D exchange at formyl groups.
Liu et al., Chem 5, 2484–2494
September 12, 2019 ª 2019 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2019.08.011

Article
Mesoionic Carbene (MIC)-Catalyzed
H/D Exchange at Formyl Groups
Wei Liu,1 Liang-Liang Zhao,1 Mohand Melaimi,2 Lei Cao,1 Xingyu Xu,1 Jean Bouffard,3,
*
1,
Guy Bertrand,2,4, and Xiaoyu Yan
*
*
SUMMARY
The Bigger Picture
Incorporation of deuterium atoms
in organic molecules is an
H/D exchange at formyl groups is the most direct approach for the synthesis of
deuterated aldehydes. Platinum-group metal complexes have been employed
to catalyze this transformation, with significant substrate scope limitations.
Although N-heterocyclic carbenes can also activate the C–H bond of aldehydes
through the formation of Breslow intermediates, benzoin condensation and
other C–C-bond-forming pathways have so far outpaced synthetically useful
H/D exchange. Investigation of the reaction of aldehydes with 1,2,3-triazolyli-
denes has revealed the reversible formation of Breslow intermediates and the
inhibition of the condensation steps in methanol solvent. 1,2,3-Triazolylidenes
catalyze the H/D exchange of aryl, alkenyl, and alkyl aldehydes in high yields
and deuterium incorporation levels using deuterated methanol as an affordable
D source. The unique properties of these mesoionic carbenes (MICs) enable a
streamlined preparation of deuterated synthetic intermediates and pharmaco-
phores that are highly valuable as mechanistic and metabolic probes.
important tool for the
identification and understanding
of chemical and biological
processes. Deuterium labeling of
organic and inorganic molecules
allows for simple and direct
incorporation of a useful analytical
probe while keeping their
structure, physical properties, and
biological activity intact.
Deuterium-labeled compounds
can be readily identified using
conventional techniques such as
NMR spectroscopy, mass
INTRODUCTION
spectrometry, and even elastic
neutron scattering. Such methods
are widely popular in life sciences
where they provide high levels of
insight into various processes and
also offer a widening range of
applications in several fields of
chemistry. Herein, we report the
cheap and efficient metal-free
catalytic synthesis of deuterium-
labeled carbonyls and related
compounds.
Deuterium-labeled chemicals find widespread uses across multiple scientific fields. In
materials chemistry, deuteration of aromatic phosphors decreases their non-radia-
tive deactivation rates, resulting in room-temperature phosphorescent compounds
with higher quantum yields.1–4 The reduced lability of C–D bonds over C–H bonds,
known as a kinetic isotope effect (KIE), is widely used in pharmaceutical sciences to
both study and alter the metabolism and pharmacokinetics of drugs.5–8 In organic
chemistry, KIE experiments are privileged tools for the study of reaction mecha-
nisms,9,10 and the strategic use of KIEs has enabled the landmark syntheses of a
growing number of complex natural products.11–15 Because of their versatility as
organic building blocks, deuterated aldehydes (R–CDO) are frequently employed
in these experiments and as intermediates for the synthesis of other deuterated com-
pounds.16–21 A number of approaches, such as the reduction of carboxylic acid deriv-
atives22–25 (Figure 1A) and the carbonylation of aryl halides26 (Figure 1B), have been
reported for the preparation of deuterated aldehydes. However, these reactions not
only use expensive transition metal catalysts and/or deuterated reductants, but they
also usually require multiple steps. Consequently, direct formyl H/D exchange reac-
tions are highly preferable.27–29 Recently, Kerr and co-workers reported a selective
deuteration of aromatic aldehydes (Figure 1C), which involves the activation of formyl
C–H bonds by an iridium catalyst and isotope exchange with D2.30 Newman and co-
workers developed a ruthenium-catalyzed formyl H/D exchange reaction of aromatic
aldehydes with D2O able to achieve up to 84% deuteration (Figure 1C).31 Neverthe-
less, these H/D exchange reactions still rely on noble-metal catalysts, and their sub-
strate scope remains mostly limited to aromatic aldehydes.
2484 Chem 5, 2484–2494, September 12, 2019 ª 2019 Elsevier Inc.

A
C
B
D
Figure 1. Synthetic Methods to Formyl-Deuterated Aldehydes
(A) Reduction of carboxylic acid derivatives with a deuterated reductant and/or a transition metal.
(B) Carbonylation of aryl halides.
(C) Transition-metal-catalyzed H/D exchange reactions of aldehydes.
(D) Our approach to H/D exchange reactions of aldehydes with a metal-free catalyst.
It is well known that the C–H bond of aldehydes can be activated by N-heterocyclic
carbenes (NHCs) through nucleophilic addition and the subsequent formation of a
Breslow intermediate.32–35 To apply this mode of activation to the preparation of
deuterated aldehydes, the reversibility of this reaction must be ensured, and unde-
sired C–C-bond-forming pathways must be blocked. Although the NHC-catalyzed
benzoin condensation reaction is reversible,36,37 recent advances in NHC-catalyzed
reactions have instead featured catalytic cycles where the Breslow intermediate re-
acts rapidly once generated, making its formation effectively irreversible.37–42 Inves-
tigating the redox esterification of cinnamaldehyde to hydrocinnamate derivatives,
Bode and co-workers observed a competing H/D exchange reaction when alde-
hydes were reacted with CH3OD in the presence of catalytic amounts of 1,2,4-triazo-
lium and triethylamine.43,44 This H/D exchange reaction was not, however, suitable
for the preparation of deuterated aldehydes, given its low yield and weak deuterium
incorporation. Out competition by the benzoin condensation and other undesired
pathways, which is responsible for these poor outcomes, has thus far only been cir-
cumvented through the use of >1 equiv catalyst in combination with phase isolation
techniques, as previously reported by Bergbreiter, Newcomb, and co-workers.45
Here, we report a catalytic metal-free direct formyl H/D exchange reaction that is
both highly selective and broad in scope (Figure 1D).
RESULTS AND DISCUSSION
Having in hand a variety of stable metal-free 1,2,3-triazolylidenes,46–48 a type of
mesoionic carbene (MIC) that has rarely been used as organocatalysts,49 we were
drawn to the observation that the MIC-catalyzed benzoin condensation was strongly
impacted by the polarity of solvents. In toluene solution, treatment of aldehyde 1a
with 5 mol % of MIC A1 cleanly afforded the benzoin 2a, which was isolated in
91% yield. However, under the same experimental conditions, the yield of 2a
decreased to 54% and <5% in tetrahydrofuran (THF) and methanol, respectively
(Figure 2).
1Department of Chemistry, Renmin University of
China, Beijing 100872, People’s Republic of China
2UCSD-CNRS Joint Research Laboratory (UMI
3555), Department of Chemistry and
Biochemistry, University of California, San Diego,
La Jolla, CA 92093-0358, USA
3Department of Chemistry and Nanoscience (BK
21 Plus), Ewha Womans University, Seoul 03760,
Korea
4Lead Contact
*Correspondence: bouffard@ewha.ac.kr (J.B.),
gbertrand@ucsd.edu (G.B.),
yanxy@ruc.edu.cn (X.Y.)
In an attempt to understand these results, we carried out stoichiometric reactions
mimicking the individual steps of the benzoin condensation mechanism. Treatment
of MIC A1 in THF with 1 equiv of aldehyde 1a afforded a dark-green solution for
https://doi.org/10.1016/j.chempr.2019.08.011
Chem 5, 2484–2494, September 12, 2019 2485

Figure 2. Influence of the Solvent on the MIC A1-Catalyzed Benzoin Condensation
Reaction conditions: 1a (0.1 mmol) and solvent (3 mL) at room temperature (RT) for 12 h. The yield of
2a in PhMe, THF, and CH3OH was determined by 1H NMR with CH2Br2 as internal standard.
which the characteristic 1H and 19F NMR signals of both reactants were not present.
The 19F NMR spectrum showed two new signals at ꢀ111.8 and ꢀ118.6 ppm (2:1 ra-
tio), but the complexity of the 1H and 13C NMR spectra did not allow for unequivocal
structure determination. However, the addition of trifluoroacetic acid (TFA) to this
THF solution afforded salt 3a, which was unambiguously characterized by X-ray
diffraction analysis (Figure 3). Moreover, addition of TFA-d1 instead of TFA afforded
3a(D) and 3a(D)’ in a 1:4 ratio. These results as a whole suggest that the dark-green
solution is composed of the Breslow intermediate B and carbene-aldehyde adduct
C. This hypothesis is reinforced by the formation of the same dark-green solution
when 3a was treated with potassium hexamethyldisilazide (KHMDS) in THF. Lastly,
DFT calculations suggest that, unlike for NHCs, the MIC-derived Breslow intermedi-
ate B and carbene-aldehyde adduct C are very close in energy, which supports their
possible co-existence in solution (see Supplemental Information).
Assignment of the mixture constituents as the Breslow intermediate B and carbene-
aldehyde adduct C was further supported by an independent synthesis of the dark-
green O-methylated analog B0, whose structure was confirmed by an X-ray
diffraction study (Figure 3, part f). By comparison with the previously reported
solid-state structures of O-methylated Breslow intermediates derived from imidazo-
lylidenes, imidazolylinylidenes, thiazolylidenes, and 1,2,4-triazolylidenes,34,50 B’
features an elongated exocyclic CC bond (138.6 pm) that is considerably twisted
out of planarity (:NCCO: 20.84ꢁ). These measurements are consistent with a highly
polarized C=C double bond, as confirmed by a computed proton affinity that is ca.
8 kcal/mol higher for Breslow intermediates derived from MICs than for other fam-
ilies of carbenes. Further calculations indicate that the differences in enthalpy be-
tween the free aldehyde and MIC pair, the initial aldehyde adduct, and the Breslow
intermediate are of ca. 2 kcal/mol, whereas for thiazolylidenes and 1,2,4-triazolyli-
denes the corresponding enthalpy gaps are far greater (5–21 kcal/mol) (see Supple-
mental Information). We postulate that these features promote the reversible addi-
tion onto aldehydes and formation of Breslow intermediates with MICs.
Interestingly, the quenching of B/C was impacted by the acidity of proton donors. When
NH4PF6, an acid weaker than TFA, was employed, 3a was not observed. Instead, A1H,
the conjugate acid of 1,2,3-triazolylidene A1, was quantitatively formed; aldehyde 1a
and benzoin derivative 2a were also observed in 30% and 25% yield, respectively. The
latter was formed by the reaction of the released aldehyde 1a with B/C. These results
imply that the reaction of 1,2,3-triazolylidene A1 with aldehyde gives the Breslow inter-
mediate reversibly. Using weakly acidic methanol as quenching agent also resulted in
the formation of A1H. Inhibition of the condensation pathway in methanol was again
observed (cf. Figure 2). Importantly, the amount of benzoin 2a formed decreased
2486 Chem 5, 2484–2494, September 12, 2019

Figure 3. Evidence for the Formation of the Breslow Intermediate B and C
Stoichiometric reaction of 1,2,3-triazolylidene A1 with aldehyde 1a (a), protonation of Breslow intermediate B and C (b), deprotonation of triazolium 3a
by KHMDS (c), deuteration of Breslow intermediate B and C (d), and solid-state structures of 3a (e) and B’ (f) with 50% probability ellipsoids obtained by
X-ray crystallography. Hydrogen atoms and counter-ions were removed for clarity.
significantly with increasing amounts of methanol added to the B/C solution (Figure 4).
From these observations, it seems reasonable to hypothesize that methanol is suffi-
ciently acidic to reversibly protonate B/C, limiting its concentration and thus preventing
the benzoin condensation. Instead, dissociation into the aldehyde and the carbene was
the prevailing outcome in this solvent.
The results summarized in Figures 3 and 4 revealed that the combination of 1,2,3-tri-
azolylidene catalysts and methanol as the solvent was ideally suited to reversibly ac-
cess the Breslow intermediate while shunting the benzoin condensation pathway
and thus should favor H/D exchange reactions. To check this hypothesis, a
CD3OD solution of 4-methoxybenzaldehyde 1b was treated with different triazolium
salts AH (5 mol %) in the presence of tBuOK as a base (Figure 5). The 4-unsubstituted
triazolium salt A2H allowed for the recovery of aldehyde 1b in 34% yield with 83%
D-incorporation (entry 1). Under the same experimental conditions, lower D-incor-
poration was observed with triazolium salts A3H, A1H, and A4H, but superior results
were obtained with the more Brønsted acidic C-bromo (A5H)51,52 and C-phosphino
(A6H)53 catalyst precursors. Indeed, using these salts, aldehyde 1b was recovered in
54% and 70% yield with 88% and 91% D-incorporation, respectively (entries 2–6).
tBuOK was found to be the most efficient base among those tested with pre-catalyst
A6H (entries 6–9). The yield and D-incorporation were increased to 87% and 97%,
respectively, by raising the reaction temperature to 90ꢁC (sealed vessels; entry
10). For comparison, imidazolium A7H, thiazolium A8H, 1,2,4-triazolium A9H, and tri-
phenylphosphine only gave low levels of D-incorporation (entries 11–14). Using the
less expensive CH3OD as deuterium source did not lead to a significant decrease in
deuteration levels (entry 15). Under the same experimental conditions, but using p-
Chem 5, 2484–2494, September 12, 2019 2487

Figure 4. Protonation of Breslow Intermediate B and C and Postulated Mechanism for the
Methanol Interruption of the Benzoin Condensation
B/C (0.1 mmol) in 3 mL THF with proton donor as indicated, RT, 1 h. The yields of 3a, A1H, 1a, and 2a
were determined by 1H NMR spectroscopy with CH2Br2 as internal standard.
anisoin 2b as the starting material, in place of the aldehyde 1b, similar high yield and
D-incorporation of 1b(D) were observed (entry 16). This result indicates that in meth-
anol, MIC catalysis of the benzoin condensation and its reversal is only kinetically
competent at temperatures that thermodynamically favor the latter.54
With the optimized reaction conditions in hand, a variety of aldehydes 1 were inves-
tigated (Figure 6). For benzaldehydes substituted with electron-donating groups
1b–1g, high yields and deuterium incorporation levels were achieved. Notably, a
number of functional groups susceptible to interfere with transition metal-catalyzed
H/D exchange reactions, including aryl iodides (1h and 1i), basic amines (1d), and
thioethers (1e) were tolerated. The increased steric demand of ortho-substituted
benzaldehydes 1l–1n slightly depressed the deuterium incorporation levels, but
polycyclic aromatic aldehydes 1o–1q, including the crowded 9-anthracenecarboxal-
dehyde 1q, smoothly underwent H/D exchange. The O-allylated salicylaldehyde 1n
highlights the differences between the catalytic behavior of MICs A and other NHCs:
whereas O-allylated salicylaldehydes were shown to undergo benzoin condensation
under benzimidazolylidene catalysis and to cyclize into chromanones via hydroacy-
lation of its double bond under the action of either thiazolylidene or 1,2,4-triazolyli-
dene catalysts,55 only the product of H/D exchange 1n(D) was observed with MIC A6.
The reaction is compatible with redox-sensitive functional groups that would not be
tolerated in classical syntheses of deuterated aldehydes. These include esters (1k)
that would clash with synthetic routes based on the addition of nucleophilic deuter-
ide on carboxylic acid derivatives and the ferrocenecarboxaldehyde 1r that would
not be readily accessible from the oxidation of the corresponding alcohol (RCD2OH)
because of its easily oxidized iron(II) center. Heterocyclic aldehydes 1s-1v gave
deuterated products with 88%–95% D-incorporation. The substrate scope of this re-
action can be extended to alkenyl and alkyl aldehydes. a,b-Unsaturated aldehydes
bearing a substituent at the a-position (1w–1x) were compatible, and high yields
and D-incorporation were observed. Branched alkyl aldehydes 1y–1z with a single
a-substituent were somewhat less reactive, requiring extended reaction times (72–
2488 Chem 5, 2484–2494, September 12, 2019

Figure 5. Optimization of 1,2,3-Triazolylidene-Catalyzed Deuteration of Aldehydes
Mes, 2,4,6-trimethylphenyl; Dipp, 2,6-diisopropylphenyl; DABCO, 1,4-diazabicyclo[2.2.2]octane;
IMes, 1,3-bis(2,4,6-trimethylphenyl)imidazolinylidene. Reaction conditions: aldehyde (0.2 mmol),
AH (5 mol %), base (30 mol %), and anhydrous CD3OD (1 mL) for 12 h. The reactions were carried out
in a 25 mL sealed tube.
aDeuterium incorporation [1b(D)/(1b + 1b(D))] and yields [(1b + 1b(D))/1binit] were determined by
1H NMR spectroscopy. Isolated yield is given in parentheses.
bCH3OD was employed instead of CD3OD.
120 h) to reach high deuteration levels. Nevertheless, the steroid-derived exocyclic
aldehydes 1aa–1ab and the proline-derived 1ac were also found to be suitable sub-
strates. H/D exchange for the a,a-disubstituted aldehyde 1ad proved to be sluggish.
It is noteworthy that aldimines 1ae–1af can also undergo the deuteration reaction,
with 87% and 62% D-incorporation, respectively. Current limitations to the substrate
Chem 5, 2484–2494, September 12, 2019 2489

Figure 6. Substrate Scope of the 1,2,3-Triazolylidene-Catalyzed Deuteration of Aldehydes
t
Reaction conditions: aldehydes or imines (0.2 mmol), A6H (0.01 mmol), and BuOK (0.06 mmol) in
CD3OD (1 mL) at 90ꢁC for 12 h. Isolated yields are given, and deuterium incorporation determined
by 1H NMR spectroscopic analysis is indicated within square brackets.
aTransesterification reaction occurred with CD3OD.
b120 h.
c72 h.
scope include a-unsubstituted cinnamaldehydes, which readily undergo internal
redox esterification;43,44,56 the more readily enolizable linear alkyl aldehydes, which
are susceptible to aldol-type side reactions under basic conditions; finally, highly
electron deficient benzaldehydes (e.g., 1j) also fared poorly.
2490 Chem 5, 2484–2494, September 12, 2019

B
A
C
D
Figure 7. Synthesis of Deuterated Compounds from the Deuterated Aldehyde 1b(D)
(A) Aldol condensation of 1b(D) with 4-methylacetophenone.
(B) Reaction of 1b(D) with DAST.
(C) Midland reduction of 1b(D) with Alpine borane.
(D) Reaction of 1b(D) with Bode’s SnAP reagent.
The one-step preparation of deuterium-labeled aldehydes from their protio precur-
sors greatly simplifies the synthesis of deuterated compounds of interest as mecha-
nistic and metabolic probes (Figure 7). Aldol condensation of 1b(D) with 4-methyla-
cetophenone afforded the b-deuterated chalcone derivative 4 in 89% yield and 92%
D-incorporation. Reaction of 1b(D) with N,N-diethylaminosulfur trifluoride (DAST)
afforded 5 (78% yield, 93% D-incorporation), demonstrating a facile access to a
deuterated difluoromethyl group, a popular lipophilic bioisostere of alcohols, thiols,
or hydroxyamic acids in medicinal chemistry.57 Midland reduction of 1b(D) with
Alpine borane gave the chiral enantiomerically enriched benzyl alcohol 6, a known
precursor to diverse chiral methylene and methyl groups,58 in 67% yield and 97%
D-incorporation with 58% ee. Finally, reaction of 1b(D) with Bode’s SnAP re-
agent59,60 provided a rapid and efficient route to the stereospecifically D-labeled
heterocycle 7 in 76% yield with negligible loss of D-incorporation.
We have shown that 1,2,3-triazolylidenes, a class of carbene widely used as ligands
for transition metals,61 but so far shunned in organocatalysis, react with aldehydes to
form mesoionic analogs of the Breslow intermediate. The formation of the latter is
rapid but reversible, and methanol inhibits the benzoin condensation. This allows
1,2,3-triazolylidenes to catalyze the H/D exchange of formyl groups. The use of
MICs as catalysts in the direct conversion of protio aldehydes into their deutero con-
geners makes it unnecessary to use redox concession steps and avoids the use of
costly transition metal catalysts. The wide scope, high yields, and deuterium incor-
poration levels, which extends to aryl, alkenyl, and alkyl aldehydes, coupled with
the versatility of aldehydes as synthetic intermediates, make the exchange reaction
an appealing option for the expedited synthesis of valuable deuterium-labeled syn-
thons. The marked differences found between the properties of the Breslow inter-
mediates formed from 1,2,3-triazolylidenes and those derived from the more widely
used imidazol(in)ylidenes, thiazolylidenes, and 1,2,4-triazolylidenes let us envision
that new types of organocatalytic reactions may yet to be discovered with MICs
and for other overlooked families of persistent carbenes.
EXPERIMENTAL PROCEDURES
Full experimental procedures are provided in the Supplemental Information.
Chem 5, 2484–2494, September 12, 2019 2491

DATA AND CODE AVAILABILITY
Crystallographic data for the structures reported in this article have been deposited
at the Cambridge Crystallographic Data Centre (CCDC) under accession numbers
CCDC: 1904320 (3a) and CCDC: 1946731 (B0). Copies of the data can be obtained
free of charge from www.ccdc.cam.ac.uk/structures/. All other data supporting the
findings of this study are available within the article and its Supplemental Informa-
tion or from the corresponding author upon reasonable request.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2019.08.011.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation of China
(21602249 to X.Y.), the US Department of Energy, Office of Science, Basic Energy
Sciences, Catalysis Science Program (award DE-SC0009376 to G.B.), and the Na-
tional Research Foundation of Korea (2018R1D1A1B07043568 to J.B.).
AUTHOR CONTRIBUTIONS
X.Y., G.B., and J.B. conceived and designed the project and wrote the manuscript.
W.L., L.-L.Z., M.M., L.C., and X.X. conducted the experiments and analyzed the data.
M.M. and J.B. carried out the computational analyses. All authors provided com-
ments on the experiments and the manuscript during its preparation.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: April 22, 2019
Revised: July 12, 2019
Accepted: August 16, 2019
Published: September 12, 2019
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