Spontaneous conversion of prenyl halides to acids: application in metal-free preparation of deuterated compounds under mild conditions

Article abstract of DOI:10.1039/d1ob01275d

Here we reveal a simple generation of deuterium halide (DX) from common and inexpensive reagents readily available in a synthetic chemistry laboratory,i.e. prenyl-, allyl-, and propargyl halides, under mild conditions. We envisaged thatin situgeneration of an acid, deuterium halide, would be useful for acid-catalyzed reactions and could be employed for organocatalytic deuteration. The present work reports a metal-free method for deuterium labeling covering a broad range of substrate including phenolic compounds (i.e. flavonoids and stilbenes), indoles, pyrroles, carbonyl compounds, and steroids. This method was also applied for commonly used drugs such as loxoprofen, haloperidol, stanolone, progesterone, androstenedione, donepezil, ketorolac, adrenosterone, cortisone, pregnenolone, and dexamethasone. A gram-scale chromatography-free synthesis of some deuterated compounds is demonstrated in this work. This work provides a simple, clean and by-product-free, site-selective deuteration, and the deuterated products are obtained without chromatographic separation. When applying these initiators for other acid-catalyzed reactions, the deuterium isotope effects of DX may provide products which are different from those obtained from reactions using common acids. Although the mechanism of the spontaneous transformation of prenyl halides to acid is unclear, this overlooked chemistry may be useful for many reactions.

Full text of DOI:10.1039/d1ob01275d

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Spontaneous conversion of prenyl halides to acids:
application in metal-free preparation of
Cite this: DOI: 10.1039/d1ob01275d
deuterated compounds under mild conditions†
a,b
Dhanushka Darshana, a Sanya Sureram,b Chulabhorn Mahidol,
a,b,c
Somsak Ruchirawat a,b,c and Prasat Kittakoop
*
Here we reveal a simple generation of deuterium halide (DX) from common and inexpensive reagents
readily available in a synthetic chemistry laboratory, i.e. prenyl-, allyl-, and propargyl halides, under mild
conditions. We envisaged that in situ generation of an acid, deuterium halide, would be useful for acid-
catalyzed reactions and could be employed for organocatalytic deuteration. The present work reports a
metal-free method for deuterium labeling covering a broad range of substrate including phenolic com-
pounds (i.e. flavonoids and stilbenes), indoles, pyrroles, carbonyl compounds, and steroids. This method
was also applied for commonly used drugs such as loxoprofen, haloperidol, stanolone, progesterone,
androstenedione, donepezil, ketorolac, adrenosterone, cortisone, pregnenolone, and dexamethasone. A
gram-scale chromatography-free synthesis of some deuterated compounds is demonstrated in this work.
This work provides a simple, clean and by-product-free, site-selective deuteration, and the deuterated
products are obtained without chromatographic separation. When applying these initiators for other acid-
catalyzed reactions, the deuterium isotope effects of DX may provide products which are different from
those obtained from reactions using common acids. Although the mechanism of the spontaneous trans-
formation of prenyl halides to acid is unclear, this overlooked chemistry may be useful for many reactions.
Received 1st July 2021,
Accepted 15th July 2021
DOI: 10.1039/d1ob01275d
rsc.li/obc
pharmaceutical industry,1–3 and recently a number of efficient
methods for the deuteration of organic compounds have been
Introduction
developed either by chemical synthesis4–8 or by biological
approaches.9,10 Deuterated forms of existing drugs can have
improved and distinct pharmacokinetic or toxicological pro-
perties because of the stability of C–D bonds,3,11 and there
have been a number of patents and clinical trials of deuterated
versions of known drugs.12 Many drug companies have filed a
number of patents on drug deuteration, showing improve-
ments in drug pharmacokinetics.12 On account of the higher
stability of the C–D bond relative to the C–H bond, deuterated
drug candidates have shown an improvement in pharmacoki-
netics and metabolic profiles with a profound enhancement of
half-lives compared to the molecules with C–H bonds without
altering the potency.12,13 With the first deuterated drug being
approved by the US FDA in 2017, deuteration of drug mole-
cules and organic compounds has become an increasingly
popular field of research.14,15 Deuterated compounds are
widely used for studies on the elucidation of reaction mecha-
nisms and biosynthetic pathways3,16–19 and as internal stan-
dards for mass spectrometry.20–23
Prenyl halides are common reagents in organic synthesis and
are widely used for many reactions. The spontaneous trans-
formation of prenyl halides to acids, hydrogen halides (HX) or
deuterium halides (DX), is observed when these reagents are
dissolved in alcohol. The generation of DX from prenyl
bromide (3,3-dimethylallyl bromide) (1), prenyl chloride (2),
allyl bromide (3), and propargyl bromide (4) under mild con-
ditions in CD3OD was observed (Fig. 1) and it was useful for
acid-catalyzed reactions. In the present work, we demonstrate
the in situ generation of DX for acid-catalyzed deuteration
reactions.
Isotopic labelling of organic compounds with deuterium is
of great interest in the fields of organic synthesis and the
aChulabhorn Graduate Institute, Chemical Biology Program, Chulabhorn Royal
Academy, Kamphaeng Phet 6 Road, Laksi, Bangkok 10210, Thailand.
E-mail: prasat@cri.or.th
bChulabhorn Research Institute, Kamphaeng Phet 6 Road, Laksi, Bangkok 10210,
Thailand
cCenter of Excellence on Environmental Health and Toxicology (EHT), CHE, Ministry
of Education, Bangkok, Thailand
Deuteration at C-3 of indoles was previously reported using
an organocatalyst flavin,24 Brønsted acid (HClO4),25 and
metals, Ru or Ag (Fig. 1A),15,26 while deuterated pyrrole deriva-
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1ob01275d
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Fig. 1 Previous works and this work: previous deuteration of (A) indole, (B) pyrrole, (C), carbonyl, and (D) phenolic compounds; the present work;
(E) organocatalytic deuteration using prenyl- and propargyl halides, and (F) the structures of initiators 1–4.
tives (Fig. 1B) were prepared using Fe,27 Lewis acid B(C6F5)3,28 irradiation of ionic liquids and DCl/D2O or with
Brønsted acid (HClO4),25 and Ir catalysts.29 A number of works CF3COOD.42–44 We report herein the generation of deuterium
have reported the deuteration of carbonyl compounds using halide from prenyl halides (1 and 2), allyl bromide (3), and
metal catalysts (i.e. Pd, Rh, and Ir),30–33 Lewis acid B(C6F5)3,34 propargyl bromide (4) under mild conditions in CD3OD, and
organocatalysts,35–37 microwave-assisted deuteration,38 and we used compounds 1–4 as initiators for the chromatography-
antibodies (Fig. 1C).39 Deuteration of phenolic compounds free synthesis of deuterated compounds (Fig. 1E). The
with an aromatic ring which is shown in Fig. 1D was achieved halogen-containing organic compounds 1–4 have boiling
by keto-enamine tautomerization,40 using a Brønsted acid points of 135 °C, 109 °C, 70–71 °C, and 88–90 °C, respectively
(HClO4),25 acid-catalyzed H/D exchange,41 and microwave (Fig. 1F); therefore, they can be removed from the reactions
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simply by evaporation under vacuum. Moreover, deuteration the deuteration of simple ketones.49 To investigate the role of
by these initiators enables a clean synthesis and has no obser- prenyl bromide (1) in the deuteration reaction, it was first per-
vable side reactions, and thus no by-products. Therefore, a formed with 3′,5′-dihydroxyacetophenone (7) in the presence
clean and by-product-free synthesis using initiators 1–4 of CD3OD as a deuterium source and solvent in the NMR tube.
enables a simple preparation of deuterated compounds, which We observed the deuteration (>95%) of aromatic and methyl
could be obtained without chromatographic separation. This protons (Scheme 1) when using only 1 mol% or 3 mol% of 1 in
work reports a repeatable and facile protocol for site-selective CD3OD. It was found that prenyl halides 1 and 2 were the two
deuteration with a broad substrate scope including indole, best substrates for deuteration, followed by allyl bromide (3)
pyrrole, carbonyl and phenolic compounds as shown in and propargyl bromide (4), respectively. In the deuteration
Fig. 1A–D. Moreover, the other merits of this work are the process, halide-containing compounds 1–4 act as the
highly selective deuteration of organic compounds and the “initiator” of the reaction producing deuterium halide, the
large scale of the reaction. To our knowledge, this is the first deuterating agent in the deuteration reaction.
in situ acid generation of DBr from organic compounds under
We then performed the deuteration of other phenolic com-
mild conditions and may be applied in acid-catalyzed pounds, orcinol (8) and olivetol (9); at least 86%–98% deuter-
reactions.
ium incorporation was observed (Scheme 1). The reactions
were performed either in an NMR tube or a small flask with
20–40 mg of substrates, and the deuterated products were
simply obtained after evaporation without using chromato-
graphic separation. We then explored natural phenolic com-
pounds, flavonoids and stilbenes, which have been widely
studied in research because they exhibit various biological
activities.50–52 Deuterated flavonoids and stilbenes, kaempferol
(10), catechin (11), naringenin (12), quercetin (13), resveratrol
(14), and genistein (15) were obtained with 91%–99% deuter-
ium incorporation at the aromatic protons of ring A, using
3 mol% of prenyl bromide (1) or 10 mol% of propargyl
bromide (4) as initiators (Scheme 1). Note that C-6 of chrysin
(16) had only 60% deuteration. We found that the deuteration
of the flavonoids 8, 9, and 11 using initiator 1 gave by-pro-
ducts, and therefore the less reactive initiator 4 was used for
deuteration. For a non-polar flavonoid, i.e. chrysin (16), THF
could be used as a co-solvent in order to increase the solubility
of the substrate. Interestingly, a stilbene butein (17) was
cyclized to a natural flavanone, butin (18) (54% yield) and
>91% deuterium incorporation was observed at the C-3 posi-
tion of the flavanone and >16% at the C-8 position of an aro-
matic ring (Scheme 1). This cyclization likely occurred via an
acid-mediated reaction. Recently, a mild method for the deu-
teration of aromatic compounds assisted by a keto-enamine
tautomeric intermediate was reported.40 The present method
gives similar deuteration positions of phenolic compounds
and the deuterated products are obtained without chromato-
graphic separation. Since clinical trials of flavonoids and stil-
benes are widely studied because of their potential appli-
cations in many aspects,53,54 there were pharmacokinetics
studies of these compounds using LC/MS analysis.53,55,56
Deuterium-labelled flavonoids and stilbenes prepared from
this simple method can be used as internal standards in LC/
MS analysis.
Method
General procedure for organocatalytic deuteration
A reaction vessel with a glass stopper was charged with a sub-
strate (20–40 mg, 0.1–0.3 mmol), 1 mol% or 3 mol% of
initiators 1 or 2, and CD3OD (0.6 mL). Note that, in some
cases, 10 mol% of an initiator 4 was used for deuteration. The
reaction mixture was stirred at room temperature for 16–24 h
and then it was evaporated under reduced pressure to remove
the initiator and solvent, giving a deuterated compound. The
deuteration percentage was determined from the 1H NMR
spectrum. Details of the experiments can be found in the ESI.†
Results and discussion
We found that prenyl halides, i.e. prenyl bromide (1) and
prenyl chloride (2), in CD3OD could generate deuterium halide
(DX), and this transformation is a spontaneous reaction
(Fig. 2). This in situ generation of DX occurs at room tempera-
ture without any catalysts. Probing the characteristics of prenyl
bromide (1) in CD3OD revealed the formation of compounds 5
and 6, whose structures were identified from NMR data (ESI†).
We envisaged that this in situ generation of the acid, deuter-
ium halide (DBr or DCl), can be used in acid-catalyzed
reactions.
Deuteration could be achieved by acid-catalyzed reactions,
for example, using Lewis acidic B(C6F5)3 as a catalyst,28,34
using H2SO4 in CD3OD for the deuteration of phenols and
phenol ethers45 and pyrroles,46 using DCl in D2O for the deu-
teration of pyrazoles (at 200–250 °C)47 and indole ring in tryp-
tamine derivatives,48 and using KDSO4 and NaOAc in D2O for
Deuteration at the position next to the carbonyl of the flava-
none, butin (18), as well as at the methyl group of 7
(Scheme 1), suggested that our method may be applicable for
carbonyl compounds. Indeed, a methyl group next to a carbo-
nyl group of compounds 19–26 was deuterated with 85%–98%
deuterium incorporation (Scheme 2). The methyl ketone of
substrates with adamantane, furan, and indole functional
Fig. 2 In situ generation of DX from prenyl halides in CD3OD.
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Scheme 1 General deuteration reaction and structures of initiators 1–4 and the deuteration of phenolic compounds. The reaction was performed
at room temperature (28 °C) with 20–40 mg (0.1–0.3 mmol) of each substrate. a Initiator 1 (3 mol%) in CD3OD; b initiator 4 (10 mol%) in CD3OD;
c 16 h reaction time; d 24 h reaction time; e mesitylene as an internal standard; f purification by C18 HPLC; and g THF as a co-solvent.
groups, i.e. compounds 24–26, was deuterated with up to protons next to a carbonyl in a five-membered ring of 32–40
90%–98% deuterium incorporation (Scheme 2). The deutera- exhibited 85%–98% deuteration (Scheme 2). It is worth men-
tion of the methylene protons of tetralone derivatives (27–29) tioning that the ortho deuteration observed in phenols
was observed with >97% deuterium incorporation. However, (Scheme 1) is not observed for anisole derivatives (Scheme 2).
unlike the methylene protons in 27–29, a lower rate of H/D Methylene protons of 2-phenylacetophenone (41) underwent
exchange (>76%) for a methine proton next to a carbonyl 88% deuteration. Natural monoterpenes, (S)-(+)-carvone (42),
group was observed for a tetralone 30. The H/D exchange of a (+)-menthone (43), (1S)-(−)-verbenone (44), (−)-piperitone (45),
methylene group of chroman-4-one (31) was >98%, while and (+)-pulegone (46), were used as substrates for deuteration.
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Scheme 2 Deuteration of carbonyl compounds. Reaction was performed at room temperature (28 °C) with 20–40 mg (0.1–0.3 mmol) of each sub-
strate. a Initiator 1 (3 mol%) in CD3OD; b 4 h reaction time; c 16 h reaction time; and d a mixture of two diastereomers.
Methylene protons or methine protons next to a carbonyl tion (Scheme 2), suggesting that deuterium incorporation
group of 42, 43, 45, and 46 were deuterated with >90% deuter- occurred at both the α- and β-faces of the methine proton next
ium incorporation (Scheme 2). Unexpectedly, the methyl to a carbonyl group. Previously, d8-labeled pulegone (46) was
protons of 44–46 and the methylene protons of 45 that were 3 prepared using sodium metal (Na) and CH3OD/D2O, followed
bonds away from a carbonyl group (γ position) were deuterated by chromatographic separation.57 The present work provides a
with >90% deuterium incorporation (Scheme 2). It is worth simple metal-free preparation of d8-labeled pulegone (46).
mentioning that, unlike those in 43 and 45, the sp3 methine
Many FDA-approved drug molecules are carbonyl com-
proton next to a carbonyl group of 44 was not deuterated. A pounds, and some drugs were selected for the H/D exchange
single enantiomer (+)-menthone (43) was used as a substrate; experiment (Scheme 3). Next, we used steroid drugs and drugs
however, there were two diastereomers obtained after the reac- with carbonyl groups as substrates. Steroid drugs include adre-
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Scheme 3 Deuteration of steroids and drugs with a carbonyl group. Reaction was performed at room temperature (28 °C) with 20–40 mg
(0.1–0.3 mmol) of each substrate. a Initiator 1 (3 mol%) in CD3OD; b 16 h reaction time; c 24 h reaction time; d CHCl3 as a co-solvent; e THF as a co-
solvent; and f initiator 2 (3 mol%) in CD3OD for 48 h.
nosterone (47), pregnenolone (48), progesterone (49), Δ4- and D2O;34 however, our method gave a slightly higher % of
androstene-3,17-dione (50), stanolone (51), cortisone (52), and deuterium incorporation for d9-labeled progesterone (49), d3-
dexamethasone (53), while other drugs are loxoprofen (54), labeled loxoprofen (54), d2-labeled haloperidol (56), and d1-
2-acetylphenothiazine (55), haloperidol (56), and donepezil labeled donepezil (57). Previously, d8-labeled Δ4-androstene-
(57) (Scheme 3). A metal-free preparation of deuterated drugs 3,17-dione (50) was prepared by a two-step method, first with a
resulted in a deuterium incorporation of 78%–97% for steroid Rh catalyst under D2 gas, followed by the use of NaOD/D2O at
drugs 47–52. Dexamethasone (53) could not be deuterated by 65 °C,59 while d3-labeled pregnenolone (48) was synthesized by
prenyl bromide (1); however, deuteration of 53 was achieved by the following two-step method: first treating with NaOD in
prenyl chloride (2), resulting in 74% deuterium incorporation D2O and then with DCl.60 The present method provides a
(Scheme 3). It is worth mentioning that dexamethasone (53) single step without a purification process for the preparation
has been recently found to be useful for the treatment of of 48 and 50. A number of methods have been reported for the
patients hospitalized with COVID-19.58 H/D exchanges were deuteration of carbonyl compounds using metals (i.e. Pd, Rh,
observed at the α- and γ-positions next to the carbonyl groups and Ir),30–33 organocatalysts,35–37 microwave-assisted deutera-
of steroids 47, 49, 50, 52, and 53 (Scheme 3). Deuteration of tion,38 and antibody.39 α-Deuterated carbonyl compounds
other drugs with a carbonyl group (54–57) was achieved with could also be prepared from enolates using MeLi/CD3COOD.61
90%–97% deuterium incorporation (Scheme 3). Recently, an These methods, except that with an antibody as a catalyst,
efficient deuteration at the α-position of carbonyl-based require harsh reaction conditions, and they employ chromato-
pharmaceutical compounds was reported using a Lewis acid graphic separation.
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Heteroarenes were the next target group of compounds for Position 3 of indoles 58–68 was selectively deuterated with a
a study on substrate scope, and we found that indoles and pyr- deuterium incorporation of 87%–99%, and the electron with-
roles could be deuterated by initiators 1 and 4 (Scheme 4). drawing or donating group on the aromatic ring of indoles did
Scheme 4 Deuteration of heteroarenes, indoles and pyrroles. Reaction was performed at room temperature (28 °C) with 20–40 mg
(0.1–0.3 mmol) of each substrate. a Initiator 1 (1 mol%); b initiator 1 (3 mol%); c initiator 4 (10 mol%); d 15 min reaction time; e 16 h reaction time; f 24 h
reaction time; and g mesitylene as the internal standard.
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not have much effect on the deuteration (Scheme 4). However, methyl protons next to the carbonyl position of compound 20
the amount (3 mol%) of the initiator 1 used for the deutera- were deuterated at >95%, which is similar to that (>96%) using
tion of indoles with electron withdrawing groups, i.e. com- CD3OD. However, deuteration of compound 65 using CH3OD
pounds 61, 63, and 65, was slightly higher than that (1 mol%) exhibited a slightly lower percentage of deuteration (>86%)
used for other indoles (Scheme 4). Moreover, some indoles, i.e. than that (>96%) using CD3OD. Therefore, CD3OD may enable
compounds 60, 64, and 66–69, were very reactive toward the slightly better H/D exchange than CH3OD for particular sub-
initiator 1, giving by-products; therefore, the less reactive strate types. However, CH3OD is much less expensive than
initiator, propargyl bromide (4), was used for the deuteration CD3OD.
of these indoles (Scheme 4). Interestingly, the deuteration of
The proposed mechanism for the deuteration of phenolic
4-substituted indole derivatives gave d3-labeled indole deriva- compounds, carbonyl compounds and steroids, and indoles is
tives 69 and 70, whereby two additional aromatic protons were depicted in Fig. 3. Deuteration is catalyzed by deuterium
deuterated with a deuterium incorporation of 68%–93% halide (DX), which is in situ generated from prenyl halides in
(Scheme 4). Deuteration of pyrroles was easily achieved by the CD3OD (Fig. 3A). For phenolic compounds, DX catalyzes the
initiator 1, giving d4-labeled pyrrole derivatives 71–73 with a formation of the intermediate PI, which in turn undergoes
deuterium incorporation of 90%–93%, as well as d2-labeled proton (H) abstraction by the X ion to give a deuterated
pyrroles 74 and 75 with a deuterium incorporation of 95%– product (Fig. 3B). Due to the kinetic isotope effect, the C–D
97% (Scheme 4). Note that the yields of 71 (b.p. 112–113 °C) bond is more stable than the C–H bond; therefore, H abstrac-
and 72 (b.p. 129 °C) were 80% and 82%, respectively; this is tion by X ions from intermediate PI occurs, giving a deuterated
because both compounds have low boiling points, and evapor- product (Fig. 3B). In the case of carbonyl compounds or
ation under vacuum led to loss of compound yields. As steroids (Fig. 3C), DX attacks a carbonyl to form an intermedi-
expected, the methyl groups of pyrroles with a ketone carbonyl ate S1, which in turn, undergoes H abstraction by X ions,
functional group were deuterated giving d4- and d6-labeled pyr- giving its enol form S2. Then, DX catalyzes the insertion of a D
roles 76 and 77, respectively, with a deuterium incorporation atom into S2 to give the intermediate S3, which in turn con-
of 93%–99%. However, unlike other pyrroles, compound 78 verts into a deuterated product by D abstraction by X ions
gave a d1-labeled derivative; only position 4 of 78 was deute- (Fig. 3C). For indoles, DX catalyzes the insertion of a D atom
rated with 81% deuteration (Scheme 4). We then applied our into an indole molecule to form an intermediate DI, and a
method to the deuteration of ketorolac (79), a nonsteroidal proton from DI is abstracted by the X ion due to the kinetic
anti-inflammatory drug (NSAID). Two positions on a pyrrole isotope effect mentioned earlier, giving a deuterated product
ring of drug 79 were deuterated with a deuterium incorpor- (Fig. 3D). As shown in the deuteration mechanisms of these
ation of 41% and 94% (Scheme 4).
compounds, HX is generated due to the H/D exchange
Next, we performed a gram-scale chromatography-free syn- between DX and individual substrates. It is interesting to
thesis of deuterated compounds using 1 mol% of the initiator mention that DX is regenerated from HX in the presence of an
1. Deuteration of 1 gram of naringenin (12) (dissolved in 8 mL excess amount of CD3OD, as depicted in Fig. 3E. To clearly
of CD3OD) was achieved with 95% deuterium incorporation. explain how catalytic amounts of initiators could efficiently
For deuteration of 2.7 grams of naringenin (12), THF was used catalyze deuteration, DBr obtained by in situ generation from
as a co-solvent (5 mL of CD3OD and 3mL of THF), giving the prenyl bromide (1) is used as a model initiator (Fig. 3F). First,
deuterated product 12 with 80% deuterium incorporation. in situ generation of DBr along with compounds 5 and 6
Deuteration of 1 gram of progesterone (49) was performed in occurs in CD3OD. During the deuteration reaction, H/D
10 mL of CD3OD, giving the deuterated product 49 with 86%– exchange between the DX and individual substrate leads to the
97% deuterium incorporation, while deuteration of 1 gram of generation of HBr, which in turn undergoes H/D exchange
a pyrrole 73 was performed in 6 mL of CD3OD, giving a deute- with excess CD3OD to give DBr that is readily utilized for
rated product 73 with 94% deuterium incorporation. Next, we further deuteration (Fig. 3F). So far, in situ generation of DX
preliminarily investigated the minimum amount of the from organic compounds has never been reported, and the
initiator required for deuteration. A carbonyl compound 20 spontaneous transformation of prenyl halides to DX presented
required at least 0.5 mol% of the initiator 1 for deuteration in this work could be useful for organic chemistry. Although
with 82% deuterium incorporation, while the indole 60 and in situ generation of hydrogen iodide (HI) was previously
pyrrole 71 required only 0.1 mol% of the initiator 1, giving d1- reported for the preparation of α-glycosyl iodides and vicinal
labeled indole 60 with 97% deuterium incorporation and d4- iodohydrins, HI was generated from molecular iodine (I2).62
labeled pyrrole 71 with 81%–87% deuterium incorporation.
Therefore, low catalyst loading of initiator 1 is required for reported so far. It is known that in situ generation of HCl from
deuteration. acetyl chloride in CH3OH occurs through a nucleophilic attack
Generation of DX from initiators 1–4 has never been
Since CH3OD is relatively inexpensive than CD3OD, we on a carbonyl carbon of acetyl chloride by CH3OH, giving HCl
attempted to perform deuteration using CH3OD as the D and methyl acetate ester.63 We performed deuteration using
source with 3 mol% of initiator 1. Experiments were performed acetyl chloride in CD3OD with 4′-methoxyacetophenone (20) as
with two model compounds, 4′-methoxyacetophenone (20) and a model substrate (ESI†). It was found that acetyl chloride
5-nitroindole (65). When using CH3OD as the D source, the could promote the deuteration of 20 with >95% incorporation
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Fig. 3 In situ generation of DX from prenyl halides in CD3OD (A); the proposed deuteration mechanism of phenolic compounds (B), carbonyl com-
pounds and steroids (C), and indoles (D); regeneration of DBr from HBr during deuteration in the presence of excess CD3OD (E); and in situ gene-
ration of DBr from prenyl bromide (1) and H/D exchange of substrates and excess CD3OD (F).
of deuterium, indicating that DCl was generated in this tion in D2O, which may cause problems for the reaction that is
system. DCl is commercially available (20% solution in D2O), sensitive to water.
and indeed, we found that compound 20 was deuterated by
Commercial reagent 1 contains silver wool as a stabilizer,
DCl with >95% incorporation of deuterium. Although deutera- while 2 does not have any stabilizer. In order to exclude the
tion by acetyl chloride or commercial DCl is anticipated, a involvement of metal traces in the generation of DX from
simple generation of deuterium (hydrogen) halide from prenyl halides, initiator 1 that contains silver wool as the
initiators 1–4 is unprecedented. Although DCl is commercially stabilizer was distilled under vacuum using Kohguller appar-
available, it is much more expensive than the initiators used in atus prior to use in deuteration. TMS-free CD3OD with purity
this work. Moreover, commercial DCl is available in 20% solu- >99.5%, which does not contain any stabilizer, was used in
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deuteration. Distilled initiator 1 provided the same deuteration the ability of cinnamyl bromide (80), an aromatic substituted
percentages as non-distilled initiator 1 for model compounds, allylic halide, to generate DBr. It was found that cinnamyl
4′-methoxyacetophenone (20) and 5-nitroindole (65), indicating bromide (80) could be used for deuteration (ESI†). It is pro-
that traces of the metal were not involved in the deuteration or posed that the generation of acid from cinnamyl bromide (80)
generation of acid. Next, we preliminarily explored the effects in CD3OD should be analogous to that of prenyl halides as
of light and temperature on deuteration using initiator 1 or shown in Fig. 2, from which compounds 5 and 6 are formed;
acetyl chloride with 20 and 65 as model substrates (ESI†). therefore, the products 81 and 82 (Fig. 4) should be produced
Deuteration with initiator 1 or acetyl chloride led to >95% or from the spontaneous conversion of cinnamyl bromide (80) to
1
>97% deuteration of 20 or 65 under dark conditions, normal acid. Indeed, the H NMR spectra of cinnamyl bromide (80) in
day light, and tungsten light, indicating that deuteration or CD3OD at different time intervals of 0 h, 0.5 h, 1 h, 3 h, 6 h
generation of acid by 1 or acetyl chloride is independent of and 24 h (Fig. 5) revealed that derivatives 81 and 82 are
light. However, when using initiator 1 for deuteration, less formed. The product 81 was the major compound, while 82
than 8% or 2% deuteration of 20 or 65 was observed at −10 °C, was the minor product (Fig. 5). The 1H and 13C NMR reso-
while >95% or >97% deuteration for 20 or 65 was observed at nances of a methylene group of cinnamyl bromide (80) were at
room temperature (28 °C) (ESI†), suggesting that the gene- δH 4.16 and δC 34.01, while those of the product 81 were at δH
ration of DBr from 1 depends on temperature. When using 4.07 and δC 73.97 (ESI†). The 13C NMR resonance of a carbon
acetyl chloride for deuteration, >95% or >97% deuteration of of the –OCD3 moiety in 81 was at δC 57.0 with characteristics
20 or 65 was achieved at both −10 °C and room temperature; of a carbon bearing D atom, and the HMBC spectrum showed
this indicates that deuteration by acetyl chloride did not the correlation from methylene protons (–CH2-O) to this
depend on temperature. In conclusion, the spontaneous con- carbon (ESI†). The exo-methylene protons of the product 82
version of prenyl halides to acids is temperature dependent, resonated at δH 5.20 (Fig. 5). We evaporated CD3OD from a
but independent of light, while the nucleophilic substitution sample of 81 and changed the NMR solvent from CD3OD to
mechanism for the generation of DCl of acetyl chloride is inde- CDCl3; we observed the presence of cinnamyl bromide (80) in
pendent of both light and temperature.
a sample of 81 (ESI†), indicating that a portion of 81 was con-
The spontaneous conversion of prenyl halides to acids at verted back to 80 possibly during the evaporation of CD3OD.
room temperature (28 °C) is unprecedented. Next, we explored The proposed mechanism for the spontaneous conversion of
Fig. 4 Proposed mechanism for the spontaneous conversion of cinnamyl bromide (80) to DBr and compounds 81 and 82 in CD3OD. (A) SN1 reac-
tion mechanism, (B) SN2 reaction mechanism, and (C) conversion of cinnamyl bromide (80) to ether 83 in CH3OH (C).
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Fig. 5 1H NMR spectral overlay of cinnamyl bromide (80) (50 mg) in CD3OD (0.6 mL) at different time intervals of 0 h, 0.5 h, 1 h, 3 h, 6 h and 24 h,
indicating the spontaneous conversion of 80 to compounds 81 and 82 at room temperature.
cinnamyl bromide (80) to the products 81 and 82 could be ated via the carbocation C, was observed in a higher ratio than
through the SN1 reaction mechanism (Fig. 4A) or the SN2 reac- compound 82 that is generated via the carbocation D; this
tion mechanism (Fig. 4B). For the SN1 type reaction mechanism, suggests that the mechanism favors the SN2 type of reaction
the allyl carbocation C is first generated from cinnamyl rather than SN1 (Fig. 4B). For the SN2 mechanism, the departure
bromide (80) after the departure of a Br ion as a leaving group, of the leaving group Br and attack by CD3OD simultaneously
and the allyl carbocation
C undergoes delocalization of occur to give oxonium ions, which in turn react with Br ions to
π-electrons to give the allyl carbocation D (Fig. 4A). Both allyl give DBr and compound 80 (Fig. 4B). Although the reaction
carbocations C and D react with CD3OD to give oxonium ions, mechanism via the SN2 type of reaction was favorable over that
which in turn react with Br ions to give DBr and compounds 81 through the SN1 mechanism, a small amount of compound 82
and 82 (Fig. 4A). Since the allyl carbocation D (tertiary carbo- was also observed in the 1H NMR spectrum, suggesting that the
cation) is more stable than the allyl carbocation C (primary car- SN1 type reaction mechanism may also occur to some extent.
bocation), compound 82, which is generated through the allyl Previously, similar allyl cation intermediates for indole alkyl-
carbocation D, is anticipated to be produced in a higher ratio ation were generated from dimethylallyl diphosphate using a
than compound 81 that is generated from the less stable allyl strong acid, H2SO4,64 whose proposed mechanism is similar to
carbocation C (Fig. 4A). However, compound 81, which is gener- the SN1 mechanism shown in Fig. 4A. When cinnamyl bromide
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(80) is dissolved in CH3OH and left stirring at room temperature Graduate Institute through the grants from the National
for 24 h, it was found that a portion of 80 spontaneously trans- Research Council of Thailand (NRCT), Thailand Science
formed to ether 83 (Fig. 4C) (ESI†).
The mechanism for the spontaneous transformation of on Environmental Health and Toxicology, Science
prenyl halides and cinnamyl bromide (80) to acid is not con- Technology Postgraduate Education and Research
Research and Innovation (TSRI) and the Center of Excellence
&
clusively established in this work. This unnoticed chemistry Development Office (PERDO), Ministry of Education. D. D.
discovered in this work needs further studies on the detailed acknowledges Chulabhorn Graduate Scholarship supported by
mechanism, both on theoretical and experimental aspects. the Thailand International Cooperation Agency (TICA),
Moreover, there is room for research to explore this chemistry Ministry of Foreign Affairs, Thailand.
for other applications, not only for deuteration presented in
this work. However, safety precautions on acid DX or HX gen-
erated from the reaction should be considered when applying
this method for research or industry. We would like to coin the
Notes and references
name “Anichcha reaction” for the spontaneous reaction of
prenyl halides to acid, in order to describe the impermanent
nature of compounds 1–4 and cinnamyl bromide (80). The
word “Anichcha” is derived from Buddhist philosophy, which
describes impermanence or instability or change and uncer-
tainty of everything.
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