Chemo- And regioselective ring-opening of donor-acceptor oxiranes with: N -heteroaromatics

Article abstract of DOI:10.1039/d1cc00600b

The first ring-opening of D-A oxiranes with N-heteroaromatics in a chemoselective C-C bond cleavage manner was achieved. In the presence of 5 mol% of Y(OTf)3 as the catalyst, diverse N-heteroaromatics, including benzotriazoles, purines, substituted benzim

Full text of DOI:10.1039/d1cc00600b

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Chemo- and regioselective ring-opening
of donor–acceptor oxiranes with
N-heteroaromatics†
Cite this: Chem. Commun., 2021,
57, 4552
Received 2nd February 2021,
Accepted 6th April 2021
Ji-Wei Sang, Ming-Sheng Xie, * Man-Man Wang, Gui-Rong Qu and
Hai-Ming Guo
*
DOI: 10.1039/d1cc00600b
rsc.li/chemcomm
The first ring-opening of D–A oxiranes with N-heteroaromatics in a
Benzotriazole and purine derived acyclic nucleosides, con-
chemoselective C–C bond cleavage manner was achieved. In the taining N-glycosidic bonds, have displayed significant bioactiv-
presence of 5 mol% of Y(OTf)3 as the catalyst, diverse N-hetero- ities and representative examples are shown in Fig. 1.7
aromatics, including benzotriazoles, purines, substituted benzimidazole, Benzotriazole I exhibits an antileishmanial activity.8 Acyclovir
imidazole and pyrazole, reacted well with various D–A oxiranes, and Ganciclovir have been approved by the FDA to treat herpes
providing acyclic nucleoside analogues containing a N-glycosidic and cytomegalovirus (CMV), respectively (Fig. 1a).9 Due to the
bond in up to 97% yield and up to 495 : 5 regioselectivity. Through existence of two tautomeric forms for benzotriazole and purines
simple transformation, the Ganciclovir analogue could also be (Fig. 1b), the construction of corresponding acyclic nucleosides
obtained.
might face the challenge of regioselectivity. In this work, we
envisage realizing the ring-opening of D–A oxiranes with a chemo-
Donor–acceptor (D–A) oxiranes are exceptionally useful three- selective C–C bond cleavage by changing the Lewis acid catalyst and
atom building blocks owing to their versatility in organic its coordination mode. Herein, we report a Y(OTf)3-catalyzed ring-
synthesis.1 In recent years, the [3+2] cycloaddition of D–A opening of D–A oxiranes to N-heteroaromatics with a C–C bond
oxiranes with various dipolarphiles (CQC, CQO, CQN, cleavage, affording diverse acyclic nucleoside analogues containing
CRC, CRN) has been elegantly conducted by the groups of a N-glycosidic bond in a chemo- and regioselective manner, which
Zhang, Feng, Zhong, and others (Scheme 1a).2–5 However, in could be derived into Ganciclovir analogues (Scheme 1c).
sharp contrast, the ring-opening reaction of D–A oxiranes has
Initially, the reaction of benzotriazole 1a with D–A oxirane
scarcely been reported in the literature (Scheme 1b). In 2017, 2a was selected as the model reaction (Table 1). With Sc(OTf)3
Pan and co-workers pioneered the ring-opening of D–A oxiranes as the Lewis acid catalyst, the ring-opening reaction occurred
with g-hydroxyenones using Sc(OTf)3 as the catalyst for the and it did encounter the challenge chemoselectivity and
synthesis of 2,5-disubstituted furans, in which a chemoselective
C–O bond cleavage of oxiranes was reported.6 To the best of our
knowledge, the ring-opening of D–A oxiranes with a chemose-
lective C–C bond cleavage has not been reported to date.
Therefore, developing a ring-opening of D–A oxiranes with
a C–C bond cleavage in a chemoselective manner is highly
desirable.
NMPA Key Laboratory for Research and Evaluation of Innovative Drug,
Key Laboratory of Green Chemical Media and Reactions, Ministry of Education,
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine
Chemicals, School of Chemistry and Chemical Engineering,
Henan Normal University, Xinxiang, Henan 453007, China.
E-mail: xiemingsheng@htu.edu.cn, ghm@htu.edu.cn
† Electronic supplementary information (ESI) available. CCDC 2018326 (3a),
2027379 (3j), 2018328 (3t), 2018329 (3w), 2018327 (5a), 2040250 (7a) and
2038626 (7j). For ESI and crystallographic data in CIF or other electronic format
Scheme 1 Profile of D–A oxiranes with cycloaddition or ring-opening.
see DOI: 10.1039/d1cc00600b
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was a kinetic product. At 80 1C, the ring-opening products were
given in 99% total yield, and the ratio of 3a/4a/5a reached into
96/4/0 (entries 12–14). Evaluation of the catalyst loading
showed that 5 mol% of Y(OTf)3 was optimal (entries 14–16).
It should be noted that the reaction did not happen without
Y(OTf)3 or 4 Å MS (entries 17 and 18). When H2O was added,
only 11% total yield was observed (entry 19), indicating that the
function of 4 Å MS might be to scavenge adventitious water.
Under the optimized reaction conditions (Table 1, entry 14),
the substrate scope of D–A oxiranes was evaluated (Scheme 2).
For oxiranes 2b–2g bearing electron-rich substituents at the aryl
moieties, the adducts 3b–3g were afforded in 76–97% yields and
92 : 8 to 495 : 5 regioselectivities. 1-Naphthyl and 2-naphthyl
substituted oxiranes 2h–2i were also suitable reactants. For
oxiranes 2j–2t with different halogen groups at the aryl fragments,
the ring-opening products 3j–3t were given in 62–86% yields and
83 : 17 to 495 : 5 regioselectivities. In the case of strongly electron-
withdrawing group at the aryl moieties, such as 4-CF3 or 4-NO2
group, the reactions did not occur. As for diethyl (E)-3-styryloxirane-
2,2-dicarboxylate, the reaction was complex (see ESI† for details).
When D–A oxiranes 2u–2v with methyl ester or benzoyl substituent
group were employed, the adducts 3u–3v were obtained in good
results. In addition, 5 mmol of benzotriazole 1a reacted smoothly
with D–A oxirane 2a, affording 1.65 g (86% yield) of the adduct 3a
with 495 : 5 regioselectivity. It should be emphasized that the ring-
opening reaction of D–A oxiranes proceeded in a chemoselective
manner with C–C bond cleavage.
Subsequently, the substrate scope of N-heteroaromatics was
explored. 5,6-Dimethylbenzotriazole 1b and 5,6-difluorobenzo-
triazole 1c were also suitable reactants to form the adducts 3w–3x.
A series of substituted purines 6a–6h with halogen, amino, or alkoxy
substituents at C2 or C6 position were examined, the corresponding
acyclic nucleoside analogues 7a–7h were obtained in a regioselective
manner with 40–80% yields. In the case of 6-hydrogen purine 6i, a
mixture of N9 adduct and N7 adduct was obtained. These results
showed that the N9/N7 regioselectivity was greatly affected by the
steric hindrance of the substituent group at the C6 position of
purine. Then, substituted benzimidazole 6j, imidazole 6k, and
pyrazole 6l were used, the ring-opening smoothly afforded the
adducts 7j–7l in 80–92% yields.
Fig. 1 (a) Examples of bioactive acyclic nucleoside analogues; (b) tauto-
mers of benzotriazole and purines.
Table 1 Optimization of the reaction conditionsa
Entry Catalyst
X
Solvent T (1C) t (h) Yieldb (%) Ratioc (3a/4a/5a)
1
2
3
4
5
6
7
8
Sc(OTf)3
Yb(OTf)3
BF3ꢀEt2O
Cu(OTf)2
Gd(OTf)3
Er(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
5
5
5
5
5
5
5
5
5
5
5
5
5
5
3
PhCH3 40
PhCH3 40
PhCH3 40
PhCH3 40
PhCH3 40
PhCH3 40
PhCH3 40
24
24 18
24 N.R.
24 N.R.
24 18
24 19
24 29
24 10
24 20
6
45 : 23 : 32
21 : 18 : 61
—
—
29 : 30 : 41
24 : 25 : 51
19 : 30 : 51
40 : 13 : 47
40 : 40 : 20
45 : 33 : 22
57 : 33 : 10
—
71 : 24 : 5
96 : 4 : 0
67 : 28 : 5
95 : 4 : 1
—
THF
40
9
CHCl3 40
10
11
12
13
14
15
16
17
18e
19f
DCM
DCE
DCE
DCE
DCE
DCE
40
40
rt
60
80
80
80
80
80
80
24 28
24 61
24 Trace
24 70
10 99(94)d
24 36
Y(OTf)3 10 DCE
—
Y(OTf)3
Y(OTf)3
10 88
—
5
5
DCE
DCE
DCE
10 N.R.
10 N.R.
10 11
—
65 : 16 : 19
a
Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), Y(OTf)3 (5 mol%),
b
4 Å MS (30 mg) and DCE (2 mL) at 80 1C for 10 h. The total yield was
determined by 1H NMR using CH2Br2 as an internal standard. The
c
ratio was determined by 1H NMR analysis of crude product. Isolated
d
e
f
yield of 3a in parentheses. Without 4 Å MS. H2O (10 mL) was added.
regioselectivity, affording a mixture of N1 alkylated with C–C
The synthetic transformations of the ring-opening adducts
bond cleavage product 3a, N2 alkylated with C–C bond cleavage were then performed (Scheme 3). Acyclic nucleoside analogue
product 4a, and N1 alkylated with C–O bond cleavage product 7g could be easily reduced to afford acyclic nucleoside 8g
5a (entry 1). Then, different Lewis acids were evaluated and bearing two hydroxymethyl groups in 91% yield. Through
Y(OTf)3 was determined as the optimal catalyst, delivering three further debenzylation, the acyclic nucleoside 9g was obtained
ring-opening products in a 29% total yield, in which the C–O (Scheme 3a). It should be noted that the acyclic nucleoside 9g
bond cleavage product 5a was the major isomer (entries 2–7). was an analogue of Ganciclovir, in which a phenyl group was
Several solvents were examined, and DCE could give a higher linked at the C10-position of the side chain in Ganciclovir. By
total yield of 61%, in which the C–C bond cleavage product 3a simple reduction, acyclic product 10a with two vicinal hydro-
was the major one (entries 6–11). The screening of temperature xymethyl groups was obtained in 85% yield (Scheme 3b-i).
showed that increasing the temperature was favor to the total Through Krapcho decarboxylation, the acyclic product 11a
yield and the formation of N1 alkylated product 3a. Further bearing one ester group was given in 43% yield, which could
studies indicated that N2 alkylated product 4a could convert be reduced into acyclic nucleoside analogue 12a in 82% yield
into product 3a at high temperature and catalytic conditions (Scheme 3b-ii). By treatment of Boc2O or MeI, the corres-
(see ESI† for details). It was proposed that N1 alkylated product ponding products 13a containing three ester groups and 14a
3a was a thermodynamic product, while N2 alkylated product 4a bearing a methyl group could be generated, respectively
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Scheme 2 Substrate scopea. a 1a–1c for benzotriazoles, 6a–6i for purines, 6j–6k for substituted imidazoles, 6l for substituted pyrazole. Unless
otherwise noted, the reaction conditions were: 1 or 6 (0.1 mmol), 2 (0.1 mmol), Y(OTf)3 (5 mol%), 4 Å MS (30 mg) and DCE (2 mL) at 80 1C for 10 h. All
yields are isolated. The ratio of N1/N2 and N7/N9 were determined by 1H NMR analysis of the crude reaction mixture. b 5.0 mmol scale. c At 100 1C. d 6c is
N,N-Ditert-butoxycarbonyl-9H-purin-6-amine.
Scheme 4 Experimental mechanistic studies.
Scheme 3 Transformation of the ring-opening products.
conductivity for the mixture of D–A oxirane 2a with Y(OTf)3 was
(Scheme 3b-iii). A fluorine atom could also be introduced into tracked in the reaction with 0.200 mS cmꢁ1 (see ESI† for details).
the acyclic side chain to form product 15a in 96% yield, which These experiment indicated that in the presence of Y(OTf)3, the
could deliver fluorine-containing acyclic nucleoside analogue oxirane first underwent C–C bond cleavage to form a zwitterionic
16a with two vicinal hydroxymethyl groups by simple reduction intermediate, which further react with nucleophilic benzotriazole
(Scheme 3b-iv).
to afford ring-opening adduct 3v.
In order to gain insight into the mechanism, isotopic-
The Hammett study was carried out on different D–A oxiranes
labeling experiment was performed with [D]benzotriazole and bearing meta-substituent in the aryl moiety. The negative slope
D–A oxirane 2a.10 Deuterium incorporation was only observed (ꢁ2.997) indicated that the smaller the electron dispersion from
at the a-position of the ester group (Scheme 4a). The reason for the benzylic carbon of D–A oxirane, the faster the reaction. These
the low deuteration rate might be that the water adsorbed in 4 Å studies showed that the reaction might proceed via a carbocation
MS participated in the H-transfer step (see ESI† for details). intermediate. The kinetic order of each reaction component was
With enantioenriched (S)-2v as the reactant,11 the ring-opening determined through studying initial rates of the reaction. The rate
reaction with benzotriazole 1a was evaluated under optimized shows that a zero-order dependence on the concentration of 1a,
conditions. However, the desired ring-opening adduct 3v was while approximately first-order dependence on the concentration
obtained in a racemic form (Scheme 4b). Besides, the electronic of 2a and catalyst Y(OTf)3 (see ESI† for details). These data
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(212101510004), the Program for Science & Technology Innova-
tion Talents in Universities of Henan Province (19HASTIT036)
and the 111 Project (No. D17007). We also thank the financial
support from Henan Key Laboratory of Organic Functional
Molecules and Drug Innovation.
Conflicts of interest
There are no conflicts to declare.
Notes and references
Fig. 2 Proposed mechanism.
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Scheme 5 Catalytic asymmetric ring-opening reaction.
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D–A oxirane 2 is activated by Y(OTf)3 via coordination with the
geminal bisketone moiety to form the intermediate A. Then, the
direct C–C bond cleavage of intermediate A will generate a
zwitterion, in which a carbocation at the benzyl position was
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details). With Y(OTf)3-L1 as the catalyst, the ring-opening
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for N1 alkylated product 3a.
In summary, we reported the first ring-opening of D–A
oxiranes with N-heteroaromatics in a chemoselective C–C bond
cleavage manner. With 5 mol% of Y(OTf)3 as the catalyst, a
variety of N-heteroaromatics, including benzotriazoles, pur-
ines, substituted benzimidazole, imidazole and pyrazole,
reacted well with diverse D–A oxiranes, providing ring-
opening adducts containing a N-glycosidic bond in 40–97%
yields and 79 : 21 to 495 : 5 regioselectivities. Furthermore,
diverse acyclic nucleoside analogues could be afforded from
the ring-opening adducts through simple derivatization. This
methodology may provide a practical route to construct acyclic
nucleosides and Ganciclovir analogues.
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We are grateful for the financial support from NSFC (No.
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This journal is © The Royal Society of Chemistry 2021
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