Visible-light induced metal-free cascade Wittig/hydroalkylation reactions

Article abstract of DOI:10.1039/d1gc00091h

Cascade reactions are green and powerful transformations for building multiple carbon-carbon bonds in one step. Through a relay olefination and radical addition process, we were able to develop the cascade Wittig/hydroalkylation reactions induced by visible light. This metal-free radical approach features mild conditions, robustness, and excellent functionality compatibility. It allows access to saturated C3 homologation products directly from aldehydes or ketones. The synthetic utility of this method is demonstrated by a two-step synthesis ofindolizidine 209D.

Full text of DOI:10.1039/d1gc00091h

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Visible-light induced metal-free cascade Wittig/
hydroalkylation reactions†
Pannan Miao,a Ruining Li,a Xianfeng Lin,a Liangming Raob,c and Zhankui Sun
Cite this: Green Chem., 2021, 23,
1638
a,b
*
Received 8th January 2021,
Accepted 8th February 2021
DOI: 10.1039/d1gc00091h
rsc.li/greenchem
Cascade reactions are green and powerful transformations for as shown in Fig. 1b. We propose to generate radical intermedi-
building multiple carbon–carbon bonds in one step. Through a ate I through the desulfurization procedure from thiol, with
relay olefination and radical addition process, we were able to triphenylphosphine sulfide as the byproduct (Fig. 1c). This
develop the cascade Wittig/hydroalkylation reactions induced by electrophilic radical I would add to the electron-rich alkene II
visible light. This metal-free radical approach features mild con- which is formed through the Wittig reaction, and generate
ditions, robustness, and excellent functionality compatibility. It intermediate III which would deliver the final product through
allows access to saturated C3 homologation products directly a hydrogen atom transfer process.6 As the Wittig reaction and
from aldehydes or ketones. The synthetic utility of this method is the radical generation step share similar byproducts and the
demonstrated by a two-step synthesis of indolizidine 209D.
following hydroalkylation process matches the polarity request
for radical reactions, we believe that this cascade reaction is
highly possible. By employing this cascade process, we could
obtain the saturated C3 homologation product (4) directly
from the aldehyde (1) in a single step, while there is only one
particular method reported by Prof. Li to complete this trans-
formation in one step (Fig. 1a).7 In Li et al.’s work, they used
Introduction
Cascade reactions are powerful, efficient and elegant processes
for building complex molecules through two or more consecu-
tive steps in a single operation.1 They are appealing because of
obvious benefits, such as atom economy, as well as economies
of time, labor, waste generation, etc.2 The design and
implementation of cascade reactions is a challenging yet inter-
esting process, and radicals are often involved.3 Herein, we dis-
close novel metal-free radical cascade Wittig/hydroalkylation
reactions induced by visible light.
The Wittig reaction allows the preparation of an alkene by
the reaction of an aldehyde or ketone with a phosphonium
ylide, typically with triphenylphosphine oxide as the bypro-
duct.4 If the following reaction could tolerate triphenyl-
phosphine oxide and use the alkene as the substrate, then a
cascade reaction would be possible. Based on the studies by
our group and other groups,5 we designed a cascade reaction
aShanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Pharma-X
Center, School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd.,
Shanghai 200240, China. E-mail: zksun@sjtu.edu.cn
bHuzhou Research and Industrialization Center for Technology, Chinese Academy of
Sciences, 1366 Hongfeng Road, Huzhou 313000, China
Fig. 1 (a) Carbonyl compounds as latent alkyl carbanions for conjugate
additions. (b) This study: Visible-light induced cascade Wittig/hydroalky-
lation reaction. (c) Proposed mechanism for the cascade Wittig/hydro-
alkylation reaction. cat. = catalytic, EWG = electron-withdrawing group.
HAT = hydrogen atom transfer.
cShanghai Institute of nutrition and health, Chinese academy of sciences,
320 Yueyang Road, Shanghai, 200031, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1gc00091h
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Table 2 Substrate scope for the cascade reactiona,b
carbonyl compounds as latent alkyl carbanions and employed
Ru(II) to catalyze the conjugate additions to electron-deficient
alkenes. As such, a proposed mechanism for this Wittig/hydro-
alkylation reaction is shown in Fig. 1c.
Results and discussion
We began our study by using benzaldehyde (1), ylide (2), and
ethyl 2-mercaptoacetate (3) as model substrates and examined
different conditions under visible light at room temperature.
As expected, when the reaction was performed in DMSO, the
desired product was isolated. But the yield was only 32% even
with 3 equivalents of 2-mercaptoacetate (Table 1, entry 1).
However, with DCM as the co-solvent, the yield was dramati-
cally increased to 93% (Table 1, entry 2). The high yield was
maintained when 2 equivalents of 2-mercaptoacetate were
used (Table 1, entry 3). With less 2-mercaptoacetate, the yield
was decreased to 88% (Table 1, entry 4). The reaction didn’t
proceed to deliver the desired product without DTBP or visible-
light irradiation.
Having established the optimized conditions, we began to
examine the scope of this transformation. We first checked
different aromatic aldehydes. A diverse range of electron-
donating (Ph, OMe and SMe) and electron-withdrawing func-
tional groups (Cl, Br, I and CF3) were entirely compatible and
delivered the products in good to excellent yields (Table 2, sub-
strates 5–9, 11–15). Even a free hydroxy group and a boronic
acid group could be tolerated, albeit with lower yields (Table 2,
substrates 10 and 16). However, a boronic ester group provided
a better yield (Table 2, substrate 17). Other aromatic aldehydes
such as nicotinaldehyde, thiazole aldehyde and thiophene
aldehyde also reacted efficiently (Table 2, substrates 18–20).
We next turned our attention to aliphatic aldehydes.
3-Phenylpropanal and 3-(furan-2-yl)propanal worked smoothly
and provided the products in moderate yields (Table 3, sub-
strates 21–23). N-Cbz-piperidine aldehyde could also work
(Table 3, substrate 24). Different linear aliphatic aldehydes
a Reaction conditions: Aldehyde (1.0 mmol), ylide (1.2 mmol), 2-mer-
captoacetate (2.0 mmol), DTBP (4.0 mmol), PPh3 (2.5 mmol), DMSO–
DCM (4 mL : 4 mL), room temperature, 55 W household CFL bulb
irradiation on two sides, 12 h. b Isolated yields. c Yields were deter-
mined by 1H-NMR.
Table 3 Substrate scope for the cascade reactiona,b
Table 1 Optimization of reaction conditionsa
a Reaction conditions: Aldehyde (1.0 mmol), ylide (1.2 mmol), 2-mer-
captoacetate (2.0 mmol), DTBP (4.0 mmol), PPh3 (2.5 mmol), DMSO–
DCM (4 mL : 4 mL), room temperature, 55 W household CFL bulb
irradiation on two sides, 12 h. b Isolated yields. c Yields were deter-
mined by 1H-NMR.
Entry
Substrate 3
DTBP
PPh3
Yieldsb
1
2
3
4
5
6
3.0 equiv.
3.0 equiv.
2.0 equiv.
1.5 equiv.
2.0 equiv.
2.0 equiv.
6.0 equiv.
6.0 equiv.
4.0 equiv.
3.0 equiv.
4.5 equiv.
4.5 equiv.
2.5 equiv.
1.9 equiv.
2.5 equiv.
2.5 equiv.
32%c
93%
93%
88%
N.D.
N.D.d
4.0 equiv.
a Reaction conditions: 1 (1.0 mmol), 2 (1.2 mmol), 2-mercaptoacetate,
DTBP, PPh3, DMSO–DCM (4 mL : 4 mL), room temperature, 55 W
household CFL bulb irradiation on two sides, 12 h. b Yields were deter-
mined by 1H-NMR. N.D. = not detected. DTBP = di-tert-butyl peroxide.
c DMSO was used as the solvent. d Without light.
reacted efficiently to give the products in moderate to good
yields (Table 3, substrates 25–30). Notable examples included
the ones bearing a hydroxy group (Table 3, substrate 26) and a
chloride group (Table 3, substrate 27). As for substrate 28
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which has a trisubstituted alkene group, the reaction took
place at the in situ formed terminal alkene due to the steric
effect. Cyclobutane aldehyde could also be tolerated (Table 3,
substrate 30). For cyclopropane aldehyde, a subsequent ring-
opening reaction occurred and provided product 31 in 59%
yield, thus suggesting a radical process for this cascade reac-
tion (Table 3, substrate 31).
Fig. 2 Cascade reaction with Wittig reagent 49.
Then, we probed different ketones. Both linear and cyclic
ketones proved to be suitable substrates. Different sized cyclic
ketones worked efficiently and provided the products in mod-
erate to good yields (Table 4, substrates 32–35). Acetophenone
and 3-acetylthiophene worked smoothly (Table 4, substrates 36
and 37). Other linear ketones also provided the products in
good yields (Table 4, substrates 38–42).
Fig. 3 Synthesis of indolizidine 209D via the cascade reaction.
Finally, we surveyed the scope of thiols (Table 5). Different
ketones (Table 5, substrates 43 and 44), amide (Table 5, sub-
strate 45), lactone (Table 5, substrate 46) and esters (Table 5,
substrates 47 and 48) bearing α-sulfide were efficiently con-
verted to the corresponding products in moderate to good
yields.
We also tested other Wittig reagents such as compound 49.
We were able to isolate the desired product, albeit with a lower
yield, probably due to the steric hindrance (Fig. 2).
To demonstrate the synthetic utility of this cascade reac-
tion, we performed the synthesis of indolizidine 209D.8 From
commercially available aldehyde 51, we were able to obtain
compound 52 in one step with 40% yield via the cascade reac-
tion. The following hydrogenation furnished the product in
86% yield. Thus, indolizidine 209D was synthesized over two
steps with 34% yield (Fig. 3).
Table 4 Substrate scope for the cascade reactiona,b
Conclusions
In conclusion, we have developed a novel cascade Wittig/
hydroalkylation reaction induced by visible light. This green
and metal-free radical process proceeds under mild conditions
and tolerates a variety of functional groups. It allows access to
saturated C3 homologation products directly from aldehydes
or ketones via radical hydroalkylation to olefins, thus provid-
ing a useful tool for synthetic chemists.
a Reaction conditions: Ketone (1.0 mmol), ylide (1.2 mmol), 2-mercap-
toacetate (2.0 mmol), DTBP (4.0 mmol), PPh3 (2.5 mmol), DMSO–DCM
(4 mL : 4 mL), room temperature, 55 W household CFL bulb irradiation
on two sides, 12 h. b Isolated yields.
Conflicts of interest
Table 5 Substrate scope for the cascade reactiona,b
There are no conflicts to declare.
Acknowledgements
We thank Shanghai Jiao Tong University for financial support.
Notes and references
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