A metal-free desulfurizing radical reductive C-C coupling of thiols and alkenes

Article abstract of DOI:10.1039/c9cc05378f

An intermolecular reductive C-C coupling of electrophilic alkyl radicals and alkenes has been developed. Thiols were used as both hydrogen-donating reagents and alkyl radical precursors in the presence of triethyl phosphite and radical initiator. A wide range of alkenes, including styrenes, and aliphatic olefins were well tolerated in this transformation. Mechanistic studies indicated that a phosphite promoted radical desulfurization of thiols to access electrophilic alkyl radicals and a radical chain propagation process may be involved in this transformation.

Full text of DOI:10.1039/c9cc05378f

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Metal-free Desulfurizing Radical Reductive C-C Coupling of Thiols
and Alkenes
Qixue Qin,a Weijing Wang,a Cheng Zhang,a Song Song,*,a Ning Jiao*,a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
An intermolecular reductive C-C coupling of electrophilic alkyl Unfortunately, the high toxicity of organotin compounds limits
radicals and alkenes has been developed. Thiols were used as its application. Recently, photoredox catalysis induced alkyl
both hydrogen-donating reagents and alkyl radical precursors in radical addition with olefins have been widely investigated
the presence of triethyl phosphite and radical initiator. A wide (Scheme 1b).10 Despite the significant progress, most of them
range of alkenes, including styrenes, aliphatic olefins were were proceed with an excess of hydrogen-donating reagent,
tolerated well in this transformation. Mechanistic studies such as Hantzsch ester, thiol, N,N-diisopropylethylamine or
indicated that a phosphite promoted radical desulfurization of formic acid. Thiols are very handy compounds that can be
thiols to access electrophilic alkyl radicals and the radical chain readily synthesized from haloalkanes, alcohols, or their
propagation process may be involved in this transformation.
derivatives in manifold ways.11 We therefore envisioned that
thiols could act as a clean and efficient alkyl radical precursor.
Such concept had been realized by Nanni and coworkers,
which performed the reductive C-C coupling with thiols and
olefins used tert-butyl isocyanide as desulfurization reagent
Transition metal catalyzed C-C bond construction have been
emerged as a powerful tool for the construction of organic
compounds.1 Of the various type reactions of C-C bond
formation, Heck or Heck-type reactions of aliphatic alkenes has
been extensively explored and applied for the synthesis of
pharmaceuticals and natural products.2 Along with the
significant progress of Heck reaction, the reductive Heck
reaction for the formation C-C single bond has also attracted
considerable attentions.3 Since its initial study Cacchi group,4
the intramolecular and intermolecular reductive Heck
cyclization of alkenes has been well-explored (Scheme 1a).5
However, the regioselectivity problem and competitive Heck
reaction still limited their further application.6 Furthermore,
the use of transition metal catalyst and the external hydrogen
source are always essential to the reductive process. Therefore,
it is highly desirable and attractive to develop new approach
for the construction of C(sp3)-C(sp3) bond under mild reaction
conditions.
Radical reactions have been widely applied in organic
synthesis due to its high efficiency and regioselectivity under
mild reaction conditions with the tolerance of many sensitive
functional groups. Carbon-centered radicals,7 which are usually
generated by reduction of alkyl halides, exhibit versatile role in
construction of C-C bond formation.8 However, reductive
electron-deficient alkyl radical addition with styrenes is still
rare. Traditional, such process was promoted with tin reagent.9
Scheme 1 Methodologies for C(sp3)-C(sp3) Bond Construction.
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(Scheme 1c).12 However, only 12 examples were reported with
large excess of alkenes (up to 10.0 equiv) and the substrates
were limited to electron-rich aliphatic olefins. Very recently,
Hashmi and coworkers reported a gold-catalyzed reductive
desulfurizing C−C coupling of electrophilic radicals and
styrenes assisted by blue LEDs (Scheme 1c).13 Despite the great
improvement of desulfurizing addition to styrenes, only one
example of aliphatic olefin was exhibited. Herein, we present a
reductive desulfurizing C-C coupling of electrophilic radicals
and alkenes, which use triethyl phosphite as desulfurization
reagent (Scheme 1d). In this work, both styrenes and aliphatic
olefins are all tolerated well in moderate to good yields while
thiols are used as both hydrogen-donating reagents and alkyl
radical precursors, providing a convenient approach to directly
C-C bond construction.
Under the optimized reaction conditions, we VnieewxAtrtisctleuOdnileinde
the generality of this desulfurizing C−CDcOoI:u1p0l.i1n0g39r/Ce9aCctCi0o5n37b8yF
exploring the scope of styrenes (Table 2). A variety of electron-
rich and electron-deficient alkenes were examined in this
transformation. Some functional groups, such as Cl, Br, OAc,
NH2, OH were well tolerated (3b-3f, 3h). It was noteworthy
when styrene with a benzyl alcohol group was used as the
substrate, which could cause the competitive reactions
between deoxygenated and desulfurized, the hydroxyl group
was not touched by this protocol, but gave the desired
desulfurized C−C coupling product in 53% yield (3i). The
heteroaromatic substrate also performed well under the
standard reaction conditions giving the corresponding product
in 56% yield (3l). Moreover, five complex alkene substrates
bearing varying functional groups could also be employed,
affording the desired C−C coupling products in moderate yields
(3m-3q). These examples clearly suggest that this strategy
represents a promising late-stage modification of complex
bioactive molecules containing alkene groups.
Our investigation was initiated by using styrene 1a and
methyl thioglycolate 2a as the substrates. To our delight, C-C
coupling product 3a was obtained in 77% NMR yield by using
triethyl phosphite as the sacrificial reagent and AIBN as the
radical initiator in the solvent of DCE under Ar atmosphere at
70 oC (entry 1, Table 1). The use of other radical initiators, such
as Benzoyl peroxide (BPO) or dilauroyl peroxide instead of
AIBN resulted in lower yields (entries 2-3). Screening the
solvents with CH3CN, PhCl, DMF, EtOH resulted in slightly low
yields (entries 4-7). Furthermore, when decreased the loading
of AIBN to 25 mol% or even 5 mol%, the yields could be
maintained which indicated the radical chain propagation
process may be involved in this transformation (entries 8-9).
Control experiment showed the essential role of triethyl
phosphite (entry 11, Table 1).
Table 2 Scope of Styrenes Partners for C-C Coupling. a, b
Table 1 Reaction Conditions Investigation.a
Entry
Initiator
AIBN
Solvent
DCE
Yieldb
77%
1
2
BPO
DCE
14%
3
(dodecylCO2)2
AIBN
DCE
19%
4
CH3CN
PhCl
DMF
EtOH
DCE
63%
5
AIBN
65%
6
AIBN
63%
7
AIBN
72%
8c
9d
10d, e
11d, f
AIBN
78%
AIBN
DCE
77% (75%)g
<5%
AIBN
DCE
AIBN
DCE
Nd
a Reaction conditions:
1 (0.2 mmol), 2a (1.5 equiv), AIBN (50 mol %), P(OEt)3
a Reaction conditions:
1 (0.5 mmol), 2a (1.5 equiv), AIBN (5 mol%), P(OEt)3
(1.2 equiv), DCE (2.0 mL), stirred at 80 oC under Ar for 12 h. b Yields were
(1.2 equiv), DCE (4.0 mL), stirred at 80 oC under Ar for 12 h. b Yields of
isolated products.
determined by 1H NMR using Cl2CH2CH2Cl2 as an internal standard. c The
d
loading of AIBN was decreased to 25 mol%. The loading of AIBN was
decreased to 5 mol%. e The reaction was conducted at 40 oC. No triethyl
f
phosphite added. g Isolated yields.
2 | J. Name., 2012, 00, 1-3
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Besides of styrenes, a variety of aliphatic olefins were also
examined in this desulfurizing C−C coupling reaction (Table 3).
Respect of the fact that hydrogen transfer from the thiol to the
alkyl radical is much faster than its addition to the olefin. We
choose to decrease the concentrations of thiol, setting thiol as
one equivalent in the presence of excess of olefins.
Electrophilic alkyl radicals are not easily trapped by the thiol
due to polar effects in the hydrogen-abstraction reaction, and
they can be smoothly generated in the presence of
nucleophilic olefins such as 2,3-Dihydrofuran and N-Vinyl-2-
pyrrolidone, giving the desulfurized C−C coupling products in
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DOI: 10.1039/C9CC05378F
good yields (4a-4b). Furthermore, some other aliphatic olefins
bearing versatile functional groups, such as OH, Br, COOMe,
TIPS all performed well in this transformation, resulting in
moderate yields (4e-4h).
Table 3. Scope of Aliphatic Olefins Partners for C-C Coupling. a, b
a Reaction conditions:
1
(0.5 mmol),
2
(1.5 equiv), AIBN (5 mol%), P(OEt)3
b
(1.2 equiv), DCE (4.0 mL), stirred at 80 oC under Ar for 12 h. Yields of
isolated products.
Based on the above experiments and reported works, 12,13 a
possible mechanism is proposed (Scheme 2). Thermal radical
initiation is followed by H-atom abstraction from thiol 2a to
produce sulfur radical
addition to triethyl phosphite. The generated phosphoranyl
radical undergoes -scission of C-S bond and radical addition
to the alkene to preferentially produce an alkyl radical 10. The
alkyl radical 10 performs a thermodynamically favorable H-
atom abstraction from another thiol to afford the desulfurized
7, which then undergoes reversible
8
β
a
Reaction conditions:
1 (1.5 equiv), 2b (0.5 mmol), AIBN (5 mol%), P(OEt)3
(1.2 equiv), DCE (4.0 mL), stirred at 80 oC under Ar for 12 h. b Yields of
isolated products. c 4.0 equivalent of alkenes were used.
product 2 and regenerates sulfur radical 7. In this context, thiol
acts as both hydrogen-donating reagent and alkyl radical
precursor.
We further investigated the viability of thiols in this
desulfurizing C−C coupling reaction (Table 4). Substrates of α-
sulfydryl ketones bearing F or OMe group are competent
reaction partners
sulfydryl ketone and α-sulfydryl ester also readily underwent
this C−C coupling (5e 5g). Significantly, Mercaptoacetic acid
(5c-5d). Secondary thiols including α-
,
could also be tolerated in the reaction condition, giving the
acid derivative in good yield which was not easily accessed in
previous reported methods (5f). Notably, when D-menthol
derivatived thiol was employed, the desired desulfurized C−C
coupling product was obtained in 76% yield (5i).
To gain mechanistic insight into this desulfurized C-C
coupling, radical inhibitor 2,2,6,6-tetramethyl-1-piperidyloxy
(TEMPO) was added to the reaction system, no desired
desulfurized product 3b was detected (eq. 1). A radical clock
experiment
cyclopropylvinyl)benzene 1z as substrate, the desired ring-
open product was obtained in 63% yield, which indicated a
was
also
performed,
using
(1-
Scheme 2 Proposed Mechanism
6
radical process may be involved in this transformation (eq. 2).
In summary, we described a highly efficient reductive C-C
coupling of a variety of alkenes and thiols. This catalytic system
Table 4. Scope of Thiols Partners for C-C Coupling. a, b
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Wu and T.-P. Loh, J. Am. Chem. Soc., 2018, 140, 9332; V(pie)wJA.rAtic.leGOunrlainke,
Jr. and K. M. Engle. ACS Catal., 2018, 8, 8987.
enabled a direct desulfurization of thiols to access electrophilic
alkyl radicals assisted by commercially inexpensive triethyl
phosphite reagent. Styrenes and aliphatic olefins bearing
varies of functional groups were all well tolerated under the
mild reaction conditions with high regioselectivity.
DOI: 10.1039/C9CC05378F
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Financial support from the National Natural Science
Foundation of China (21632001, 21602005, 81821004), the
Drug Innovation Major Project (2018ZX09711-001), Peking
University Health Science Center (No. BMU20160541), and the
Open Research Fund of Shanghai Key Laboratory of Green
Chemistry and Chemical Processes are greatly appreciated. We
thank Yachong Wang in our group for reproducing the results
of 3j and 4g
.
Conflicts of interest
There are no conflicts to declare.
8
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