Radical C(sp3)-H alkenylation, alkynylation and allylation of ethers and amides enabled by photocatalysis

Article abstract of DOI:10.1039/c7gc00840f

An efficient radical addition/elimination reaction that enables selective incorporation of alkenyl, alkynyl and allyl functional groups into the C(sp³)-H bond under green reaction conditions is developed. The process is based on the catalytic formation of α-alkoxyl/α-amidyl radicals via the homolytic activation of the C(sp³)-H bond of ethers/amides with a catalytic amount of diarylketone in the presence of a household fluorescent light bulb. This simple reaction protocol features good functional group tolerance, scalability, convenient reagents and operating systems. Synthetic application of the method has been demonstrated via the preparation of natural products and different valuable synthones.

Full text of DOI:10.1039/c7gc00840f

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Radical C(sp3)‐H Alkenylation, Alkynylation and Allylation of
Ethers and Amides Enabled by Photocatalysis
Received 00th January 20xx,
Accepted 00th January 20xx
Subhasis Paul and Joyram Guin*
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient radical addition/elimination reaction that enables halides are found to be tolerated in this environmentally
selective incorporation of alkenyl, alkynyl and allyl functional friendly C(sp3)‐H alkenylation/alkynylation protocol.
groups at C(sp3)‐H bond under a green reaction condition is
developed. The process is based on the catalytic formation of α‐
alkoxyl/α‐amidyl radical via homolytic activation of C(sp3)‐H bond
of ether /amide with a catalytic amount of diarylketone in the
presence of a household fluorescent light bulb. This simple
reaction protocol features good functional group tolerance,
scalability, convenient reagents and operating system. Synthetic
application of the method has been demonstrated via the
preparation of natural product and different valuable synthones.
Catalytic transformation of abundant chemicals to high value
compounds via C(sp3)–H functionalization is of great
significance in organic synthesis.1 In particular, direct C(sp3)‐H
alkenylation of ethers and amides receives considerable
attention, as alkene2 would allow further functionalization of
such compounds. The existing methods for the direct C(sp3)‐H
alkenylation of ethers/amides primarily proceed through α‐
alkoxyl/α‐amidyl radical intermediates.3,4 These reactive
radicals are typically generated in situ via homolytic C(sp3)‐H
bond activation of ethers/amides using stoichiometric amount
of organometallic reagent/peroxide3 or diarylketone in the
presence of high energy UV light5 (Scheme 1). Herein, we
report an efficient and green method for the direct C(sp3)‐H
Scheme 1 Different protocols for the generation of α‐alkoxyl/α‐amidyl radical via
homolytic activation of C(sp3)‐H bond
R
R
R
SO2Ph
SO2Ph
R
or
R
X
R
R
X
R
R
or
SO2Ph
or
R
R
R
R
X
X
R
V
SO2Ph
PhSO2
R
R
H
H
R
Ar
R
X
R
H
X
IV
Ar
OH
X = O, NH, NR
Propagation
HAT
III
PCET
HAT
Ar
Photo
catalysis/initiation
H
R
PhSO2H
O
alkenylation/alkynylation of ethers/amides employing
a
R
X
H
I
R
O
catalytic amount of diarylketone in the presence of a house
hold fluorescent light bulb. This method allows incorporation
of alkenyl, alkynyl and allyl functional groups to C(sp3)‐H bond
of simple ethers/amides in excellent yield and stereoselectivity
avoiding the use of stoichiometric amount of reagent or toxic
UV light. Furthermore, a broad range of synthetically useful
functional groups particularly UV light sensitive aromatic
X
H
II
X = O, NH, NR
Ar
Ar
IV
Scalable
Ar
Broad substrate scope
Up to 97% yield
> 50 Examples
Scheme 2 Proposed reaction pathway
Visible‐light mediated photocatalysis has emerged as a new
strategy for homolytic activation of C‐H bond toward
sustainable organic synthesis.6 Along this line, C‐H fluorination7
and arylation8 reactions have recently been reported using a
catalytic amount of diarylketone and house hold fluorescent
light bulb. Being inspired by these work and our recent studies
on C‐H functionalization9, we wondered whether a catalytic
Department of Organic Chemistry, Indian Association for the Cultivation of
Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata‐700032 (India)
E‐mail: ocjg@iacs.res.in.
†Electronic Supplementary Information (ESI) available. See
DOI: 10.1039/x0xx00000x
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C(sp3)–H alkenylation/alkynylation of ethers and amides can electron deficient cyano (34), ester (35
Journal Name
,
36) and trifluoromethyl
be achieved with diarylketone and visible light. The
I
(37) substituents found to be suitable substrates. Vinyl sulfone
electrophilic oxyl‐radical of the short‐lived photoexcited with OH or both OMe and OH functional groups at 4 or both 3
ketone II is known to preferentially abstract hydrogen atom and 4 positions of the aromatic ring furnished the products 38‐
adjacent to a heteroatom. 10 The nucleophilic C‐centred radical 41 in good yields and selectivity; however, an extended
I
V
thus generated is expected to combine with electron reaction time was required. On the contrary, the catalytic C‐H
deficient conjugated sulfone leading to the β‐sulfonyl radical vinylation of amide exhibited good reactivity when OH group
intermediate
V, which upon elimination of a sufinyl radical at phenyl ring of vinyl sulfone was replaced with acetoxy
would enable C‐H alkenylation/alkynylation.11 Reduction of the substituent (42). The reaction furnished ether 43 in 75% yield
sulfinyl radical (for PhSO2 /PhSO2Na, E1/2red = +0.50 V vs SCE) 12 with naphthyl substituted vinyl sulfone. Importantly, vinyl
∙
with radical III (E1/2red [Ph2CO/Ph2HCO∙] = ‐1.68 V vs SCE) 6d via sulfones having furan (44) and thiophine (45) heterocycles
most likely a proton coupled electron transfer (PCET)13 would were amenable to this protocol. Trisubstituted alkene adducts
provide sulfinic acid along with the regeneration of
I
.
could be obtained using β,β‐disubstituted vinyl sulfones that
Alternatively, a radical chain mechanism may also be involved, introduce aryl‐aryl (46) and aryl‐ester moieties (47). The
where in situ formed sulfinyl radical could propagate the chain reaction allowed access to ether/amide with ene‐yne
reaction by producing the radical IV through homolytic functionality (48
activation of C(sp3)‐H bond of ether/amide (Scheme 2).
β‐phenyl allyl sulfone (50
In line with above concept, we began our study by the limited to styrenyl reagent, as sulfonyl methacrylates were
exposure of THF to vinyl sulfone 1a in the presence of a found to be viable substrates for this reaction (52 53).
,
49). C‐H Allylation could also be achieved with
,
51). Scope of the reaction is not
,
catalytic amount of diarylketone and a 36 W white compact
fluorescent lamp (CFL). Optimized reaction conditions using 1
equiv of sulfone 1a and 20 mol% of 4,4'‐
dichlorobenzophenone in THF at rt, delivered the alkenyl
Table 1 Substrate scopea
product
with 2.5 g of 1a, which afforded 1.47 g of
2
in 97% yield.14 The reaction was then performed
2
in 83% yield with
97:3 E:Z ratio (Eq. 1). The reaction exhibited similar efficiency
when carried out in sunlight. The scalability of the reaction was
also established using amide coupling partner, delivering the
allyl amide
3 in excellent yield and E:Z ratio (Eq. 2). Notably,
the diarylketone could be reused up to five cycles without
realizing significant loss of its catalytic activity15 (see ESI).
We next explored scope of this transformation with
respect to ether and amide substrates (Table 1). Accordingly,
substituted THF, pyran and 1,4‐dioxane could be effectively
converted to the vinyl derivatives
viable substrates to the simple C‐H vinylation reaction (7‐9
like ether, cyclic tertiary amide (10) found to be suitable along
with acyclic substrate (11). Secondary amides could also be
4
‐
6
. Acyclic ethers were
). As
aReaction conditions: sulfone 1a or 1b (1.0 equiv), catalyst (20 mol%)
ether/amide (0.02 M), isolated yields, E:Z ratio determined by GC analysis,
regioisomeric ratio (rr) determined by 1H NMR analysis. bPh2CO as catalyst. c30
mol% catalyst loading. dNMR yield.
converted to the products 12
stereoselectivity. With this simple reaction protocol, vinylation
of urea derivatives were achieved (15 16). Interestingly, the
method enabled synthesis of propargyl group substituted
amides (17 18) and ethers (19 20) in equal efficiency.
‐14 in good yields and
To demonstrate synthetic application of the method, a
variety of useful compounds (54‐56) were prepared via olefin
,
epoxidation and palladium catalyzed C‐C, C‐N coupling (see
ESI). Furthermore, synthesis of protected chiral γ‐amino acid
57 was completed by an olefin hydrogenation of amide 47. A
,
,
Substrate scope was then evaluated using a broad range of
functionalized vinyl sulfones (Table 2). Vinyl sulfone having
alkyl or phenyl substituent at p‐ or o‐ position of the aryl
moiety exhibited good reactivity (21‐25). The reaction could be
carried out in good yield and stereoselectivity with halide
substituted vinyl sulfones (26‐33). Vinyl sulfone bearing
concise total synthesis of (±)‐norruspoline16
(58) was achieved
by LAH reduction of the amide 42 in good yield (Fig. 1).
To support the proposed activation pathway depicted in
Scheme 2, a series of control experiments was carried out (see
ESI). When the reaction was performed with cis and trans
2 | J. Name., 2012, 00, 1‐3
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Table 2 Substrate scopea
aReaction conditions: sulfone 1a (0.2 mmol, 1.0 equiv), catalyst (20 mol%) ether or amide (0.02 M, 10 mL), isolated yields, E:Z ratio determined by GC analysis. b30
mol% catalyst loading was used. cNMR yield using mesitylene as internal standard.
Figure 1 Synthetic application of the C‐H alkenylation reaction.
can be switched on and off, which further proves the necessity
isomer of sulfone 1j (Eq. 3), both isomers delivered alkene 30
of light for the reaction. Complete decomposition of the
in essentially identical yield with E:Z ratio. This result suggests
photocatalyst was observed in absence of sulfone, suggesting
that both the reactions may occur through a common
that the reduction of sulfinyl radical with ketyl radical III of
intermediate 59, which upon elimination of a sulfinyl radical17
Scheme 2 is essential for the regeneration of ketone. However,
affords thermodynamically more stable trans alkene as a
the UV‐vis absorption spectrum of 4,4’‐dichlorobenzophenone
major product. Furthermore, the reaction exhibited sluggish
reveals very weak absorbance above 400 nm suggesting that
reactivity in the presence of TEMPO. This result indicates that
the formation of intermediate II with white compact
the reaction may involve a radical mechanism. Additionally,
fluorescent lamp (CFL) might be inefficient. As a result, the
the reaction found to be inefficient in the absence of both
observed reactivity could be attributed via a competing radical
ketone
I and light. No product formation was also realized
chain mechanism, where sulfinyl radical generated after
addition/elimination process may contribute in radical chain
propagation step (Scheme 2).18 This was further supported by
the observation that the reaction found to be promoted with
when the reaction mixture was stirred in dark at 50 °C with or
without a catalyst indicating that the reaction did not proceed
with thermal energy. By turning light on and off the reaction
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Ir(ppy)3 as photocatalyst, albeit with low yield of the desired
product (see Eq. S7 in ESI).
4
For non‐radical approaches to alkenylated/alkynylated
ethers and amides, see: (a) N. T. Patil, L. M. Lutete, H. Wu, N. K.
In conclusion, we have developed an efficient method for Pahadi, I. D. Gridnev and Y. Yamamoto, J. Org.Chem., 2006, 71
,
the direct C(sp3)‐H alkenylation/alkynylation of ethers/amides 4270; (b) K. Tsuchikama, M. Kasagawa, K. Endo and T. Shibata,
with household fluorescent light bulb and a catalytic amount Org. Lett., 2009, 11, 1821; (c) D. S. B. Daniels, A. L. Thompson
of diaryketone. This process allows easy access to alkenyl, and E. A. Anderson, Angew. Chem. Int. Ed., 2011, 50, 11506; (d)
alkynyl and allyl substituted ethers/amides in good yield with D. Banerjee, R. V. Jagadeesh, K. Junge, H. Junge and M. Beller,
moderate to excellent stereoselectivity. Furthermore, the Angew. Chem. Int. Ed., 2012, 51, 11556.
ability to perform the reaction with UV light sensitive aromatic
5
Synthesis of alkenylated/alkynylated ethers/amides using
halide and alcohol functional groups adds value to this green stoichiometric amount of benzophenone and UV light: (a) T.
protocol. This process represents a straightforward entry to Hoshikawa, S. Kamijo and M. Inoue, Org. Biomol. Chem., 2013,
different synthetically valuable compounds and natural 11, 164; (b) Y. Amaoka, M. Nagatomo, M. Watanabe, K. Tao, S.
product such as (±)‐norruspoline. Further studies toward Kamijo and M. Inoue, Chem. Sci., 2014,
5
, 4339.
reaction mechanism and application of this process with other
class of substrates are currently being pursued in our group.
6
Some selected reviews on visible light mediated
photocatalysis: (a) K. Zeitler, Angew. Chem. Int. Ed., 2009, 48
9785; (b) J. Xuan and W.‐J. Xiao, Angew. Chem. Int. Ed., 2012, 51
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4

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DOI: 10.1039/C7GC00840F
A photocatalytic radical addition/elimination reaction that enables direct C(sp3)-H alkenylation,
alkynylation and allylation of ethers/amides in good yield and stereoselectivity.