Photoredox-Catalyzed Intramolecular Difluoromethylation of N-Benzylacrylamides Coupled with a Dearomatizing Spirocyclization: Access to CF2H-Containing 2-Azaspiro[4.5]deca-6,9-diene-3,8-diones

Article abstract of DOI:10.1021/acs.orglett.6b00168

A visible light-mediated difluoromethylation of N-benzylacrylamides with HCF₂SO₂Cl as the HCF₂ radical precursor is described. The reaction incorporates a tandem cyclization/dearomatization process to afford various difluoromethylated 2-azaspiro[4.5]deca-6,9-diene-3,8-diones bearing adjacent quaternary stereocenters under mild conditions in moderate to excellent yields.

Full text of DOI:10.1021/acs.orglett.6b00168

Letter
pubs.acs.org/OrgLett
Photoredox-Catalyzed Intramolecular Difluoromethylation of
N‑Benzylacrylamides Coupled with a Dearomatizing Spirocyclization:
Access to CF H‑Containing 2‑Azaspiro[4.5]deca-6,9-diene-3,8-diones
2
Zuxiao Zhang, Xiao-Jun Tang, and William R. Dolbier, Jr.*
Department of Chemistry, University of Florida, Gainesville, Florida 32611-7200, United States
*
S Supporting Information
ABSTRACT: A visible light-mediated difluoromethylation of N-benzylacrylamides with HCF SO Cl as the HCF radical
2
2
2
precursor is described. The reaction incorporates a tandem cyclization/dearomatization process to afford various
difluoromethylated 2-azaspiro[4.5]deca-6,9-diene-3,8-diones bearing adjacent quaternary stereocenters under mild conditions
in moderate to excellent yields.
rganofluorine compounds have found wide application
within pharmaceutical, agrochemical, and materials
been demonstrated as an excellent approach to constructing
complex organic skeletons bearing fluoroalkyl groups, in
particular the difluoromethyl group (Scheme 1).
O
research due to their unique physical, chemical, and biological
1
properties. Thus, selective fluorination and fluoroalkylation
have attracted considerable interest in recent years. Further, the
Scheme 1. Photoredox-Catalyzed Difluoromethylation of
Unsaturated Bonds
development of methods for trifluoromethylation has been a
2
key area of research over the last several decades. In contrast,
incorporation of difluoromethyl groups has received much less
attention, although great strides have recently been made in this
3
area. Indeed, the CF H group has become an increasingly
2
4
attractive component of drug and agrochemical design. The
lack of good nucleophilic or electrophilic difluoromethylation
reagents has made difluoromethylation considerably more
5
challenging than trifluoromethylation. In answer to this
challenge, there have been several elegant reports of
difluoromethylation, mainly transition-metal-mediated or -cata-
lyzed coupling reactions that introduce CF H into aromatic
2
6
rings. There have also been papers describing direct
difluoromethylation via radical processes. For example, in
2
012, the Baran group described an elegant direct C−H
difluoromethylation of heteroarenes using a zinc sulfinate salt as
the CF H radical precursor. Later, Hu and co-workers
7
2
developed a concise preparation of sodium difluoromethane-
sulfinate which was also used as a good CF H radical
precursor. However, both of these reactions require an excess
amount of oxidant to generate the radical.
2
8
Azaspirocycles are a structural feature frequently found in
natural products. Indeed, azaspirocyclic cyclohexadienones are
pivotal intermediates in the preparation of an extensive range of
In recent years, visible light-driven photoredox catalysis has
become recognized as an ecofriendly and powerful tool for
11
biologically active molecules. Moreover, dearomatization
reactions have drawn increasing attention as a powerful strategy
to construct ring systems from readily available aromatic
9
organic synthesis. Within our own group’s efforts, difluor-
omethanesulfonyl chloride, in combination with photoredox
catalysis, has provided what is arguably a more efficient method
for generating the difluoromethyl radical under conditions that
12
compounds. The dearomatization of phenols to cyclo-
10
allowed good reactivity toward various unsaturated bonds. In
our work, photoredox-catalyzed radical cascade reactions have
Received: January 18, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00168
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
hexadienones is a process that has been used several times in
complex total syntheses. Several examples of radical
Therefore, an attempt was made to promote the reaction by
raising the temperature. However, this led to no product being
formed, with most of the sulfonyl chloride being destroyed by
the base (entry 9). Reasoning that the low yield was due to
ineffective oxidation of the intermediate cyclohexadienyl
radical, other catalysts were tried. [Ir(dtbpy) (ppy) ]PF give
1
3
spirocyclization onto a p-methoxyaryl ring have been
1
4
reported. In addition, the Xia group reported visible-light
induced trifluoromethylation of N-arylcinnamamides, using
Togni’s reagent, which afford a variety of CF -containing
3
2
6
1
5
dihydroquinolin-2(1H)-ones and 1-azaspiro[4.5]decanes.
a somewhat higher yield, but Cu(dap) Cl only afforded 21% of
2
Zhu and co-workers have used the same strategy successfully
product (entries 10 and 11). Water was added to the reaction
mixture (entry 12) with the hope of increasing the polarity of
the medium and thus stabilizing the desired carbocation
intermediate, and the desired reaction was enhanced, giving
50% yield of product. By increasing the amount of catalyst to 2
mol % under these condition the yield was increased to 80%,
with all of the starting materials being consumed (entry 13).
The use of alternative protecting groups on the phenol such as
benzyl (1b) or p-methoxybenzyl (1c) also resulted in good
reactivity and afforded product 1a in very good yields (entry 14
and 15).
to introduce difluoroacetyl into quinoline-2-ones and 1-
16
azaspiro[4.5]decanes. Regarding 2-azaspiro[4.5]decyl sys-
tems, the Wang group has developed a copper-catalyzed
intramolecular trifluoromethylation of N-benzylacrylamides
coupled with dearomatization using the Togni reagent as the
1
7
CF source. Until the present work, there have been no
3
methods for introduction of the CF H group into this kind of
2
azaspiro cyclic system. Consistent with our group’s previous
work, we hereby report our current results on the introduction
of not only the difluoromethyl group but also the CF group
3
and perfluoroalkyl groups into azaspiro[4,5]decyl systems.
The reaction conditions were optimized using N-(4-
methoxy)benzylacrylamide (1a) as a model substrate and
difluoromethanesulfonyl chloride as the radical source (Table
Using the conditions described in Table 1, entry 14, we
investigated the scope of variously substituted N-benzylacryla-
mides that might be effective in this reaction (Scheme 2).
1
). Various solvents were initially screened, and it was found
Scheme 2. Substrate Scope of Photoredox-Catalyzed
Difluoromethylation/Spirocyclization
a,b
a
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
Ir(ppy)3
solvent
base
yield (%)
1
2
3
4
5
6
7
8
CH CN
K HPO
2
40
3
4
4
4
4
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
dioxane
HOAc
DCE
K HPO
2
9
K HPO
2
20
K HPO
2
30
CH CN
K CO
3
trace
trace
trace
trace
trace
44
3
2
CH CN
Na CO
2
3
3
CH CN
KOAc
3
CH CN
NaOAc
3
c
9
CH CN
K HPO
2
3
4
4
1
1
1
1
1
1
0
1
2
3
4
5
[Ir(dtbpy) (ppy) ]PF
CH CN
K HPO
2
2
6
3
d
e
Cu(dap) Cl
DCE
Ag CO
2
21
2
3
Ir(ppy)3
CH CN
K HPO
2
50
3
4
4
4
4
e
Ir(ppy) (2 mol %)
CH CN
K HPO
2
80
3
3
e
,
,
f
Ir(ppy) (2 mol %)
CH CN
K HPO
2
82
3
3
e
g
Ir(ppy) (2 mol %)
CH CN
K HPO
2
81
3
3
a
Reactions were run with 0.1 mmol of 1a (R = Me), 0.2 mmol of
HCF SO Cl, 0.2 mmol of base, and 0.001 mmol of catalyst in 1 mL of
a
Reactions were run with 0.2 mmol of 1b, 0.4 mmol of HCF SO CI,
2
2
2
2
b
0.4 mmol of base, and 0.002 mmol of catalyst in 2 mL of dioxane with
8 mg water under visible light. Isolated yield. Yields were determined
by F NMR using N,N-dimethyltrifluoroacetamide as internal
standard.
solvent under visible light. All yields were based on 1a using N,N-
dimethyltrifluoroacetamide as the internal standard. Reaction runs at
b c
c
19
d
e
5
0 °C. Reaction runs at 75 °C. 2.0 equiv of water as additive.
f
g
Substrate 1b (R = benzyl). Substrate 1c (R = p-methoxybenzyl).
Initially, various N-substituents (R ) were examined. Those
1
that when CH CN (entry 1) was used as solvent the desired
with n-butyl, cyclohexyl, isopropyl, or the more bulky tert-butyl
substituent all afforded the corresponding 2-azaspiro[4.5]deca-
6,9-diene-3,8-diones 2a−f in very good yields. However, when
an N-phenyl substituent was used, the reaction became more
complex, and the reaction only gave 48% of the desired product
2g along with 50% yield of a byproduct 2g′, both of which
could be isolated. This side product derived, of course, from
competitive cyclization of the radical onto the N-phenyl
substituent. Use of an N-benzyl substituent gave only the
3
difluoromethyl-containing product, 2-azaspiro[4.5]decane 2a,
1
9
was obtained in 40% yield as determined by F NMR (entry
1
). Encouraged by the results, we examined alternative bases in
attempting to improve the yield. Unfortunately, the use of
K CO , Na CO , KOAc, and NaOAc all hindered the reaction,
2
3
2
3
with only trace amounts of product being detected (entries 5−
). In these experiments, considerable starting material and
difluoromethanesulfonyl chloride remained after workup.
8
B
DOI: 10.1021/acs.orglett.6b00168
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
normal product, 2h, in good yield. When a much smaller group,
such as methyl, was on the nitrogen, the reaction become
sluggish and only 20% of product 2i could be detected. This
indicates that the steric influence of the N-substituent plays an
important role in facilitating the cyclization.
Scheme 4. Substrates Scope with SO Group Retained
2
When substrates with various substituents R on the aromatic
2
ring were investigated, it was found that those with either
electron-donating groups (i.e., methoxy) or electron-with-
drawing groups such as F, Cl, or Br all react smoothly to
afford products 2j−m in moderate to good yield. In addition, all
of the nonaxisymmetric substrates gave pairs of diastereomers
in an approximately 1:1 ratio. When the phenol was replaced by
a naphthol, the desired product 2p was also obtained in good
yield. Interestingly, in contrast to our previous report on
10a
cyclizations of phenylacrylamides (Scheme 1), acrylamide 1q
without the α-methyl substituent (R = H) proved to be a good
3
substrate in this reaction, producing desired product 2q in 83%
yield.
In order to develop a unified strategy to introduce various
fluoroalkyl groups into the azaspiro ring system, other sulfonyl
chlorides were also investigated (Scheme 3). Since
a
Reactions were run with 0.2 mmol of 1, 0.4 mmol of R SO CI, 0.4
f
2
mmol of base, and 0.004 mmol of catalyst in 2 mL of CH CN with 8
mg of water under visible light. Isolated yield.
3
b
Considering the contrasting results, the reaction was attempted
at 105 °C, using DCE as solvent, but unfortunately, no desired
product was formed. It appears that at the higher temperature
Scheme 3. Photoredox-Catalyzed Difluoromethylation/
Dearomatization with Other Fluoroalkyl Radical Sources
a
(
see Table 1, entry 9) the sulfonyl chlorides were quickly
destroyed by the base. A few substrates were also examined
using these sulfonyl chlorides, and both provided the sulfonyl
products (6 and 7) in medium to very good yields.
The proposed mechanism for these reactions is shown in
Scheme 5. First, the sulfonyl chloride is reduced by the excited
Scheme 5. Proposed Mechanism
a
Reactions were run with 0.2 mmol of 1b, 0.4 mmol of HCF SO CI,
2
2
0
8
.4 mmol of base, and 0.002 mmol of catalyst in 2 mL of CH CN with
mg of water under visible light. Isolated yield.
3
b
Ir catalyst forming the difluoromethyl radical. Then the radical
attacks the double bond to form intermediate radical A, which
would quickly undergo cyclization to form the intermediate
radical B. Intermediate B is then oxidized by the hyper Ir
catalyst to form intermediate cation C, regenerating the
catalyst. The water might stabilize carbocation C and thus
promote the catalytic cycle. Finally, water under the basic
conditions reacts with the carbocation to form the product.
In conclusion, a photoredox-catalyzed cascade reaction
involving difluoromethylation of substituted N-benzylacryla-
mides, 5-exo cyclization, and resultant dearomatization has
been described. It is the first example of introduction of the
difluoromethyl group into the azaspiro ring system. This
reaction also supplied a unified strategy to introduce other
fluoroalkyl groups into spirocyclohexadienones bearing adja-
cent quaternary stereocenters under mild conditions in good to
excellent yield. Considering the wide substrate scope and
simple procedure, this reaction should be useful for the
BrCF COOEt is commercially available and also had been
proved to be efficiently reduced by the photoredox catalyst, this
2
bromide was used as the CF COOEt radical source, which in
2
the event produced the desired, analogous product 3 in good
yield. Then it was shown that both CF SO Cl and C F SO Cl
3
2
4
9
2
gave their corresponding products, 4 and 5, in very good yield.
To our surprise, when CH FSO Cl and CF CH SO Cl were
2
2
3
2
2
used as radical sources, the only products to be observed were
products that had retained the SO group, 6 and 7, which were
2
obtained in good yield (Scheme 4). This result can be
contrasted with the results in our previous report when we used
10a
these same sulfonyl chlorides, where the SO was lost. We
2
reasoned that the smaller electronegativity of the CH F and
2
CF CH groups would make the loss of SO more difficult.
3
2
2
Thus, under the present room temperature reaction conditions,
SO was not eliminated. (The reactions with these sulfonyl
2
chlorides in the earlier report were carried out at 105 °C.)
C
DOI: 10.1021/acs.orglett.6b00168
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Notes
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̈
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.6b00168
Org. Lett. XXXX, XXX, XXX−XXX