Organic Letters
Letter
a
class of chiral thiyl radical catalysts that enabled the first
Table 1. Condition Optimization
example of enantioselective radical [3 + 2] cyclization of
9
b
vinylcyclopropanes and alkenes. Despite these elegant
advances, however, the development of general and efficient
catalytic paradigms employing readily tunable heteroatom-
centered radical catalysts is still in high demand.
Over the past decade, visible-light-driven photoredox
catalysis has emerged as a robust platform for generation of
various radical species via single-electron transfer events,
enabling numerous previously inaccessible reaction pathways
1
0
to be explored. On the basis of this catalytic mode, a plethora
b
b
entry
photocatalyst
NCR cat.
yield (%)
d.r.
of mild and efficient methods have been invented toward
generation of a diverse range of nitrogen-centered radicals
NCRs) under photoredox catalysis, which have found
1
2
3
4
5
6
7
8
9
Ir(ppy) dtbbpyPF6
4
5
6
7
8
8
8
8
8
−
8
8
19
N.R.
75
88
96
28
66
84
N.R.
N.R.
N.R.
N.R.
3:1
−
2
3
Ir(ppy) dtbbpyPF6
2
(
Ir(ppy) dtbbpyPF6
3.5:1
3:1
2.7:1
7.6:1
3.8:1
3.8:1
−
2
extensive application in C−N bond formation, C−H bond
2g,3
Ir(ppy) dtbbpyPF6
2
activation, and C−C bond cleavage.
Notably, the group of
Ir(ppy) dtbbpyPF6
2
MacMillan recently disclosed that a photogenerated amine
eosin Y
radical cation could function as an efficient HAT catalyst to
3
Na
-eosin Y
2
abstract a hydrogen atom from the C(sp )−H and aldehyde
1
1a−c
4CzIPN
C−H bonds.
Kanai and Ooi reported that netural NCR
−
can work as an efficient HAT catalyst to activate various
3
11d,e
10
Ir(ppy)
dtbbpyPF
2
6
−
−
−
activated C(sp )−H bonds.
Despite these impressive
c
1
1
1
2
Ir(ppy) dtbbpyPF6
2
advances, to our knowledge, use of NCRs in radical covalent
catalysis has not been explored. In connection with our
ongoing project on the chemistry of NCRs and in the hope of
d
Ir(ppy) dtbbpyPF6
2
a
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), photocatalyst
(1 mol %), NCR catalyst (20 mol %), K CO (0.1 mmol), CH CN
2.0 mL), 7 W blue LEDs, Ar, rt, 5 h. Yields and d.r. were
determined by H NMR spectroscopy using 1,3,5-trimethoxybenzene
as the internal standard. Without K CO . Without visible light. N.R.
12
2
3
3
extending the their synthetic potential, we became interested
in examing the use of photogenerated NCRs as catalysts. As a
proof of this concept, we attempted to apply such a catalytic
strategy to the benchmark radical [3 + 2] cyclization of
vinylcyclopropanes and N-tosyl vinylaziridines with alkenes
b
(
1
c
d
2
3
=
No reaction.
(
Scheme 1c). Despite many precedents of transition metal and
Lewis acid catalyzed [3 + 2] cyclization reactions of
vinylcyclopropanes and vinylaziridines with alkenes, these
reactions are mainly limited to electron-deficient alkenes.
because it allows a systemic variation of its both substituents.
Moreover, it was reported that the substitution pattern on the
nitrogen atom significantly influenced both of the reactivity
13,14
1
6
Owing to the polarity-reversal property of the NCR catalysis,
our method provides an electronically reversed sense of
reactivity, thus favoring electron-rich alkene substrates.
However, this seemingly facile transformation might be
severely hampered by several competing processes, such as
NCR catalyst degradation, hydrogen atom abstraction of the
NCR catalyst itself, or radical intermediates I and II (Scheme
and stability of the neutral NCRs. Thus, we further
performed structural modification of NCR catalysts and
disclosed that, while the simple N-alkyl sulfonamide 5 was
not effective for the reaction (entry 2), aldehyde and ketone-
derived hydrazones such as 6−8 remarkably increased the yield
(entries 3−5). Notably, hydrazone 8, stable and easily
accessible in one step from acetone and p-toluenesulfonhy-
drazide, proved to be the best choice, giving product 3aa in
96% yield (entry 5). With hydrazone 8 as the optimal NCR
catalyst, we further briefly examined several organic photo-
1
c). We hypothesized that these issues might be circumvented
by appropriate design of sterically and electronically tunable
N−H bond-containing NCR precursors, as they can be
converted to NCRs with variable stability by our previously
developed photocatalytic single-electron-transfer (SET) oxida-
catalysts such as eosin Y, Na -eosin Y, and 4CzIPN. However,
2
all of these organic photocatalysts only led to moderate to
good yields (entries 6−8), confirming the superiority of the
photocatalyst Ir(ppy) dtbbpyPF . In the control experiments,
12
tion of the in situ generated nitrogen anion. In addition to
tuning the stability of NCRs, different photocatalysts with
distinct oxidation potential as well as back electron transfer
between the NCR and the reduced form of photocatalysts can
help regulate the concentration of the catalytically active NCR
2
6
no reaction occurred in the absence of photocatalyst, NCR
catalyst, base, or visible light, and large amounts of both
substrates remained unreacted (entries 9−12).
1
5
species.
With the optimal conditions in hand (Table 1, entry 5), we
then investigated the generality of this protocol by reacting a
representative set of vinylcyclopropane derivatives with
electron-rich alkenes. As shown in Scheme 2, this catalytic
system showed a broad substrate scope and high functional
group tolerance with respect to both components. For
instance, vinylcyclopropanedicarboxylates 1a−d with variable
As a starting point of this investigation, we first evaluated the
catalytic activity of a variety of NCR catalysts in the model
reaction of dibenzyl vinylcyclopropanedicarboxylate 1a and
tert-butyl vinyl ether 2a using Ir(ppy) dtbbpyPF as a
2
6
photocatalyst and K CO as a base under irradiation of 7 W
2
3
blue LEDs (Table 1). To our delight, we found that the target
reaction did indeed work to give the desired product 3aa in
steric encumbrance at the alkyl ester moiety (e.g., CO Bn,
2
i
2
1
9% yield with 3:1 d.r., when using N-(2-acetylphenyl)
CO Me, CO Et, CO Pr) reacted well with tert-butyl vinyl
2
2
benzenesulfonamide 4 as an NCR catalyst (entry 1).
ether 2a, giving the corresponding products 3aa−da in
generally good yields (73−88%) with moderate d.r. (Scheme
2a). In addition to vinylcyclopropane diesters, vinylcyclopro-
Compared to the odorous thiyl radical catalysts, an obvious
3
advantage of the sp hybridized nitrogen atom is its modularity,
B
Org. Lett. XXXX, XXX, XXX−XXX