Constructing Quaternary Carbons from N -(Acyloxy)phthalimide Precursors of Tertiary Radicals Using Visible-Light Photocatalysis

Article abstract of DOI:10.1021/acs.joc.5b00795

Tertiary carbon radicals have notable utility for uniting complex carbon fragments with concomitant formation of new quaternary carbons. This article explores the scope, limitations, and certain mechanistic aspects of Okada's method for forming tertiary c

Full text of DOI:10.1021/acs.joc.5b00795

Article
pubs.acs.org/joc
Constructing Quaternary Carbons from N‑(Acyloxy)phthalimide
Precursors of Tertiary Radicals Using Visible-Light Photocatalysis
Gerald Pratsch, Gregory L. Lackner, and Larry E. Overman*
Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California 92697-2025, United States
*
S Supporting Information
ABSTRACT: Tertiary carbon radicals have notable utility for
uniting complex carbon fragments with concomitant formation
of new quaternary carbons. This article explores the scope,
limitations, and certain mechanistic aspects of Okada’s method
for forming tertiary carbon radicals from N-(acyloxy)-
phthalimides by visible-light photocatalysis. Optimized con-
ditions for generating tertiary radicals from N-(acyloxy)-
phthalimide derivatives of tertiary carboxylic acids by visible-light irradiation in the presence of 1 mol % of commercially available
Ru(bpy) (PF ) , diethyl 1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (8), and i-Pr NEt and their coupling in
3
6
2
2
dichloromethane at room temperature with alkene acceptors were developed. Four representative tertiary N-(acyloxy)-
phthalimides and 15 alkene radical acceptors were examined. Both reductive couplings with electron-deficient alkenes and radical
substitution reactions with allylic and vinylic bromides and chlorides were examined with many such reactions occurring in good
yield using only a slight excess (typically 1.5 equiv) of the alkene. In general, the yields of these photocatalytic reactions were
higher than the analogous transformations of the corresponding N-phthalimidoyl oxalates. Deuterium labeling and competition
experiments reveal that the reductive radical coupling of tertiary N-(acyloxy)phthalimides with electron-deficient alkenes can be
terminated by both hydrogen-atom transfer and single-electron reduction followed by protonation, and that this mechanistic
duality is controlled by the presence or absence of i-Pr NEt.
2
INTRODUCTION
RESULTS
■
■
In one of the earliest applications of visible-light photocatalysis
to organic synthesis, Okada and co-workers reported in 1991
the coupling with electron-deficient alkenes of primary,
secondary, and tertiary carbon radicals generated from N-
Synthesis of N-(Acyloxy)phthalimides. We were initially
attracted to the use of N-(acyloxy)phthalimide substrates as
radical precursors because of their ease of preparation and
1
,3
stability.
These intermediates are reliably formed by
carbodiimide-mediated coupling of carboxylic acids with N-
hydroxyphthalimide (Figure 1A). To prepare more sterically
demanding substrates, coupling of acid chlorides with the
potassium salt of N-hydroxyphthalimide in the presence of a
(
acyloxy)phthalimides upon visible-light irradiation in the
presence of catalytic Ru(bpy) Cl and 1-benzyl-1,4-dihydroni-
3
2
1
,2
cotinamide (BNAH). The utility of this general method for
combining complex carbon fragments has recently been
highlighted in several total synthesis investigations in our
4
crown ether is most effective (Figure 1B). As summarized in
Figure 1, N-(acyloxy)phthalimides of variable structural
complexity were prepared in high yield by these methods.
These radical precursors are typically crystalline solids, which
are stable to benchtop storage, ambient light, biphasic aqueous
purification conditions, and chromatography on silica gel. In
preliminary studies comparing N-(acyloxy)phthalimides to the
more conventionally employed Barton esters, we observed that
the former exhibit superior stability and are more easily
synthesized and handled.
Coupling of N-(Acyloxy)phthalimides with Alkene
Acceptors. We next evaluated conditions for generating
nucleophilic tertiary radicals from these substrates and their
coupling with electron-deficient olefins. In the original report,
Okada disclosed the coupling of N-(acyloxy)phthalimides with
Michael acceptors such as methyl vinyl ketone (MVK) in the
3
,4
laboratories.
In our studies, the conditions of Okada were modified to
allow the photocatalytic coupling of tertiary carbon radicals to
be carried out in nonaqueous solvents. In this article, we
provide details of our modification of the Okada method, and a
broader survey of the notable utility of this visible-light
photocatalytic method for C−C bond formation and the
construction of quaternary carbon centers. In particular, we
examine a selection of coupling reactions to allow a direct
comparison of N-(acyloxy)phthalimides and N-phthalimidoyl
7
5
,6
oxalates as precursors of tertiary carbon radicals for C−C
bond-forming reductive coupling and allylic and vinylic
substitution reactions. We also report investigations that
identify both hydrogen-atom transfer and single-electron
reduction followed by protonation as viable termination steps
of these C−C bond-forming coupling reactions.
Received: April 9, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00795
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Table 1. Optimization of the Visible-Light Photoredox
Coupling of N-(Acyloxy)phthalimide 4 with MVK
entry
modification
yield of 9 (%) ,
ab
1
2
3
4
5
6
7
8
9
−
1.5 h
86
85
74
68
67
71
65
81
78
ND
41
49
61
15
CH Cl /THF (1:1)
2
2
THF
i-Pr NEt (0.2 equiv)
2
i-Pr NEt (1 equiv)
2
Figure 1. Synthesis of N-(acyloxy)phthalimides by (A) carbodiimide-
assisted coupling, and (B) reaction of an acid chloride intermediate
with potassium phthalimide N-oxide.
Hantzsch ester 8 (0.5 equiv)
Hantzsch ester 8 (1 equiv)
MVK (1 equiv)
10
11
12
13
14
no light
no Hantzsch ester 8
presence of 1 equiv of 1-benzyl-1,4-dihydronicotinamide and
1
no i-Pr NEt
the visible light photocatalyst Ru(bpy) Cl in aqueous THF.
2
3
2
no photocatalyst (18 h)
no photocatalyst (2 h)
Although various alkyl radicals were generated and coupled
with electron-deficient alkenes under these conditions, the only
tertiary radical generated in this way was the atypical 1-
adamantyl radical (eq 1). As we anticipated that an aqueous
reaction medium might be problematic with highly lipophilic
substrates, we chose to explore related nonaqueous reaction
a
b
[4] = 0.15 M. Isolated yield after silica gel chromatography. ND =
not detected.
conditions initially disclosed by Gagne
́
for the photocatalytic8
inclusion of THF as a solvent, which was found to be beneficial
in the visible light photocoupling of related tert-alkyl N-
phthalimidoyl oxalates, did not improve the yield of 9 (entries
generation of glycosyl radicals from glucosyl halides (eq 2).
These conditions employ the Hantzsch ester, diethyl 1,4-
dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (8), the photo-
catalyst Ru(bpy) (BF ) , and i-Pr NEt in dichloromethane as
5
3 and 4). Decreasing the excess of Hantzsch ester 8, i-Pr NEt,
2
or MVK proved detrimental (entries 5−9), although the
reduction in yield using 1 equiv of the Hantzsch ester was
minimal (entry 8). The yield of the coupled product 9 was only
slightly diminished when equal amounts of the coupling
partners were used (entry 9), suggesting that this photocatalytic
reaction would be appropriate for uniting structurally complex
fragments. In the absence of light, no conversion was observed
(entry 10). Omission of either the Hantzsch ester (entry 11) or
3
4 2
2
solvent.
Our efforts to optimize the coupling of 1-methyl-1-cyclohexyl
N-(acyloxy)phthalimide (4) with methyl vinyl ketone (MVK)
quickly identified useful conditions employing 1 mol % of
commercially available Ru(bpy) (PF ) , 1.5 equiv of Hantzsch
3
6 2
ester 8, and 2.2 equiv of i-Pr NEt in dichloromethane with
2
irradiation at room temperature with blue LEDs. Using these
conditions, the coupled product 9 was formed in 85−86% yield
i-Pr NEt (entry 12) resulted in a decreased yield of 9,
2
(
Table 1, entries 1 and 2). Although the coupling of 4 with
suggesting that the combination of these reductants was most
effective. Significantly, slower reactivity was observed in the
absence of the photocatalyst, with a 61% yield of 9 being
MVK was complete after stirring for only 1.5 h (entry 2),
longer reaction times were not detrimental (entry 1). The
B
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obtained after 18 h (entries 13 and 14). A related observation
was noted by Okada and co-workers in their initial report.
N-(Acyloxy)phthalimides were also tested as precursors of
tertiary radicals in allylation and vinylation reactions. We
1
14
We next examined the reaction of N-(acyloxy)phthalimide 4
with a selection of conjugate acceptors to allow N-(acyloxy)-
phthalimides and the analogous tert-alkyl N-phthalimidoyl
initiated these studies in a similar fashion by performing control
and optimization experiments of the reaction of N-(acyloxy)-
phthalimide 4 with α-(bromomethyl)styrene (14) (Table 3).
6
oxalates to be compared as radical precursors under their
respective optimized visible-light photoredox coupling con-
ditions. Reaction of N-(acyloxy)phthalimide 4 with MVK
provided product 9 in 85% yield (Table 2), essentially the same
Table 3. Visible-Light Photoredox Coupling of N-
(Acyloxy)phthalimide 4 with α-(Bromomethyl)styrene (14)
Table 2. Visible-Light Photocatalytic Reductive Coupling of
N-(Acyloxy)phthalimide 4 with Various Electron-Deficient
Alkenes
a
entry
modification
yield of 15 (%)
1
2
3
4
5
6
7
8
9
−
74
b
no light
ND
no Hantzsch ester 8
no photocatalyst (18 h)
no photocatalyst (2 h)
2 h
14
75
11
76
70
48
55
62
acceptor (1 equiv)
no i-Pr NEt
2
i-Pr NEt (0.2 equiv)
2
1
0
i-Pr NEt (1 equiv)
2
a
b
Isolated yield after silica gel chromatography. Product formation
after resubjection to light. ND = not detected.
a
b
Isolated yield after silica gel chromatography. Yield measured by
Using the conditions optimized for reductive coupling with
electron-deficient alkenes, N-(acyloxy)phthalimide 4 reacted
with α-(bromomethyl)styrene (14) to give substitution product
15 in 74% yield (entry 1). No synthetically useful product
formation was observed in the absence of light or the Hantzsch
ester (entries 2 and 3). In contrast to the related reaction with
NMR relative to an internal standard (1,4-dimethoxybenzene).
efficiency as realized in the reaction of MVK with 1-methyl-1-
9
cyclohexyl N-phthalimidoyl oxalate. However, in the coupling
with 2-cyclopentenone, N-(acyloxy)phthalimide 4 gave product
1
0 in 80% yield, 25% higher than the yield obtained from the
corresponding N-phthalimidoyl oxalate. The reaction of N-
acyloxy)phthalimide 4 with benzyl methacrylate provided
6
the tert-alkyl N-phthalimidoyl oxalate precursor, the absence of
(
the Ru(bpy) (PF ) , did not diminish the yield of allylation
3 6 2
product 11 in 59% yield, again the yield being considerably
higher than that achieved from the corresponding N-
phthalimidoyl oxalate (41%). The greatest difference in
product 15 after 18 h (entry 4). However, entries 5 and 6 show
that the reaction without the photocatalyst proceeds consid-
erably slower. The yield of 15 was only slightly lower using 1
equiv of the acceptor (entry 7), again showing that the coupling
of valuable fragments likely could be accomplished without the
need of an excess of either coupling component. Finally, entries
9
reactivity between these two classes of tertiary radical
precursors was observed in couplings with methacrylonitrile.
N-(Acyloxy)phthalimide 4 coupled with this acceptor to give
coupled product 12 in 83% yield, while the similar coupling
with 1-methyl-1-cyclohexyl N-phthalimidoyl oxalate yielded
8 to 10 confirmed that an excess of i-Pr NEt led to higher
2
yields, but even without this additive, product 15 was isolated
in 48% yield.
9
−11
only trace amounts of 12.
We also examined the reaction of (N-acyloxy)phthalimide 4
with styrene (eq 3). In this case, the product of reductive
With suitable reaction conditions in hand, we explored
further the scope of radical substitution reactions of this type
(
Table 4). α-(Chloromethyl)styrene coupled with N-(acyloxy)-
phthalimide 4 to give allylation product 15 in 80% yield, which
was slightly higher than that realized with the corresponding
bromide 14. Methyl 2-(bromomethyl)acrylate and methyl 2-
(
(
chloromethyl)acrylate coupled in excellent yield with N-
acyloxy)phthalimide 4 to give product 16. Vinylation reactions
with methyl 3-bromoacrylate and β-bromostyrene proceeded in
lower yield, but with high (>20:1) E stereoselectivity, to form
products 17 and 18, respectively. To realize the moderate yields
in these vinylic coupling reactions, 5 equiv of the bromide
coupling partner had to be employed. Products resulting from a
second addition of the tertiary radical were never isolated,
although allylation products 15 and 16 are potential excellent
radical acceptors themselves. This selectivity likely results from
steric shielding by the quaternary carbon fragment in these
products.
coupling was not obtained but rather product 13 (83% as a 1:1
mixture of stereoisomers) resulting from the recombination of
12
benzylic radical intermediates. Identical products were formed
6
from the corresponding N-phthalimidoyl oxalate precursor. As
found in that case, efforts to trap the coupled benzylic radical by
modifying the reaction conditions, or by adding common
hydrogen-atom transfer reagents such as Bu SnH, Et SiH,
3
3
13
Ph SiH, or PhSH, were unsuccessful.
3
C
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Table 4. Substitution Products Formed from Visible-Light
Photocatalytic Coupling of Selected Allylic and Vinylic
Bromides and Chlorides with N-(Acyloxy)phthalimide 4
of chiral N-(acyloxy)phthalimide 5 with allylic bromide 14 was
only 3:1, reflecting the lack of dominant steric influence in the
proximity to C19 in the 18-β-glycyrrhetinic acid series.
Evaluating the Generality of the Radical Coupling in
the Absence of Ru(bpy)3 . After observing during our
optimization studies that the reductive coupling of (N-
acyloxy)phthalimides with electron-deficient alkenes occurs in
the absence of the Ru(bpy)32+ photocatalyst (Table 1, entries
a
2
+
1
3 and 14), we investigated further the generality of this
reaction. As our preliminary studies had shown that the
reductive coupling with MVK was significantly slower in the
absence of the photocatalyst, reactions were carried out for 18 h
(
Table 6). Reductive coupling of N-(acyloxy)phthalimide 4
with MVK or acrylonitrile provided products 9 and 22 in 61%
and 57% yield, respectively (entries 1 and 2). Attempted
reactions of N-(acyloxy)phthalimide 4 with methacrylonitrile or
three cyclopent-1-ene-1-carbonitriles afforded no products of
reductive coupling (entries 4−7). In these four cases, both
coupling partners were recovered in high yield.
a
Isolated yield after silica gel chromatography (average of two
b
experiments). 5 equiv of the halide was used; in other entries 1.5
equiv was used.
Allylic and vinylic substitution reactions were also surveyed
in the absence of the Ru(bpy)32+ photocatalyst (Table 7). In
contrast to the results of the reductive coupling reactions, allylic
substitution reactions of N-(acyloxy)phthalimide 4 with α-
To explore further the scope of allylic coupling reactions of
tertiary carbon radicals generated by visible-light photocatalysis,
we examined the reaction of a selection of (N-acyloxy)-
phthalimides with α-(bromomethyl)styrene (14) (Table 5). In
all cases, the product of 2-phenylallylation was isolated in high
yield (71−91%). The coupling reactions of (N-acyloxy)-
phthalimides 3 and 5, derived from gemfibrozil and 18-β-
glycyrrhetinic acid, illustrate the utility of (N-acyloxy)-
phthalimide derivatives to efficiently elaborate drug and natural
product carboxylic acids to products containing new quaternary
carbons (entries 3 and 4). Diastereoselectivity in the coupling
(
chloromethyl)- and α-(bromomethyl)styrene afforded ally-
lated product 15 in identical high yields to that observed in the
presence of Ru(bpy) (PF ) . The allylic substitution product
3
6 2
16 and the vinylic substitution products 17 and 18 were also
formed in the absence of the photocatalyst, although in these
cases yields were approximately 40% lower than those realized
in the presence of the photocatalyst (Table 4). Attempted
coupling of styrene with N-(acyloxy)phthalimide 4 in the
Table 5. Visible-Light Photocatalytic Coupling of Various Tertiary N-(Acyloxy)phthalimides with (α-Bromomethyl)styrene
a
(
14)
a
N-(Acyloxy)phthalimide (1 equiv), Ru(bpy) (PF ) (1 mol %), 14 (1.5 equiv), Hantzsch ester 8 (1.5 equiv), i-Pr NEt (2.2 equiv), blue LEDs, 0.15
3
6
2
2
b
M in CH Cl , rt, 18 h. Isolated yield after silica gel chromatography (average of two experiments).
2
2
D
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Table 6. Reaction of N-(Acyloxy)phthalimide 4 with Various
Alkenes in the Absence of a Photocatalyst
presence of a dihydropyridine reductant and catalytic Ru-
(bpy)32+ (vide infra) is consistent with the results of our
investigations. However, our experimental results suggest that
the termination of the reductive coupling of N-(acyloxy)-
phthalimides with electron-deficient alkenes can take place by
two pathways (Scheme 1). After addition of a tertiary radical to
1
Scheme 1. Possible Termination Pathways in Reductive
Coupling of Tertiary Radicals and Alkenes
a C−C π-bond, the product radical can be terminated either by
hydrogen atom abstraction (path A) or by a two-step process of
single-electron transfer followed by protonation of the resulting
anion (path B).
To probe the role of the Hantzsch ester in the termination
sequence, we examined the coupling of N-(acyloxy)phthalimide
4
with MVK employing 4,4-dideuterio Hantzsch ester 23 (eq
15
4
). Coupled product 9 was obtained from this reaction in
a
b
Isolated yield after silica gel chromatography. 50% of 2-cyclo-
c
pentenone was recovered. Both 4 and the alkene acceptor were
recovered in >90% yield.
Table 7. Substitution Products Formed from Visible-Light
Photocatalytic Coupling of Selected Allylic and Vinylic
Bromides and Chlorides with N-(Acyloxy)phthalimide 4 in
47% yield and was determined to have only 33% deuterium
incorporation (at C2 of the butanone side chain). This result
a
16
the Absence of Ru(bpy) (PF )
3
6 2
contrasts sharply with the essentially complete deuterium
incorporation observed in the related coupling of the
6
corresponding N-phthalimidoyl oxalate. As the protic acid
generated by oxidation of dideutero Hantzsch ester 23 would
be a mixture of protio and deuterio species, the low level of
deuterium incorporation in product 9 (eq 4) is consistent with
significant termination by the two-step electron transfer/
protonation sequence.
To examine in more depth the termination stage of reductive
coupling of N-(acyloxy)phthalimides with alkenes, we inves-
tigated coupling reactions of N-(acyloxy)phthalimide 4 with
various α,β-unsaturated nitriles containing a leaving group at
the allylic α′ position, a strategy introduced in the preceding
6
a
b
article. Coupling of 1-methyl-1-cyclohexyl N-(acyloxy)-
Isolated yield after silica gel chromatography. 5 equiv of the acceptor
were used.
phthalimide (4) with cyanocyclopentene allylic benzoate 24,
under our optimized conditions for reductive couplings, gave
products 25 and 26 in 28% and 45% yield, respectively
(Scheme 2). The product of reductive coupling was formed as a
mixture of four stereoisomers, with the major isomer being
represented by structure 25. As β-scission of intermediate E
to eject a high-energy benzoyloxy radical is implausible, the
significant formation of allylic substitution product 26 requires
absence of Ru(bpy) (PF ) gave only trace amounts of product
3
6 2
13 (see eq 3) resulting from recombination of benzylic radical
intermediates.
17
Mechanistic Investigations. The basic mechanism origi-
nally suggested by Okada for the formation of carbon radicals
upon visible-light irradiation of N-(acyloxy)phthalimides in the
E
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Scheme 2. Products Formed upon Visible-Light Photoredox
Coupling of N-(Acyloxy)phthalimide 4 with
Cyanocyclopentene Allylic Benzoate 24
exclusive formation of allylic substitution product 26 in 36%
yield, with no trace of product 25 of reductive coupling being
observed. These results implicate the combination of i-
19
Pr NEt and the photocatalyst as the single-electron donors in
2
20−22
the reduction of the initially formed product radical,
and
show that the aminium radical cation generated upon oxidation
of the amine during the course of the reaction does not act as a
hydrogen-atom donor in the termination step.
As expected, the coupling of N-(acyloxy)phthalimide 4 with
cyclopentenyl bromide 27 provided only the allylic substitution
product 26 (eq 7). As 26 was also formed exclusively in the
coupling of 1-methyl-1-cyclohexyl N-phthalimidoyl oxalate with
bromoalkene 27, a process that undoubtedly involves
homolytic β-scission, single-electron reduction would not be
that the intermediate radical E first suffers single-electron
reduction to α-cyanocarbanion F.
18
6
To examine whether the nature of the radical precursor, or
more likely the reaction conditions used for radical generation,
has an effect on the termination mechanism, N-(acyloxy)-
phthalimide 4 was allowed to react with cyclopentene allylic
benzoate 24 under the conditions typically used for the
reductive coupling of N-phthalimidoyl oxalates (eq 5). In this
required for the formation of substitution product 26 in the
transformation depicted in eq 7.
We conclude with one additional example of the critical role
the stoichiometric reductant can play. As already described, the
coupling of N-(acyloxy)phthalimide 4 with α-(bromomethyl)-
styrene (14) proceeded in the absence of the photocatalyst
23
(
Table 7) or i-Pr NEt, albeit the latter in poorer yield (Table 3,
2
entries 1 and 8). In contrast, the reaction of N-(acyloxy)-
phthalimide 4 with α-(acetoxymethyl)styrene (28) fails in the
absence of either i-Pr NEt or Ru(bpy) (PF ) (eq 8).
2
3
6 2
case, only products of reductive coupling were obtained (67%
yield). As the conditions of the reactions reported in Scheme 2
and eq 5 differ most notably in the presence of i-Pr NEt in the
2
former, the electron-rich trialkylamine appeared to be
potentially critical for single-electron reduction of the coupled
radical E to generate intermediate carbanion F of Scheme 2.
DISCUSSION
■
1
,2
On the basis of our investigation and existing precedent, we
propose the following mechanism for the coupling of tertiary
N-(acyloxy)phthalimides with conjugate acceptors (Scheme 3).
Irradiation of Ru(bpy)32+ with visible light generates the
excited-state catalyst Ru(bpy)32+*, which is reductively
To further study the role of i-Pr NEt in the termination
2
process, we subjected N-(acyloxy)phthalimide 4 to photoredox-
catalyzed coupling with cyclopentene 24, omitting the
Hantzsch ester 8 (eq 6). This experiment resulted in the
quenched by i-Pr NEt or the Hantzsch ester 8 to provide the
2
+
3
strong reductant Ru(bpy) . The N-(acyloxy)phthalimide 29
then receives an electron from Ru(bpy)3 (E1/2 = −1.33 V vs
+
SCE), or potentially, but less likely, from the Hantzsch ester
intermediate H that is produced in the termination step (vide
infra), to transiently form radical anion I. Homolytic
fragmentation and decarboxylation of I releases phthalimide
or phthalimide anion, CO , and the tertiary radical intermediate
2
A. Addition of this radical to a conjugate acceptor generates
stabilized radical J, which can be terminated either by
hydrogen-atom abstraction from dihydropyridine 8 or derived
F
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Scheme 3. Proposed Mechanism for the Ru(bpy)32+-Catalyzed Coupling of Tertiary N-(Acyloxy)phthalimides with MVK in the
Presence of Visible Light
Scheme 4. Potential Chain Mechanism for the Visible-Light Promoted Coupling of Tertiary N-(Acyloxy)phthalimides with
2
+
MVK in the Absence of Ru(bpy)3
intermediate G or by single-electron transfer from Ru(bpy)3+
followed by protonation to provide the product 30.
We turn to consider the related transformation in the
absence of the photocatalyst, a transformation that is poorly
understood at this time. Owing to the observed requirement of
the Hantzsch ester 8 for significant reaction progress (Table 1,
2
+
entry 11), the observed reactivity in the absence of Ru(bpy)3
most likely is mediated by the Hantzsch ester. This suggestion
G
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would be consistent with Okada’s observation of a related
obtained reagents were used as received. Ru(bpy)
3
(PF
6
)
2
was obtained
2
+
from Sigma-Aldrich. Methyl vinyl ketone (MVK), acrylonitrile, benzyl
methacrylate, and methacrylonitrile were distilled from neat solutions
prior to use. Hantzsch ester 8 is commercially available; however, we
transformation in the absence of Ru(bpy)3 under reaction
conditions in which a dihydropyridine was the only reductant
present (see eq 1). The noncatalyzed reaction could be initiated
by oxidation of the Hantzsch ester 8 by trace amounts of
3
1
prepared it by a straightforward literature procedure. The 4,4-d2-
14a
8
Hantzsch ester 23,
i-Pr NEt·HBF methyl 2-(bromomethyl)-
2 4,
33
2
4,25
oxygen to form intermediate G (depicted in Scheme 3),
potentially by electron transfer from photoexcited 8 to the N-
acyloxy)phthalimide. Loss of a proton from radical cation G
would form the vinylogous α-amino radical H. Intermediate H
or
32
acrylate, methyl 2-(chloromethyl)acrylate, (E)-methyl 3-bromoa-
crylate, α-(chloromethyl)styrene, α-(bromomethyl)styrene (14),
and α-(acetoxymethyl)styrene (28) were prepared according to
34
35
35
3
6
(
3
4
6
6
literature procedures. The syntheses of 2, 7, 24, and 27 have been
reported previously. Usually one representative coupling reaction and
yield of the product is described in detail; isolated yields reported in
Results are the average yields obtained from duplicate experiments.
Reaction temperatures were controlled using a temperature modulator,
and unless stated otherwise, reactions were performed at room
temperature (rt, approximately 23 °C). Thin-layer chromatography
2
6
is a strong one-electron reductant (E1/2 = −0.71 V vs SCE);
however, not sufficiently strong that rapid electron transfer to a
6
,27
N-(acyloxy)phthalimide (E1/2 = −1.26 to −1.37 V vs SCE)
would be expected. Presumably single-electron transfer form H
occurs in concert with cleavage of the N−O bond of the N-
2
8−30
(
acyloxy)phthalimide.
The propagation steps of the
(
TLC) was conducted with E. Merck silica gel 60 F254 precoated
31
resulting chain reaction are depicted in Scheme 4.
plates (0.25 mm) and was visualized by exposure to UV light (254
nm) or anisaldehyde, ceric ammonium molybdate, iodine, or
potassium permanganate. EMD silica gel 60 (particle size 0.040−
The observation that the visible-light reductive coupling is
slower in the absence of a photocatalyst, and succeeds only with
highly reactive coupling partners, would be consistent with a
chain mechanism (Scheme 4). However, much additional
investigation will be required to elucidate in any detail the
mechanism of the reductive coupling in the absence of the
photocatalyst.
1
0.063 mm) was used for flash column chromatography. H NMR
spectra were recorded at 500 or 600 MHz and are reported relative to
1
deuterated solvent signals. Data for H NMR spectra are reported as
follows: chemical shift (δ ppm), multiplicity, coupling constant (Hz),
13
and integration. C NMR spectra were recorded at 125 or 150 MHz.
Data for 13C NMR spectra are reported in terms of chemical shift. IR
spectra were recorded on an FT-IR spectrometer and are reported in
CONCLUSION
−1
■
terms of frequency of absorption (cm ). Blue LEDs (30 cm, 1 W)
were purchased from Creative Lighting (http://www.creativelightings.
com, product code CL-FRS5050-12WP-12 V) and powered by 8 AA
batteries.
N-(Acyloxy)phthalimide derivatives of tertiary carboxylic acids
are shown to be excellent precursors of tertiary radicals upon
visible-light irradiation in the presence of 1 mol % of
commercially available Ru(bpy) (PF ) , 1.5 equiv of Hantzsch
N-(Acyloxy)phthalimide 1. A round-bottom flask was charged
with adamantane-1-carboxylic acid (1.08 g, 6.00 mmol, 1 equiv) and
THF (28 mL) under argon. After sequential addition of N-
hydroxyphthalimide (1.64 g, 10.0 mmol, 1.66 equiv), DMAP (35
mg, 0.29 mmol, 0.05 equiv), and N,N′-diisopropylcarbodiimide (1.4
mL, 8.93 mmol, 1.5 equiv), the reaction mixture was maintained at rt
with stirring overnight. After this time, the heterogeneous mixture was
filtered and the filtrate concentrated under reduced pressure. The
crude residue was purified by silica gel chromatography (10% EtOAc/
hexanes). Subsequent recrystallization from hot hexanes gave 1 (1.75
3
6 2
ester 8, and 2.2 equiv of i-Pr NEt in dichloromethane at room
2
temperature. Tertiary radicals generated in this way reductively
couple with a variety of electron-deficient alkenes and undergo
substitution reactions with allylic and vinylic halides, in
moderate to excellent yields to form new C−C σ-bonds and
new quaternary centers. In nearly all cases examined, the yields
of these photocatalytic reactions were higher than the
analogous transformations of the corresponding N-phthalimi-
1
6
g, 5.38 mmol, 90%) as a colorless solid. Rf 0.53 (20% EtOAc/
doyl oxalates. In some cases, the coupling of N-(acyloxy)-
1
hexanes); mp: 143−144 °C; H NMR (500 MHz, CDCl ): δ 7.88−
3
phthalimide derivatives of tertiary carboxylic acids can be
accomplished in the absence of the photocatalyst Ru-
7
6
.86 (m, 2H), 7.78−7.76 (m, 2H), 2.14 (s, 6H), 2.10 (s, 3H), 1.78 (s,
13
H); C NMR (125 MHz, CDCl ): δ 173.4, 162.3, 134.8, 129.2,
3
(
bpy) (PF ) ; however, this reaction is of less preparative
3 6 2
124.0, 40.7, 38.6, 36.3, 27.8; IR (thin film): 2907, 2852, 1776, 1741,
1466, 1356 cm ; HRMS-CI (m/z) [M + NH ] calculated for
−1
+
significance, because it is slower than the photocatalytic
reaction and only succeeds with highly reactive radical
acceptors.
4
C H NO NH 343.1658, found 343.1643.
19
19
4
4
N-(Acyloxy)phthalimide 3. Following the procedure described
for the preparation of 1, gemfibrozil (1.50 g, 6.00 mmol, 1 equiv), N-
hydroxyphthalimide (1.64 g, 10.0 mmol, 1.66 equiv), DMAP (35 mg,
The ability to include or exclude the electron-rich trialkyl-
amine i-Pr NEt in photocatalytic reactions of N-(acyloxy)-
2
0
8
.29 mmol, 0.05 equiv), and N,N′-diisopropylcarbodiimide (1.4 mL,
phthalimides allows one to dictate whether the coupling
reaction is terminated by hydrogen-atom transfer or single-
electron reduction followed by protonation. With some alkene
radical acceptors, this choice can dictate the reaction outcome.
The ease of synthesis and purification and high crystallinity
of N-(acyloxy)phthalimides, together with their efficient
photocatalytic generation of tertiary radicals at room temper-
ature upon irradiation with visible light, combine to make these
carboxylic acid derivatives highly attractive precursors of tertiary
carbon radicals for use in C−C bond formation.
.90 mmol, 1.5 equiv) in THF (28 mL) gave, after purification of the
crude product by silica gel chromatography (10% EtOAc/hexanes), 3
2.12 g, 5.37 mmol, 90%) as a colorless solid. R 0.52 (20% EtOAc/
(
f
1
hexanes); mp: 79−80 °C; H NMR (500 MHz, CDCl ): δ 7.89−7.88
3
(
m, 2H), 7.80−7.78 (m, 2H), 7.00 (d, J = 7.2, 1H), 6.67−6.65 (m,
2H), 4.03−4.00 (m, 2H), 2.32 (s, 3H), 2.19 (s, 3H), 1.97−1.92 (m,
4H), 1.45 (s, 6H); 13C NMR (125 MHz, CDCl
): δ 173.9, 162.2,
57.1, 136.6, 134.8, 130.4, 129.2, 124.0, 123.7, 120.8, 112.1, 67.8, 42.1,
7.5, 25.3, 25.1, 21.6, 15.9; IR (thin film): 2923, 2870, 1782, 1744,
3
1
3
1
−1
509, 1468, 1370, 1264, 1130, 1043 cm ; HRMS-ESI (m/z) [M +
+
H] calculated for C H NO H 396.1811, found 396.1823.
23
25
5
N-(Acyloxy)phthalimide 4. A round-bottom flask was charged
with 1-methyl-1-cyclohexanecarboxylic acid (5.00 g, 35.2 mmol, 1
equiv), N-hydroxyphthalimide (8.61 g, 52.8 mmol, 1.5 equiv), and
N,N′-dicyclohexylcarbodiimide (10.90 g, 52.8 mmol, 1.5 equiv) under
argon. After sequential addition of THF (350 mL) and DMAP (430
mg, 3.52 mmol, 0.1 equiv), the reaction mixture was maintained at rt
with stirring overnight. After this time, the heterogeneous mixture was
EXPERIMENTAL SECTION
■
Materials and Methods. Unless stated otherwise, reactions were
conducted in oven-dried glassware under an atmosphere of nitrogen or
argon using anhydrous solvents (either freshly distilled or passed
through activated alumina columns). For all radical coupling reactions,
CH Cl was sparged with argon for 5 min prior to use. Commercially
2
2
H
DOI: 10.1021/acs.joc.5b00795
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
concentrated under reduced pressure and the resulting residue
1.5 equiv), and i-Pr NEt (100 μL, 0.57 mmol, 2.2 equiv) in CH Cl
2
2
2
suspended in Et O (400 mL). The mixture was filtered through
cotton, transferred to a separatory funnel, and washed with saturated
(1.7 mL, sparged with Ar for 5 min) gave a crude product. The yield of
11 (59%) was determined by examining the relative integration of
NMR signals in this crude mixture using an internal standard (1,4-
dimethoxybenzene). An analytically pure sample of 11 was obtained
by silica gel chromatography (2.5% EtOAc/hexanes) to provide 11 as
a colorless oil. Characterization data for 11 are included in the
2
aqueous NH Cl (3 × 200 mL). The organic layer was dried over
4
MgSO , filtered, and concentrated under reduced pressure. The crude
4
residue was purified by silica gel chromatography (7% EtOAc/
hexanes) to give 4 (9.05 g, 31.5 mmol, 90%) as a colorless solid. R
f
1
6
0
.26 (10% EtOAc/hexanes); mp: 52−54 °C; H NMR (600 MHz,
preceding article.
CDCl ): δ 7.90−7.84 (m, 2H), 7.79−7.75 (m, 2H), 2.26−2.20 (m,
(± )-2-Methyl-3-(1-methylcyclohexyl)propanenitrile (12). Fol-
lowing the general procedure for optimization experiments, N-
(acyloxy)phthalimide 4 (75 mg, 0.26 mmol, 1 equiv), Ru(bpy) (PF )
3
2
(
H), 1.69−1.51 (m, 5H), 1.42 (s, 3H), 1.40−1.34 (m, 2H), 1.33−1.23
m, 1H); 13C NMR (125 MHz, CDCl ): δ 173.7, 162.3, 134.7, 129.2,
3
3
6 2
1
1
23.9, 43.2, 35.8, 26.8, 25.5, 23.1; IR (thin film): 2934, 2860, 1807,
782, 1743 cm ; HRMS-ESI (m/z) [M + Na] calculated for
(
2 mg, 2.6 μmol, 0.01 equiv), Hantzsch ester 8 (100 mg, 0.39 mmol,
.5 equiv), methacrylonitrile (33 μL, 0.39 mmol, 1.5 equiv), and i-
Pr NEt (100 μL, 0.57 mmol, 2.2 equiv) in CH Cl (1.7 mL, sparged
−1
+
1
C H NO Na 310.1055, found 310.1051.
16
17
4
2
2
2
N-(Acyloxy)phthalimide 5. A round-bottom flask was charged
with 18β-glycyrrhetinic acid (1.00 g, 2.12 mmol, 1 equiv) and THF
21 mL) under argon. After sequential addition of N-hydroxyph-
thalimide (520 mg, 3.19 mmol, 1.5 equiv), DMAP (52 mg, 0.43 mmol,
with Ar for 5 min) gave 12 (36 mg, 0.22 mmol, 83%) as a colorless oil.
1
R 0.47 (10% EtOAc/hexanes); H NMR (500 MHz, CDCl ): δ 2.64−
f
3
(
2
1
3
2
.57 (m, 1H), 1.77 (dd, J = 14.1, 13.4, 1H), 1.58−1.4 (m, 5H), 1.39−
.22 (m, 8H), 0.97 (s, 3H); C NMR (125 MHz, CDCl ): δ 124.5,
8.0, 37.6, 33.2, 26.3, 22.0, 21.9, 20.8, 20.2; IR (thin film): 2927, 2853,
237, 1455, 1382 cm ; HRMS-ESI (m/z) [M + Na] calculated for
13
3
0
.2 equiv), and N,N′-diisopropylcarbodiimide (0.4 mL, 2.6 mmol, 1.2
equiv), the reaction mixture was maintained at rt while stirring
−1
+
overnight. After this time, the heterogeneous mixture was filtered and
C H NNa 188.1415, found 188.1408.
11
19
the filtrate quenched with saturated aqueous NaHCO (20 mL). The
3
(
± )-(1,4-Bis(1-methylcyclohexyl)butane-2,3-diyl)dibenzene
aqueous phase was extracted with Et O (3 × 50 mL). The combined
2
(13) (eq 3). A 1-dram vial was charged with N-(acyloxy)phthalimide 4
(43 mg, 0.15 mmol, 1 equiv), Ru(bpy) (PF ) (1 mg, 1.5 μmol, 0.01
organic layer was dried over MgSO , filtered, and concentrated under
4
3
6 2
reduced pressure. The crude residue was purified by silica gel
chromatography (20−40% EtOAc/hexanes) to give 5 (1.02 g, 1.66
equiv), Hantzsch ester 8 (57 mg, 0.23 mmol, 1.5 equiv), and a
magnetic stir bar under argon. After sequential addition of CH Cl
2
2
mmol, 78%) as a colorless solid. R 0.27 (40% EtOAc/hexanes); mp
f
(0.5 mL, sparged with Ar for 5 min), styrene (26 μL, 0.23 mmol, 1.5
D
2
577
1
546
24
435
2
+
79−283 °C (dec); [α] +179, [α]
+188, [α]
+216, [α]
4
24
24
equiv), and i-Pr NEt (55 μL, 0.33 mmol, 2.2 equiv), the vial was
384, [α]4
05
2
+486 (c 0.78 (CHCl ); H NMR (500 MHz, CDCl ): δ
24
3
3
capped and placed in the center of a 30 cm loop of blue LEDs. The
reaction mixture was stirred for 18 h, after which it was concentrated
under reduced pressure. The crude residue was purified by silica gel
chromatography (100% pentane) to provide 13 (25 mg, 0.063 mmol,
7
1
1
.89−7.87 (m, 2H), 7.80−7.78 (m, 2H), 5.76 (s, 1H), 3.22 (dd, J =
1.0, J = 5.2, 1H), 2.78 (td, J = 6.6, 3.1, 1H), 2.54 (dd, J = 13.4, J = 3.3,
H), 2.33 (s, 1H), 2.13 (d, J = 13.5, 1H), 2.09−2.01 (m, 2H), 1.86 (dt,
J = 13.6, 4.5, 1H), 1.78 (t, J = 13.8, 1H), 1.69−1.58 (m, 5H), 1.51−
8
3%), a 1:1 mixture of stereoisomers, as a colorless solid.
1
1
0
.40 (m, 7H), 1.38 (s, 3H), 1.34−1.24 (m, 1H), 1.21 (d, J = 13.4, 1H),
6
Characterization data for 13 are included in the preceding article.
3-(1-Methylcyclohexyl)prop-1-en-2-yl)benzene (15) (Table
, entry 1, coupling with α-(bromomethyl)styrene and general
.14 (s, 3H), 1.12 (s, 3H), 1.09−1.04 (m, 1H), 1.00 (s, 3H), 0.98−
(
.93 (m, 1H), 0.91 (s, 3H), 0.80 (s, 3H), 0.70 (d, J = 11.0, 1H); 13
C
3
NMR (125 MHz, CDCl ): δ 200.2, 172.7, 168.5, 162.2, 134.9, 129.2,
3
procedure for allylic and vinylic substitution). A 1-dram vial was
charged with N-(acyloxy)phthalimide 4 (43 mg, 0.15 mmol, 1 equiv),
Ru(bpy) (PF ) (1 mg, 1.5 μmol, 0.01 equiv), Hantzsch ester 8 (57
1
3
1
1
29.0, 124.1, 78.9, 61.9, 55.1, 47.8, 45.5, 44.0, 43.2, 41.3, 39.3, 39.2,
7.4, 37.2, 32.9, 32.0, 31.6, 28.5, 28.2, 28.1, 27.4, 26.6, 26.5, 23.5, 18.8,
7.6, 16.5, 15.7; IR (thin film): 3519, 2968, 2931, 2868, 1806, 1782,
3
6 2
mg, 0.23 mmol, 1.5 equiv), and a magnetic stir bar under argon. After
−1
+
744, 1655, 1039 cm ; HRMS-ESI (m/z) [M + Na] calculated for
sequential addition of CH Cl (1 mL, sparged with Ar for 5 min), α-
2
2
C H NO Na 638.3458, found 638.3438.
38
49
6
(bromomethyl)styrene (14) (33 μL, 0.23 mmol, 1.5 equiv), and i-
4-(1-Methylcyclohexyl)butan-2-one (9). (Table 1, entry 1,
Pr NEt (55 μL, 0.33 mmol, 2.2 equiv), the vial was capped and placed
2
and general procedure for optimization experiments). A 1-
dram vial was charged with N-(acyloxy)phthalimide 4 (75 mg, 0.26
mmol, 1 equiv), Ru(bpy) (PF ) (2 mg, 2.6 μmol, 0.01 equiv),
in the center of a 30 cm loop of blue LEDs. The reaction mixture was
stirred for 18 h, after which it was concentrated under reduced
pressure. The crude residue was purified by silica gel chromatography
3
6 2
Hantzsch ester 8 (100 mg, 0.39 mmol, 1.5 equiv), and a magnetic stir
(
100% pentane) to provide 15 (24 mg, 0.11 mmol, 74%) as a colorless6
bar under argon. After sequential addition of CH Cl (1.7 mL, sparged
2
2
oil. Characterization data for 15 are included in the preceding article.
Preparation of 15 from α-(Chloromethyl)styrene. In an
identical fashion, N-(acyloxy)phthalimide 4 (43 mg, 0.15 mmol, 1
equiv) was coupled with α-(chloromethyl)styrene (32 μL, 0.23 mmol,
with Ar for 5 min), methyl vinyl ketone (33 μL, 0.39 mmol, 1.5 equiv),
and i-Pr NEt (100 μL, 0.57 mmol, 2.2 equiv), the vial was capped and
2
placed in the center of a 30 cm-loop of blue LEDs (see Supporting
Information for a picture of the reaction setup). The reaction mixture
was stirred for 18 h, after which time it was concentrated under
reduced pressure. The crude residue was purified by silica gel
chromatography (2.5% EtOAc/hexanes) to provide 9 (40 mg, 0.24
mmol, 91%) as a colorless oil. Characterization data obtained for 9
1
.5 equiv) to provide 15 (26 mg, 0.12 mmol, 82%).
Methyl 2-((1-Methylcyclohexyl)methyl)acrylate (16). In an
identical fashion, N-(acyloxy)phthalimide 4 (43 mg, 0.15 mmol, 1
equiv) was coupled with methyl 2-(bromomethyl)acrylate (27 μL, 0.23
mmol, 1.5 equiv) to give a crude residue, which was purified by silica
gel chromatography (3% diethyl ether/pentane) to provide 16 (25 mg,
5
matched those previously reported.
3-(1-Methylcyclohexyl)cyclopentan-1-one (10). Following the
0
.13 mmol, 83%) as a colorless oil. Characterization data for 16 are
general procedure for optimization experiments, N-(acyloxy)-
phthalimide 4 (75 mg, 0.26 mmol, 1 equiv), Ru(bpy) (PF ) (2 mg,
6
included in the preceding article.
3
6 2
Preparation of 16 from Methyl 2-(Chloromethyl)acrylate. In
an identical fashion, N-(acyloxy)phthalimide 4 (43 mg, 0.15 mmol, 1
equiv) was coupled with methyl 2-(chloromethyl)acrylate (26 μL, 0.23
mmol, 1.5 equiv) to provide 16 (25 mg, 0.13 mmol, 83%) as a
2
μmol, 0.01 equiv), Hantzsch ester 8 (100 mg, 0.39 mmol, 1.5 equiv),
cyclopentenone (33 μL, 0.39 mmol, 1.5 equiv), and i-Pr NEt (100 μL,
2
0
.57 mmol, 2.2 equiv) in CH Cl (1.7 mL, sparged with Ar for 5 min)
2 2
gave 10 (37 mg, 0.21 mmol, 80%) as a colorless oil. Characterization
6
5
colorless oil.
data obtained for 10 matched those previously reported.
Methyl (E)-3-(1-Methylcyclohexyl)acrylate (17). In an identical
fashion, N-(acyloxy)phthalimide 4 (43 mg, 0.15 mmol, 1 equiv) was
coupled with (E)-methyl 3-bromoacrylate (72 μL, 0.75 mmol, 5 equiv)
to provide a crude residue, which was purified by silica gel
chromatography (5% diethyl ether/pentane) to give 17 (16 mg,
(
± )-Benzyl 2-Methyl-3-(1-methylcyclohexyl)propanoate
11). Following the general procedure for optimization experiments,
N-(acyloxy)phthalimide 4 (75 mg, 0.26 mmol, 1 equiv), Ru-
bpy) (PF ) (2 mg, 2.6 μmol, 0.01 equiv), Hantzsch ester 8 (100
(
(
3
6 2
mg, 0.39 mmol, 1.5 equiv), benzyl methacrylate (66 μL, 0.39 mmol,
I
DOI: 10.1021/acs.joc.5b00795
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
0
.088 mmol, 59%) as a colorless oil. Characterization data for 17 are
Deuterium Incorporation in Product 9 Using 4,4-d -
2
6
included in the preceding article.
E)-(2-(1-Methylcyclohexyl)vinyl)benzene (18). In an identical
fashion, N-(acyloxy)phthalimide 4 (43 mg, 0.15 mmol, 1 equiv) was
coupled with β-bromostyrene (97 μL, 0.75 mmol, 5 equiv) to give a
crude residue, which was purified by silica gel chromatography (100%
pentane) to provide 18 (18 mg, 0.089 mmol, 59%) as a colorless oil.
Hantzsch Ester 23. A 1-dram vial was charged with N-(acyloxy)-
(
phthalimide 4 (75 mg, 0.26 mmol, 1 equiv), Ru(bpy)
2.6 μmol, 0.01 equiv), 4,4-d -Hantzsch ester 23 (100 mg, 0.39 mmol,
1.5 equiv), and a magnetic stir bar under argon. After sequential
addition of CH Cl (1.7 mL, sparged with Ar for 5 min), methyl vinyl
ketone (32 μL, 0.39 mmol, 1.5 equiv), and i-Pr NEt (100 μL, 0.57
3 6 2
(PF ) (3 mg,
2
2
2
2
6
Characterization data for 18 are included in the preceding article.
mmol, 2.2 equiv), the vial was capped and placed in the center of a 30
cm loop of blue LEDs. The reaction mixture was stirred for 18 h, after
which time it was concentrated under reduced pressure. Purification by
silica gel chromatography (2.5% EtOAc/hexanes) provided ketone 9
(21 mg, 0.13 mmol, 48%) as a colorless oil. Deuterium incorporation
1-(2-Phenylallyl)adamantane (19). In an identical fashion, N-
(
acyloxy)phthalimide 1 (49 mg, 0.15 mmol, 1 equiv) was coupled with
α-(bromomethyl)styrene (14) (33 μL, 0.23 mmol, 1.5 equiv) to give a
crude residue, which was purified by silica gel chromatography (100%
pentane) to provide 19 (27 mg, 0.11 mmol, 72%) as a colorless solid.
1
was determined by comparing the relative H NMR integrations of the
6
Characterization data for 19 are included in the preceding article.
α-keto methyl singlet resonance with the multiplet signal correspond-
1
2-((4,4-Dimethyl-6-phenylhept-6-en-1-yl)oxy)-1,4-dimethyl-
ing to protons at C2 (see ref 6 for an H NMR spectrum of this
1
benzene (20). In an identical fashion, N-(acyloxy)phthalimide 3 (59
mg, 0.15 mmol, 1 equiv) was coupled with α-(bromomethyl)styrene
product with high deuterium incorporation). H6 NMR analysis
determined the deuterium incorporation to be 33%.
(
14) (33 μL, 0.23 mmol, 1.5 equiv) to give a crude residue, which was
Preparation of the Product of Reductive Coupling 25 and
purified by silica gel chromatography (0−2% diethyl ether/pentane) to
provide 20 (44 mg, 0.14 mmol, 91%) as a colorless oil. R 0.16 (100%
hexanes); H NMR (500 MHz, CDCl ): δ 7.41 (d, J = 7.4, 2H), 7.33
(
7
6
1
1
1
Allylation 26 (Scheme 2). A 1-dram vial was charged with N-
(acyloxy)phthalimide 4 (75 mg, 0.26 mmol, 1 equiv), Ru(bpy) (PF )
3 6 2
(3 mg, 2.6 μmol, 0.01 equiv), Hantzsch ester 8 (100 mg, 0.39 mmol,
f
1
3
t, J = 7.5, 2H), 7.28−7.25 (m, 1H), 7.04 (d, J = 7.5, 1H), 6.69 (d, J =
.5, 1H), 6.61 (s, 1H), 5.28 (d, J = 1.9, 1H), 5.07 (s, 1H), 3.81 (t, J =
1.5 equiv), and a magnetic stir bar under argon. After sequential
6
addition of CH
Cl
2
(1.7 mL, sparged with Ar for 5 min), acceptor 24
2
.6, 2H), 2.54 (s, 2H), 2.34 (s, 3H), 2.21 (s, 3H), 1.79−1.72 (m, 2H),
(84 mg, 0.39 mmol, 1.5 equiv), and i-Pr
2
NEt (100 μL, 0.57 mmol, 2.2
1
3
.37−1.31 (m, 2H), 0.82 (s, 6H); C NMR (125 MHz, CDCl ): δ
equiv), the vial was capped and placed in the center of a 30 cm loop of
blue LEDs. The reaction mixture was stirred for 18 h, after which time
3
57.2, 147.4, 144.0, 136.5, 130.4, 128.3, 127.1, 126.7, 123.7, 120.7,
16.9, 112.1, 68.7, 47.0, 38.6, 34.2, 27.8, 24.5, 21.6, 16.0; IR (thin
it was diluted with Et
funnel. The ether layer was washed with aqueous 4 N HCl (4 × 20
mL) and aqueous 2 N NaOH (3 × 20 mL) and dried over MgSO
O (30 mL) and transferred to a separatory
2
film): 2953, 2925, 2867, 1616, 1585, 1509, 1469, 1265, 1157, 1130,
1
3
−1
+
044 cm ; HRMS-CI (m/z) [M + H] calculated for C H OH
.
4
23
30
23.2375, found 323.2386.
-Phenylallylation of the N-(Acyloxy)phthalimide Derivative
of 18β-Glycyrrhetinic Acid to Form 21. In an identical fashion,
The organic layer was filtered and concentrated under reduced
pressure. The crude residue was subjected to silica gel chromatography
(4% acetone/hexanes) to provide 25 (23 mg, 0.07 mmol, 29%, dr
8:2:1:1) and 26 (25 mg, 0.13 mmol, 51%) as colorless oils.
Characterization data for 25 and 26 are included in the preceding
2
5
N-(acyloxy)phthalimide 5 (92 mg, 0.15 mmol, 1 equiv) was coupled
with α-(bromomethyl)styrene (14) (33 μL, 0.23 mmol, 1.5 equiv).
After 18 h, the reaction mixture was diluted with CH Cl , the resulting
6
article.
2
2
organic phase was washed with 4 M HCl (3 × 10 mL), dried over
Preparation of Reductive-Coupling Product 25 (eq 5). A 1-
dram vial was charged with N-(acyloxy)phthalimide 4 (100 mg, 0.35
Na SO , and evaporated under reduced pressure. The crude residue
2
4
was purified by silica gel chromatography (20−30% acetone/hexanes)
mmol, 1.5 equiv), Ru(bpy)
Hantzsch ester 8 (88 mg, 0.35 mmol, 1.5 equiv), i-Pr
mg, 0.23 mmol, 1 equiv), and a magnetic stir bar under argon. After
sequential addition of THF (1.1 mL, sparged with Ar for 5 min),
3
(PF
6
)
2
(3 mg, 3.5 μmol, 0.015 equiv),
NEt·HBF (50
to provide an inseparable 3:1 mixture of C19 epimers of 21 (61 mg,
2
4
0
.11 mmol, 75%) as a colorless solid. Mixture of two epimers: R 0.53
f
1
(
30% acetone/hexanes); mp 72−74 °C; H NMR (500 MHz,
6
CDCl ): δ 7.37−7.27 (m, 5.7H), 7.25−7.21 (m, 1H), 5.49 (s, 1H),
CH
Cl
2
2
(1.1 mL, sparged with Ar for 5 min), and acceptor 24 (49
3
5
0
2
2
1
.25 (d, J = 1.8, 1H), 5.21 (d, J = 1.7, 0.3H), 5.10 (s, 0.3H), 5.04 (s,
.3H), 5.00 (s, 1H), 3.24−3.19 (m, 1.3H), 2.77 (d, J = 13.4, 1.3H),
.72 (d, J = 13.3, 0.3H), 2.51 (d, J = 13.3, 1H), 2.43−2.36 (m, 1.3H),
.25 (d, J = 14.5, 1.3H), 2.08−1.99 (m, 1.7H), 1.91−1.80 (m, 1.3H),
.80−1.69 (m, 1.7H), 1.67−1.54 (m, 7.7), 1.45−1.31 (m, 6.7H), 1.29
mg, 0.23 mmol, 1 equiv), the vial was capped and placed in the center
of a 30 cm loop of blue LEDs. The reaction mixture was stirred for 18
h, after which time it was diluted with Et O (30 mL) and transferred
2
to a separatory funnel. The ether layer was washed with aqueous 4 N
HCl (4 × 20 mL) and aqueous 2 N NaOH (3 × 20 mL) and dried
(
8
s, 1.3H), 1.26−1.19 (m, 2.3H), 1.18−1.02 (m, 14.7), 1.02−0.91 (m,
over MgSO . The organic layer was filtered and concentrated under
4
13
H), 0.90−0.77 (m, 15H), 0.70−0.64 (m, 2.7H); C NMR (125
reduced pressure. The crude residue was subjected to silica gel
chromatography (4% acetone/hexanes) to provide 25 (52 mg, 0.17
mmol, 72%, dr 8:2:1:1) as a colorless oil.
Preparation of Allylated Product 26 (eq 6). A 1-dram vial was
MHz, CDCl ): δ 200.5, 200.4, 170.7, 170.1, 147.3, 146.5, 144.1, 143.8,
3
6
1
5
3
2
28.4, 128.3, 128.1, 127.4, 127.2, 126.7, 126.5, 117.3, 117.2, 78.9, 61.8,
5.0, 55.0, 50.7, 47.4, 46.9, 45.5, 43.4, 43.3, 43.2, 42.4, 40.4, 39.3, 37.2,
6.2, 36.1, 35.2, 34.8, 34.0, 32.9, 32.8, 32.5, 32.3, 32.2, 30.8, 29.0, 28.7,
8.2, 27.4, 26.8, 26.5, 26.4, 23.5, 23.2, 22.7, 18.8, 17.6, 16.5, 15.7; IR
charged with N-(acyloxy)phthalimide 4 (75 mg, 0.26 mmol, 1 equiv),
Ru(bpy)
(PF )
(3 mg, 2.6 μmol, 0.01 equiv), and a magnetic stir bar
Cl (1.7 mL, sparged
with Ar for 5 min), acceptor 24 (84 mg, 0.39 mmol, 1.5 equiv), and i-
Pr NEt (100 μL, 0.57 mmol, 2.2 equiv), the vial was capped and
3
6 2
−1
(thin film): 3435, 2925, 2863, 1654, 1461, 1386, 1208, 1044 cm ;
under argon. After sequential addition of CH
2
2
+
6
HRMS-ESI (m/z) [M + Na] calculated for C H O Na 565.4022,
38
54
2
found 565.3996.
2
General Procedure for Coupling Reactions in the Absence
of a Photocatalyst (Tables 6 and 7). Preparation of 9. A 1-dram
vial was charged with N-(acyloxy)phthalimide 4 (75 mg, 0.26 mmol, 1
equiv), Hantzsch ester 8 (100 mg, 0.39 mmol, 1.5 equiv), and a
placed in the center of a 30 cm loop of blue LEDs. The reaction
mixture was stirred for 18 h, after which time it was diluted with Et O
(30 mL) and transferred to a separatory funnel. The ether layer was
washed with aqueous 4 N HCl (4 × 20 mL) and aqueous 2 N NaOH
(3 × 20 mL) and dried over MgSO . The organic layer was filtered and
concentrated under reduced pressure. The crude residue was subjected
2
magnetic stir bar under argon. After sequential addition of CH Cl2
2
4
(1.7 mL, sparged with Ar for 5 min), methyl vinyl ketone (33 μL, 0.39
mmol, 1.5 equiv), and i-Pr NEt (100 μL, 0.57 mmol, 2.2 equiv), the
to silica gel chromatography (4% acetone/hexanes) to provide 26 (19
mg, 0.10 mmol, 39%) as colorless oils.
2
6
vial was capped and placed in the center of a 30 cm loop of blue LEDs.
The reaction mixture was stirred for 18 h, after which time it was
concentrated under reduced pressure. The crude residue was purified
by silica gel chromatography (2.5% EtOAc/hexanes) to provide 9 (27
mg, 0.16 mmol, 61%) as a colorless oil. Characterization data obtained
Preparation of Allylated Product 26 (eq 7). A 1-dram vial was
charged with N-(acyloxy)phthalimide 4 (75 mg, 0.26 mmol, 1 equiv),
Ru(bpy) (PF ) (3 mg, 2.6 μmol, 0.01 equiv), Hantzsch ester 8 (100
3
6 2
mg, 0.39 mmol, 1.5 equiv), and a magnetic stir bar under argon. After
5
for 9 matched those previously reported.
sequential addition of CH Cl (1.7 mL, sparged with Ar for 5 min),
2
2
J
DOI: 10.1021/acs.joc.5b00795
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
6
acceptor 27 (67 mg, 0.39 mmol, 1.5 equiv), and i-Pr NEt (100 μL,
0
Villemin, D. J. Chem. Soc., Chem. Commun. 1980, 732−733. (c) Barton,
D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron Lett. 1983, 24,
4979−4982. (d) Barton, D.; Chern, C.-Y.; Jaszberenyi, J. Tetrahedron
1995, 51, 1867−1886. (e) For a brief review, see: Saraiva, M. F.;
Couri, M. R. C.; Hyaric, M. L.; de Almeida, M. V. Tetrahedron 2009,
65, 3563−3572.
2
.57 mmol, 2.2 equiv), the vial was capped and placed in the center of
a 30 cm loop of blue LEDs. The reaction mixture was stirred for 18 h,
after which time it was concentrated under reduced pressure. The
crude residue was subjected to silica gel chromatography (2% EtOAc/
hexanes) to provide 26 (30 mg, 0.16 mmol, 60%) as a colorless oil.
Preparation of Allylated Product 15 (eq 8). A 1-dram vial was
6
́
(8) Andrews, R. S.; Becker, J. J.; Gagne, M. R. Angew. Chem., Int. Ed.
charged with N-(acyloxy)phthalimide 4 (43 mg, 0.15 mmol, 1 equiv),
2010, 49, 7274−7276.
(9) Compare the results reported in this table with the synthesis of
the identical products reported in Table 5 of ref 6.
Ru(bpy) (PF ) (1 mg, 1.5 μmol, 0.01 equiv), Hantzsch ester 8 (57
3
6
2
mg, 0.23 mmol, 1.5 equiv), and a magnetic stir bar under argon. After
sequential addition of CH Cl (1 mL, sparged with Ar for 5 min), α-
acetoxymethyl)styrene (28) (38 μL, 0.23 mmol, 1.5 equiv), and i-
2
2
(10) This latter reaction exhibited low conversion of the N-
phthalimidoyl oxalate and rapid consumption of methacrylonitrile,
suggesting that methacrylonitrile was polymerized under these
(
Pr NEt (55 μL, 0.33 mmol, 2.2 equiv), the vial was capped and placed
2
1
1
in the center of a 30 cm loop of blue LEDs. The reaction mixture was
stirred for 18 h, after which it was concentrated under reduced
pressure. The crude residue was purified by silica gel chromatography
100% pentane) to provide 15 (19 mg, 0.090 mmol, 60%) as a
colorless oil.
conditions.
11) Similar photoredox catalysis conditions have been employed to
(
initiate radical polymerization of methacrylates. See: Fors, B. F.;
Hawker, C. J. Angew. Chem., Int. Ed. 2012, 51, 8850−8853.
(
6
(
12) Only a few radical addition−dimerization cascades of styrene
̈
derivatives are known in literature: (a) Schafer, H. Angew. Chem., Int.
ASSOCIATED CONTENT
■
Ed. 1970, 9, 158−159. (b) Kambe, N.; Miyamoto, M.; Terao, J.;
Watabe, H. Bull. Chem. Soc. Jpn. 2003, 76, 2209−2214. (c) Shen, Z.-L.;
Cheong, H.-L.; Loh, T.-P. Tetrahedron Lett. 2009, 50, 1051−1054.
* Supporting Information
S
Copies of H and 13C NMR spectra of new compounds. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.joc.5b00795.
1
(13) (a) Bockrath, B.; Bittner, E.; McGrewt, J. J. Am. Chem. Soc.
1
984, 106, 135−138. (b) Mayer, J. M. Acc. Chem. Res. 2011, 44, 36−
4
6. (c) Wille, U. Chem. Rev. 2013, 113, 813−853. (d) Crich, D.; Grant,
D.; Krishnamurthy, V.; Patel, M. Acc. Chem. Res. 2007, 40, 453−463.
AUTHOR INFORMATION
Corresponding Author
E-mail: leoverma@uci.edu.
■
*
(
14) For other radical allylations realized using visible-light
photocatalysis, see: (a) Larraufie, M.-H.; Pellet, R.; Fensterbank, L.;
Goddard, J.-P.; Lacote, E.; Malacria, M.; Ollivier, C. Angew. Chem., Int.
̂
Ed. 2011, 50, 4463−4466. (b) Dai, X.; Cheng, D.; Guan, B.; Mao, W.;
Notes
Xu, X.; Li, X. J. Org. Chem. 2014, 79, 7212−7219.
The authors declare no competing financial interest.
(
15) (a) Norcross, B. E.; Klinedinst, P. E., Jr.; Westheimer, F. H. J.
Am. Chem. Soc. 1962, 84, 797−802. (b) For recent use of 4,4-
dideuterio-Hantzsch esters in studies of reactions promoted by visible-
light photoredox catalysis, see: Neumann, M.; Zeitler, K. Chem.Eur.
J. 2013, 19, 6950−6955.
ACKNOWLEDGMENTS
■
Financial support was provided by the National Science
Foundation (CHE1265964) and the National Institute of
General Medical Sciences (R01-GM098601). We thank the
Alexander von Humboldt Foundation for the support of G.P.
by a Feodor Lynen Postdoctoral Research Fellowship and the
ACS Organic Chemistry Division for partial support of G.L.L.
by a Graduate Fellowship. NMR and mass spectra were
determined at UC Irvine using instruments purchased with the
assistance of NSF and NIH shared instrumentation grants. We
are grateful to Dr. Martin Schnermann for early optimization of
the generation of carbon radicals from N-(acyloxy)phthalimides
in aprotic solvents, and Kyle B. Schenthal for assistance in
synthesizing N-(acyloxy)phthalimide starting materials.
(16) The position and amount of deuterium in product 9 was
1
determined by integration of relevant signals by H NMR analysis; see
Experimental Section for details.
(17) The relative configuration was assigned on the basis of
diagnostic NOE enhancements observed upon irradiation of the α-
cyano-methine hydrogens of the two major diastereomers isolated
from this reaction. See ref 6 for details.
(
18) Resubjection of 25 to the reaction conditions in Scheme 2
resulted in full recovery of 25 and no detection of 26, suggesting that
6 is not formed from 25 by base-promoted elimination.
19) Unreacted N-(acyloxy)phthalimide 4 was recovered in 60%
yield.
2
(
(
20) Ru(bpy)3+ is the most reasonable electron-transfer agent under
REFERENCES
these conditions, as its reduction potential is much more negative (E1/2
■
=
−1.33 V vs SCE) than that of a tertiary amine (for Et N, the
(
1) Okada, K.; Okamoto, K.; Morita, N.; Okubo, K.; Oda, M. J. Am.
Chem. Soc. 1991, 113, 9401−9402.
2) For a comprehensive review of visible-light photocatalysis, which
discusses the reactivity and electrochemical potentials of common
photoredox catalysts, see: Prier, C. K.; Rankic, D. A.; MacMillan, D. W.
C. Chem. Rev. 2013, 113, 5322−5363. For a complementary method
for generating carbon radicals from carboxylic acids using visible-light
photocatalysis, see: Chu, L.; Ohta, C.; Zuo, Z.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2014, 136, 10886−10889.
3
21
corresponding E1/2 = +1.0 V vs SCE) and more negative than that of
the α-amino radical formed from i-Pr NEt (for Et N, the
(
2
3
2
2
corresponding E1/2 = −1.12 V vs SCE).
(21) Wayner, D. D. M.; Dannenberg, J. J.; Griller, D. Chem. Phys.
Lett. 1986, 131, 189−191.
(22) Wayner, D. D. M.; McPhee, D. J.; Griller, D. J. Am. Chem. Soc.
1988, 110, 132−137.
(23) Addition of a tertiary radical to 27, followed by homolysis of the
C−Br bond is the most plausible mechanism. An alternative pathway
involving coupling of the tertiary radical with an allylic radical derived
from 27 is unlikely, as products derived from allylic radical
homodimerization were not observed.
(24) Wang, D.; Liu, Q.; Chen, B.; Zhang, L.; Tung, C.; Wu, L. Chin.
Sci. Bull. 2010, 55, 2855−2858.
(25) However, we have been unable to experimentally verify this
suggestion: Exclusion of oxygen from a coupling reaction to the best of
our ability by use of the freeze−pump−thaw degassing method did not
affect the yield of product 9 obtained after a reaction time of 2 h.
(
5
(
3) Schnermann, M. J.; Overman, L. E. Angew. Chem., Int. Ed. 2012,
1, 9576−9580.
4) Muller, D. S.; Untiedt, N. L.; Dieskau, A. P.; Lackner, G. L.;
Overman, L. E. J. Am. Chem. Soc. 2015, 137, 660−663.
5) Lackner, G. L.; Quasdorf, K. W.; Overman, L. E. J. Am. Chem. Soc.
013, 135, 15342−15345.
6) Lackner, G. L.; Quasdorf, K. W.; Pratsch, G.; Overman, L. E. J.
Org. Chem. 2015. 10.1021/acs.joc.5b00794.
7) (a) Barton, D. H. R.; Serebryakov, E. P. A. Proc. Chem. Soc. 1962,
09. (b) Barton, D. H. R.; Dowlatshahi, H. A.; Motherwell, W. B.;
̈
(
2
(
(
3
K
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The Journal of Organic Chemistry
Article
(
26) This potential is reported as −1.11 V vs ferrocene; see: Zhu, X.-
Q.; Tan, Y.; Cao, C.-T. J. Phys. Chem. B 2010, 114, 2058−2075.
27) Okada reports reduction potentials in the range of −1.28 to
1.37 V (vs SCE) for three N-(acyloxy)phthalimides in acetonitrile,
see: Okada, K.; Okamoto, K.; Oda, M. J. Am. Chem. Soc. 1988, 110,
736−8738.
28) Savea
(
−
8
(
́
nt, J.-M. Electron Transfer, Bond Breaking and Bond
Formation. In Advances in Physical Organic Chemistry; Tidwell, T. T.,
Ed.; Academic: New York, 2000, Vol. 35, pp 117− 192.
(
29) (a) Owing to the low barrier for decarboxylation of carboxy
radicals, K may well not be an intermediate, with decarboxylation
occurring at the same time as fragmentation of the N−O bond. (b)
The rate constant for the loss of CO from a carboxyl radical is
2
9
−1
estimated to be on the order of 10 s ; see: Togo, H. Advanced Free
Radical Reactions for Organic Synthesis; Elsevier Science: New York,
2004.
(
30) Alternatively, although less likely in our view, electron transfer
could be coupled with proton transfer to the phthalimide oxygen,
avoiding the formation of an imide ketyl radical anion intermediate.
For a comprehensive review of proton-coupled electron transfer
(
PCET), see: Warren, J. J.; Tronic, T. A.; Mayer, J. M. Chem. Rev.
2
010, 110, 6961−7001. (b) For a detailed mechanistic investigation
2+
establishing concerted PCET in a Ru(bpy)3 photocatalyzed ketone−
alkene coupling, see: Taratino, K. T.; Liu, P.; Knowles, R. R. J. Am.
Chem. Soc. 2013, 135, 10022−10025.
(
(
31) Eey, S. T. C; Lear, M. J. Org. Lett. 2010, 12, 5510−5513.
32) (a) Huang, H.; Liu, X.; Deng, J.; Qiu, M.; Zheng, Z. Org. Lett.
2
2
(
006, 8, 3359−3362. (b) Kippo, T.; Fukuyama, T.; Ryu, I. Org. Lett.
011, 13, 3864−3867.
33) (a) Reference 32a. (b) Young, W. G.; Caserio, F. F., Jr.;
Brandon, D. D., Jr. J. Am. Chem. Soc. 1960, 82, 6163−6168.
(
(
34) Ma, S.; Lu, X.; Li, Z. J. Org. Chem. 1992, 57, 709−713.
35) Tripathi, C. B.; Mukherjee, S. Angew. Chem., Int. Ed. 2013, 52,
8
(
2
450−8453.
36) Hatch, L. F.; Patton, T. L. J. Am. Chem. Soc. 1954, 76, 2705−
707.
L
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J. Org. Chem. XXXX, XXX, XXX−XXX