Fragment Coupling and the Construction of Quaternary Carbons Using Tertiary Radicals Generated from tert -Alkyl N -Phthalimidoyl Oxalates by Visible-Light Photocatalysis

Article abstract of DOI:10.1021/acs.joc.5b00794

The coupling of tertiary carbon radicals with alkene acceptors is an underdeveloped strategy for uniting complex carbon fragments and forming new quaternary carbons. The scope and limitations of a new approach for generating nucleophilic tertiary radicals

Full text of DOI:10.1021/acs.joc.5b00794

Article
pubs.acs.org/joc
Fragment Coupling and the Construction of Quaternary Carbons
Using Tertiary Radicals Generated From tert-Alkyl N‑Phthalimidoyl
Oxalates By Visible-Light Photocatalysis
Gregory L. Lackner, Kyle W. Quasdorf, Gerald Pratsch, and Larry E. Overman*
Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California 92697-2025
S
* Supporting Information
ABSTRACT: The coupling of tertiary carbon radicals with alkene
acceptors is an underdeveloped strategy for uniting complex carbon
fragments and forming new quaternary carbons. The scope and
limitations of a new approach for generating nucleophilic tertiary
radicals from tertiary alcohols and utilizing these intermediates in
fragment coupling reactions is described. In this method, the tertiary
alcohol is first acylated to give the tert-alkyl N-phthalimidoyl oxalate,
which in the presence of visible-light, catalytic Ru(bpy)3(PF6)2, and a reductant fragments to form the corresponding tertiary
carbon radical. In addition to reductive coupling with alkenes, substitution reactions of tertiary radicals with allylic and vinylic
halides is described. A mechanism for the generation of tertiary carbon radicals from tert-alkyl N-phthalimidoyl oxalates is
proposed that is based on earlier pioneering investigations of Okada and Barton. Deuterium labeling and competition
experiments reveal that the reductive radical coupling of tert-alkyl N-phthalimidoyl oxalates with electron-deficient alkenes is
terminated by hydrogen-atom transfer.
tertiary alcohols for generating tertiary radicals using visible-
light photocatalysis.3b
INTRODUCTION
■
The bimolecular coupling of tertiary nucleophiles with carbon-
based electrophiles is a straightforward, yet underdeveloped,
approach for fragment coupling with concomitant formation
of sterically encumbered quaternary carbons. Recent total
synthesis endeavors in our laboratories have suggested the
potentially broad utility of both trialkyl-tertiary cuprates and
nucleophilic carbon radicals in such constructions.1−3 Tertiary
carbon radicals are often generated from halide precursors.
However, the synthesis of structurally elaborate tertiary
halides can be complicated by competing elimination and
rearrangement reactions. As a result, methods to generate
tertiary carbon radicals from other common functional groups
have particular significance. Barton’s methods for forming
carbon radicals by homolytic fragmentation of carboxylic acid-
derived thiohydroxamate esters4 or alcohol-derived thiohy-
droxamate oxalates,5 introduced more than 25 years ago, are
pioneering examples.6,7
In an early application of visible-light photocatalysis in
organic synthesis, Okada reported in 1991 the utility of
carboxylic acid-derived (N-acyloxy)phthalimides for generating
nucleophilic carbon radicals and their use in radical conjugate
addition reactions to construct carbon−carbon bonds.8,9
These precursors are particularly attractive as they are readily
prepared, highly stable, and often crystalline. This method for
generating structurally complex tertiary radicals was a central
feature of our total syntheses of the diterpenoid (−)-aplyvio-
lene1a,b and several trans-clerodane diterpenoids.1c To extend
this approach to other readily available precursors, we recently
described the utility of N-phthalimidoyl oxalate derivatives of
Since our recent studies of photoredox-catalyzed generation
of tertiary radicals and their use in fragment coupling
reactions,1b,c,3b several other research programs contributed
important new methods for accessing tertiary carbon radical
intermediates. Baran described the reaction of substituted
alkenes with Fe(acac)3/PhSiH3 to generate secondary and
tertiary radicals and their use in both intramolecular and
bimolecular C−C bond formation.3c In addition, recent
reports by the MacMillan group detail the generation of
radical intermediates by single-electron oxidation and
decarboxylation of carboxylates.3d Although heteroatom-
stabilized secondary radicals are most easily formed under
these conditions, the adamantyl radical was also produced in
this way.
Even though several approaches for producing tertiary
carbon radicals from common precursors are now available,
the prevalence and accessibility of tertiary alcohols warrants
comprehensive investigation of the utility of tert-alkyl N-
phthalimidoyl oxalates as precursors of these intermediates.
Presented herein is a detailed exploration of the preparation
and visible-light photocatalytic coupling of tert-alkyl N-
phthalimidoyl oxalates with alkenes.10,11 In addition, studies
revealing how small modifications in reaction conditions and
resulting changes in termination steps can affect the outcome
of coupling reactions of these radical precursors are also
disclosed. A comparison of tert-alkyl N-phthalimidoyl oxalates
Received: April 9, 2015
© XXXX American Chemical Society
A
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to (N-acyloxy)phthalimide derivatives of tertiary carboxylic
acids for initiating coupling reactions of tertiary radicals is
provided in the accompanying paper.12
However, resubjection of pure phthalimidoyl oxalate 3a to this
extraction procedure resulted in substantial cleavage to release
N-hydroxyphthalimide, suggesting that even this mild workup
was problematic. tert-Alkyl N-phthalimidoyl oxalates were best
isolated by diluting a concentrated CH2Cl2 solution of the
crude acylation reaction products with hexanes (typically a 25-
fold excess by volume) and filtering the resulting suspension.
After concentration of the filtrate, the mixed oxalate diesters 3
were obtained in good purity (typically > 95%) and high
yield. As illustrated in Table 1, this method proved quite
general, converting even highly hindered tertiary alcohols to
the corresponding mixed oxalates efficiently (e.g., formation of
3g and 3h). Solid tert-alkyl N-phthalimidoyl oxalates prepared
in this way could be stored indefinitely at −20 °C, whereas
those that are oils could be stored at this temperature for only
1 week before decomposition was apparent.
RESULTS AND DISCUSSION
■
Synthesis of tert-Alkyl N-Phthalimidoyl Oxalates. A
general strategy for synthesizing tert-alkyl N-phthalimidoyl
oxalates from tertiary alcohols consists of the direct acylation
of the tertiary alcohol with N-phthalimidoyl chlorooxalate 2,
as exemplified in the formation of N-phthalimidoyl oxalate 3a
from 1-methylcyclohexanol (1) (eq 1). After careful
The structure of the adamantyl N-phthalimidoyl oxalate
(3f) was confirmed by single-crystal X-ray analysis.3b The
reduction potential of N-phthalimidoyl oxalate 3a measured
by CV in acetonitrile is −1.14 V versus SCE and, as expected,
is slightly less negative than that of the (N-acyloxy)-
phthalimide derivative of 1-methylcyclohexanecarboxylic acid
(−1.26 V vs SCE) under identical conditions (see the
Supporting Information).13
Coupling of tert-Alkyl N-Phthalimidoyl Oxalates with
Conjugate Acceptors. We anticipated that tert-alkyl N-
phthalimidoyl oxalates would react in the presence of a
photocatalyst and a stoichiometric reductant via single-
electron transfer to the tetracarbonyl substrate, followed by
homolytic cleavage of the N−O σ-bond with ejection of
phthalimide and two equivalents of CO2 to generate the
radical intermediate (Scheme 1).5,8 Addition of the
nucleophilic tertiary radical to an electron-deficient olefin
and hydrogen-atom transfer to the resulting radical
intermediate would yield the product.
optimization, the following procedure was developed.
Chlorooxalate 2 was initially prepared as a colorless solid by
adding an excess of oxalyl chloride (5 equiv) to a THF
solution of N-hydroxyphthalimide at −78 °C, allowing the
reaction to warm to room temperature (typically overnight),
and then concentrating the reaction mixture under reduced
pressure. This reactive acylating agent was then most easily
manipulated as a 0.06 M solution in THF. The subsequent
acylation of tertiary alcohols took place efficiently in THF in
the presence of 2 equiv each of chlorooxalate 2 and
triethylamine and a catalytic amount of DMAP.
The sensitivity of tertiary N-phthalimidoyl oxalates toward
protic nucleophiles complicates their isolation and purification.
For example, oxalate 3a could not be purified by
chromatography on silica gel. Washing a dilute Et2O solution
of crude 3a with saturated aqueous NaHCO3 did remove
unreacted N-hydroxyphthalimide from the product mixture.
In our earlier investigations of the use of carboxylic acid-
derived (N-acyloxy)phthalimides in fragment coupling reac-
Table 1. Synthesis of tert-Alkyl N-Phthalimidoyl Oxalates (NPhth = N-Phthalimidoyl)
B
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Scheme 1. Proposed Mechanism for the Coupling N-
Phthalimidoyl Oxalates 3 with Conjugate Acceptors
Table 2. Coupling of N-Phthalimidoyl Oxalate 3a with
Methyl Vinyl Ketone (MVK) Under Various Reaction
a
Conditions
b
entry
modification
yield of 5 (%)
1
2
none
82
reaction time of 2 h
no light
81
3
<5%
ND
28
4
no Hantzsch ester 4
no photocatalyst (2 h)
no photocatalyst (18 h)
no i-Pr2NEt·HBF4
oxalate 3a (1 equiv)
oxalate 3a (1.1 equiv)
5
6
67
7
72
8
67
9
68
10
oxalate 3a (1 equiv)
MVK (1.5 equiv)
57
tions,1b we found that aprotic conditions similar to those
reported by Gagne for the generation and reaction of radicals
́
a
b
Conditions of eq 2 using i-Pr2NEt·HBF4; [3a] = 0.15 M. Isolated
yield after silica gel chromatography. ND = not detected.
derived from glucosyl halides, visible light, Ru(bpy)3(BF4)2,
diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (4),
i-Pr2NEt, in CH2Cl2,14 were preferable to the aqueous
conditions originally described by Okada.8,12 The reaction of
tert-alkyl N-phthalimidoyl oxalate 3a with methyl vinyl ketone
(MVK) under related conditions in CH2Cl2 employing 1−2
mol % of the commercially available bis(hexafluorophosphate)
Table 3. Coupling of N-Phthalimidoyl Oxalate 3a with
MVK in the Presence of Various Photocatalysts and Visible
a
Light
b
entry
photocatalyst
Ru(bpy)3(BF4)2
yield of 5 (%)
1
2
3
4
5
82
75
74
76
62
2+
Ir(ppy)3
salt of Ru(bpy)3 indeed did provide the coupled product 5,
albeit in low yield (eq 2). The low yield was easily traced to
Ir[dF(CF3)ppy]2(dtbbpy)PF6
Ir(dtbbpy)(ppy)2PF6
Ru(bpz)3(PF6)2
a
Conditions of eq 2 using i-Pr2NEt·HBF4 and a reaction time of 2 h;
b
1
[3a] = 0.15 M. Yield measured by H NMR relative to an internal
standard (1,4-dimethoxybenzene).
Table 4. Visible-Light Photocatalytic Coupling of N-
Phthalimidoyl Oxalate 3a with MVK in the Presence of
a
Potential Stoichiometric Reductants
competitive decomposition of the N-phthalimidoyl oxalate
under these conditions, as control experiments established
that the red conjugate base of N-hydroxyphthalimide was
rapidly formed when oxalate 3a was exposed at room
temperature to amines such as i-Pr2NEt, Bu3N, or Cy2NMe
in CH2Cl2. As a result of these observations, further
experimentation was carried out using i-Pr2NEt·HBF4 instead
of i-Pr2NEt. Additional improvement was realized by replacing
CH2Cl2 with a 1:1 mixture of CH2Cl2/THF. This solvent
change was necessitated because oxalate 3a slowly decom-
posed in CH2Cl2 overnight, presumably by ionization to form
the 1-methylcyclohexyl cation. In addition to commercially
available blue LEDs, a commercially available compact
fluorescent light was found to be equally effective as the
light source.15
We then performed a series of reactions to evaluate the
necessity of each reaction component (Table 2). Although we
initially carried out the coupling reactions for 18 h, because
the oxalate substrates were not amenable to TLC analysis, the
yield of 5 was nearly identical when the reaction was run for
only 2 h (entries 1 and 2). Visible light proved to be essential
for reactivity, as no conversion of oxalate 3a was observed
when the reaction was conducted in the dark (entry 3).
Omission of Hantzsch ester 4 also resulted in complete
recovery of 3a (entry 4). In contrast, we observed significant
product formation in the absence of the photocatalyst (entries
5 and 6). This background reaction was slower than the
photocatalyzed reaction, producing product 5 in only 28%
yield after 2 h, although the yield was improved to 67% after
a
b
Conditions of eq 2 using i-Pr2NEt·HBF4; [3a] = 0.15 M. Isolated
c
1
yield after silica gel chromatography. Yield measured by H NMR
relative to an internal standard (1,4-dimethoxybenzene); ND = not
detected.
18 h. This background reaction, which we believe is mediated
by Hantzsch ester 4,16 was also observed by Okada and co-
workers when the photocatalyst was not present.8 Omitting
the ammonium additive resulted in a somewhat depressed
C
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Table 5. Optimized Visible-Light Photocatalytic Coupling of N-Phthalimidoyl Oxalates with Various Electron-Deficient
a
Alkenes
a
Isolated yield based upon the radical acceptor after purification by silica gel chromatography (average of two experiments). The yield of 27 was
b
measured by 1H NMR relative to an internal standard (1,4-dimethoxybenzene). Isolated yield using 1 equiv each of the phthalimidoyl oxalate and
the alkene acceptor. ND = not detected.
yield of 5 (entry 7). Finally, revisiting the stoichiometry of the
coupling substrates (entries 8−10) confirmed that the highest
yield of 5 was obtained when oxalate 3a was used in a slight
(50%) excess.
using Hantzsch ester 4 (entries 4 and 5).19 No conversion to
adduct 5 was observed using N-methylacridane (10), a known
reductive quencher of Ru(bpy)32+* (entry 6).20
The results of our initial survey of the coupling of tert-alkyl
N-phthalimidoyl oxalates with various electron-deficient
alkenes are summarized in Table 5. A wide variety of N-
phthalimidoyl oxalate substrates and conjugate acceptors are
tolerated in the transformation, which generally gives good
yields of the coupled products. The highest yields were
realized in the coupling reactions with alkenes such as MVK,
acrylonitrile, and phenyl vinyl sulfone, which are unsubstituted
at the β-carbon. The three chiral N-phthalimidoyl oxalates
that we examined coupled with MVK from the less-sterically
hindered face of the tertiary radical to give products 14, 15,
and 16 with >20:1 diastereoselection, with coupled products
14 and 15 being formed in >80% yield. The yield was
somewhat lower in the construction of a quaternary center at
C17 in the estrone series (16, 68%), likely reflecting the steric
demand in forming vicinal quaternary carbon centers. Many of
these transformations require only 2−3 h, as shown by the
entries in the first row of Table 5. As expected from our
Several other photoredox catalysts were examined to
promote the formation of adduct 5 from N-phthalimidoyl
oxalate 3a and MVK (Table 3). Although no catalyst
2+
performed as well as Ru(bpy)3 (entry 1), several strongly
reducing iridium photoredox catalysts were nearly as effective
18
(entries 2−4).17 Even Ru(bpz)3 (E1/2 −0.80 V vs SCE),
2+
II/I
2+
II/I
a significantly weaker reductant than Ru(bpy)3 (E1/2
−1.33 V vs SCE), gave a 62% yield (by NMR analysis) of
ketone 5 (entry 5).
We also explored replacing Hantzsch ester 4 with other
potential stoichiometric reductants (Table 4). Introduction of
a substituent at the 4-position of the Hantzsch ester rendered
the dihydropyridine unreactive under the reaction conditions
(entries 2 and 3). The use of 2-phenylbenzothiazoline (8) or
N,N’-dimethyl-2-phenylbenzimidazoline (9) successfully re-
sulted in the formation of product 5, although the yield was
somewhat lower than that observed under identical conditions
D
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exploratory studies, yields were somewhat lower when equal
amounts of the N-phthalimidoyl oxalate and alkene were
employed: 63% versus 85% in forming 14 and 43% versus
68% in forming 16. In a number of the coupling reactions
summarized in Table 5, we observed that the yield was nearly
the same when i-Pr2NEt·HBF4 was omitted. Nonetheless, we
have found that product yields were more reproducible when
this additive was present.
Scheme 2. Trapping of an Alkoxycarbonyl Radical by a 5-
Exo Cyclization
Several radical acceptors having a substituent at the β-
carbon also provided coupled products in useful yields.
Dimethyl fumarate gave adduct 25 in 85% yield from N-
phthalimidoyl oxalate 3a and cyclopenten-2-one coupled with
3a to give product 13 in 55% yield. The yield of adduct 26
resulting from the coupling of 3a with 2-carbomethoxycyclo-
penten-2-one (62%) was only slightly higher than that
observed with cyclopenten-2-one.21 Butenolides were also
competent acceptors, with the presence of a γ-methoxy
substituent enhancing the yield of the coupled product (72%
for 23 and 52% for 22) and completely regulating face-
stereoselectivity. Unfortunately, radical additions to acceptors
possessing electron-donating alkyl groups at the α-position
were much less successful under these conditions. Benzyl
methacrylate coupled with 3a to provide product 27 in only
41% yield, whereas no product was detected in the coupling
of 3a with methacrylonitrile.22
Table 6. Optimization and Control Experiments for the
Reaction of N-phthalimidoyl Oxalate 3a with α-
(Bromomethyl)styrene (32)
It is well-known that alkoxycarbonyl radicals decarboxylate
many powers of ten more slowly than carboxy radicals,23,24
with the activation barrier decreasing with the stability of the
carbon radical produced.25 In two cases, the alkoxycarbonyl
radical (intermediate B of Scheme 1) was trapped by the
radical acceptor more rapidly than it underwent decarbox-
ylation to generate the tertiary radical intermediate.
Adamantyl N-phthalimidoyl oxalate (3f) when coupled with
MVK gave γ-ketoester 29 and product 30 of trapping the
adamantyl radical in a 3:1 ratio (eq 3). Trapping of the
a
a
entry
modification
yield of 33 (%)
yield of 34 (%)
1
2
3
4
5
6
7
8
9
none
60
16
b
b
no light
ND
ND
no Hantzsch ester 4
no photocatalyst (18 h)
no photocatalyst (2 h)
reaction time of 2 h
oxalate (1 equiv)
traces
37
ND
7
24
3
47
9
48
8
oxalate (1.1 equiv)
oxalate (1 equiv)
50
9
49
16
acceptor (1.5 equiv)
i-Pr2NEt·HBF4 (1 equiv)
10
59
16
a
b
Isolated yield after silica gel chromatography. These products were
formed when the light was turned on after 18 h. ND = not detected.
the reductive coupling reactions, substitution product 33 was
obtained in 60% yield (entry 1). To our surprise, minor
product 34, arising from allylation of the intermediate
alkoxycarbonyl radical, was isolated in 16% yield. Formation
of this product must be the result of an unusually fast rate of
addition of the alkoxycarbonyl radical to α-(bromomethyl)-
styrene (32). Attempted reactions in the absence of light
(entry 2) or the Hantzsch ester (entry 3) gave no product
formation or only traces of the coupled product. The
photocatalyst also appears to be essential to achieve useful
yields (entry 4). Stopping the reaction after 2 h led to
incomplete conversion and lower yields (entries 5 and 6). It is
also advantageous to use an excess of the oxalate (1.5 equiv),
since reactions in which an excess of acceptor was present
gave lower overall yields (entries 7−9). Finally, the additive i-
Pr2NEt·HBF4 has no influence on the outcome of the reaction
of 3a with α-(bromomethyl)styrene (32) (entry 10).
adamantyl oxycarbonyl radical by MVK to give 29 as the
major product is a reflection of the higher energy of the
nonplanar tertiary adamantyl radical than the tertiary radicals
generated in the reactions reported in Table 5. In the second
example illustrated in Scheme 2, it is the high rate of 5-exo
radical cyclizations (D → E) that results in capture of the
intermediate alkoxycarbonyl radical to yield lactone 31 from
phthalimidoyl oxalate 3k.26
Further Investigations of the Reaction Scope. To
expand the scope of C−C bond-formation using nucleophilic
tertiary carbon radicals generated by visible-light photo-
catalysis, we examined the coupling of tertiary N-phthalimi-
doyl oxalates with several allylic and vinylic halide substrates
to engage tertiary radical intermediates in addition−
fragmentation reactions.27 The coupling of oxalate 3a with
α-(bromomethyl)styrene (32) was examined in detail (Table
6). Using the reaction conditions that we had optimized for
With optimized reaction conditions in hand, the coupling of
tert-alkyl N-phthalimidoyl oxalate 3a with three additional
allylic halides and two vinylic halides was surveyed (Table 7).
E
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different fashions by modifying the reaction conditions or by
adding common hydrogen atom transfer reagents such as
Bu3SnH, Et3SiH, Ph3SiH, and PhSH were unsuccessful.29 As
expected, couplings of adamantyl N-phthalimidoyl oxalate (3f)
and homoallylic N-phthalimidoyl oxalate 3k with α-
(bromomethyl)styrene (32) resulted in the first case in
predominant formation of ester 45 (eq 4) and in the latter of
γ-butyrolactone 47 (eq 5).
Table 7. Visible-Light Photocatalytic Allylic and Vinylic
Substitution Reactions of N-phthalimidoyl Oxalate 3a
a
Radical Coupling in the Absence of Ru(bpy)32+. To
pursue whether the reductive coupling reaction in the absence
of the photocatalyst could be a suitable method, we repeated
four of the reductive radical coupling reactions reported
earlier with omission of the photocatalyst. In all cases, the
yield of the coupled product was lower than that obtained
using the photocatalyst (compare results in Tables 2 and 8).
Useful yields of products after 18 h were obtained in the
coupling of two oxalates with MVK: formation of product 14
in 78% yield and 5 in 67% yield. In general, the conversion to
a
b
Reaction conditions of Table 6, entry 1. Isolated yield after silica gel
c
chromatography (average of two experiments). 5 equiv of the
Table 8. Coupling of N-Phthalimidoyl Oxalates with
Conjugate Acceptors in the Presence of Visible Light and
Absence of a Photocatalyst
acceptor and 1 equiv of the oxalate were used. ND = not detected.
Methyl 2-(bromomethyl)acrylate (35) coupled with 3a in
69% yield (entry 1). However, the reaction with the chlorine
analog 37 provided no coupled product (entry 2). In lower
yield, methyl 3-bromoacrylate (38) gave methyl (E)-3-(1-
methylcyclohexyl)acrylate (39) with high E stereoselectivity
(entry 3). α-(Chloromethyl)styrene (40) and β-bromostyrene
(41) also reacted successfully with N-phthalimidoyl oxalate 3a,
albeit in yields of only 47% and 19%, respectively (entries 4
and 5). The efficiency of vinylic substitution reactions was
enhanced by the use of 5 equiv of the radical acceptor
(entries 3 and 5). Allylic substitution products 36 and 33 are
potentially good radical acceptors themselves; nonetheless,
products resulting from a second addition of the tertiary
radical were not observed. We attribute this selectivity to the
steric shielding provided by the quaternary carbon fragment in
these products. Furthermore, products resulting from the
addition of the intermediate alkoxycarbonyl radical to the
acceptor were not detected with any substrate other than α-
(bromomethyl)styrene (32).
The reaction of N-phthalimidoyl oxalate 3a with styrene
(43) was also investigated (entry 6). In this case, only
product 44, resulting from recombination of two benzylic
radical intermediates, was formed in 42% as a 1:1 mixture of
stereoisomers.28 Efforts to capture the benzylic radical in
F
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coupled products was sluggish and yields were inconsistent in
the absence of the photocatalyst.
The role of the Hantzsch dihydropyridine 4 in the
termination mechanism is readily examined by using its 4,4-
dideuterio derivative 48.31 The coupling of N-phthalimidoyl
oxalate 3a with MVK under our standard conditions using
Hantzsch dihydropyridine 48 gave coupled product 5 with
nearly quantitative incorporation of deuterium at carbon 2 of
the ketone side chain (eq 6).32 This result is consistent with
To further investigate the influence of the photocatalyst,
addition−fragmentation reactions were also carried out in the
absence of Ru(bpy)3(PF6)2 (Table 9). Using five different
acceptors, allylic substitution products were formed in yields
approximately half of that (47−62%) realized in the presence
of the photocatalyst.30
Table 9. Products and Yields Obtained in Reactions of N-
Phthalimidoyl Oxalate 3a With Allylic and Vinylic Halides
in the Presence of Visible Light and Absence of a
a
Photocatalyst
hydrogen atom-transfer being the predominant termination
step in reductive coupling of tertiary N-phthalimidoyl
oxalates.33 To further explore whether hydrogen-atom transfer
or single-electron reduction is involved in the termination
steps of radical coupling reactions of N-phthalimidoyl oxalate
precursors, we examined coupling reactions of N-phthalimi-
doyl oxalate 3a with an α,β-unsaturated nitrile containing a
leaving group at the allylic α′ position (eq 7). The reaction of
a
Reaction conditions of Table 8, but no i-Pr2NEt·HBF4; isolated yield
b
c
after silica gel chromatography. Ester 34 is formed in 7% yield. 5
equiv of the acceptor and 1 equiv of the oxalate were used.
Similar radical coupling reactions of (N-acyloxy)-
phthalimides carried out in the absence of a photocatalyst
and a discussion of possible mechanisms of such reactions of
tertiary radicals generated from both N-phthalimidoyl oxalate
and (N-acyloxy)phthalimide precursors is provided in the
accompanying article.12
Mechanistic Investigations and Discussion. The
results of our exploratory studies and substantial precedent
are consistent with the generation of tertiary carbon radicals
from the visible-light photoredox-catalyzed fragmentation of
both tertiary N-phthalimidoyl oxalates and (N-acyloxy)-
phthalimide derivatives of tertiary carboxylic acids. With the
oxalate precursors, the slower rate of the second decarbox-
ylation step (B → C, Scheme 1) can lead to the
alkoxycarbonyl radical being intercepted by competing fast
intramolecular or bimolecular reactions. In the reductive
coupling reactions discussed herein, the radical intermediate F
produced upon addition of a tertiary radical to an alkene
could in principle be terminated by a hydrogen-atom transfer
(path A, Scheme 3) or by a two-step process involving single-
electron reduction to give the resonance-stabilized anion G
followed by protonation to give product H (path B).
3a with allylic benzoate 49a (X = OBz) under our optimized
reaction conditions provided addition products 50 in 50%
yield, with the depicted isomer being formed predominantly.
No trace of the allylic substitution product 51 was seen. In
contrast, the coupling of 3a under identical conditions with
allylic bromide 49b (X = Br) gave exclusively allylic
substitution product 51 in 56% yield. Both results are fully
consistent with the absence of single-electron reduction of the
radical intermediate I, which undergoes β-scission only when
the leaving group is bromide (Scheme 4).
Scheme 3. Two Potential Termination Pathways
The overall mechanism that we suggest for the reductive
coupling reactions of tertiary N-phthalimidoyl oxalates is
summarized in Scheme 5. Visible-light excitation of Ru-
2+
(bpy)3 provides access to the excited state Ru(bpy)32+*.
This complex is quenched by Hantzsch ester 4, which
produces radical cation L and the strongly reducing
+
+
Ru(bpy)3 . Single-electron transfer from Ru(bpy)3 to the
substrate oxalate then occurs to form radical anion A and
regenerate the ground-state photocatalyst. Alternatively,
G
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Article
oxalate derivative, which in the presence of visible light, 1.5
mol % Ru(bpy)3(PF6)2, and Hantzsch dihydropyridine 4
fragments at room temperature to form the corresponding
tertiary carbon radical. Nucleophilic tertiary radicals generated
in this way add to electrophilic alkenes to give reduced
products in good to moderate yield and react with allylic and
vinylic bromides to provide allylation and vinylation products
in moderate yield. With chiral precursors, stereoselection in
forming a new quaternary stereocenter can be high (>20:1).
This method offers advantages over the original Barton
method for forming tertiary radicals from tertiary alcohols,5 as
a result of the higher stability of the intermediate mixed
oxalate diester in the present method.37
Scheme 4. Potential Homolytic Termination Pathways of
the Carbon Radical Intermediate Generated Upon
Coupling in the Absence of Single-Electron Transfer
A mechanism for the generating tertiary carbon radical from
tert-alkyl N-phthalimidoyl oxalates is proposed that is based
on the earlier pioneering investigations of Okada8 and Barton
(Scheme 5).5 The high incorporation of deuterium in a
coupled product when using 4,4-dideuterio Hantzsch ester 48
(eq 6), and the observation that allylic substitution products
are formed from allylic bromide but not allylic ester reactants
(eq 7), are consistent with the reductive radical coupling of
tert-alkyl N-phthalimidoyl oxalates with electron-deficient
alkenes being terminated by hydrogen-atom transfer. The
importance of the reaction conditions in determining the fate
of the coupled radical intermediate is discussed in detail in the
accompanying article.12 In the absence of the photocatalyst, a
slower background reaction has been identified that appears
to be mediated by Hantzsch ester 4. This sequence is also
considered in more detail in the accompanying article.12
electron transfer to the oxalate substrate could be
accomplished by the strongly reducing dihydropyridine radical
M, formed by deprotonation of L at C4.34 Homolytic
fragmentation of A next occurs to release phthalimide anion,
CO2, and alkoxycarbonyl radical intermediate B; alternatively,
fragmentation of the N−O bond occurs subsequent to proton
donation to the phthalimide fragment by pyridinium acid P.35
A second slower decarboxylation then ensues, forming tertiary
carbon radical intermediate C. Addition of this radical to an
acceptor provides stabilized radical N, which abstracts a
hydrogen atom from Hantzsch ester 4.36 This event forms the
product O and regenerates intermediate M, which is capable
of propagating the reaction as a radical chain carrier. In the
absence of a photoredox catalyst, we propose that a radical
chain mechanism mediated by Hantzsch ester 4 is operative.
This sequence is discussed in more detail in the
accompanying article.12
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, THF and CH2Cl2 were sparged with argon for 5 min
CONCLUSION
■
A new method for directly transforming a tertiary alcohol to a
quaternary carbon was developed. In this method, the tertiary
alcohol is first acylated to give a tert-alkyl N-phthalimidoyl
Scheme 5. Proposed Mechanism for Reductive Coupling of N-Phthalimidoyl Oxalates with MVK in the Presence of
2+
Ru(bpy)3
H
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Article
prior to use. All commercially obtained reagents were used as
received. Ru(bpy)3(PF6)2 and other photocatalysts were obtained
from Sigma-Aldrich. Methyl vinyl ketone (MVK), acrylonitrile,
benzyl methacrylate, and methacrylonitrile were distilled from neat
solutions prior to use. All reaction components Hantzsch ester 4,38
4,4-d2-Hantzsch ester 48,27a 4-Me Hantzsch ester 6,39 4-Ph Hantzsch
ester 7,39 2-Ph-benzothiazoline 8,40 N,N’-dimethyl-2-phenylbenzimi-
(3-(1-Methylcyclohexyl)prop-1-en-2-yl)benzene (33) and 1-
Methylcyclohexyl 3-Phenylbut-3-enoate (34). (Table 6, Entry
1, and General Procedure for Allylic and Vinylic Substitu-
tion). A 1-dram vial was charged with oxalate 3a (50 mg, 0.15 mmol,
1.5 equiv), Ru(bpy)3(PF6)2 (1 mg, 1.5 μmol, 0.015 equiv), Hantzsch
ester 4 (38 mg, 0.15 mmol, 1.5 equiv), and a magnetic stir bar under
argon. After sequential addition of CH2Cl2 (0.5 mL, sparged with Ar
for 5 min), THF (0.5 mL, sparged with Ar for 5 min) and α-
(bromomethyl)styrene (32, 15 μL, 0.10 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 it was concentrated
under reduced pressure. The crude residue was purified by silica gel
chromatography (0−5% diethyl ether/pentane) to provide 33 (13
mg, 0.062 mmol, 62%) and 34 (3.4 mg, 0.013 mmol, 13%) as
colorless oils.
14
dazoline 9,19b N-methylacridane 10,41 i-Pr2NEt·HBF4, methyl 2-
(bromomethyl)acrylate (35),42 methyl 2-(chloromethyl)acrylate
(37),43 (E)-methyl 3-bromoacrylate (38),44 α-(chloromethyl)styrene
(40),45 and α-(bromomethyl)styrene (32)45 were prepared according
to literature procedures. Usually one representative coupling reaction
and yield of the product is described in detail; isolated yields
reported in the Results section 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 (TLC) was conducted with E. Merck silica gel
60 F254 precoated plates (0.25 mm) and visualized by exposure to
UV light (254 nm) or by anisaldehyde, ceric ammonium molybdate,
iodine, and potassium permanganate staining. EMD silica gel 60
(particle size 0.040−0.063 mm) was used for flash column
chromatography. 1H NMR spectra were recorded at 500 or 600
MHz and are reported relative to deuterated solvent signals. Data for
1H NMR spectra are reported as follows: chemical shift (δ ppm),
multiplicity, coupling constant (Hz), and integration. 13C NMR
spectra were recorded at 125 or 150 MHz and chemical shifts
reported in ppm. IR spectra were recorded on a FT-IR spectrometer
and are reported in terms of frequency of absorption (cm−1). Blue
Data for 33: Rf = 0.74 (100% pentane). 1H NMR (500 MHz,
CDCl3): δ 7.38 (d, J = 7.5, 2H), 7.30 (t, J = 7.4, 2H), 7.25−7.22 (m,
1H), 5.23 (d, J = 1.7, 1H), 5.03 (bs, 1H), 2.49 (s, 2H), 1.45−1.32
(m, 5H), 1.27−1.12 (m, 5H), 0.74 (s, 3H). 13C NMR (125 MHz,
CDCl3): δ 147.3, 144.3, 128.2, 127.0, 126.7, 116.7, 38.4, 34.3, 26.5,
22.3. IR (thin film): 3079, 2924, 2855, 1622, 1491, 1445 cm−1.
HRMS-CI (m/z) [M + H]+: calcd for C16H22H, 215.1800; found,
215.1798.
1
Data for 34: Rf = 0.29 (5% EtOAc/hexanes). H NMR (500 MHz,
CDCl3): δ 7.46 (d, J = 7.8, 2H), 7.32 (t, J = 7.7, 2H), 7.29−7.26 (m,
1H), 5.52 (s, 1H), 5.23 (s, 1H), 3.47 (s, 2H), 2.07−2.02 (m, 2H),
1.46−1.40 (m, 1H), 1.38−1.33 (m, 4H), 1.31−1.22 (m, 5H), 1.20−
1.12 (m, 1H). 13C NMR (125 MHz, CDCl3): δ 170.6, 141.7, 140.1,
128.4, 127.8, 126.1, 116.0, 82.5, 43.0, 36.6, 25.4, 21.9. IR (thin film):
2932, 2860, 1726, 1447, 1243, 1146 cm−1. HRMS-CI (m/z) [M +
NH4]+: calcd for C17H22O2NH4, 276.1964; found, 276.1956.
LEDs (30 cm,
1 W) were purchased from http://www.
creativelightings.com (product code CL-FRS5050-12WP-12 V) and
powered by 8 AA batteries.
Methyl 2-((1-Methylcyclohexyl)methyl)acrylate (36). In an
identical fashion, oxalate 3a (50 mg, 0.15 mmol, 1.5 equiv) was
coupled with methyl 2-(bromomethyl)acrylate (35, 12 μL, 0.10
mmol, 1 equiv) to give a crude residue, which was purified by silica
gel chromatography (3% diethyl ether/pentane) to provide 36 (14
mg, 0.069 mmol, 70%) as a colorless oil. Rf = 0.78 (10% diethyl
4-(1-Methylcyclohexyl)butan-2-one (5). [Table 2, entry 1
and General Procedure for Optimization Experiments,
Photocatalyst Screen (Table 3) and Reductant Screen (Table
4)]. A 1-dram vial was charged with oxalate 3a (100 mg, 0.30 mmol,
1.5 equiv), Ru(bpy)3(PF6)2 (3 mg, 3.0 μmol, 0.015 equiv), Hantzsch
ester 4 (76 mg, 0.30 mmol, 1.5 equiv), i-Pr2NEt·HBF4 (44 mg, 0.20
mmol, 1 equiv), and a magnetic stir bar under argon. After sequential
addition of CH2Cl2, (1 mL, sparged with Ar for 5 min), THF (1 mL,
sparged with Ar for 5 min), and methyl vinyl ketone (17 μL, 0.20
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 concentrated under reduced pressure. For all
experiments reported in Table 2, the crude residue was purified by
silica gel chromatography (3% EtOAc/hexanes) to yield ketone 5 as
a colorless oil. For all experiments reported in Tables 3 and 4, the
yield of product obtained was determined by comparison of
1
ether/pentane). H NMR (500 MHz, CDCl3): δ 6.16 (d, J = 1.3,
1H), 5.44 (bs, 1H), 3.73 (s, 3H), 2.30 (s, 2H), 1.50−1.38 (m, 5H),
1.26−1.21 (m, 5H), 0.81 (s, 3H). 13C NMR (125 MHz, CDCl3): δ
169.1, 138.4, 127.4, 52.0, 37.5, 34.0, 26.5, 22.2. IR (thin film): 2926,
2850, 2359, 2342, 1726, 1457, 1445, 1201, 1154 cm−1. HRMS-CI
(m/z) [M + NH4]+: calcd for C12H20NO2NH4, 214.1807; found,
214.1813.
Methyl (E)-3-(1-Methylcyclohexyl)acrylate (39). In an identi-
cal fashion, oxalate 3a (50 mg, 0.15 mmol, 1.5 equiv) was coupled
with (E)-methyl 3-bromoacrylate (38, 72 μL, 0.75 mmol, 5 equiv) to
give a crude residue, which was purified by silica gel chromatography
(3% diethyl ether/pentane) to provide 39 (11 mg, 0.058 mmol,
1
diagnostic H NMR signals in the crude reaction mixture to those
1
39%) as a colorless oil. Rf = 0.51 (10% diethyl ether/pentane). H
of an internal standard (1,4-dimethoxybenzene). Characterization
data for 5 matched those previously reported.3b
NMR (500 MHz, CDCl3): δ 6.96 (d, J = 16.2, 1H), 5.77 (d, J =
16.1, 1H), 3.73 (s, 3H), 1.55−1.31 (m, 10H), 1.02 (s, 3H). 13C
NMR (125 MHz, CDCl3): δ 167.9, 159.1, 117.7, 51.6, 37.2, 26.2,
22.4. IR (thin film): 2929, 2853, 1727, 1650, 1435, 1310, 1274, 1171
cm−1. HRMS-CI (m/z) [M + NH4]+: calcd for C11H18O2NH4,
200.1651; found, 200.1648.
Preparation of 33 from α-(Chloromethyl)styrene) (40). In an
identical fashion, oxalate 3a (50 mg, 0.15 mmol, 1.5 equiv) was
coupled with α-(chloromethyl)styrene (40, 14 μL, 0.10 mmol, 1
equiv) to give 33 (10 mg, 0.048 mmol, 48%).
(
)-Benzyl 2-Methyl-3-(1-methylcyclohexyl)propanoate
(27). Following the general procedure for optimization experiments,
oxalate 3a (100 mg, 0.30 mmol, 1.5 equiv), Ru(bpy)3(PF6)2 (3 mg,
3.0 μmol, 0.015 equiv), Hantzsch ester 4 (76 mg, 0.30 mmol, 1.5
equiv), i-Pr2NEt·HBF4 (44 mg, 0.20 mmol, 1 equiv), and benzyl
methacrylate (34 μL, 0.20 mmol, 1 equiv) in a mixture of CH2Cl2 (1
mL, sparged with Ar for 5 min), and THF (1 mL, sparged with Ar
for 5 min) gave a crude product mixture. The yield of 27 obtained
1
(41%) was determined by comparison of diagnostic H NMR signals
to those of an internal standard (1,4-dimethoxybenzene). An
analytically pure sample was obtained by silica gel chromatography
(2.5% EtOAc/hexanes) to provide 27 as a colorless oil. Rf = 0.57
(E)-(2-(1-Methylcyclohexyl)vinyl)benzene (42). In an identical
fashion, oxalate 3a (50 mg, 0.15 mmol, 1.5 equiv) was coupled with
β-bromostyrene (41, 97 μL, 0.75 mmol, 5 equiv) to give a crude
residue, which was purified by silica gel chromatography (100%
pentane) to provide 42 (6 mg, 0.029 mmol, 19%) as a colorless oil.
1
(10% EtOAc/hexanes). H NMR (600 MHz, CDCl3): δ 7.38−7.30
(m, 5H), 5.12−5.07 (m, 2H), 2.61−2.55 (m, 1H), 1.90 (dd, J = 14.2,
9.0, 1H), 1.44−1.31 (m, 5H), 1.28−1.15 (m, 9H), 0.83 (s, 3H). 13C
NMR (125 MHz, CDCl3): δ 178.0, 136.3, 128.6, 128.4, 128.2, 66.3,
38.1, 37.7, 35.4, 33.3, 26.5, 22.11, 22.10, 20.7. IR (thin film): 2925,
2850, 1736, 1455, 1145 cm−1. HRMS-ESI (m/z) [M + Na]+: calcd
for C18H26O2Na, 297.1830; found, 297.1835.
1
Rf = 0.78 (100% pentane). H NMR (500 MHz, CDCl3): δ 7.37 (d,
J = 7.1, 2H), 7.32−7.28 (m, 2H), 7.21−7.17 (m, 1H), 6.32 (d, J =
16.5, 1H), 6.22 (d, J = 16.3, 1H), 1.62−1.58 (m, 1H), 1.55−1.49 (m,
5H), 1.44−1.35 (m, 4H), 1.07 (s, 3H). 13C NMR (125 MHz,
CDCl3): δ 128.6, 126.8, 126.1, 38.1, 26.5, 22.6. IR (thin film): 2926,
I
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2855, 1491, 1447, 1260 cm−1. HRMS-CI (m/z) [M]+: calcd for
C15H20, 200.1565; found, 200.1558.
1187, 1090 cm−1. HRMS-CI (m/z) [M + NH4]+: calcd for
C17H22O2NH4, 276.1964; found, 276.1962.
( )-(1,4-Bis(1-methylcyclohexyl)butane-2,3-diyl)dibenzene
(44). A 1-dram vial was charged with oxalate 3a (50 mg, 0.15 mmol,
1.5 equiv), Ru(bpy)3(PF6)2 (1 mg, 1.5 μmol, 0.015 equiv), Hantzsch
ester 4 (38 mg, 0.15 mmol, 1.5 equiv), and a magnetic stir bar under
argon. After sequential addition of CH2Cl2, (0.5 mL, sparged with Ar
for 5 min), THF (0.5 mL, sparged with Ar for 5 min), and styrene
(43, 12 μL, 0.10 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 it was concentrated under reduced
pressure. The crude residue was purified by silica gel chromatography
(100% pentane) to provide 44 (9 mg, 0.022 mmol, 44%), a 1:1
mixture of stereoisomers, as a colorless solid.
General Procedure for Coupling Reactions in the Absence
of a Photocatalyst (Tables 8 and 9). Preparation of 5. A 1-
dram vial was charged with oxalate 3a (100 mg, 0.30 mmol, 1.5
equiv), Hantzsch ester 4 (76 mg, 0.30 mmol, 1.5 equiv), i-Pr2NEt·
HBF4 (44 mg, 0.20 mmol, 1 equiv), and a magnetic stir bar under
argon. After sequential addition of CH2Cl2 (1 mL, sparged with Ar
for 5 min), THF (1 mL, sparged with Ar for 5 min), and methyl
vinyl ketone (17 μL, 0.20 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 concentrated
under reduced pressure. The crude residue was purified by silica gel
chromatography (3% EtOAc/hexanes) to yield ketone 5 (23 mg,
0.14 mmol, 67%) as a colorless oil. Characterization data for 5
matched those previously reported.3b
Data for diastereomer 1: Rf = 0.66 (100% hexanes). Mp: 90−92
1
°C. H NMR (500 MHz, CDCl3): δ 7.25−7.21 (m, 4H), 7.16 (d, J =
Deuterium Incorporation in Product 5 using 4,4-d2-
Hantzsch ester 48. A 1-dram vial was charged with oxalate 3a
(100 mg, 0.30 mmol, 1.5 equiv), Ru(bpy)3(PF6)2 (3 mg, 3.0 μmol,
0.015 equiv), 4,4-d2-Hantzsch ester 48 (77 mg, 0.30 mmol, 1.5
equiv), i-Pr2NEt·HBF4 (44 mg, 0.20 mmol, 1 equiv), and a magnetic
stir bar under argon. After sequential addition of CH2Cl2 (1 mL,
sparged with Ar for 5 min), THF (1 mL, sparged with Ar for 5 min),
and methyl vinyl ketone (17 μL, 0.20 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
concentrated under reduced pressure. Purification of the crude
residue by silica gel chromatography (2.5% EtOAc/hexanes)
provided ketone 5 (13 mg, 0.070 mmol, 37%)46 as a colorless oil.
Integration of all 1H NMR signals determined the deuterium
incorporation to be >95%. Rf = 0.43 (10% EtOAc/hexanes). 1H
NMR (600 MHz, CDCl3): δ 2.39−2.30 (m, 1H), 2.15 (s, 3H), 1.49
(d, J = 8.4, 2 H), 1.46−1.38 (m, 5H), 1.33−1.20 (m, 5H), 0.83 (s,
3H). 13C NMR (125 MHz, CDCl3): δ 210.2, 38.1 (t, J = 20.2), 37.7,
32.3, 30.0, 29.8, 26.5, 24.7, 22.1. IR (thin film): 2925, 2853, 1716,
1356 cm−1. HRMS-ESI (m/z) [M + Na]+: calcd for C11H19DONa,
192.1475; found, 192.1484.
7.3, 2H), 7.12 (d, J = 7.4, 4H), 2.72 (d, J = 9.0, 2H), 1.58−1.53 (m,
2H), 1.39 (d, J = 14.1, 2H), 1.26−1.19 (m, 6H), 1.14−1.08 (m, 5H),
1.05−0.98 (m, 5H), 0.83 (bs, 4H), 0.46 (s, 6H). 13C NMR (125
MHz, CDCl3): δ 146.7, 129.5, 127.9, 125.8, 49.2, 38.8, 38.4, 33.4,
29.9, 26.4, 22.1, 21.9. IR (thin film): 2924, 2854, 1494, 1452 cm−1.
HRMS-CI (m/z) [M + NH4]+: calcd for C30H46N, 420.3630; found,
420.3647.
Data for diastereomer 2: Rf = 0.50 (100% hexanes). Mp: 87−89
1
°C. H NMR (500 MHz, CDCl3): δ 7.10−7.07 (m, 4H), 7.04−7.00
(m, 2H), 6.95 (d, J = 7.1, 4H), 2.82 (d, J = 7.3, 2H), 1.79−1.70 (m,
4H), 1.37−1.32 (m, 6H), 1.22−1.17 (m, 10H), 1.00−0.95 (m, 4H),
0.63 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 145.4, 129.7, 127.3,
125.4, 49.1, 38.6, 33.8, 29.9, 26.6, 22.2, 22.1. IR (thin film): 2924,
2858, 1494, 1452 cm−1. HRMS-CI (m/z) [M + NH4]+: calcd for
C30H46N, 420.3630; found, 420.3627.
Adamantan-1-yl 3-Phenylbut-3-enoate (45) and 1-(2-
Phenylallyl)adamantane (46). In an identical fashion, oxalate 3f
(55 mg, 0.15 mmol, 1.5 equiv) was coupled with α-(bromomethyl)-
styrene (32, 15 μL, 0.10 mmol, 1 equiv) to give a crude residue,
which was purified by silica gel chromatography (0−3% diethyl
ether/pentane) to provide 45 (20 mg, 0.066 mmol, 66%) and 46 (1
mg, 5.0 μmol, 5%) as colorless solids.
2-Cyanocyclopent-2-en-1-yl Benzoate (49a). A round-bottom
flask was charged with 5-hydroxycyclopent1-ene 1-carbonitrile47 (500
mg, 4.58 mmol, 1 equiv) and Et3N (1.3 mL, 9.17 mmol, 2 equiv).
DMAP (56 mg, 0.45 mmol, 0.1 equiv) and THF (15 mL) were
added sequentially under argon. The solution was cooled to 0 °C,
and benzoyl chloride (1.1 mL, 9.17 mmol, 2 equiv) was added
dropwise. The cloudy suspension was stirred while warming to rt
over 18 h. After this time, the reaction mixture was cooled to 0 °C
and quenched with saturated aqueous NH4Cl solution (10 mL). The
contents of the flask were transferred to a separatory funnel, diluted
with Et2O (50 mL), and the layers separated. The organic layer was
washed with saturated aqueous NH4Cl solution (3 × 40 mL),
aqueous 1 N NaOH (3 × 40 mL), and brine (2 × 40 mL). The
organic layer was dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude residue was purified by silica gel
chromatography (10−20% EtOAc/hexanes) to provide 49a (862 mg,
4.04 mmol, 88%) as a colorless oil that solidified after storage at −20
1
Data for 45: Rf = 0.36 (4% EtOAc/hexanes). Mp: 47−49 °C. H
NMR (500 MHz, CDCl3): δ 7.43 (d, J = 7.1, 2H), 7.32 (t, J = 7.6,
2H), 7.29−7.25 (m, 1H), 5.50 (s, 1H), 5.21 (s, 1H), 3.43 (s, 2H),
2.11 (s, 3H), 2.00 (d, J = 3.1, 6H), 1.61 (s, 6H). 13C NMR (125
MHz, CDCl3): δ 170.5, 141.8, 140.3, 128.4, 127.7, 126.0, 115.8, 80.9,
42.9, 41.2, 36.3, 30.9. IR (thin film): 2911, 2853, 1727, 1455, 1342,
1252, 1165, 1057 cm−1. HRMS-CI (m/z) [M + NH4]+: calcd for
C20H24O2NH4, 314.2120; found, 314.2130.
1
Data for 46: Rf = 0.72 (100% hexanes). Mp: 39−41 °C. H NMR
(500 MHz, CDCl3): δ 7.40 (d, J = 7.1, 2H), 7.30 (t, J = 7.4, 2H),
7.25−7.21 (m, 1H), 5.26 (d, J = 2.0, 1H), 4.97 (s, 1H), 2.34 (s, 2H),
1.86 (s, 3H), 1.62 (d, J = 12.1, 3H), 1.53 (d, J = 13.3, 3H), 1.38 (s,
6H). 13C NMR (125 MHz, CDCl3): δ 146.1, 144.0, 128.2, 127.0,
126.6, 116.3, 49.9, 43.1, 37.1, 33.8, 28.9. IR (thin film): 2901, 2846,
1450 cm−1. HRMS-CI (m/z) [M]+: calcd for C19H24, 252.1878;
found, 252.1870.
1
°C. Rf = 0.14 (10% EtOAc/hexanes). H NMR (500 MHz, CDCl3):
3,5,5-Trimethyl-3-(3-phenylbut-3-en-1-yl)dihydrofuran-
2(3H)-one (47). In an identical fashion, oxalate 3k (50 mg, 0.15
mmol, 1.5 equiv) was coupled with α-(bromomethyl)styrene (32, 15
μL, 0.10 mmol, 1 equiv). After 18 h, the reaction mixture was diluted
with CH2Cl2. The resulting organic phase was washed with 4 M HCl
(3 × 10 mL) and 2 N NaOH (3 × 10 mL), dried over Na2SO4, and
evaporated under reduced pressure. The crude residue was purified
by silica gel chromatography (10% acetone/hexanes) to provide 47
(12 mg, 0.047 mmol, 47%) as a colorless oil. Rf = 0.53 (10%
δ 8.04 (d, J = 7.9, 2H), 7.57 (t, J = 7.9, 1 H), 7.44 (t, J = 7.9, 2H),
7.03−7.00 (m, 1H), 6.08−6.04 (m, 1H), 2.81−2.73 (m, 1H), 2.64−
2.56 (m, 2H), 2.09−2.02 (m, 1H). 13C NMR (125 MHz, CDCl3): δ
165.8, 154.3, 133.3, 129.7, 129.5, 128.4, 115.1, 114.9, 79.3, 32.1, 30.6.
IR (thin film): 3069, 2950, 2226, 1972, 1915, 1720 cm. HRMS-ESI
(m/z) [M + Na]+: calcd for C13H11NO2Na, 236.0687; found,
236.0678.
Preparation of Reductive-Coupling Product 50. A 1-dram
vial was charged with oxalate 3a (100 mg, 0.30 mmol, 1.5 equiv),
Ru(bpy)3(PF6)2 (3 mg, 3.0 μmol, 0.015 equiv), Hantzsch ester 4 (76
mg, 0.30 mmol, 1.5 equiv), i-Pr2NEt·HBF4 (44 mg, 0.20 mmol, 1
equiv), and a magnetic stir bar under argon. After sequential addition
of CH2Cl2 (1 mL, sparged with Ar for 5 min), THF (1 mL, sparged
with Ar for 5 min), and acceptor 49a (43 mg, 0.20 mmol, 1 equiv),
the vial was capped and placed in the center of a 30 cm loop of blue
1
acetone/hexanes). H NMR (500 MHz, CDCl3): δ 7.38 (d, J = 7.1,
2H), 7.33 (t, J = 7.5, 2H), 7.29−7.27 (m, 1H), 5.29 (s, 1H), 5.09 (s,
1H), 2.67−2.60 (m, 1H), 2.48−2.41 (m, 1H), 2.15 (d, J = 13.3,
1H),1.95 (d, J = 13.5, 1H), 1.77−1.72 (m, 2H), 1.46 (s, 3H), 1.42
(s, 3H), 1.35 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 181.3, 147.8,
140.9, 128.6, 127.7, 126.2, 112.9, 81.1, 46.7, 45.1, 38.4, 30.6, 30.3,
30.2, 25.9. IR (thin film): 2974, 2934, 2874, 1758, 1455, 1376, 1268,
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Article
LEDs. The reaction mixture was stirred for 18 h, after which time it
was diluted with Et2O (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 was dried over
MgSO4. The organic layer was filtered and concentrated under
reduced pressure. The crude residue was subjected to silica gel
chromatography (4% acetone/hexanes) to provide 50 (34 mg, 0.11
mmol, 55%, dr 8:2:1:1) as a colorless oil.
AUTHOR INFORMATION
Corresponding Author
*E-mail: leoverma@uci.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Data for 50 (major diastereomer, 8:2:1:1): Rf = 0.40 (10%
Financial support was provided by the National Science
Foundation (Grant CHE1265964) and the National Institute
of General Medical Sciences (Grant 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 Juliet F. K. Kotyk
and Professor Jenny Y. Yang for assistance in conducting
cyclic voltammetry measurements.
1
EtOAc/hexanes). H NMR (600 MHz, CDCl3): δ 8.10 (d, J = 8.0, 2
H), 7.58 (t, J = 7.4, 1 H), 7.45 (t, J = 8.0, 2H), 5.30 (app. q, J = 7.6,
1H), 3.42−3.39 (m, 1H), 2.31−2.24 (m, 1H), 2.10−1.96 (m, 3H),
1.82−1.76 (m, 1H), 1.60−1.55 (m, 2H), 1.53−1.45 (m, 6H), 1.31−
1.22 (m, 2H), 1.14 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 166.2,
133.5, 130.0, 129.6, 128.6, 118.6, 74.4, 37.01, 37.0, 35.3, 34.5, 28.2,
26.2, 21.9, 21.62, 21.61. IR (thin film): 2925, 2853, 1722, 1271 cm−1.
HRMS-ESI (m/z) [M + Na]+: calcd for C20H25NO2Na, 334.1783;
found, 334.1789.
Data for 50 (minor diastereomer, 8:2:1:1): Rf = 0.44 (10%
1
EtOAc/hexanes). H NMR (600 MHz, CDCl3): δ 8.00 (d, J = 8.1,
2H), 7.6 (t, J = 7.6, 1H), 7.46 (t, J = 7.6, 2H), 5.52−5.50 (m, 1H),
3.08−3.05 (m, 1H), 2.53−2.46 (m, 1H), 2.25−2.19 (m, 1H), 1.96−
1.78 (m, 3H), 1.60−1.45 (m, 8H), 1.34−1.23 (m, 2H), 1.13 (s, 3H).
13C NMR (125 MHz, CDCl3): δ 165.6, 133.5, 129.8, 129.7, 128.6,
119.9, 78.5, 37.5, 37.1, 36.9, 34.1, 30.6, 26.3, 23.1, 22.0, 21.7.
5-Bromocyclopent-1-enecarbonitrile (49b). A round-bottom
flask was charged with 5-hydroxycyclopent1-ene 1-carbonitrile47 (500
mg, 4.58 mmol, 1 equiv) and Et2O (20 mL) and CBr4 (3.04 g, 9.17
mmol, 2 equiv) were added sequentially under argon. The solution
was cooled to 0 °C and PPh3 (2.40 g, 9.17 mmol, 2 equiv) was
added in one portion. The resulting heterogeneous mixture was
warmed to rt and stirred for 2 h. After this time, the reaction mixture
was filtered through a plug of Celite, and the filtrate was
concentrated under reduced pressure. The crude residue was purified
by silica gel chromatography (10−15% EtOAc/hexanes) to yield 49b
(481 mg, 2.81 mmol, 61%) as a colorless oil. Rf = 0.26 (10% EtOAc/
hexanes). 1H NMR (500 MHz, CDCl3): δ 6.87−6.82 (m, 1H),
5.09−5.04 (m, 1H), 2.86−2.75 (m, 1H), 2.63−2.52 (m, 2H), 2.50−
2.42 (m, 1H). 13C NMR (125 MHz, CDCl3): δ 151.9, 119.1, 114.7,
53.1, 35.5, 32.3. IR (thin film): 2927, 2227, 1607, 1189, 1010 cm−1.
HRMS-ESI (m/z) [M + Na]+: calcd for C6H6BrNNa, 193.9581;
found, 193.9582.
DEDICATION
■
Dedicated to Stephen Hanessian, a friend and leader in the
practice and pedagogy of organic synthesis.
REFERENCES
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Preparation of Allylated Product 51. A 1-dram vial was
charged with oxalate 3a (100 mg, 0.30 mmol, 1.5 equiv),
Ru(bpy)3(PF6)2 (3 mg, 3.0 μmol, 0.015 equiv), Hantzsch ester 4
(76 mg, 0.30 mmol, 1.5 equiv), i-Pr2NEt·HBF4 (44 mg, 0.20 mmol,
1 equiv), and a magnetic stir bar under argon. After sequential
addition of CH2Cl2 (1 mL, sparged with Ar for 5 min), THF (1 mL,
sparged with Ar for 5 min), and acceptor 49b (43 mg, 0.20 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
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was subjected to silica gel chromatography (4% acetone/hexanes) to
provide 51 (22 mg, 0.11 mmol, 57%) as a colorless oil: Rf = 0.47
1
(10% EtOAc/hexanes). H NMR (500 MHz, CDCl3): δ 6.79−6.76
(m, 1H), 2.89−2.83 (m, 1H), 2.50−2.34 (m, 2H), 2.01−1.92 (m,
1H), 1.87−1.79 (m, 1H), 1.64−1.38 (m, 7H), 1.36−1.18 (m, 3H),
0.88 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 152.4, 118.7, 116.7,
36.7, 36.1, 36.0, 33.0, 26.3, 25.2, 22.0, 21.8. IR (thin film): 2926,
2853, 2215, 1459 cm−1. HRMS-ESI (m/z) [M + Na]+: calcd for
C13H19NNa, 212.1415; found, 212.1405.
ASSOCIATED CONTENT
■
S
* Supporting Information
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1
Image of a typical photocatalysis reaction setup, copies of H
and 13C NMR spectra of new compounds, NOE data for
compound 50, and cyclic voltammetry data. The Supporting
Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.joc.5b00794.
K
DOI: 10.1021/acs.joc.5b00794
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The Journal of Organic Chemistry
Article
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