Direct construction of quaternary carbons from tertiary alcohols via photoredox-catalyzed fragmentation of tert-alkyl N-phthalimidoyl oxalates

Article abstract of DOI:10.1021/ja408971t

A convenient method for the direct construction of quaternary carbons from tertiary alcohols by visible-light photoredox coupling of tert-alkyl N-phthalimidoyl oxalate intermediates with electron-deficient alkenes is reported.

Full text of DOI:10.1021/ja408971t

Communication
pubs.acs.org/JACS
Direct Construction of Quaternary Carbons from Tertiary Alcohols
via Photoredox-Catalyzed Fragmentation of tert-Alkyl
N‑Phthalimidoyl Oxalates
Gregory L. Lackner,† Kyle W. Quasdorf,† and Larry E. Overman*
Department of Chemistry, University of California, Irvine, California 92697-2025, United States
S
* Supporting Information
ABSTRACT: A convenient method for the direct
construction of quaternary carbons from tertiary alcohols
by visible-light photoredox coupling of tert-alkyl N-
phthalimidoyl oxalate intermediates with electron-deficient
alkenes is reported.
orming sterically demanding quaternary carbons by the
reaction of nucleophilic carbon radicals with electron-
F
deficient alkenes is attractive for several reasons: the forming
bond is unusually long in calculated transition structures (2.2−
2.5 Å);1 the rates of addition of tertiary radicals to electron-
deficient alkenes are faster than those of Me, primary, and
secondary radicals;2 and stereoselectivity in the addition of
tertiary radicals to prochiral alkenes is typically larger than that
of primary or secondary radicals.2a,3,4 Although these appealing
features have been recognized for many years,2a,5 this method is
not mentioned in a recent comprehensive survey of methods to
construct quaternary carbons.6 The considerable potential such
bond constructions hold was suggested in our recent formal
total synthesis of (−)-aplyviolene, wherein the stereoselective
coupling of a tertiary carbon radical, generated by visible-light
photoredox decarboxylative fragmentation of N-(acyloxy)-
phthalimide 1, to α-chlorocyclopentenone 2 was the central
step (eq 1).7a This result represented the first utilization of such
a
Figure 1. Synthesis of tert-alkyl N-phthalimidoyl oxalates. Isolated
b
yield. Phth = N-phthalimido.
thionyl oxalates for generating carbon radicals from alcohols.10
Although Barton oxalate intermediates can be formed from
tertiary alcohols, the instability of these intermediates, which
prevents their isolation, and their light sensitivity are likely
responsible for their limited use in the formation of quaternary
carbons.11−15 Anticipating that related tert-alkyl N-phthalimi-
doyl oxalates would be more convenient precursors of tertiary
carbon radicals, we initially explored conditions to access these
compounds.
After examining several potential methods for preparing
these mixed oxalate diesters, we found that tertiary alcohols
smoothly underwent acylation with chloro N-phthalimidoyl
oxalate (4, generated in situ from oxalyl chloride and N-
hydroxyphthalimide) at room temperature in the presence of
Et3N and catalytic DMAP to afford tert-alkyl N-phthalimidoyl
substrates in a C−C bond-forming reaction since their initial
disclosure by Okada.8 We surmise that the reason tertiary
carbon radicals have not heretofore played a significant role in
assembling quaternary carbons is the lack of convenient
methods for generating these intermediates from widely
available tertiary alcohols.4 Furthermore, despite the pro-
nounced advancement of visible-light photoredox-catalyzed
transformations in recent years, methods that generate tertiary
carbon radicals remain largely unexplored.7b,9 In this
Communication, we report such a method.
The method we developed was inspired by Barton’s
pioneering introduction of tert-alkyl N-hydroxypyridine-2-
Received: August 29, 2013
© XXXX American Chemical Society
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Journal of the American Chemical Society
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Table 1. Optimization for the Coupling of 6a with Methyl Vinyl Ketone
a
entry
oxalate equiv
MVK equiv
Hantzsch ester equiv
additive (equiv)
solvent
CH2Cl2
X
yield (%)
b
1
2
1.0
1.0
1.0
1.0
1.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
5.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
1.5
1.5
1.5
1.5
i-Pr2NEt (2.2)
BF4
BF4
BF4
BF4
BF4
BF4
BF4
BF4
PF6
PF6
16
b
none
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
36
b
3
i-Pr2NEt·HBF4 (2.2)
i-Pr2NEt·HBF4 (2.2)
i-Pr2NEt·HBF4 (2.2)
i-Pr2NEt·HBF4 (2.2)
i-Pr2NEt·HBF4 (1.0)
i-Pr2NEt·HBF4 (1.0)
i-Pr2NEt·HBF4 (1.0)
none
40
b
4
22
b
5
56
b
6
77
b
7
82
a
a
a
b
8
THF/CH2Cl2
THF/CH2Cl2
92
b
c
9
92 82
c
10
THF/CH2Cl2
65
a
b
1:1 mixture of THF/CH2Cl2; Hantzsch ester = diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate. Yield determined by 1H NMR.
c
Isolated yield after silica gel chromatography.
oxalates in high yields (5→6, Figure 1). In contrast to N-
(acyloxy)phthalimides, which are generally quite stable to
aqueous workup and silica gel chromatography, oxalates 6
proved to be much more sensitive. However, we found that the
byproducts of their synthesis typically could be removed by
simple filtration to furnish the desired product in acceptable
purity. tert-Alkyl N-phthalimidoyl oxalates 6a−6k are stable to
ambient light and can be easily prepared on multigram scale.
Confirmation that this sequence did provide the previously
unknown alkyl N-phthalimidoyl oxalates was secured by single-
crystal X-ray analysis of oxalate diester 6j.
coupling of indole-containing oxalate 6i proceeded in
diminished yield. As expected from our exploratory studies,
carrying out the coupling of 6d and 6e with equal equivalents of
the oxalate precursor and MVK gave the coupled products in
somewhat diminished yields (entries 4 and 5). The reaction of
adamantyl oxalate 6j led to the expected product 7j in low
yield, with the major product deriving from coupling of the
intermediate alkoxycarbonyl radical with MVK (entry 9). To no
surprise, homoallylic oxalate 6k coupled with MVK to give
butyrolactone 7k (entry 7).15a,17
The scope of this new coupling reaction with respect to the
conjugate acceptor is summarized in Table 3. Acceptors
possessing a terminal double bond generally performed best
in the reaction, with acrylonitrile, phenyl vinyl sulfone, and
methyl acrylate providing the coupled products in excellent
yield (entries 1−3); the yields were somewhat lower with
dimethyl acrylamide (entry 4). Dimethyl fumarate also served
as an excellent coupling partner, producing 9e in 85% yield
(entry 5).
Cyclic acceptors could be utilized also, although the yields of
coupled products were slightly lower (entries 6−9). Use of a
butenolide acceptor (entry 8) furnished the desired product in
72% yield, with addition occurring exclusively from the face
opposite the methoxy substiuent.18 Finally, the activated
trisubstituted acceptor 2-carbomethoxycyclopent-2-en-1-one
coupled with tert-alkyl N-phthalimidoyl oxalate 6a to afford
trans product 9i in 62% yield (entry 9).
With a general route to tert-alkyl N-phthalimidoyl oxalates in
hand, we examined the coupling of oxalate 6a with methyl vinyl
ketone (MVK). Employing conditions similar to those used in
our earlier studies with N-(acyloxy)phthalimides7 resulted
largely in decomposition of the oxalate, furnishing coupled
product 7a in only small amounts (Table 1, entry 1). Omission
of i-Pr2NEt provided an improvement in yield (entry 2),
reflecting the instability of 6a to the presence of this amine. The
use of i-Pr2NEt·HBF4 resulted in improved yields of 7a (entries
3−9). Whereas using an excess or equal amount of MVK
relative to 6a proved detrimental (entries 1−5),16 optimal
yields were obtained when oxalate 6a was present in slight
excess (entries 6−10). It was also found that a 1:1 THF/
CH2Cl2 solvent mixture was superior to either CH2Cl2 or THF
alone (entries 8 and 9). The i-Pr2NEt·HBF4 additive was found
to be beneficial even under optimized conditions, as its
omission led to lower product yields (entry 10). Finally,
[Ru(bpy)3](BF4)2 or the commercially available [Ru(bpy)3]-
(PF6)2 performed comparably in the reaction (entries 8 and 9).
Under the optimized reaction conditions, the coupling of
oxalate 6a with MVK gave ketone product 7a in 82% yield.
The results of our initial survey of the scope of the coupling
of tert-alkyl N-phthalimidoyl oxalates with MVK are summar-
ized in Table 2. In most cases, yields of the coupled products
were excellent, 68−85% (entries 1−7). Chiral oxalates 6c, 6d,
and 6e coupled with high diastereoselectivity (>20:1) from the
sterically most accessible face (entries 3−5). The coupling of
the estrone-derived precursor 6e is significant as it demon-
strates the construction of vicinal-quaternary carbon centers
(entry 5). Two nitrogen-containing heterocyclic substrates
were also investigated (entries 7 and 8). Piperidinone-derived
6h furnished coupled product 7h in 82% yield, whereas the
A plausible mechanism for the visible-light photoredox
coupling reported herein is outlined in Scheme 1. As proposed
by Okada8 for the fragmentation of N-(acyloxy)phthalimides,
+
single-electron transfer from Ru(bpy)3 to the tert-alkyl N-
phthalimidoyl oxalate, followed by homolytic cleavage of the
N−O bond and subsequent decarboxylation, generates
alkoxycarbonyl radical 12. A second, slower decarboxylation
leads to the formation of tertiary radical 13,10,19 which after
addition to an electron-deficient alkene provides α-acyl radical
14. Hydrogen atom abstraction from Hantzsch ester radical
cation 10b would furnish the final product (14→7). An
alternative pathway (not shown), involving reduction of α-acyl
radical 14 to the corresponding enolate and subsequent
protonation, could also lead to the formation of 7. While the
presence of Hantzsch ester 10a is necessary to realize catalytic
turnover, the role of the ammonium additive is not fully
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Journal of the American Chemical Society
Communication
Table 2. Coupling of tert-Alkyl N-Phthalimidoyl Oxalates
Table 3. Coupling of 6a with Various Acceptors
with Methyl Vinyl Ketone
a
b
1:1 mixture of THF/CH2Cl2. Isolated yield after silica gel
chromatography (average of two experiments).
Scheme 1
a
b
1:1 mixture of THF/CH2Cl2. Isolated yield after silica gel
c
chromatography (average of two experiments). Isolated yield after
silica gel chromatography with 1:1 ratio of oxalate precursor to
d
acceptor. Phth = N-phthalimido.
understood at this time. However, it could potentially serve to
protonate intermediate radical anion 11 and also act as a source
−
of BF4 to undergo anion exchange with [Ru(bpy)3](PF6)2,
leading to the formation of the more soluble [Ru(bpy)3](BF4)2
complex.
In conclusion, we have developed a convenient method for
the direct construction of quaternary carbons from tertiary
alcohols by visible-light photoredox coupling of tert-alkyl N-
phthalimidoyl oxalate intermediates with electron-deficient
alkenes. In three examples, in which the intermediate tertiary
carbon radical is chiral and sterically biased, diastereoselection
in forming the new quaternary carbon stereocenter was
C
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Journal of the American Chemical Society
Communication
(12) Tertiary bromides and iodides are the most widely employed
precursors of tertiary radicals.4,7b However, as a result of competing
rearrangement and elimination reactions, these halides will not be
available from many structurally complex tertiary alcohols.7a
(13) Although many alcohol derivatives have found use in the
deoxygenation of tertiary alcohols,14 to our knowledge there are only
scattered reports of the bimolecular trapping of tertiary radicals
generated from these precursors to construct quaternary carbons.10,15
(14) McCombie, S. W.; Motherwell, W. B.; Tozer, M. J. Org. React.
2012, 77, 161.
(15) For examples, see: (a) Togo, H.; Fujii, M.; Yokoyama, M. Bull.
Chem. Soc. Jpn. 1991, 64, 57. (b) Togo, H.; Matsubayashi, S.;
Yamazaki, O.; Yokoyama, M. J. Org. Chem. 2000, 65, 2816.
(c) Blazejewski, J.-C; Diter, P.; Warchol, T.; Wakselman, C.
Tetrahedron Lett. 2001, 42, 859. (d) Sunazuka, T.; Yoshida, K.;
Kojima, N.; Shirahata, T.; Hirose, T.; Handa, M.; Yamamoto, D.;
Harigaya, Y.; Kuwajima, I.; Omura, S. Tetrahedron Lett. 2005, 46, 1459.
(16) Excess MVK contributes to diminished product yields by the
addition of intermediate 14 to a second equivalent of MVK. See ref 8
for similar observations.
excellent. Additional synthetic applications of tert-alkyl N-
phthalimidoyl oxalates, as well as mechanistic studies of their
reactivity in photoredox-mediated processes, are currently
under investigation and will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, characterization data, and CIF files for 6j
and 7d. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
leoverma@uci.edu
■
Author Contributions
†G.L.L. and K.W.Q. contributed equally.
Notes
The authors declare no competing financial interest.
(17) Togo, H.; Yokoyama, M. Heterocycles 1990, 31, 437.
(18) Morikawa, T.; Washio, Y.; Harada, S.; Hanai, R.; Kayashita, T.;
Nemoto, H.; Shiro, M.; Taguchi, T. J. Chem. Soc., Perkin Trans. 1 1995,
271.
(19) Simakov, P. A.; Martinez, F. N.; Horner, J. H.; Newcomb, M. J.
Org. Chem. 1998, 63, 1226.
ACKNOWLEDGMENTS
■
Support was provided by the National Science Foundation
(CHE1265964) and the National Institute of General Medical
Sciences (R01GM098601). NMR and mass spectra were
determined at UC Irvine using instruments purchased with
the assistance of NSF and NIH shared instrumentation grants.
We thank Dr. Joseph Ziller and Dr. John Greaves, Department
of Chemistry, UC Irvine, for their assistance with X-ray and
mass spectrometric analyses.
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