Intermolecular addition of glycosyl halides to alkenes mediated by visible light

Article abstract of DOI:10.1002/anie.201004311

Catching photons: Visible light, an amine reductant, and a [Ru(bpy) ₃]²⁺ photocata-lyst can be used to mediate the addition of glycosyl halides into alkenes to synthesize important C-glycosides (see scheme). This method shows the growing potential of photocatalysis to effectively drive useful and difficult chemical transformations. (Figure presented).

Full text of DOI:10.1002/anie.201004311

Communications
DOI: 10.1002/anie.201004311
C-Glycosides
Intermolecular Addition of Glycosyl Halides to Alkenes Mediated by
Visible Light**
R. Stephen Andrews, Jennifer J. Becker, and Michel R. Gagnꢀ*
C-glycosides are an important class of bioactive compounds
most notable for their resistance to metabolic processing and
their prevalence in natural products.[1–3] Perhaps the most
identifiable methodology for their synthesis is the Bu3SnH-
mediated radical addition of glycosyl bromides to activated
alkenes.[4] Since its discovery, several variations of this
reaction have been reported, including the utilization of
transition metals[5] or UV light[6] to initiate the reaction. Our
group recently developed a nickel-catalyzed reductive cou-
pling of glycosyl bromides and alkenes, mechanistic studies on
which suggested that the nickel catalyst was playing an
electron-transfer (ET) role,[7] which implied that other com-
pounds that are known to facilitate ET processes might
behave even better (for example, [Ru(bpy)3]2+; bpy = 2,2’-
bipyridyl).
that electrophilic radicals could be generated in this fashion
and intramolecularly trapped in a cascade process.[8] We
report herein that the combination of visible light and
[Ru(bpy)3]2+ yields nucleophilic C1 sugar radicals[9] that
react intermolecularly with electron-deficient alkenes to
provide C-glycosides in yields approaching or exceeding
previous bests and with outstanding C1 diastereoselectivites.
Guided by our previous nickel-based methodology,[7] we
initiated our investigation on the reaction of a-glucosyl
bromide
1
and methyl acrylate with [Ru(bpy)3]X2
(5 mol%), a stoichiometric reductant, and an acid source to
protonate a presumed enolate.[10] The best reductant proved
to be N,N-diisopropylethylamine (3), as it provided promising
yields of the a-C-glycoside (2) and did not require highly
polar solvents (Table 1, entries 2 and 7).[3–5]
The photoredox properties of [Ru(bpy)3]2+ and visible
light has generated recent excitement as an environmentally
benign method of promoting odd-electron organic reactions
to drive complex bond constructions.[8] The initiating event in
these reactions is the reduction of the photogenerated MLCT
state, *[RuIII(bpy)2(bpyCÀ)]2+, by amine to generate a potent
ligand centered reducing equivalent (herein referred to as
[RuII(bpy)3]+; Scheme 1). Stephenson recently demonstrated
Table 1: Optimization of C-glycoside formation.
Entry[a]
Acid
Additive
Solvent
X
Yield[a]
1
2
3
4
5
6
7
8
3·HBr
3·HBr
3·HBF4
3·HBF4
3·HBF4
3·HBF4
3·HBF4
–
–
–
–
–
–
5
5
5
DMA
Cl
Cl
Cl
Cl
BF4
BF4
BF4
BF4
0
MeCN
MeCN
MeCN[c]
MeCN[c]
MeCN[c]
26[b]
44[b]
50[b]
61[b]
72[b]
80[d]
92[d]
[c]
CH2Cl2
CH2Cl2
[a] DMA=N,N-dimethyl acetamide. Conditions: glucosyl bromide
(0.12 mmol, 0.12 mm in solvent), methyl acrylate (0.24 mmol), reduc-
tant (0.36 mmol), [Ru(bpy)3]X2 (0.06 mmol), 5 (0.24 mmol) at room
temperature with overnight irradiation with a 14W fluorescent bulb.
[b] Yield of isolated product. [c] 0.06m. [d] Yield determined by super-
critical fluid chromatography.
Scheme 1. Formation of alkyl radicals mediated by visible light.
R=alkyl, bpy=2,2’-bipyridyl.
[*] R. S. Andrews, Prof. Dr. M. R. Gagnꢀ
Department of Chemistry
University of North Carolina at Chapel Hill
Chapel Hill, NC 27599-3290 (USA)
E-mail: mgagne@email.unc.edu
In these trials, the mass balance was dominated by over-
conjugate addition (4), indicating that a-radical reduction and
its subsequent conjugate addition to additional acrylate were
competitive. Stimulated by Stephensonꢀs success with HC
trapping of benzylic radicals, we found that Hantzsch ester (5)
Dr. J. J. Becker
US Army Research Office
P.O. Box 12211, Research Triangle Park, NC 27709 (USA)
[**] We thank Aaron J. Francis for his contribution to optimization and
Prof. Malcolm Forbes for his help with EPR experiments. The Army
Research Office Staff Research Funding and Department of Energy
(DE-FG02-05ER15630) are gratefully acknowledged for their sup-
port.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004311.
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Chemie
successfully suppressed the oligomerization and led to
improved yields, as did a switch to dichloromethane as
solvent (suppressed hydrolysis). Final optimization showed
the acid to be unnecessary and high reaction concentrations to
be beneficial (Table 1, entry 8).[11]
The conditions arrived at in entry 8 were adopted to
examine the scope of the coupling (Table 2). In general,
alkenes known to rapidly react with alkyl radicals worked
omitted, 5 was quickly converted into the pyridine (< 2 h)
accompanied by only a 25% consumption of 1 to 2; 2) In the
presence of an electrophilic hydrogen atom source (tBuSH),
C1 reductive debromination was the major product accom-
panied by small amounts of the C-glycoside; 3) Consistent
with a C1 radical intermediate was the cyclopropane ring-
opening observed in 16 [Eq. (1)] and the detection of carbon-
based radicals in time-resolved EPR measurements after
pulsed irradiation of the reaction mixture.[9,15]
Table 2: Scope of the C-alkylation with activated alkenes.[a]
Entry
1
Product
Entry
Yield[b]
6, R=CO2Me: 94%[c]
(75%[d])
Based on these observations, we propose Scheme 2 as a
plausible mechanism. ET from photogenerated [RuII(bpy)3]+
to glycosyl bromide generates the C1 radical, which can be
2
3
4
7, R=COMe: 86%
8, R=CHO: 85%
9, R=CN: 85%
5
6
10, 98%,
11, 42% (63%[e])
d.r.=1.5:1
7
9
8
12, 51%
13, 98% (90%[d]),
d.r.=1.8:1
10
14, 81%[c]
15, 80%
[a] R’=Ac or Bz. [b] Yield of isolated product; conditions: glycosyl
bromide (0.12 mmol, 0.12 mm in CH2Cl2), alkene (0.24 mmol), 3
(0.36 mmol), [Ru(bpy)3](BF4)2 (0.06 mmol), 5 (0.24 mmol), irradiation
overnight at room temperature with
[c] 0.134 mmol 5. [d] 1.2 mmol glucosyl bromide. [e] 1.2 mmol alkene.
a 14W fluorescent bulb.
Scheme 2. A plausible mechanism for the reactions described herein.
reduced (k1) or added to the alkene (k2); for electron deficient
alkenes k2 > k1. When k1 ꢀ k2, reductive debromination is
competitive, though this can be partially compensated with an
increase in the alkene concentration. Termination of the
electron-deficient a radical is subject to the relative rates of
over-conjugate addition (k3) and reduction (k4), the latter
being accelerated by Hantzsch ester.[16,17]
In summary, we have developed a reductive room-
temperature visible-light-mediated conjugate addition of
glycosyl halides into activated alkenes, which leads to fully
saturated C-glycosides with exclusive a selectivity. The pro-
cedure improves upon the classic Bu3Sn-H mediated method-
ologies pioneered by Giese and achieves near best results for
each substrate class. Moreover, this procedure advances the
well,[12] though when they became too electron deficient,
over-conjugate addition became problematic. Typical reac-
tion times were about 15 h, though less electrophilic or
bulkier substrates were slower. Higher alkene concentrations
were helpful when over-conjugate addition was not rapid
(Table 2, entry 6).[13] Mannosyl and galactosyl bromides were
also well-behaved (entries 9 and 10), as were acetate and
benzoate protecting groups (not pivaloate), and reactions
could be successfully scaled to 1.2 mmol of substrate without
complications (entry 1 and 6).[14] Although 1,1-disubstituted
alkenes were tolerated, b-substituted enoates were not (e.g.
methyl crotonate, methyl maleate).
Several control experiments helped to elucidate the role
of the reaction components: 1) No products were formed in
the absence of [Ru(bpy)3]2+ or visible light, and when 3 was
À
growing role of photoredox catalysis in important C C bond
formations and generates an experimentally optimal proce-
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Communications
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free). Efforts to observe and characterize the photogenerated
radical intermediates by trapping or EPR measurements are
underway.
[8] For recent reviews on [Ru(bpy)3]2+ catalysis with visible light,
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tion of aldehydes; see: D. A. Nicewicz, D. W. C. MacMillan,
Science 2008, 322, 77 – 80; D. A. Nagib, M. E. Scott, D. W. C.
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J. W. Tucker, C. R. J. Stephenson, J. Am. Chem. Soc. 2009, 131,
8756 – 8757. For intramolecular addition into alkenes, see: J. W.
Tucker, J. M. R. Narayanam, S. W. Krabbe, C. R. J. Stephenson,
Org. Lett. 2010, 12, 368 – 371; J. W. Tucker, J. D. Nguyen, J. M. R.
Narayanam, S. W. Krabbe, C. R. J. Stephenson, Chem. Commun.
2010, 46, 4985 – 4987. For intermolecular addition into arenes,
see: L. Furst, B. S. Matsuura, J. M. R. Narayanam, J. W. Tucker,
C. R. J. Stephenson, Org. Lett. 2010, 12, 3104 – 3107.
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[10] The reduction potential of glucosyl bromide tetraacetate has
been measured to be À1.27 V (versus SCE). See: S. B. Rondi-
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[11] Salt electrolytes were also added, but they were less effective
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[13] The major competing byproduct was reductive debromination of
the starting material. Hydrolysis of the glucosyl bromide was
also observed in small amounts (< 20%).
Experimental Section
General procedure: A flame-dried Schlenk tube equipped with a stir
bar under argon was charged with [Ru(bpy)3](BF4)2 (0.006 mmol,
5 mol%), Hantzsch ester 5 (0.268 mmol, 2.2 equiv), and glycosyl
bromide (0.122 mmol, 1 equiv). The flask was evacuated and then
backfilled with argon. Solvent (to a sugar concentration of 0.12 mm)
was added, forming a bright orange heterogeneous solution, followed
by iPr2NEt (0.366 mmol, 3 equiv) and alkene (0.244 mmol, 2 equiv).
The reaction tube was placed 6–10 cm from a 14W fluorescent light
bulb and stirred at room temperature until thin-layer chromatogra-
phy showed consumption of starting material (12–72 h). The reaction
was quenched by passing it through a plug of silica in Et2O (100 mL).
Flash column chromatography provided the product as a white solid
or a colorless oil after removal of solvents.
Received: July 14, 2010
Published online: August 25, 2010
Keywords: alkenes · C-glycosides · homogeneous catalysis ·
.
photooxidation · ruthenium
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