Synthesis of highly substituted tetrahydrofurans by catalytic polar-radical-crossover cycloadditions of alkenes and alkenols

Article abstract of DOI:10.1002/anie.201210111

Light up my ring: The title reaction is catalyzed by an acridinium/phenylmalononitrile photoredox system. A variety of readily available olefins and unsaturated alcohols can be employed to furnish tetrahydrofuran adducts with complete regiocontrol and up to four contiguous stereogenic centers.

Full text of DOI:10.1002/anie.201210111

Angewandte
Chemie
DOI: 10.1002/anie.201210111
Photoinduced Electron Transfer
Synthesis of Highly Substituted Tetrahydrofurans by Catalytic Polar-
Radical-Crossover Cycloadditions of Alkenes and Alkenols**
Jean-Marc M. Grandjean and David A. Nicewicz*
Tetrahydrofuran rings are common structural elements pres-
ent in numerous biologically active naturally occurring
molecules, including a number of lignans and polyether
antibiotics.[1] Perhaps owing to their prevalence in natural
products, there have been a number of direct catalytic
synthetic methods devised to construct this motif.[1b]
Common strategies include carbonyl ylide dipolar cycloaddi-
tions,[2] the Prins-Pinacol reaction,[3] the Oshima–Utimoto
reaction[4] and Lewis acid catalyzed [3+2] cycloadditions of
donor–acceptor cyclopropanes and aldehydes.[5] Herein, we
report the development of a new organocatalytic synthetic
method for the construction of tetrahydrofurans employing
simple and readily available allylic alcohols and alkenes. The
reaction is catalyzed by a commercially available organic
single electron photooxidant coupled with a redox-active
hydrogen atom donor. This catalytic method provides the
direct synthesis of valuable tetrahydrofurans from common
organic reagents.
catalytic strategy afforded the opportunity to directly synthe-
size highly substituted tetrahydrofurans from allylic alcohols
and alkenes by
a polar-radical-crossover cycloaddition
(PRCC) sequence that capitalizes on the simultaneous polar
and radical nature of radical cation species [Eq. (2)]. In
support of this mechanistic hypothesis, Giese,[7a] Newcomb,[7b]
and Crich[7c] have previously demonstrated the fundamental
steps of this proposal through radical cation generation from
b-(phosphatoxy)alkyl selenides and PTOC esters, respec-
tively.
In combining successive polar and radical steps, polar-
radical-crossover reactions have the potential to become
a powerful strategy for the development of reactions relying
on multiple bond-forming events.[8] Despite the promise held
by this mechanistic approach, few practical examples of this
strategy have been brought into practice.[9] In prior reports in
which this mechanism is operative, superstoichiometric
quantities of either an oxidant or reductant are typically
needed to access the requisite reactive intermediates. To our
knowledge, there are no examples of truly redox-neutral polar
radical crossover reactions.
We have recently established an organic photoredox
catalytic system for the direct intramolecular anti-Markovni-
kov hydroetherification of alkenols that produces five- to
seven-membered cyclic ethers with complete regiocontrol
[Eq. (1); Mes = mesityl, DCE = 1,2-dichloroethane].[6] The
To directly access the tetrahydrofuran ring system, we
envisioned that upon single-electron oxidation of a suitable
olefinic substrate, an allylic alcohol would add to the
corresponding radical cation with anti-Markovnikov selectiv-
ity (Scheme 1).[6,10] This initial polar step would afford radical
6, which is poised to undergo a 5-exo radical cyclization with
the pendant alkene. Finally, hydrogen-atom abstraction from
PhCH(CN)2 (2) and the loss of a proton furnishes the
tetrahydrofuran adduct. In order for turnover of 1 to occur,
radical 9 would have to act as a single-electron oxidant for 11.
Additionally, the phenyl malononitrile anion (10) can neu-
tralize the acid generated during the reaction course and
regenerate hydrogen-atom donor 2. Importantly, this pro-
posed mechanism would maintain overall redox neutrality by
employing redox-active hydrogen-atom donor 2.
reaction proceeds via the intermediacy of a radical cation.
The key innovation in this method is the ability to segregate
polar and radical reaction vectors by employing a redox-
active hydrogen atom donor. We realized that this unique
[*] J.-M. M. Grandjean, Prof. D. A. Nicewicz
Department of Chemistry, University of North Carolina at Chapel
Hill, Chapel Hill, NC 27599-3290 (USA)
E-mail: nicewicz@unc.edu
To begin, we investigated the reaction of allyl alcohol and
b-methyl styrene with acridinium perchlorate salt 1[11] as
a photoredox catalyst and phenyl malononitrile as the
hydrogen-atom donor (Table 1, entry 1). We were pleased to
find that irradiation of this mixture with 450 nm LEDs
Homepage: http://www.chem.unc.edu/people/faculty/nicewicz/
[**] This project was supported by The University of North Carolina at
Chapel Hill and an Eli Lilly New Faculty Award.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201210111.
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Scheme 1. Postulated mechanism for the photoredox PRCC reaction between allyl alcohol and b-methyl styrene. ÆeÀ =redox couple,
ÆH+ =proton transfer, SET=single electron transfer.
afforded the anticipated tetrahydrofuran as a single regioiso-
Table 1: PRCC reactions of alkenes and allyl alcohol.[a]
mer in nearly quantitative yield in a 10:6:1 ratio of diaste-
reomers, as determined by 1H NMR spectroscopy. Somewhat
lower yields of isolated product were obtained (63%),
presumably owing to the volatility of the product. Attempts
to increase the diastereoselectivity by employing different
catalysts, or by varying reaction concentrations and solvents
unfortunately failed to improve upon this preliminary result.
Omission of 2 or the use of [Ru(bpy)3]2+ (bpy = bipyridine) as
photooxidant failed to furnish even trace amounts of the
desired product, likely due to the lower oxidizing power of
Entry
1
Alkene
Product
12/13[b]
Yield [%]
63
1.7:1[c]
*[Ru(bpy)3]2+ [12,13]
.
2
3
1.7:1[c]
1.7:1[c]
80
70
Next, we surveyed the scope of the reaction with respect
to the alkene component. Employing cis-b-methyl styrene
gave an identical mixture of diastereomers as trans-b-methyl
styrene (Table 1, entries 1 and 2), demonstrating the loss of
alkene geometry during the course of the reaction. In probing
the electronics of the reaction with respect to the alkene
component, we found that 4-chloro-b-methylstyrene (entry 3)
gave the corresponding tetrahydrofuran adduct in good yield,
whereas 4-methoxy-b-methylstyrene was not reactive under
these conditions, presumably because of the relative stability
of the resultant radical cation intermediate. Cyclic alkene
substrates, such as indene (entry 4) and 1-phenylcyclohexene
(entry 5), were also competent reaction partners and afforded
good yields of the corresponding cyclic ether adducts.
Importantly, the indenyl tetrahydrofuran motif formed in
entry 4 comprises the core of the Schisandra rubriflora isolate,
rubriflordilactone B, which has documented anti-HIV activ-
ity.[14]
4
5
2.6:1
1.2:1
63
60
6
7
2.1:1[c]
3.3:1
55
42
8
3:1
95[d]
As demonstrated by entries 6 and 7, this catalytic method
is also tolerant of free alcohols and ester functional groups. It
is noteworthy that the reaction in entry 6 proceeds with
complete chemoselectivity despite the presence of two differ-
ent alkenols in the reaction. Aliphatic trisubstituted alkenes
with higher oxidation potentials, such as 2-methylbut-2-ene,
can also be employed to give highly substituted cyclic ethers
[a] Average of two experiments using alkenol (5.0 equiv) for 48–144 h.
[b] Diastereomeric ratio determined by 1H NMR analysis of the crude
reaction mixture. [c] Small amounts (>7%) of a third diastereomer were
observed; see the Supporting Information for details. [d] Determined by
1H NMR spectroscopy with an internal standard. Bz=benzoyl.
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Table 2: PRCC reaction of b-methyl styrene and unsaturated alcohols.[a]
the amount of 2 were unsuccessful. Current efforts are
underway to design more effective hydrogen-atom donors for
this reaction. Lastly, we were pleased to find that propargyl
alcohol afforded a 4-exo-methylene tetrahydrofuran in good
yield and with excellent levels of diastereoselectivity (60%
yield, 10:1 d.r., entry 7), thus providing additional opportu-
nities to expand the synthetic potential of this catalytic
sequence.[15]
Non-styrenyl substrates also undergo the PRCC reaction,
and a subset of these alkenes and dienes were tested with cis-
butene-1,4-diol (Table 3). Methylcyclopentene afforded the
Entry Alkenol
1
Product
14/15[b] Yield [%]
1.1:1[c]
>20:1
1.2:1
79
70
58
2
3
Table 3: PRCC reaction of cis-butene-1,4-diol and non-styrenyl alkenes
and dienes.[a]
4[d]
2.6:1
78
71
2.2:1[c]
Entry
1
Alkene
Product
d.r.[b]
1.6:1
Yield [%]
43
5
6[d]
2.6:1[c]
10:1
32
60
2
3
3:1
5:1
54
57
7
[a] Average of two experiments using alkenol (5.0 equiv) for 12–120 h.
[b] Diastereomeric ratio determined by 1H NMR analysis of the crude
reaction mixture. [c] Small amounts (>7%) of a third diastereomer were
observed; see the Supporting Information for details. [d] Nitromethane
solvent. PhthN=phthalimide.
[a] Average of two experiments using alkenol (5.0 equiv) for 96–120 h.
[b] Diastereomeric ratio determined by 1H NMR analysis of the crude
reaction mixture.
(entry 8). However, prolonged reaction times (1–6 days) are
often required for high reaction conversion.
corresponding bicyclic ether adduct in moderate yield to
afford the corresponding bicyclic ether as a single regioisomer
(entry 1). Similarly, 2-methylbut-2-ene gave the expected
Next, a variety of unsaturated alcohols were examined in
reactions with b-methylstyrene (Table 2). Prenol afforded
good yields of the expected tetrahydrofuran adduct, albeit in
a 1.1:1 ratio of diastereomers (entry 1). We were pleased to
find that the use of methallyl alcohol furnished essentially
a single diastereomer (> 20:1 d.r.) of product (entry 2). To
probe the effect of resident stereochemistry on the reaction,
2-methallyl alcohol was employed (entry 3) and furnished
only 2 out of 8 possible diastereomeric tetrasubstituted
tetrahydrofurans. Finally, further evidence demonstrating
the functional group compatibility of this reaction is indicated
in entries 4 and 5 of Table 2. Indeed, alkenols bearing free
alcohols (entry 4) or protected amines (entry 5) furnished the
intended cycloadducts in good yields, leaving the functional
groups unperturbed.
In addition to the synthesis of tetrahydrofuran adducts, we
attempted the formation of tetrahydropyran ring systems by
using homoallyl alcohol (entry 6). A modest yield (32%, 1.2:1
d.r.) of the desired six-membered ring was obtained with the
remainder of the mass balance attributed to the non-cyclized
anti-Markovnikov hydroalkoxylation adduct. Attempts to
increase the yield of the tetrahydropyran adduct by lowering
tetrasubstituted cycloadduct bearing
a pendant alcohol
(entry 2). The reaction of cis-butene-1,4-diol with cyclohexa-
diene furnished the intended cycloadduct in 57% yield with
an intact olefin for further possible synthetic manipulations,
a result which further demonstrates both the functional group
tolerance and the chemoselectivity of this method.
Control of the relative stereochemistry at C2 and C3 is
high in all cases (> 15:1), however, as is often the case with
neutral open-shell cyclizations, this transformation proceeds
with lower diastereoselectivity in the radical cyclization.
1
Analysis by H NMR and NOESY experiments, as well as
literature precedent,[16] indicates that the major diastereomer
produced has a cis relationship between the C3 and C4
groups. A Beckwith-type model can be invoked to rationalize
this observation (Scheme 2).[17] Envelope-like conformer 16 is
presumed to be the lowest energy conformer and leads to the
major stereoisomer. A third diastereomer that is occasionally
observed in some reactions (Table 1, entries 1–3 and 6;
Table 2, entries 5 and 6) is presumed to be the fully saturated
furan in which all of the substituents have a cis relationship.
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0.0033 mmol, 0.025 equiv) were added to a four-dram vial containing
a magnetic stir bar. The vial containing the solids was then brought
into a glove box where solvent (1.5 mL) was added. The alkenol
(4.2 mmol, 5.0 equiv) and alkene (0.85 mmol, 1.0 equiv) were then
introduced via syringe. The vial was fitted with a septum cap,
transferred from the glove box, and placed on a magnetic stirring
plate in front of a blue-light flood lamp (450 nm). The course of the
reaction was monitored by TLC and, upon completion, the solvent
was removed and the crude reaction mixture purified by silica gel
chromatography.
Scheme 2. Proposed Beckwith transition state.
We hypothesize that this stereoisomer arises by rapid
equilibration between the two alkene radical cation geo-
metrical isomers.
Received: December 18, 2012
We considered that diastereoselective hydrogenation of
the exo-methylene adducts formed from reactions with
propargyl alcohol might provide a means to circumvent the
lower levels of diastereoselectivity observed in the radical
cyclization step. We were pleased to find that reaction of
dihydronaphthalene and propargyl alcohol under the organo-
catalytic conditions followed by diastereoselective hydro-
genation of the derived exo-methylene intermediate, afforded
tetrahydrofuran 18 in 14:1 d.r. and 40% overall yield
[Eq. (3)]. We attribute the high levels of diastereocontrol to
Published online: February 25, 2013
Keywords: organocatalysis · photoredox catalysis · radicals ·
.
tetrahydrofuran
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In summary, we have demonstrated a new PRCC reaction
catalyzed by an organic photoredox system to synthesize
highly substituted tetrahydrofurans from readily available
allylic alcohols and oxidizable alkenes. This is a simple
synthetic disconnection that provides valuable cyclic ether
scaffolds. The method demonstrates a broad range of func-
tional group compatibility and could find unique applications
in complex molecule synthesis. The expansion of this method
to allow the construction of additional classes of heterocyclic
compounds is currently underway.
Experimental Section
Typical procedure for the PRCC reaction: Phenylmalononitrile
(120 mg, 0.85 mmol, 1.0 equiv) and the acridinium catalyst (8.7 mg,
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