Synthesis of allylic and homoallylic alcohols from unsaturated cyclic ethers using a mild and selective C-O reduction approach

Article abstract of DOI:10.1039/c2cc33551d

Unsaturated cyclic ethers can be mildly and selectively reduced with catalytic amounts of B(C₆F₅)₃ in the presence of an alkylsilane. The allylic position is preferentially reduced with minimal or no scrambling of olefin geometry. For electronically equivalent substrates, steric factors guide the reducing agent to the least substituted site.

Full text of DOI:10.1039/c2cc33551d

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COMMUNICATION
Synthesis of allylic and homoallylic alcohols from unsaturated cyclic
ethers using a mild and selective C–O reduction approachw
Daniel J. Mack,b Boying Guoa and Jon T. Njardarson*ab
Received 16th May 2012, Accepted 28th May 2012
DOI: 10.1039/c2cc33551d
Unsaturated cyclic ethers can be mildly and selectively reduced
with catalytic amounts of B(C6F5)3 in the presence of an
alkylsilane. The allylic position is preferentially reduced with
minimal or no scrambling of olefin geometry. For electronically
equivalent substrates, steric factors guide the reducing agent to
the least substituted site.
Fluorinated boron Lewis acids have gained popularity in
recent years as catalysts for a variety of interesting synthetic
Scheme 1 Challenges with Unsaturated Cyclic Ether Reductions.
transformations. Within this class of Lewis acids, B(C6F5)3 is
most commonly employed.1 While the majority of applications
scrambled during the reaction, this would represent an attractive
approach for accessing allylic and homo-allylic alcohols.10,11
olefin polymerizations,2 new reductions3 and the formation of
The results from the 2,5-dihydrofuran catalytic reduction
are in its utilization as a co-catalyst for metallocene-driven
frustrated Lewis acid–base pairs4 have surfaced as new applica-
studies are shown in Table 1. All of the etheral reductions
proceeded cleanly in high yield. With the exception of entries 3
and 6, the product olefins have not migrated or scrambled.
tion avenues for B(C6F5)3. We first learned of this reagent
during two of our synthetic campaigns,5 wherein catalytic
amounts of B(C6F5)3 in the presence of a silane proved to be
the only conditions that successfully deprotected the complex
aryl methyl ether substrates we were employing. Inspired by the
mildness of this etheral reduction approach first reported by
Gevorgyan and Yamamoto,6 absence of further investigations
and lack of synthetic applications beyond the deprotection of
aryl methyl ethers,7 we decided to study how unsaturated cyclic
ethers (2,5-dihydrofurans8 and 3,6-2H-dihydropyrans)9 behaved
when subjected to this reduction approach (Scheme 1).
Table 1 Catalytic Reduction of 2,5-Dihydrofuran C–O bonds
Entry Substrate
Product
Time (h) Yielda (%)
1
2
3
1
79
88
91
2
There are several reasons why we chose 2,5-dihydrofurans and
3,6-2H-dihydropyrans as substrates for this study: (1) 2,5-dihydro-
furans contain two allylic etheral C–O bonds, which allow evalua-
tion of the impact of sterics vs. electronics in the reduction step as
well as any E–Z olefin scrambling arising from potential
intermediate cationic species; (2) 3,6-2H-dihydropyrans would
provide an opportunity to compare the B(C6F5)3 reduction
behaviour of allylic vs. non-allylic C–O bonds as a function of
steric and electronic parameters; (3) reduction results from these
two heterocyclic classes could provide valuable new mechanistic
insights; and (4) if the olefin geometry of the heterocycle is not
0.5
4
2
87
5
6
2
4
91
94
7
8
8
4
83
a Department of Chemistry and Biochemistry, University of Arizona,
1306 E. University Blvd., 85721, AZ, USA.
72b
E-mail: njardars@email.arizona.edu; Fax: +1 520 621 8407;
Tel: +1 520 626 0754
b Department of Chemistry and Chemical Biology, Baker Laboratory,
Cornell University, Ithaca, NY, USA
a
Conditions: 5 mol% B(C6F5)3, 1.1 equiv. Et3SiH, CH2Cl2, rt then
TBAF, 4.5 equiv. Et3SiH, CH2Cl2, rt.12
b
w Electronic supplementary information (ESI) available: Experimental
section and spectroscopic data. See DOI: 10.1039/c2cc33551d
c
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The data suggests that the reducing agent is impacted by steric
and electronic factors. For example, entries 2 and 8 suggest
that sterics play a key role while entries 3 and 6 suggest that for
a strongly cation stabilizing group this selectivity can be
reversed to favour electronics. For entry 8, the less hindered
and electronically richer ether bond is selectively reduced.
Following the success in reducing 2,5-dihydrofurans, we were
eager to learn how selective reductions of 3,6-2H-dihydropyran
substrates would be. All of the fifteen substrates presented in
Table 2 were reduced in high yield to produce homoallylic
alcohol products using these catalytic reduction conditions.
Olefin migration or scrambling was observed for three sub-
strates (entries 4–6), wherein in one case the double bond
migrated into conjugation with the phenyl group (entry 6)
while for the other two it isomerized (entries 4–5). It is
important to note, as we observed for entry 3 in Table 1, that
when the phenyl group in the 2-position is replaced with an
alkyl group olefin isomerization is suppressed for all but one
substrate (entry 5). These results demonstrate that electronics
dictate which C–O bond is reduced. In all cases, the allylic
C–O bond is reduced regardless of whether it is sterically more
incumbered than the non allylic C–O bond (entries 3–8 and
11–15). This new method provides a mild controlled access to
homoallylic alcohols with di- (entries 6–8), tri- (entries 1, 3–4,
9–10 and 12–15) or tetra- (entries 2, 5 and 11) substituted
olefins that might otherwise be challenging to access selectively
using standard carbonyl olefination protocols. Although
isomerization is observed for entry 4 it is an impressive
reminder of the electronic control of this reaction, which
completely favors reduction of the quaternary substituted
allylic site over unsubstituted non-allylic site. Entry 15 is
noteworthy as it illustrates how this mild method could be
used to selectively incorporate deuterium at allylic positions
simply by replacing Et3SiH with Et3SiD.
Table 2 Catalytic Reduction of 3,6-2H-dihydropyran C–O bonds
Entry Substrate Product Time (h) Yield (%)
1
0.7
0.7
1.5
87
2
3
4
5
96
90
10
75 (1 : 5 : 1)
82 (1 : 5 : 1)
1
6
7
8
0.25
2
94 (1 : 1 : 2)
98
88
3
9
1.5
88
10
11
12
1.5
3
86
90
90
The twenty three examples presented in Tables 1 and 2
clearly demonstrate that this mild catalytic reduction reaction
is controlled by electronic factors. This is most apparent in the
reduction of 3,6-2H-dihydropyrans (Table 2), where in all cases
the more stabilized allylic position is preferentially reduced
regardless of how sterically congested it is. The 2,5-dihydrofuran
examples showcase how this reduction proceeds when presented
with two similar allylic bonds. For this scenario, sterics trump
electronics in all cases except when a strongly stabilizing group
(Table 1, entry 3) is present. Based on our results and
mechanistic studies done by Gevorgyan and Yamamoto,6 we
propose the following catalytic cycle (Scheme 2). A silylium
ion, generated by the reaction of triethylsilane (Et3SiH) with
the catalyst (B(C6F5)3), reacts with the ether oxygen atom of
the unsaturated cyclic ether. Our data strongly suggests, as
shown by vast majority of substrates studied, that reduction of
this silylium activated ether proceeds fast to the product as
suggested by the lack of any olefin isomerization for these
substrates. The substrates that undergo olefin isomerization
(entries 3 and 6 in Table 1 and entries 4–6 in Table 2) all
contain a strongly cation stabilizing groups (phenyl or dialkyl).
These special substitutents facilitate carbocation formation,
olefin migration followed by reduction.
2
13
2.5
82
14
3
78
94
15a
2.5
Conditions: 5 mol% B(C6F5)3, 1.1 equiv. Et3SiH, CH2Cl2, rt then
a
TBAF, Et3SiD was used instead.
In conclusion, we have shown that B(C6F5)3 in combination
with Et3SiH can be used to mildly and selectively reduce the
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Chem. Commun., 2012, 48, 7844–7846 7845

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J. R. Binner, G. Markopolous, M. Brichacek and J. T. Njardarson,
Chem. Commun., 2011, 47, 209.
6 (a) V. Gevorgyan, J.-X. Liu, M. Rubin, S. Benson and Y. Yamamoto,
Tetrahedron Lett., 1999, 40, 8919; (b) V. Gevorgyan, M. Rubin,
S. Benson, J.-X. Liu and Y. Yamamoto, J. Org. Chem., 2000, 65, 6179.
7 (a) D. F. Taber and S. C. Malcolm, J. Org. Chem., 2001, 66, 944;
(b) D. F. Taber, Q. Jiang, B. Chen, W. Zhang and C. L. Campbell,
J. Org. Chem., 2002, 67, 4821; (c) J. R. Vyvyan, J. M. Oaksmith,
B. W. Parks and E. M. Peterson, Tetrahedron Lett., 2005, 46, 2457.
8 For our contribution toward the synthesis of 2,5-dihydrofurans, see:
(a) L. A. Batory, C. E. McInnis and J. T. Njardarson, J. Am. Chem.
Soc., 2006, 128, 16054; (b) M. Brichacek, L. A. Batory and J. T.
Njardarson, Angew. Chem. Int. Ed., 2010, 49, 1648; (c) M. Brichacek,
L. A. Batory, N. A. McGrath and J. T. Njardarson, Tetrahedron, 2010,
66, 4832.
Scheme 2 Proposed Mechanism for Reduction of 3,6-2H-dihydropyrans.
C–O bond of cyclic unsaturated ethers without scrambling the
initial olefin geometry of the starting material. For this
catalytic reduction approach electronics play a key role with
allylic/benzylic C–O bonds being preferentially reduced over
less hindered non-stabilized C–O bonds. These mechanistic
insights strongly suggest the reduction of the activated ether
occurs fast so as to suppress formation of a free allyl cation
and therefore scrambling of olefin geometry. This etheral
reduction strategy should prove especially attractive in acces-
sing allylic and homo-allylic alcohols containing tri- and tetra-
substituted olefins, which can be challenging to access using
other methods. Furthermore, this approach lends itself well to
selective deuterium labelling applications.
9 For our contribution toward the synthesis of 3,6-2H-dihydropyrans,
see: B. Guo, G. Schwarzwalder and J. T. Njardarson, Angew. Chem.
Int. Ed., 2012, 51, 5675.
10 Although the reduction of unsaturated cyclic ethers has been
investigated in the past, there are only a handful of examples all
of which use harsher reaction conditions. Professor Brown showed
in a single example that stoichiometric amounts of both lithium tri-
tert-butoxyaluminohydride and triethylborane could be used to
reduce a 2,5-dihydrofuran: S. Krishnamurthy and H. C. Brown,
J. Org. Chem., 1979, 44, 3678. This approach was used recently in a
total synthesis: B. Yamamoto, H. Fujii, S. Imaide, S. Hirayama,
T. Nemoto, J. Inokoshi, H. Tomoda and H. Nagase, J. Org.
Chem., 2011, 76, 2257. Professor Tsuruta demonstrated lithium
metal in ethylamine can be used to open 3,6-2H-dihydropyrans
(5 examples): T. Kobayashi and H. Tsuruta, Synthesis, 1980, 492.
11 For reviews on ether cleavages, see: (a) M. V. Bhatt and
S. U. Kulkarni, Synthesis, 1983, 249; (b) A. Maercker, Angew.
Chem. Int. Ed., 1987, 26, 972. A particularly notable recent
contribution is from Professor Panek. He has demonstrated that
aryl—substituted pyrans can be reduced at the benzylic carbon
using excess of scandium(III) triflate and triethylsilane: J. Am.
Chem. Soc., 2007, 129, 38. We have subjected two of the com-
pounds in Table 2 to his reaction conditions and have found that
the allylic positions is indeed reduced, but also followed by over
reduction and unwanted carbocation rearrangements not observed
for our reduction protocol
We would like to thank The University of Arizona and the
NSF (CHE-0848324) for financial support and Dr Nicholas A.
McGrath for early exploratory experimental contributions.
Notes and references
1 (a) W. E. Piers and T. Chivers, Chem. Soc. Rev., 1997, 26, 345;
(b) G. Ecker, Dalton Trans., 2005, 1883; (c) G. Ecker, C. R. Chim.,
2011, 14, 831.
2 (a) X. Yang, C. L. Sterns and T. J. Marks, J. Am. Chem. Soc.,
1991, 113, 3612; (b) X. Yang, C. L. Sterns and T. J. Marks, J. Am.
Chem. Soc., 1994, 116, 10015.
3 For catalytic B(C6F5)3 mediated reductions of carbonyl groups,
consult: (a) D. J. Parks and E. W. Piers, J. Am. Chem. Soc., 1996,
118, 9440; (b) D. J. Parks and J. M. Blackwell, J. Org. Chem., 2000,
65, 3090; (c) V. Gevorgyan, M. Rubin, J.-X. Liu and
Y. Yamamoto, J. Org. Chem., 2001, 66, 1672; (d) S. Rendler and
M. Ostereich, Angew. Chem. Int. Ed., 2008, 47, 5997.
4 (a) D. W. Stephan, Dalton Trans., 2009, 3129; (b) D. W. Stephan
and G. Erker, Angew. Chem. Int. Ed., 2010, 49, 46.
5 (a) N. A. McGrath, E. S. Bartlett, S. Sittihan and J. T. Njardarson,
Angew. Chem. Int. Ed., 2009, 48, 8543; (b) N. A. McGrath,
12 As shown in entry 8 the triethylsilyl ethers, which are the initial
reduction products, can be isolated and used. For this study, we
chose to treat the crude reduction mixture with TBAF to make
isolation of products (alcohols) a trivial column filtration.
c
7846 Chem. Commun., 2012, 48, 7844–7846
This journal is The Royal Society of Chemistry 2012