Iridium-catalyzed hydrosilylative reduction of glucose to hexane(s)

Article abstract of DOI:10.1021/ja3110494

In light of diminishing petroleum feedstocks, there is significant interest in developing carbohydrate defunctionalization reactions. In this context we have examined the use of iridium pincer catalysts for the hydrosilylative reduction of sugars, and we report herein complete reduction of silyl-protected glucose to a mixture of hexane isomers.

Full text of DOI:10.1021/ja3110494

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Communication
Iridium-catalyzed hydrosilylative reduction of glucose to hexane(s)
Matthew P. McLaughlin, Laura L. Adduci, Jennifer Becker, and Michel R Gagné
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja3110494 • Publication Date (Web): 11 Jan 2013
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Iridium-catalyzed hydrosilylative reduction
of glucose to hexane(s)
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Matthew P. McLaughlin,† Laura L. Adduci,† Jennifer J. Becker,*,‡ and Michel R. Gagné*,†
†Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290.
‡U.S. Army Research Office, P.O. Box 12211, Research Triangle Park, North Carolina 27709, United States
Supporting Information Placeholder
Brookhart has reported a cationic iridium pincer
ABSTRACT: In light of diminishing petroleum feed-
complex, 1, which acts as a potent catalyst (<1 mol%)
stocks, there is significant interest in developing carbo-
for the hydrosilylative reduction of alkyl ethers to al-
hydrate defunctionalization reactions. In this context
kanes (e.g. Scheme 1).7 In combination with tri-
we have examined the use of iridium pincer catalysts
ethylsilane, 1 mediates the complete reduction of pri-
for the hydrosilylative reduction of sugars, and we re-
mary and methyl ethers to the hydrocarbon. In the case
port herein complete reduction of silyl-protected glu-
of secondary ethers, only a single C-O cleavage occurs
cose to a mixture of hexane isomers.
and the secondary silyl ether is obtained. Despite these
potential limitations, we surmised that the enhanced
stability of the C1-carbocation of a sugar might support
an alternative, Murai-like4 mechanism for the reduction
The dwindling of petroleum resources has made
carbohydrates attractive targets for renewable energy
and chemical feedstocks.1 Chemists have sought to
defunctionalize sugars to simpler chemical feedstocks,
which are compatible with modern chemical processes
and infrastructure.2 Despite significant effort, most
systems relevant to carbohydrate defunctionalization
utilize harsh conditions (high temperatures, pressures,
and strong acids) and are generally low yielding for de-
functionalized products.3 To date, the mildest systems
for the reduction of carbon-oxygen bonds are hydrosi-
lylative, but for sugars these methods have been lim-
ited to defunctionalization at the activated C1 position
and take many hours.4-6
of at least one secondary C-O bond in glucose (Scheme
2). In this scenario we anticipated C1 reduction to be
especially rapid.
Scheme 2
OP
O
OP
O
6
R3Si+
4
5
MeOSiR3
PO
PO
PO
PO
1
2
PO
3
PO
O
Me
OMe
SiR3
P = SiMe2Et
Axial (!) OMe , 2
Equatorial (") OMe, 3
A
OP
O
OP
O
H–
(Ir-H or Si-H)
PO
PO
PO
PO
PO
PO
B
4
Scheme 1
Initial experiments with 1% catalyst, 1.2 equiv of
SiMe2EtH, and the α and β anomers of silylated MeO-
glucose (2 and 3), showed that reduction to 4 was rapid
and complete within minutes (over 90% by NMR). Alt-
hough both the α and β anomers reacted too fast to
monitor rates, a competition between 1 equiv each of 2
and 3, with 1 equiv of SiMe2EtH (1% catalyst), estab-
lished (by NMR) the near exclusive consumption of the
equatorial (β) OMe isomer. The reduction of 5, on the
other hand, was substantially slower, requiring hours of
reduction time and either many equivalents SiMe2EtH
or the more reactive SiEt2H28 for complete conversion.
In addition to a slower rate, the selectivity for C1 deox-
ygenation was compromised (Eq 1). Although reduc-
tion of 5 still yielded 4 through cleavage site “a”, a
[Ir]H(H-SiR3)+
O
O
tBu2P
Ir
PtBu2
O
H
H
SiR3
R3Si-H
O
SiR3
O
O
O
O
PtBu2
tBu2P
Ir
PtBu2
tBu2P
Ir
H
L
H
H
[Ir]H2
[Ir]H(L)+
1
H3C CH3
+
O
SiR3
OSiR3
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number of other products were also formed, including
Scheme 3
1
2
3
4
5
6
7
8
OP
6
OP
O
OP
O
[Ir]
[Ir]
[O5]
D-glucitol (6), which would require cleavage at site “b.”
In situ monitoring by NMR spectroscopy of the reduc-
tion of 5 indicated that like the C1-OMe case, the β-
anomer reacts faster (greater than 10x the rate), lead-
ing to the following comparative C-O hydrosilylation
rates: C1 equatorial, OMe > C1 axial, OMe >> C1 equatorial, OSiR3 > C1
axial, OSiR3 > Cn, OSiR3 (n = 2,3,4,6). This trend can be rational-
ized by noting the importance of a basic ether in form-
ing the key silyloxonium ion, A, and the enhanced sta-
bility of the C1-oxocarbenium ions (B, Scheme 2).
OP
OP
OP
[O5-6
]
4
5
O
PO
PO
+
PO
PO
PO
PO
PO
PO
1
silane
OP R = SiR3
silane
R = Me
2
PO
PO
3
PO
PO
OR
2 and 5
4
6
4
C2
OP
C6
C1
OP
O
OP
O
+ C5', C3,
C4, etc
PO
PO
PO
PO
[O4]
PO
PO
PO
PO
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24 isomers (not including stereoisomers)
15 isomers (not including stereoisomers)
[O3]
OP
O
OP
OSiR3
1.0 eq. R3Si+
O
b
[O2]
OP
OP
PO
PO
PO
PO
+
a
PO
PO
(eq 1)
PO
PO
PO
PO
OP
OP
R3SiOSiR3
P = SiMe2Et (5)
"/# mix
1-hexanol, 2-hexanol,
[O1]
8
6 (!20%)
4 (!15%)
11 (GC-MS, NMR)
3-hexanol, 2-Me-pyran
+
other detected intermediate
Increasing the catalyst loadings, silane concentra-
tion, and using the more reactive diethylsilane8 re-
vealed that 2 could be completely reduced to hexane
isomers (eq 2).9 13C NMR and the spiking of reaction
mixtures with authentic products verified the for-
mation of the indicated hexanes: n-hexane (7), 2- and
3-methylpentane (8 and 9), and trace amounts of 2,3-
dimethylbutane (10). Using 13C6 and 13C1 labeled 5 to
follow the reaction showed that both 13C-labeled sug-
ars converged on a similar mixture of hexanes, with one
enhanced signal for 7 and 10 and two for 8 and 9. Over
the course of the reduction of 13C-5, hexanes were ob-
servable within 12 hours but the signal continued to
develop for weeks. Over the course of 2 weeks, all the
13C NMR peaks associated with C-O bonds (50-100
ppm) diminished below the detection limit, accompa-
nied by continual growth of peaks in the alkyl region
(10-50 ppm).
10
9
other observed products
7
(a)
(b)
(c)
ppm
Figure 1. In situ 13C NMR spectra of hydrosilylation of
13C1-5 at various time points: (a) starting material (b) 14
hours (c) 7 days. Peaks upfield of 10 ppm are silane relat-
ed.
*
*
*
*
*
*
OP
+
*
O
7
8
5 mol% 1
PO
PO
*
PO
OP
(eq 2)
20 eq Et2SiH2
shown in Figure 1, numerous intermediates are ob-
served both in the C-O region (50-100 ppm) and in the
upfield alkane region. Contributing to this diversity of
intermediates are traces of unsaturated compounds
(100-150 ppm, not shown), which appear transiently,
including a match for 1-hexene. Such an observation
not unreasonably suggests that elimination is also a
competitive process.
P = -SiMe2Et (5)
* *
*
*
+
*
*
* = 13C1
* = 13C6
10
9
The in situ monitoring of the non-labeled sugars
proved fascinating. As discussed above 2 and 3 quickly
convert to 4, but as the signals of this C1-deoxy product
diminish they are not replaced with new signals until
much later when hexane begins appearing. For com-
pound 5, a dramatic loss of signal intensity occurs im-
mediately upon its consumption. As shown in Scheme
3, we surmised that a non-selective C-O reduction
would lead to a large increase in the number of compo-
nents, and a concomitant decrease in spectral intensi-
ty. This hypothesis was verified by monitoring the re-
duction of 13C-labeled 5 by 13C NMR spectroscopy. As
To overcome the technical challenges of quantify-
ing the volatile hexane products, the yields were esti-
mated by an in situ 13C NMR spectroscopy experiment
utilizing internal standard and a calibrated 90-degree
pulse sequence (see SI for details).10 Both the α and β
anomers of MeO-glu, 2 and 3, consistently yielded a
higher proportion of the rearranged products than 5
(Figure 2). A possible source for this surprising diver-
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Supporting Information. Experimental procedures, car-
gence in hexane isomer production was suggested by
1
bohydrate protections/characterization, and NMR spec-
tra. This material is available free of charge via the Inter-
net at http://pubs.acs.org.
the comparative deoxygenation of 4 and 6 (glucitol).
Like 2, the C1-deoxy 4 gives significant rearrangement,
consistent with rapid conversion of 2 to 4 during the
reaction. Reduction of 6, however, gives predominantly
n-hexane suggesting that 2 and 5 may bifurcate at the
first reaction steps. It thus seems likely that pyranose 4
is the species most likely to initiate branching, presum-
ably through carbocation(s)11 that may or may not in-
volve neighboring group participation.
2
3
4
5
6
7
8
9
AUTHOR INFORMATION
Corresponding Author
mgagne@unc.edu
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+!"
*!"
)!"
Funding Sources
MPM thanks the National Research Council for a postdoc-
toral fellowship, LLA thanks the UNC Institute for the En-
vironment/Progress Energy Foundation for a fellowship,
MRG thanks the Department of Energy (FG02-
05ER15630), and JJB thanks the Army Research Office for
funding.
(!"
,-./01,/"
'!"
&!"
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$!"
#!"
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$-2/3.45"6/,31,/"
%-2/3.45"6/,31,/"
37315"
ACKNOWLEDGMENT We wish to thank Dr. Sehoon
Park, Dr. Thomas W. Lyons, and Prof. Maurice
Brookhart for stimulating conversations and initial ex-
perimental assistance; and Dr. Marc ter Horst, for ad-
vice in preparing a 13C NMR quantification protocol.
Figure 2. Absolute yields (%) of the hexane isomers 7-9 for
the hydrosilylation of 2 and 4-6 as determined by semi-
quantitative 13C NMR spectroscopy. General reaction condi-
tions: 5% catalyst 1 and 20 equivalents of SiEt2H2 (see SI for
details).
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In summary, we have identified a system that
catalyzes the full reduction of silyl protected sugars to a
mixture of hexane isomers. MeO- sugars 2 and 3 pro-
ceed by selective C1 reduction to 4 whereas the persilyl
glucose, 5, is reduced to a mixture that includes 4 and
the ring opened sugar 6. The hexane isomer distribu-
tion is sensitive to the C1-substituent, with the 1-OMe
protected sugars 2 and 3 yielding mostly 2- and 3-
methylpentane, whereas the C1-OSiR3, 5, yielded most-
ly n-hexane. The reaction rate is affected by the silane,
with the less hindered Et2SiH2 giving the fastest rates.
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efficiency and hexane selectivity of this reaction are
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(4) Hydrosilylative reduction of alcohols with metal or borane
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10701-10714.
(9) Unprotected glucose also yielded hexanes under the reaction
conditions. Preferable were pre-protected carbohydrates that
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revealed only trace [B(C6F5)4]– decomposition and no observable
borane; spiking completed reactions with borane show it to be
readily detectable at 0.1 mol%. Since reactions containing 0.1
mol% borane do not proceed in the absence of iridium catalyst,
and significantly higher concentrations of borane give a different
product distribution, we conclude that Ir predominately catalyzes
the reaction. For B(C6F5)3/silane hydrosilylation, see for example
references 4c-4f.
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17509-17518 .
TOC Graphic
OP
+
O
[Ir]
[Ir]
PO
PO
silane
R = Me
silane
PO
+
OR
R = SiR3
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