Improved method for the diimide reduction of multiple bonds on solid-supported substrates

Article abstract of DOI:10.1021/jo0622173

(Chemical Equation Presented) A mild and improved method for reducing multiple bonds on various resins with diimide is described. The simple procedure readily generates diimide from 2-nitrobenzenesulfonohydrazide and triethylamine at room temperature. A number of representative multiple bonds in various steric and electronic environments were examined, including polar double bonds such as carbonyl and azo, for ease and selectivity of reduction. A general trend of reactivity was identified which revealed, inter alia, that terminal olefins, 1,2-disubstituted olefins, electron-poor olefins, and terminal alkynes were the most easily reduced.

Full text of DOI:10.1021/jo0622173

TABLE 1. Methods of Diimide Generation in the Presence of a
Solid-Support (PS-DES)
Improved Method for the Diimide Reduction of
Multiple Bonds on Solid-Supported Substrates
conversion
entry
conditions
solvent
EtOH
i-PrOH/THF
i-PrOH/THF
i-PrOH/THF
glyme
(5 to 7)
Keith R. Buszek*,†,‡,§ and Neil Brown‡,§
1
2
3
4
5
6
7
H2NNH2, CuSO4, air, rt
H2NNH2, CuSO4, H2O2, rt
H2NNH2, NaIO4, AcOH, rt
H2NNH2, CuSO4, O2, rt
PTS, Et3N, reflux
13%
40%
none
50%
none
5%
Department of Chemistry, Kansas State UniVersity, 111 Willard
Hall, Manhattan, Kansas 66506, Center for Chemical Methods
and Library Design, UniVersity of Kansas, 1501 Wakarusa
DriVe, Lawrence, Kansas 66047, Department of Chemistry,
UniVersity of Missouri, 205 Spencer Chemical Laboratories,
5100 Rockhill Road, Kansas City, Missouri 64110
2,4,6-TIBS, Et3N, rt
2-NBSH, Et3N
i-PrOH
DCM
100%
one recent report of successful homogeneous hydrogenation with
Wilkinson’s catalyst at 60 psi in a polypeptide substrate on a
modified Rink amide resin.3c Diimide reduction, on the other
hand, would appear to offer an attractive solution to this
important problem.4 The reasons are manifold: diimide can be
generated from numerous precursors; it is compatible with most
functional groups; reaction yields are typically excellent; and
the reduction is operationally simple.
buszekk@umkc.edu
ReceiVed October 25, 2006
In connection with a program of research designed to create
compound libraries inspired by medium-ring natural products,
including the powerful antitumor agent octalactin A,5 we
required the synthesis and subsequent reduction of several THP-
linked6 unsaturated primary and secondary alcohols, such as
those depicted in Scheme 1. Cognizant of the inherent difficul-
ties with hetereogenous catalytic hydrogenation, we initially
looked to homogeneous hydrogenation using the Wilkinson,
Crabtree, and similar catalysts. Unfortunately, after repeated
attempts with Wilkinson’s catalyst, no detectable reduction
products could be isolated, and it was further found that metallic
rhodium was precipitated over the course of the reaction,
indicating slow decomposition of the catalyst. After several
additional failed hydrogenation attempts with the other catalysts,
we turned our attention to diimide reduction. The only previous
report concerning the use of diimide with solid supported
systems examined cinnamic or styryl derivatives with a stable
ester linked Merrifield-type resin.7 The relatively harsh reaction
conditions required for complete reductions (e.g., 100 °C in
DMF) were unlikely to be compatible with our more labile
linkers. Accordingly, we decided to investigate other diimide-
forming reaction protocols that would be suitable for use with
our supports. Additionally, we were interested in examining the
scope of diimide reduction with a more representative range of
substrates in various steric and electronic environments. Herein
we describe an improved method for the reduction of double
and triple carbon-carbon bonds in several solid supported
substrates, including natural products. We also present the first
A mild and improved method for reducing multiple bonds
on various resins with diimide is described. The simple
procedure readily generates diimide from 2-nitrobenzene-
sulfonohydrazide and triethylamine at room temperature. A
number of representative multiple bonds in various steric
and electronic environments were examined, including polar
double bonds such as carbonyl and azo, for ease and
selectivity of reduction. A general trend of reactivity was
identified which revealed, inter alia, that terminal olefins,
1,2-disubstituted olefins, electron-poor olefins, and terminal
alkynes were the most easily reduced.
The range of useful reactions available for solid-phase organic
synthesis has expanded significantly in the past decade.1
However, one area that has received comparatively little
attention is the reduction of multiple bonds on solid supported
substrates. Carbon-carbon multiple bonds have rarely been
reduced on the solid-phase, largely due to the inherent incom-
patibility with traditional heterogeneous catalytic hydrogenation
conditions, as a consequence of the unfavorable kinetics of solid-
on-solid reactions.2 Even with non-cross-linked polymers,
catalytic hydrogenation, though successful, is rare.3a,b There is
* Address correspondence to this author. Current address: University of
Missouri-Kansas City.
(4) For a review of methods for generating diimide and its use in the
reduction of multiple bonds in homogeneous environments, see: (a) Pasto,
D. J.; Taylor, R. T. Org. React. 1991, 40, 91. (b) Miller, C. E. J. Chem.
Ed. 1965, 42, 254.
† Kansas State University.
‡ University of Kansas.
§ University of Missouri-Kansas City.
(1) Dolle, R. E. J. Comb. Chem. 2005, 7, 739.
(5) (a) Buszek, K. R.; Sato, N.; Jeong, Y. J. Am. Chem. Soc. 1994, 116,
5511. (b) Buszek, K. R.; Jeong. Y. Tetrahedron Lett. 1995, 36, 5677. (c)
Perchellet, J.-P.; Perchellet, E. M.; Newell, S. W.; Freeman, J. A.; Ladesich,
J. B.; Jeong, Y.; Sato, N.; Buszek, K. R. Anticancer Res. 1998, 18, 97. (d)
Buszek, K. R.; Sato, N.; Jeong, Y.; Sill, P. C.; Muino, P. L.; Ghosh, I.
Synth. Commun. 2001, 31, 1781. (e) Buszek, K. R.; Sato, N.; Jeong, Y.
Tetrahedron Lett. 2002, 43, 181.
(6) Thompson, L. A.; Ellman, J. A. Tetrahedron Lett. 1994, 35, 9333.
(7) Lacombe, P.; Castagner, B.; Gareau, Y.; Ruel, R. Tetrahedron Lett.
1998, 39, 6785.
(2) For an example of a multipolymer solution-phase reaction: Harned,
A. M.; He, H. S.; Toy, P. H.; Flynn, D. L.; Hanson, P. R. J. Am. Chem.
Soc. 2005, 127, 52.
(3) An example of a Lindlar reduction on a non-cross-linked polystyrene
support has been reported: (a) Chen, S.; Janda, K. D. J. Am. Chem. Soc.
1997, 119, 8724. (b) Chen, S.; Janda, K. D. Tetrahedron Lett. 1998, 39,
3943. For catalytic homogeneous hydrogenation with Wilkinson’s catalyst
on a Rink resin, see: (c) Whelan, A. N.; Elaridi, J.; Harte, M.; Smith, S.
V.; Jackson, W. R.; Robinson, A. J. Tetrahedron Lett. 2004, 45, 9545.
10.1021/jo0622173 CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/17/2007
J. Org. Chem. 2007, 72, 3125-3128
3125

TABLE 2. Reduction of Unsaturated Compounds on PS-DHP
SCHEME 1
SCHEME 2
SCHEME 3
a Isolated yields. b The Fmoc group was removed on the resin (20%
piperidine in CH3CN) prior to diimide reduction. c Two reaction cycles were
required.
sulfonohydrazide9,10 (NBSH, 10 equiv) with an excess of
triethylamine in DCM at rt for 24 h gave superior results (Table
1, entry 7), and afforded quantitatively 3-phenylpropanol after
1
cleavage from the resin and analysis by H NMR.
With the preferred diimide generation conditions identified
for the PS-DES resin, several representative unsaturated alcohol
primary and secondary substrates were selected. The compounds
to be reduced were loaded onto Ellman’s cross-linked polystrene
dihydropyran6 (PS-DHP) support (Scheme 3). The results are
summarized in Table 2.11 In all cases the extent of reduction
and product yields were determined by first cleaving the
substrates from the resin with catalytic TFA in 1:1 dichlo-
romethane/methanol in a microwave reactor, followed by
expanded study involving the ease of reduction of many different
multiple bonds, including polar bonds, in various steric and
electronic environments.
For our initial attempts to find milder diimide reduction
conditions, we employed cross-linked polystyrene diethyl silyl
ethers (PS-DES)8 since we found them to be highly susceptible
to both hydrolysis and decomposition at elevated temperatures.
It was anticipated that any successful diimide reduction condi-
tions would then likely be compatible with more stable linkers.
Cinnamyl alcohol was selected as the model substrate for
screening various methods of diimide generation. With this
substrate attached to the resin (Scheme 2), several methods of
diimide generation were examined (Table 1).
These methods include copper-catalyzed oxidation of hydra-
zine as well as decomposition of arylsofonylhydrazides with
various bases and solvents.4a After surveying several methods
of diimide generation in the presence of the resin-bound
substrate, it was found decomposition of 2-nitrobenzene-
1
analysis of the products by H NMR. The yields in all cases
were based on purification (chromatography or distillation) of
the isolated materials. Mono- and disubstituted primary and
secondary allylic alcohols (entries 1, 2, and 7) were cleanly
reduced, with the reaction of the more hindered substrate (entry
2) giving a somewhat lower yield. Cyclic olefins of five to eight
members are completely and in most cases quantitatively
reduced (entries 3-6), while the secondary propargylic alcohol
(entry 10) gave the saturated compound in 86% yield. Simple
terminal acetylenes also gave complete and quantitative conver-
(9) Synthesis of 2-nitrobenzeneslfonohydrazide (NBSH): Myers, A. G.;
Zheng, B.; Movassaghi, M. J. Org. Chem. 1997, 62, 7507.
(10) Recent use of NBSH as a diimide source: Haukaas, M. H.;
O’Doherty, G. A. Org. Lett. 2002, 4, 1771.
(8) Hu, Y.; Porco, J. A., Jr.; Labadie, J. W.; Gooding, O. W.; Trost, B.
M. J. Org. Chem. 1998, 63, 4518.
(11) All compounds exhibited satisfactory spectroscopic data consistent
with their structure.
3126 J. Org. Chem., Vol. 72, No. 8, 2007

TABLE 3. Reduction of Natural Products on PS-DHP
TABLE 4. Attempted Reduction of Polar Double Bonds on
PS-DHP
a Isolated yields. b Remainder of material is the 2-nitrobenzenesulfonyl-
hydrazone derivative.
subjected twice to our conditions for diimide reduction (i.e.,
two reaction cycles were ran) and a separate sample of PS-
THP-bound cholecalciferol was subjected to the conditions
reported by Lacombe7 (benzenesulfonohydrazide in DMF at
100 °C). After washing (CH2Cl2 twice, Et2O four times) and
cleavage from the resin (CH2Cl2, MeOH, cat. TFA, microwave,
140 °C, 4 min) the products were analyzed. Under our reaction
conditions, a 82% yield of a 56:44 mixture of two reduced
compounds was obtained. Analysis of the wash showed only
material resulting from 2-nitrobenznesulfonohydrazide and
triethylamine. However, with Lacombe’s original procedure,
decomposition was observed after only 3 h. From a sample of
109 mg of resin (load ) 0.76 mmol/g) subjected to Lacombe’s
conditions, the isolated mass of resin after reaction was only
91 mg, corresponding to a 58% loss in material originally loaded
onto the resin. 1H NMR analysis of the wash from the reaction
showed broad signals in the range of δ 2.0 to 0.0 ppm, consistent
with decomposition of cholecalciferol. Cleavage of the resin
resulted in an isolated yield of only 40% of material in which
the 1H NMR did not match either that of cholecalciferol or the
reduced product obtained by our method. This experiment
clearly demonstrates that under our conditions, thermally
unstable resin-bound substrates can be reduced without decom-
position.
In summary, a practical and improved method for the
reduction of solid-supported unsaturated compounds in excellent
yields has been achieved. It is clear from the results that very
sterically hindered olefins (e.g., cholesterol) are recovered
unchanged by these reduction conditions. With some substrates,
a second reaction cycle at room temperature was necessary to
obtain an acceptable level of reduction. Even so, the mild
reaction conditions and simple operation make this an attractive
method. The procedure takes place under mild conditions, which
should be compatible with many labile linked resins. Further-
more, the procedure is operationally simple, even in those cases
where repeated cycles are required. We are now examining
additional complex resin-bound substrates to define further the
generality of this approach to the reduction of unsaturated
systems on solid-supported platforms. These results will be
reported as developments warrant.
a Isolated yields. b Two reaction cycles were required. c The saturated
and unsaturated alcohols were obtained in 82% combined yield after two
reaction cycles in a 56:44 ratio. Separation was achieved after chromato-
graphic separation of their corresponding 4-nitrobenzoate esters.
sion to the alkane (entry 9). The cinnamyl ester (entry 8) was
completely and quickly reduced, an observation consistent with
the fact that electron-deficient alkenes in general are also the
most rapid to react with diimide under conventional homoge-
neous conditions.12,13
The results with some complex unsaturated natural products
are also shown (Table 3). Geraniol (entry 1) was converted to
its corresponding saturated alcohol in 86% yield after two
reaction cycles. Resin-bound cholecalciferol (entry 2) revealed
some regioselectivity with diimide among the three olefins, and
gave the saturated alcohol and the conjugated diene in a 56:44
ratio. After conversion to their 4-nitrobenzoate esters, separation
could be achieved via chromatography. The attempted reduction
of cholesterol (entry 3) gave only recovered starting material.
This result was not surprising given that the very hindered olefin
is only reduced up to 20% with conventional solution diimide
protocols.4a The additional steric demand conferred on the
substrate by the resin probably accounts for the small difference.
Finally, the reduction of some azo and carbonyl functional
groups with diimide on the same resins was examined for the
sake of completeness (Table 4), even though this method is
generally considered less useful for inherently polar bonds.14
The azo benzene (entry 1) gave a 29% isolated yield of the
hydrazine. The benzaldehyde (entry 2) afforded a 19% yield of
the alcohol, with the remaining material consisting of its
hydrazone, which formed as a result of the much faster reaction
with the sulfonylhydrazide. Interestingly, the aryl ketone (entry
3) did not give detectable reduction products, nor did it appear
to react with the hydrazide.
To illustrate the advantage of our method, a comparison study
was undertaken. A sample of PS-THP-bound cholecalciferol was
(12) van Tamelen, E. E.; Timmons, R. J. J. Am. Chem. Soc. 1962, 84,
1067.
(13) (a) Corey, E. J.; Pasto, D. J.; Mock, W. L. J. Am. Chem. Soc. 1961,
83, 2957. (b) Corey, E. J; Mock, W. L.; Pasto, D. L. Tetrahedron Lett.
1961, 347.
(14) March’s AdVanced Organic Chemistry. Reactions, Mechanisms, and
Structure; Smith, M. B., March, J., Eds.; John Wiley and Sons: New York,
2001; Chapter 15, pp 1007-1008.
Experimental Section
Preparation of 2-Nitrophenylsulfonylhydrazide. Following the
method of Myers9 a flame dried 250 mL 3-necked round-bottom
J. Org. Chem, Vol. 72, No. 8, 2007 3127

flask was flushed with nitrogen and charged with 22.2 g (100 mmol)
of 2-nitrophenylsulfonyl chloride, which was subsequently dissolved
in 100 mL of dry THF. The solution was then cooled to -30 °C.
To the cooled solution was then added 12.1 mL (250 mmol) of
hydrazine hydrate, dropwise over 5 min. The mixture was then
stirred for 40 min at -30 °C, after which time thin layer
chromatography indicated complete reaction. The reaction mixture
was then diluted with 200 mL of ethyl acetate and transferred to a
separatory funnel and washed five times with 100 mL of a 10 wt
% solution of ice-cold aqueous sodium chloride. The combined
organic phase was then dried over sodium sulfate at 0 °C and
filtered. This solution was then slowly added to 1200 mL of hexanes
and the resulting off-white solid was filtered and washed with 20
mL of hexane. The solid was dried under vacuum at room
temperature in the dark for 14 h to yield 19.0 g (87%) of the title
compound as an off-white solid.
General Procedure for Loading of Alcohols to PS-DHP Resin.
In a dry 25 mL round-bottom flask was added 250 mg (0.35 mmol)
of PS-DHP resin pre-swollen in 1,2-dichloroethane. To the resin
is added 176 mg (0.7 mmol) of PPTS followed by a solution of
the alcohol (1.75 mmol, 5 equiv based on resin substitution) in 5
mL of 1,2-dichloroethane. The slowly stirring suspension is then
heated to reflux under nitrogen atmosphere. After stirring for 20 h
at reflux, the suspension is cooled to rt and filtered, then washed
with dichloromethane, dimethylformamide (four times), and dichlo-
romethane (four times). The resin is then dried under vacuum and
stored in a desiccator. Yields vary from 74% to 100% (based upon
mass gain of the resin).
PS-DHP-Bound (3S,4R)-3-sec-Butylhex-5-ene-1,4-diol. In a dry
25 mL round-bottom flask 340 mg (0.255 mmol) of PS-DHP-bound
(9H-fluoren-9-yl)methyl (3S, 4R)-3-sec-butyl-4-hydroxyhex-5-enyl
carbonate was suspended in 4 mL of acetonitrile. To this was added
1 mL of piperidine and the contents gently stirred under nitrogen
for 1 h. The resin was then filtered off and washed with
dichloromethane (twice), dimethylformamide (twice), and dichlo-
romethane (three times). The resin was then dried under vacuum
for 20 min to yield 280 mg (100%) of the title compound as pale
yellow beads.
General Procedure for Diimide Reduction of Resin-Bound
Unsaturated Compounds. To a dry 25 mL round-bottom flask is
added 100 mg of the resin. To this is added 1 mL of dichlo-
romethane, followed by 20 equiv (based on resin substitution) of
2-nitrophenylsulfonylhydrazide. Another 8 mL of dichloromethane
is added, followed by 1 mL of triethylamine. The suspension is
gently stirred for 6 h at rt under nitrogen. The mixture is then filtered
and washed with dichloromethane, dimethylformamide (three
times), dimethylformamide/water 1:1 (three times), THF (three
times), and finally dichloromethane (three times). The resin is then
dried under vacuum and stored in a desiccator.
General Procedure for Cleavage of Reduced Compounds
from PS-DHP Resin. The cleavage is performed with a microwave
synthesis reactor. In a 5.0 mL vial was added 50 mg of the resin.
To this was added 0.9 mL of dichloromethane, 0.9 mL of methanol,
and 2-3 drops of TFA. The vial was sealed and placed in the
reactor. The reaction was run at 140 °C for a total time of 4.0 min
(2 min fixed hold time). After cooling to room temperature, the
vial was opened and the solution was filtered off from the resin.
The solution was then concentrated under reduced pressure and
further dried under high vacuum for 20-30 min. The products were
then analyzed by 1H NMR spectroscopy to determine the extent of
reduction. Isoated yields of products after chromatography or
distillation ranged from 85% to 100%. Representative com-
pounds: (3R,4R)-3-sec-butylhexane-1,4-diol (Table 2, entry 2):
25 mg of PS-DHP-bound (3S,4R)-3-sec-butylhexane-1,4-diol (as
an optically active mixture of diastereomers) was subjected to the
above procedure and the crude material obtained was purified via
column chromatography to give 3.3 mg (85%) of 3-sec-butylhexane-
1
1,4-diol as a colorless oil. H NMR (δ, ppm) 3.78 (m, 2 H), 3.58
(m, 2 H), 1.77-1.02 (m, 9 H), 0.98-0.76 (m, 9 H); 13C NMR (δ,
ppm) 74.8, 73.9, 62.6, 61.8, 46.2, 45.4, 35.0, 34.7, 29.3, 29.2, 28.5,
27.9, 27.5, 25.1, 16.9, 14.7, 11.9, 11.7, 10.0, 9.5. HRMS calcd for
C10H22O2 174.1620, found 174.1618.
1
1-phenylheptan-3-ol (Table 2, entry 10): H NMR (δ, ppm)
7.31 (m, 5 H), 3.64 (m, 1 H), 2.81 (m, 1 H), 2.70 (m, 1 H), 1.80
(m, 2 H), 1.49-1.30 (series of m, 7 H), 0.91 (t, 3 H, J ) 6.8 Hz);
13C NMR (δ, ppm) 142.2, 128.4, 128.37, 125.8, 71.4, 39.1, 37.3,
32.1, 27.8, 22.7, 14.1. HRMS (EI) m/e calcd for C13H20O 192.1514,
found 192.1511.
3,7-Dimethyloctan-1-ol (Table 3, entry 1): 1H NMR (δ, ppm)
3.71 (m, 2 H), 1.62-1.11 (series of m, 10 H), 0.90 (d, 3 H, J )
6.8 Hz), 0.88 (d, 6 H, J ) 6.8 Hz); 13C NMR (δ, ppm) 61.2, 40.0,
39.2, 37.3, 29.5, 27.9, 24.7, 22.7, 22.6, 19.6. HRMS (EI) m/e calcd
for C10H22O 158.1671, found 158.1675.
Acknowledgment. We acknowledge support of this work
by the National Institutes of Health (The University of Kansas
Chemical Methodology and Library Development Center of
Excellence), P50 GM069663. We wish to thank Mr. Benjamin
Neuenswander from the KU-CMLD Library Design and Analy-
sis Core for performing the LC-MS work.
Supporting Information Available: 1H NMR data for all
reduced compounds reported in Tables 2-4. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO0622173
3128 J. Org. Chem., Vol. 72, No. 8, 2007