Development of a polymer bound Wittig reaction and use in multi-step organic synthesis for the overall conversion of alcohols to β-hydroxyamines

Article abstract of DOI:10.1039/a803612h

An efficient combinatorial access to β-hydroxyamines suitable for automation is achieved by the mild oxidation of alcohols to aldehydes by polymer supported perruthenate (PSP), the subsequent clean olefination of the obtained aldehydes by polymer supported Wittig reagents followed by the epoxidation of the olefins by dimethyldioxirane (DMDO), and the final aminolysis of the epoxides with various amines is described.

Full text of DOI:10.1039/a803612h

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Development of a polymer bound Wittig reaction and use in
multi-step organic synthesis for the overall conversion of alcohols
to â-hydroxyamines
Martin H. Bolli and Steven V. Ley*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge,
UK CB2 1EW
An efficient combinatorial access to â-hydroxyamines suit-
O
O
O
able for automation is achieved by the mild oxidation of
alcohols to aldehydes by polymer supported perruthenate
H
H
H
(PSP), the subsequent clean olefination of the obtained
aldehydes by polymer supported Wittig reagents followed
Cl
by the epoxidation of the olefins by dimethyldioxirane
(DMDO), and the final aminolysis of the epoxides with
A
B
C
various amines is described.
O
O
O
H3CO
H
H
H
In the preceding two papers1 we demonstrated the use of a
combination of polymer supported reagents to effect clean
multi-step organic synthesis leading to products with potential
H3CO
OCH3 H3CO
application in combinatorial chemistry. Here we continue the
ideas by developing polymer supported Wittig reagents2 which
when reacted with aldehydes, which in turn may be derived
from alcohols by oxidation with polymer supported per-
ruthenate,1a,3 afford alkenes. These are prepared in excellent
yields and require only simple filtration to obtain pure products
which are useful for further synthetic transformations. In order
to exemplify potential applications many of these alkenes were
converted in essentially quantitative yields to epoxides using
dimethyldioxirane.4 Once again pure products are obtained
simply by removing solvent by evaporation. Likewise these
epoxides were themselves excellent precursors for further steps
such as the reaction with amines to produce β-hydroxyamines
since these are considered as privileged structures in many
pharmaceutical and agrochemical products (Scheme 1).
D
E
F
O
O
O
H
H
H
O2N
N
N
G
H
I
O
O
O
H
15C7
H
M
CH3
O
K
L
+
–
N
H
NMe3 RuO4
OH
O
Fig. 1
R1
R1
R3
R2
Ph
P
can be prepared from their corresponding alcohol precursors
in excellent yields and high purities by PSP oxidation.1a,3
Although a diphenylphosphine derivatised polystyrene was
developed to perform Wittig olefinations in the early 1970s2a–d
and many examples have been reported since,2e a protocol
which allows automation of the process and therefore opens up
a combinatorial access to olefins has not been disclosed.
However the phosphonium salt formation on such a polymer
supported triphenylphosphine has recently been exploited as a
linking procedure in solid phase synthesis.5
Ph
O
O
H
R3
R2
O
R3
R2
H
R1
R1
R4NH2
For this study a set of six Wittig reagents was prepared
according to a literature procedure6 starting from commercial
diphenylphosphine derivatised polystyrene (Scheme 2). Thus to
the support (1–2 g, 3–6 mmol phosphine) suspended in dry
DMF (10–20 ml) was added 2–4 equivalents of the alkyl halide.
The slurry was stirred for 48 hours at 50–70 ЊC. Eventually the
support was carefully filtered off under argon and extensively
washed with dry toluene (40 ml), dry dichloromethane (40 ml)
and dry diethyl ether (60 ml). The grey to brown powders were
dried in vacuo. According to the weight increase the loading was
HO
H
R3
R2
NHR4
R1
Scheme 1
The carbonyl compounds that were subjected to the polymer
supported Wittig olefination are given in Fig. 1. As we have
shown previously, with the exception of pentan-3-one N they all
J. Chem. Soc., Perkin Trans. 1, 1998
2243

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Table 1 Summary of polymer supported Wittig olefinations
Entry Wittig reagent Carbonyl compound
Olefin
GLC Conversiona (%)
Isolated yield (%) (cis:trans)
Ph
1
2
3
1
A–G, I
M
>98
88–100 (2:1–1:3)
R
H
Ph
97
87 (1:3)
H13C7
H5C2
H5C2
c
N
50b
—
Ph
CH3
4
5
6
7
2
C, F, H, I
у99
>99
>99
>99
70–95
CH3
R
H
CH3
CH3
c
M
—
H13C7
CH3
3
4
D–F
77–90 (3:1–6:1)
83–99
R
R
H
D, F, I
H
R
8
9
K, L
D
>99
—c, >99
80 (1:3)
CN
5
6
~92d
H3CO
H3CO
I
10
D
50
>95
— (3:1)e
— (2:1)f
All olefins were satisfactorily identified by their 1H and 13C NMR spectra and where possible by comparison with authentic samples. a GLC
Conversions determined after 20 min reaction time. b After 28 h. c Yields not determined due to partial loss of the volatile product during evaporation.
d After 24 h. e 1 g resin per mmol aldehyde, the crude product consists of 45% of iodoolefin (4-methoxy-β-iodostyrene), 3% of the deiodinated olefin
(4-methoxystyrene), ~1% of 4-methoxyethynylbenzene and 48% starting material. f 3 g resin per mmol aldhyde, the crude product consists of 69% of
4-methoxy (2-iodovinyl)benzene, 7% of 4-methoxystyrene and 21% of presumably 4-methoxyethynylbenzene.
estimated to be in the range of 1.8–3.0 mmol phosphonium salt
per gram support. The choice of the base and the solvent for
the deprotonation of the phosphonium salt as well as the
subsequent olefination step was evaluated and the procedure
was carefully optimised. With a view to automating the process
all steps were carried out in a column technique manner. Hence
in a typical experiment a syringe equipped with a sintered
Teflon frit was charged with the polymer supported phospho-
nium salt (300 mg, 0.54–0.9 mmol phosphonium salt). The
support was placed under an argon atmosphere and washed
with dry THF (8 ml). Addition of a 1  solution of sodium
bis(trimethylsilyl)amide (NaHMDS) in THF (1.8 ml) at room
temperature effected the generation of the ylide within 30 min-
utes. Excess base was carefully removed by extensive washing of
the reddish brown to black support with dry THF (25 ml).
Eventually the support was resuspended in dry THF (3 ml) and
the carbonyl compound (0.25–0.3 mmol) was added at room
temperature. According to GLC analysis the olefination reac-
tion was generally complete within 20–40 minutes (conversion
>95%). The olefin containing solution was collected together
with additional support washings (15 ml of dry THF) and
filtered over a small amount of silica gel (0.5–1 g). Evaporation
in vacuo furnished the crude olefins. Some examples are
summarised in Table 1. While aliphatic and benzylic aldehydes
as well as phenones were rapidly converted to furnish olefins
of high purity (>90%) and in good to excellent yields
(70–100%), pentan-3-one N reacted only very slowly. In general
the observed cis:trans ratios were in accordance with those
reported in literature.2e,6,7 However, some examples with the
phosphonium salt
1 showed a slightly enhanced trans-
selectivity. The olefination with the cyanomethylene ylide was
slow yet very clean. Neither the use of a larger excess of ylide
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J. Chem. Soc., Perkin Trans. 1, 1998

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R3
R2
R3
R2
Ph
P
Ph
Ph
i
+
+
–
–
P
X
P
X
Ph
Ph
Ph
i
Ph
Ph
Ph
CH3
CH3
+
+
+
–
–
–
I
R3
R2
Ph
P
P
P
P
Br
I
CH3
ii +
Ph
Ph
Ph
H
H
R3
R2
O
iii
Ph
O
H
R3
R2
R1
R1
R1
1
2
3
Scheme 3 Reagents and conditions: i, 2 equiv. NaHMDS in THF, rt,
30–60 min; ii, THF, rt, 20–40 min, iii, ~2 equiv. DMDO in acetone, rt,
40–120 min
Ph
Ph
Ph
H
H
+
+
+
–
–
–
I
P
P
P
I
Br
I
CN
Ph
Ph
Ph
equiv.) of the amine was added. The reaction mixture was
stirred at 75 ЊC. While most of the epoxides were converted into
their corresponding β-hydroxyamines in less than 24 hours
(GLC analysis), the sterically hindered 1,1-dimethyl-2-(3,4-
dimethoxyphenyl)oxirane needed considerably longer reaction
times. Work up consisted of the evaporation of the solvent
and the excess of amine followed by careful drying. In the
case of piperazine the excess of reagent was removed under
high vacuum (0.2 torr) at 40 ЊC within 12 hours. In general
the purity of the obtained amino alcohols exceeded 85%.
Some examples are given in Table 3. While stilbene deriv-
atives (Table 3, entries 1–4) furnished a nearly 1:1 mixture
of the two regioisomeric β-hydroxyamines A and B (Scheme 4),
styrene oxides (Table 3, entries 5–8) opened to give preferen-
tially regioisomer B.
4
5
6
Scheme 2 Reagents and conditions: i, for 1–5 2–4 equivalents alkyl
halide, DMF, 50–70 ЊC, 48 h, for 6 4 equiv. diiodomethane, DMF, rt,
16 h
nor elevated temperatures greatly affected the rate of the
reaction. In the case of the polymer supported iodomethyl-
phosphonium salt 6 the olefination proceeded less cleanly. In
all experiments the isolated iodoolefin contained various
amounts of the corresponding deiodinated Wittig product8
together with another side product which is considered to be
the corresponding acetylene.
Epoxidation of some of the above olefins (0.1 mmol) was
achieved by the addition of a ~0.075  solution of dimethyl-
dioxirane (DMDO) in acetone (2 ml) at room temperature. In
general within two hours conversion was complete according to
GLC analysis. Stilbenes reacted slightly slower than styrene
derivatives. 4-Nitrostilbene was the slowest needing 18 hours for
complete conversion. Work-up simply consisted of evaporation
of excess reagent and solvent. Pure epoxides were obtained in
nearly quantitative yields (Table 2).
R4HN
HO
O
i or ii or iii
R3
R2
R2
R3
+
R1
R1
H
R3
R2
R1
NHR4
OH
B
A
Finally, the aminolysis is exemplified with the above epoxides
using either ammonia, cyclohexylamine or piperazine as amine
(Scheme 3). Typically the epoxide (0.1 mmol) was dissolved in
either methanol or ethanol (1 ml) and a large excess (25–100
Scheme 4 Reagents and conditions: 0.1 mmol epoxide in: i, 0.75 ml
methanol ϩ 0.75 ml sat. aq. NH3; ii, 10 mmol cyclohexylamine in 1 ml
methanol; iii, 2.5–5.0 mmol piperazine in 2 ml ethanol; all at 75 ЊC, for
reaction times see Table 3
Table 2 Some examples of the epoxidation with DMDO of olefins obtained from the polymer supported Wittig reaction
Entry
Olefin
GLC Conversiona (%)
Isolated yield (%)
Riii
Riv
Ri
Rii
Ri
H
Cl
OCH3
NO2
OCH3
OCH3
OCH3
OCH3
Rii
H
H
H
H
OCH3
H
OCH3
OCH3
Riii
H
H
H
H
H
H
H
Riv
Ph
Ph
Ph
Ph
1
2
3
4
5
6
7
8
>99
95b
87b
>99c
>99
>99d
>99
>99
>99
>99
100b
100b
96
H
CH3
CH3
CH3
98b
100b
100
CH3
9
>99
100
All epoxides were satisfactorily identified by their 1H and 13C NMR spectra and where possible by comparison with authentic samples.
a Reaction conditions: ~2 equiv. of DMDO in acetone, rt, GLC conversions determined after 40 min reaction time. b As the alkene was obtained
as a cis:trans mixture the epoxide was isolated as a mixture of two racemic diastereoisomers. c After 120 min (~80% after 40 min). d 4 equiv.
DMDO, 24 h.
J. Chem. Soc., Perkin Trans. 1, 1998
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Table 3 Summary of some examples of the aminolysis of epoxides with ammonia, cyclohexylamine and piperazine
GLC Conversiona (reaction time) with
NH3
Cyclohexylamine
Piperazine
% (h)
ratio A:Bb
Entry
Epoxide
% (h)
ratio A:Bb
% (h)
ratio A:Bb
O
Riii
Riv
Ri
Rii
Ri
H
Cl
OCH3
NO2
OCH3
OCH3
OCH3
OCH3
Rii
H
H
H
H
OCH3
H
OCH3
OCH3
Riii
H
H
H
H
H
H
H
CH3
Riv
Ph
Ph
Ph
Ph
1
2
3
4
5
6
7
8
97 (30)
95 (20)
c
98 (44)
c
99 (6)
99 (6)
c
1:1c
1:1c
99 (48) 1:2c
99 (7)
>99 (16)
99 (6)
2:1c
1:2
H
CH3
CH3
CH3
99 (8)
<1:10c
<1:10c
99 (20) 1:9c
17 (72)
d
d
99 (72) ~1:5
—
62 (72)
—
O
9
98 (24) >10:1
All β-hydroxyamines were satisfactorily identified by their 1H, 13C NMR as well as their high resolution mass spectra. Where possible the obtained
NMR spectra were compared with literature data. a For reaction conditions see Scheme 4. b The constitution of the two regioisomers A and B is given
in Scheme 4. c Isolated as racemic erythro/threo mixtures. d Ratio not determined.
Ann. Chem., 1973, 227; (e) W. T. Ford, in ACS Symposium Series
308: Polymeric Reagents and Catalysts, ed. W. T. Ford, ACS
Washington, 1986, p. 155.
3 (a) B. Hinzen and S. V. Ley, J. Chem. Soc., Perkin Trans. 1, 1997,
1907; (b) B. Hinzen and S. V. Ley, J. Chem. Soc., Perkin Trans. 1,
1998, 1; (c) B. Hinzen, R. Lenz and S. V. Ley, Synthesis, 1998, in the
press.
In summary we have elaborated an efficient procedure for the
clean preparation of β-hydroxyamines starting from alcohols
using polymer supported reagents in combination with solution
chemistry. Throughout the whole process work-up is achieved
by mere filtration and evaporation. We believe this work,
together with the preceding two communications, further illus-
trates the power of using polymer bound reagents to effect
clean multi-step organic synthesis for potential application in
combinatorial chemistry programmes.
4 R. Curci, M. Fiorentino, L. Troisi, J. O. Edwards and R. H. Pater,
J. Org. Chem., 1980, 45, 4758; W. Adam, R. Curci and J. O. Edwards,
Acc. Chem. Res., 1989, 22, 205; W. Adam, J. Bialas and
L. Hadjiarapoglou, Chem. Ber., 1991, 124, 2377.
5 I. Hughes, Tetrahedron Lett., 1996, 37, 7595.
6 M. Bernard and W. T. Ford, J. Org. Chem., 1983, 48, 326.
7 For homogenous Wittig reactions see e.g. H. J. Bestmann and
O. Vostrowsky, in Topics in Current Chemistry, Wittig Chemistry, ed.
F. L. Boschke, Springer-Verlag, Berlin, Heidelberg, New York, 1983,
vol. 109, p. 85.
8 Deiodination is also observed in homogenous Wittig reactions with
iodomethyltriphenylphosphonium iodide: D. Seyferth, J. K. Heeren,
G. Singh, S. O. Grim and W. B. Hughes, J. Organomet. Chem., 1966,
5, 267; G. Stork and K. Zhao, Tetrahedron Lett., 1989, 30, 2173;
H. J. Bestmann, H. C. Rippel and R. Dostalek, Tetrahedron Lett.,
1989, 30, 5261.
Acknowledgements
We are grateful to the Swiss National Science Foundation
(Fellowship to M. H. B.), the BP endowment and the Novartis
Research Fellowship (to S. V. L.) for financial support.
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Paper 8/03612H
Received 14th May 1998
Accepted 16th June 1998
2246
J. Chem. Soc., Perkin Trans. 1, 1998