Borrowing hydrogen in an indirect asymmetric Wittig reaction

Article abstract of DOI:10.1016/j.tetasy.2007.11.019

An asymmetric C-C bond formation has been achieved by iridium-catalysed coupling of benzyl alcohol with a phosphonium ylide using a borrowing hydrogen strategy.

Full text of DOI:10.1016/j.tetasy.2007.11.019

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2845–2848
Borrowing hydrogen in an indirect asymmetric Wittig reaction
Duncan J. Shermer,a Paul A. Slatford,a Dean D. Edneyb and Jonathan M. J. Williamsa,*
aDepartment of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
bGlaxoSmithKline Research and Development, Old Powder Mills, Tonbridge, Kent TN11 9AN, UK
Received 4 November 2007; accepted 15 November 2007
Abstract—An asymmetric C–C bond formation has been achieved by iridium-catalysed coupling of benzyl alcohol with a phosphonium
ylide using a borrowing hydrogen strategy.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
to the intermediate alkene. Whilst the metal-catalysed
asymmetric reduction of alkenes by direct hydrogenation
is very well-known,5 the related process using an alcohol
as the hydrogen donor has received little attention.6 We
therefore chose to screen the asymmetric reduction of pro-
chiral alkene 1 using isopropanol as a model for the asym-
metric step of an indirect Wittig reaction. This particular
prochiral alkene was chosen because the combination of
a primary benzylic alcohol with a stabilised phosphonium
ylide is known to be effective in the achiral process.1,2 Addi-
tionally, the alkene-forming step from PhCHO and
Ph3P@C(Me)CO2Et is known to be highly (E)-selective,7
thus reducing the possibility of compromising the enantio-
selectivity of the reaction by the reduction of a mixture of
alkene isomers.
We have been developing an indirect Wittig reaction on
alcohols using iridium1 and ruthenium2 complexes which
proceeds via the route shown in Scheme 1. The metal cat-
alyst ‘borrows hydrogen’ from an alcohol to generate an
aldehyde which then undergoes a Wittig reaction to form
an alkene. The hydrogen is then returned to provide an
overall alkylation process.
R
Ph
OH
Ph
M
MH2
R
The reduction of alkene 1 by isopropanol was performed
using an Anachem RS12 48-position stem block and
Gilson 215 autosampler, using ligands 3–11 (Fig. 1) with
catalyst precursors 12–14 (Fig. 2). In addition, the commer-
cially available complexes 15–17 (Fig. 3) were screened for
activity (Scheme 2). Reactions were performed in toluene,
diglyme, DMSO and DMF.
Ph
Ph
O
Ph3P=CHR
Scheme 1. Borrowing hydrogen in an indirect Wittig reaction.
Similar approaches have been reported involving the
conversion of the intermediate aldehyde into an alkene
via aldol and related condensation reactions.3,4
Initially the reactions were analysed for conversion to
product by HPLC. Samples with a reasonable level of con-
version were then further analysed by chiral HPLC to
establish the level of asymmetric induction obtained in
the reaction.8 These results are presented in Table 1.
2. Results and discussion
For an asymmetric variant of the indirect Wittig reaction,
the enantioselective step will be the addition of hydrogen
From the results in Table 1, it was clear that from the
reactions screened, the combination of BINAP 5 and the
iridium catalyst 14 was the most suitable for further devel-
opment. Many of the reactions involving the ruthenium
*
Corresponding author. Tel.: +44 1225 386 231; fax: +44 1225 383 942;
e-mail: j.m.j.williams@bath.ac.uk
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.11.019

2846
D. J. Shermer et al. / Tetrahedron: Asymmetry 18 (2007) 2845–2848
PPh2
P
P
OH
PPh2
PPh2
P
P
NH2
PPh2
6
3
4
5
7
Et
Et
NHTs
NH2
Et
Et
P
O
O
O
NH HN
Fe
N
P
Ph2P
PPh2 Ph2P
iPr
8
9
10
11
Figure 1. Ligands screened in the asymmetric transfer hydrogenation of alkene 1.
Cl
Cl
Ru
12
Rh
Ir
Rh
Ir
Cl
13
Cl
14
Figure 2. Catalyst precursors screened in the asymmetric transfer hydrogenation of alkene 1.
Bn Bn
Xy2
Cl
Ru
Cl
Cl
Ph2
P
H2
N
CF3
CF3
H2
N
P
Ph
Ph
Ph
Ph
_
O
O
Ru
B
N
PPh2
P
N
N
+
Ir
(cod)
P
Ph2
H2
H2
Ph
Cl
16
Xy2
4
15
17
Figure 3. Pre-formed complexes screened in the asymmetric transfer hydrogenation of alkene 1.
catalyst 12 provided good conversions into product, but the
highest enantioselectivity was a modest 31% ee. None of the
reactions involving the rhodium catalyst 13 gave sufficient
conversion to warrant examination of the enantioselectivi-
ty. The reaction of benzyl alcohol 18 with phosphonium
ylide 19 was then investigated using the iridium/BINAP cat-
alytic system (Scheme 3).
i-PrOH
ligand
CO2Et
CO2Et
*
Ph
Ph
Me
Me
catalyst
1
2
90 oC, 72 h
Scheme 2. Reduction of prochiral alkene 1 by transfer hydrogenation.
Table 1. Reduction of alkene 1 by metal-catalysed transfer hydrogenation
Entry
Metal
Ligand
Toluene conversion
(%); ee (%)
Diglyme conversion
(%); ee (%)
DMSO conversion
(%); ee (%)
DMF conversion
(%); ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Ru (12)
Ru (12)
Ru (12)
Ru (12)
Ru (12)
Ru (12)
Ru (12)
Ru (12)
Ru (12)
Rh (13)
Rh (13)
Rh (13)
Rh (13)
Rh (13)
Rh (13)
Rh (13)
Rh (13)
Rh (13)
Ir (14)
3
4
85; 11
42; 23
13; 30
13; 9
57; 31
8; —
62; 11
33; 5
22; 1
2; —
4; —
0; —
0; —
1; —
0; —
2; —
2; —
3; —
40; 10
100; 12
53; 19
16; 7
10; —
89; 3
9; —
55; 7
21; 3
31; 3
2; —
2; —
2; —
0; —
2; —
1; —
0; —
16; —
1; —
16; 6
17; 1
2; —
0; —
0; —
12; 1
0; —
4; —
24; —
3; —
2; —
3; —
2; —
3; —
3; —
0; —
2; —
0; —
3; —
3; —
97; 6
55; 18
28; 1
35; 8
57; 8
12; —
43; 11
57; 10
60; 3
2; —
1; —
0; —
0; —
0; —
0; —
0; —
0; —
0; —
19; 1
5
6
7
8
9
10
11
3
4
5
6
7
8
9
10
11
3

D. J. Shermer et al. / Tetrahedron: Asymmetry 18 (2007) 2845–2848
2847
Table 1 (continued)
Entry
Metal
Ligand
Toluene conversion
(%); ee (%)
Diglyme conversion
(%); ee (%)
DMSO conversion
(%); ee (%)
DMF conversion
(%); ee (%)
20
21
22
23
24
25
26
27
28
29
30
Ir (14)
Ir (14)
Ir (14)
Ir (14)
Ir (14)
Ir (14)
Ir (14)
Ir (14)
4
5
25; 1
85; 57
0; —
79; 15
2; —
55; 9
7; —
5; —
7; —
1; —
11; 0
27; 6
46; 55
4; —
81; 12
3; —
31; 6
8; —
4; —
3; —
2; —
37; 0
0; —
22; 67
2; —
4; —
5; —
13; 0
11; —
14; —
0; —
0; —
7; —
17; 6
100; 66
3; —
52; 10
0; —
64; 16
8; —
5; —
6
7
8
9
10
11
Complex 15
Complex 16
Complex 17
6; —
11; 0
16; 0
We were pleased to find that the enantiomeric excess in
these reactions was marginally higher than for the simple
alkene reduction. The solvent, catalyst and ligand were var-
ied, as shown in Table 2. Toluene was found to provide a
higher enantiomeric excess than either DMF or DMSO.
The use of (R)-TolBINAP and (R)-XylylBINAP slightly
compromised both the conversion and the enantiomeric
excess. The cationic iridium catalyst (cod)2IrBF4 essentially
afforded racemic product, whilst the use of Cp*IrCl2 pro-
vided a slightly improved enantiomeric excess, but with
lower conversion.
provided a further increase in the enantioselectivity of the
reaction (Scheme 4).9 The isolated product was examined
by polarimetry and by comparison with the literature
assigned as the (R)-enantiomer when (S)-BINAP was used
as the ligand.10
3. Conclusion
In conclusion, we have reported the first example of an
asymmetric indirect Wittig reaction on an alcohol.
The reaction was performed on a 2 mmol scale under argon
and rigorously anhydrous and anaerobic conditions, which
Acknowledgements
The authors thank GlaxoSmithKline and the EPSRC for
funding.
5 mol% Ir catalyst
5.5 mol% ligand
Ph
OH
18
CO2Et
Ph
+
solvent
Ph3P
CO2Et
Me
110 oC, 72 h
References
(S)-2
Me
19
1. (a) Edwards, M. G.; Williams, J. M. J. Angew. Chem., Int. Ed.
2002, 41, 4740–4743; (b) Black, P. J.; Cami-Kobeci, G.;
Edwards, M. G.; Slatford, P. A.; Whittlesey, M. K.; Williams,
J. M. J. Org. Biomol. Chem. 2006, 4, 116–125.
2. (a) Edwards, M. G.; Jazzar, R. F. R.; Paine, B. M.; Shermer,
D. J.; Whittlesey, M. K.; Williams, J. M. J. Chem. Commun.
2004, 90–91; (b) Burling, S.; Paine, B. M.; Nama, D.; Brown,
V. S.; Mahon, M. F.; Prior, T. J.; Pregosin, P. S.; Whittlesey,
M. K.; Williams, J. M. J. J. Am. Chem. Soc. 2007, 129, 1987–
1995.
Scheme 3. Asymmetric C–C bond formation from benzyl alcohol.
Table 2. Iridium/ligand combinations employed
Solvent
Catalyst/liganda
Conv (%)
ee (%)
PhMe
DMF
DMSO
PhMe
PhMe
PhMe
PhMe
PhMe
[Ir(cod)Cl]2/(R)-BINAP
[Ir(cod)Cl]2/(R)-BINAP
[Ir(cod)Cl]2/(R)-BINAP
[Ir(cod)Cl]2/(R)-TolBINAP
[Ir(cod)Cl]2/(R)-XylylBINAP
[Ir(coe)2Cl]2/(R)-BINAP
(cod)2IrBF4/(R)-BINAP
Cp*IrCl2/(R)-BINAP
60
58
58
56
48
47
55
52
81
77
69
65
74
66
1
3. For recent representative examples, see: (a) Cho, C. S.; Kim,
B. T.; Kim, T.-J.; Shim, S. C. J. Org. Chem. 2001, 66, 9020–
9022; (b) Cho, C. S. J. Mol. Catal. A 2005, 240, 55–60; (c)
´
´
Martınez, R.; Ramon, D. J.; Yus, M. Tetrahedron 2006, 62,
8982–8987; (d) Yamada, Y. M. A.; Uozumi, Y. Org. Lett.
2006, 8, 1375; (e) Kwon, M. S.; Kim, N.; Seo, S. H.; Park, I.
S.; Cheedrala, R.; Park, K. J. Angew. Chem., Int. Ed. 2005,
44, 6913–6915; (f) Taguchi, K.; Nakagawa, H.; Hirabayashi,
T.; Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc. 2004, 126, 72–
73; (g) Slatford, P. A.; Whittlesey, M. K.; Williams, J. M. J.
Tetrahedron Lett. 2006, 47, 6787–6789; (h) Black, P. J.; Cami-
Kobeci, G.; Edwards, M. G.; Slatford, P. A.; Whittlesey, M.
K.; Williams, J. M. J. Org. Biomol. Chem. 2006, 1, 116–125;
(i) Lo¨fberg, C.; Grigg, R.; Whittaker, M. A.; Keep, A.;
Derrick, A. J. Org. Chem. 2006, 71, 8023–8027; (j) Motokura,
K.; Nishimura, D.; Mori, K.; Mizugaki, T.; Ebitani, K.;
Kaneda, K. J. Am. Chem. Soc. 2004, 126, 5662–5663.
83
a 5 mol % in Ir, 5.5 mol % in ligand.
2.5 mol% [Ir(cod)Cl]2
6 mol% (S)-BINAP
Ph
OH
18
CO2Et
Ph
+
Me
(R)-2
toluene
reflux, 72 h
Ph3P
CO2Et
68% conversion
58% isolated yield
87% ee
Me
19
4. For recent reviews in the area of borrowing hydrogen, see: (a)
Scheme 4. Optimised conditions for the asymmetric process.
´
Guillena, G.; Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed.

2848
D. J. Shermer et al. / Tetrahedron: Asymmetry 18 (2007) 2845–2848
2007, 46, 2358; (b) Hamid, M. H. S. A.; Slatford, P. A.;
Williams, J. M. J. Adv. Synth. Catal. 2007, 349, 1555–1575.
5. Noyori, R. Chem. Soc. Rev. 1989, 18, 209.
6. (a) Saburi, M.; Ohnuki, M.; Ogasawara, M.; Takahashi, T.;
Uchida, Y. Tetrahedron Lett. 1992, 33, 5783–5786; (b)
Alberico, E.; Nieddu, I.; Taras, R.; Gladiali, S. Helv. Chim.
Acta 2006, 89, 1716–1729.
7. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863–927.
8. HPLC conditions used were Chiralcel OJ, hexane (100%),
1 mL/min, 14.83 min (S), 15.39 min (R).
carousel tube and purged with argon. Benzyl alcohol (216 mg,
2.0 mmol) and dry toluene (2 mL) were added under a flow of
argon. The tap was closed and the reaction heated at
reflux for 72 h. Removal of toluene in vacuo and an analysis
of the NMR of the crude material indicated 68% conver-
sion. Purification by column chromatography (silica;
petroleum ether/ether 19:1) gave a (R)-2 as a colourless
liquid (223 mg, 58%). NMR data was consistent with the
literature.10 Enantiomeric excess was determined by chiral
HPLC.8
9. Experimental procedure: Commercially available (carboxy-
10. Colwell, A. R.; Duckwell, L. R.; Brooks, R.; McManus, S. P.
J. Org. Chem. 1981, 46, 3097–3102, which reports;
ethylidene)triphenylphosphorane
(870 mg,
2.4 mmol),
22:2
[Ir(cod)Cl]2 (33.6 mg, 2.5 mol %; 5 mol % in Ir) and (S)-
BINAP (74.7 mg, 6 mol %) were charged to a Young’s tap
½aꢀD ¼ þ15:0 (c 2.836, EtOH) for (S)-2. The compound
21
isolated from Scheme 4 gave; ½aꢀD ¼ ꢁ13:7 (c 2.85, EtOH).