Enantioselective reduction of benzofuranyl aryl ketones

Article abstract of DOI:10.1055/s-0030-1259080

Enantioselective transfer hydrogenation of benzofuranyl aryl ketones proceeds with moderate to good enantioselectivity even when the aryl group is not sterically differentiated by ortho-substituents. The best results are obtained with substrates that are functionalised by electron-withdrawing aryl groups that contrast with the electron-rich benzofuran, which is consistent with [Ru-ArC-H]·Ar π interactions acting as a control element. Enantioselective pressure hydrogenation gives lower enantioselectivity irrespective of electronic effects, unless the aryl group is ortho-substituted, in which case up to 86% ee can be realised. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259080

LETTER
65
Enantioselective Reduction of Benzofuranyl Aryl Ketones
E
nantios
a
elective Re
n
duction of
B
enzofu
C
ranyl
A
ryl
K
eton
a
es rpenter, Matthew L. Clarke*
School of Chemistry, University of St Andrews, EaStCHEM, St. Andrews, Fife, KY16 9ST, UK
Fax +44(1334)463008; E-mail: mc28@st-andrews.ac.uk
Received 27 August 2010
(14–78% ee).6 Transfer hydrogenation of 4-cyano-4¢-
methoxybenzophenone proceeds with 33% ee using
[RuCl(NH^O)(C6H6)] type catalysts;5a it is proposed that
an enhanced ArC–H·Ar p interaction between the Ru-
Abstract: Enantioselective transfer hydrogenation of benzofuranyl
aryl ketones proceeds with moderate to good enantioselectivity
even when the aryl group is not sterically differentiated by ortho-
substituents. The best results are obtained with substrates that are
functionalised by electron-withdrawing aryl groups that contrast benzene moiety and the electron-donating aryl ring con-
with the electron-rich benzofuran, which is consistent with [Ru–
tributes to this moderate selectivity. We speculated that
ArC–H]·Ar p interactions acting as a control element. Enantioselec-
the slightly different shape, combined with the electron-
tive pressure hydrogenation gives lower enantioselectivity irrespec-
rich character of benzofuran, could lead to an asymmetric
tive of electronic effects, unless the aryl group is ortho-substituted,
reduction of benzofuranyl aryl ketones even if they were
in which case up to 86% ee can be realised.
not strongly differentiated by ortho substituents. Here, we
Key words: asymmetric transfer hydrogenation, asymmetric hy-
report an investigation into the asymmetric transfer hy-
drogenation, heterocyclic ketones, asymmetric catalysis, electronic
drogenation of benzofuranyl aryl ketones and compare the
control
selectivities observed to those found using pressure hy-
drogenation.
The desired ketones were prepared by a slight modifica-
tion of the method reported by Gill,7 using 2-trimethyl-
silylbenzofuran and a range of acid chlorides (Scheme 1).
Significantly improved yields were found using these
aromatic acid chlorides compared with the attempt at
benzoylation reported by Gill.7
Asymmetric hydrogenation and transfer hydrogenation of
aryl alkyl ketones is now the preferred technology for the
synthesis of enantiomerically enriched aryl-substituted
secondary alcohols.1 Many drugs and natural products can
be synthesised from heteroaryl secondary alcohols.2 Al-
though not exhaustively investigated, some studies have
shown that acetyl-substituted heterocycles can also take
part in these asymmetric reductions with good to excellent
enantioselectivity. Most relevantly, several publications
establish that alkyl benzofuranyl ketones such as 2-acetyl-
benzofuran can be reduced with high enantioselectivity.3
A project on heterocycle hydrogenation led us to require
secondary alcohols flanked with benzofuran and aryl sub-
stituents. There do not appear to be any studies dealing
with asymmetric transfer hydrogenation of benzofuranyl
aryl ketones. Since benzofuranyl and dihydrobenzofura-
nyl heterocycles, including benzofuranyl aryl alcohols are
found in several classes of drugs and biologically active
compounds,3,4 a study dedicated to asymmetric reduction
of benzofuranyl ketones seemed somewhat overdue. In
addition to the synthetic uses of such alcohols, we were
also intrigued by the implications for selectivity that arise
when the C=O bonds are flanked by two electronically
different aromatic substituents.
O
O
O
ArC(O)Cl (1.1. equiv)
TiCl4 (1.25 equiv)
SiMe3
Ar
7: Ar = 4-ClC6H4, commercial
8: Ar = 4-MeOC6H4 (67%)
9: Ar = 4-F3CC6H4 (25%)
10: Ar = 2-MeC6H4 (66%)
11: Ar = 2-EtOC6H4 (78%)
12: Ar = 2-F3CC6H4 (49%)
Scheme 1
Typical transfer hydrogenation catalysts employed in this
study are pictured in Scheme 2. These catalysts were pre-
pared in situ since there is ample precedent that this results
in formation of the complexes 1–5.1 The Noyori pressure
hydrogenation catalyst was synthesised by a literature
method.1h Sodium borohydride reductions were carried
out for each ketone for the purpose of developing a suit-
able analytical method. The transfer hydrogenation of
ketones 7–12 was examined using five of the state-of-the-
art catalyst systems as shown in Scheme 2.
The most relevant studies in the literature for comparative
purposes are the hydrogenation of aryl aryl ketones. In
pressure hydrogenation, reduction of aryl aryl ketones
proceeds with poor to moderate enantioselectivity (8–
47% ee),5b unless (only) one of the aryl groups is ortho-
substituted. Somewhat higher ee values have been rea-
lised in pressure hydrogenation of pyridyl aryl ketones
The results, which are summarised in Table 1, show that
there was significant enantioselectivity in the hydrogena-
tion of para-substituted benzofuranyl aryl ketones, with
significantly better enantioselectivity being observed
when the para-substituent was electron-withdrawing
(compare Table 1, entries 6–10 with entries 1–5 and 11–
15).
SYNLETT 2011, No. 1, pp 0065–0068
x
x.
x
x.
2
0
1
1
Advanced online publication: 07.12.2010
DOI: 10.1055/s-0030-1259080; Art ID: D23010ST
© Georg Thieme Verlag Stuttgart · New York

66
I. Carpenter, M. L. Clarke
LETTER
i-Pr
Table 1 Asymmetric Reduction of Substituted Benzofuranyl Aryl
i-Pr
Ketonesa
Ru
N
NH2
Ph
Ru
N
Ru
O
NH2
NH2
Ph
Cl
Ts
Cl
Ts
Cl
Ph
Entry
1
Catalystb Ketone
Temp (°C) Conv. (%)c
ee (%)d
64
Ph
1
2
3
4
5
1
2
3
4
5
1
2
3
4
5
1
2
3
4
5
1
2
3
4
5
1
2
3
4
5
7
7
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
80
80
80
80
80
80
80
80
80
80
73
3
1
2
2
86
59
Ph2
P
H2
N
Ph
Ph
3
7
95
33
Cl
Ru
Cl
Ru
O
NH2
Rh
NH2
Cl
Cl
4
7
89
30
O
N
P
Ph2
H2
5
7
>99 (97)
47
4
5
6
6
8
46
55
O
OH
Ar
O
O
catalysts 1–5 (0.5 mol%)
7
8
71
32
KOt-Bu (1 mol%)
i-PrOH
Ar
8
8
87
26
13: Ar = 4-ClC6H4
9
8
59
29
7: Ar = 4-ClC6H4
14: Ar = 4-MeOC6H4
15: Ar = 4-F3CC6H4
16: Ar = 2-MeC6H4
17: Ar = 2-EtOC6H4
18: Ar = 2-F3CC6H4
8: Ar = 4-MeOC6H4
9: Ar = 4-F3CC6H4
10: Ar = 2-MeC6H4
11: Ar = 2-EtOC6H4
12: Ar = 2-F3CC6H4
10
11
12
13
14
15
16
17
18
8
>99 (87)
28
9
>99
69
9
20
64
For catalyst 6: 6 (0.5 mol%) , KOt-Bu (1 mol%), 50 bar H2, i-PrOH
9
>99
42
Scheme 2 Asymmetric reduction catalysts and the asymmetric re-
duction of benzofuranyl aryl ketones
9
98
57
9
>99 (98)
55
Kinetic investigations were outside the scope of this
study, but it is clear from the conversions that the rhodium
catalysts are more active in these reductions. In the case of
the o-tolyl ketone 10, the substrate is reduced more slug-
gishly, at least with catalysts 1–4, and high conversions
are not reached (Table 1, entries 16–19). This is not an is-
sue for the rhodium catalyst since high conversion and 19
moderately high enantioselectivity can be achieved (entry
20). Asymmetric transfer hydrogenation of ketones 11
and 12 was especially challenging, with no conversion be-
ing realised at 40 °C, and low conversions being achieved
at 80 °C for catalysts 1–4 (entries 21–24 and 26–29). Cat-
alyst 5 did reduce these ketones at 80 °C and, in the case
of 12, 75% conversion and 76% ee could be realised.
10
10
10
10
10
11
11
11
11
11
12
12
12
12
12
0
n.d.
n.d
73
0
17
87
87
20
>99 (99)
7
74
21
22
23
24
25
26
27
28
29
30
n.d.
58
24
20
61
32
47
There seems to be a consensus that enantioselection in
transfer hydrogenation is under significant electronic con-
trol as a result of arene·H–CAr–Ru interactions, and the
results obtained here support this. This is somewhat less
clear in the case of pressure hydrogenation.5b,c We there-
fore carried out pressure hydrogenation of these substrates
using [RuCl2(R-BINAP)(R,R-DPEN)] with the results
shown in Table 2.
66e
2
45
n.d.
52
12
36
53
16
25
The selectivity pattern for these catalysts is quite differ-
ent. The para-substituted ketones all gave very similar
enantioselectivities regardless of electronic effects, which
is in contrast with the ~30% ee increase observed in the
electron-withdrawing ketones using the Ru /Ts-DPEN
catalysts. The ortho-substituted ketones 10–12 all gave
significantly better enantioselectivity; the 86% ee value
obtained using ketone 11, which is of some practical val-
75 (51)
76
a Reactions performed in i-PrOH (3 mL) for 16 h.
b Catalysts formed in situ from 0.5% ligand and 0.25% of appropriate
dimeric Ru or Rh species.
c Determined against an internal standard of Et4Si. Isolated yields of
product after chromatography given in brackets.
d Determined by HPLC.
e 99% yield obtained using 1% catalyst.
Synlett 2011, No. 1, 65–68 © Thieme Stuttgart · New York

LETTER
Enantioselective Reduction of Benzofuranyl Aryl Ketones
67
Table 2 Pressure Hydrogenation Using Catalyst 6a
Discovery Dev. 2003, 6, 855. (d) Lennon, I. C.; Ramsden, J.
A. Org. Process Res. Dev. 2005, 9, 110. (e) Diaz-
Venezuela, M. B.; Phillips, S. D.; France, M. B.; Gunn,
M. E.; Clarke, M. L. Chem. Eur. J. 2009, 15, 1227.
(f) Chen, C.-Y.; Reamer, R.; Chilenski, J. R.; McWilliams,
C. J. Org. Lett. 2003, 5, 5039. (g) Ohkuma, T.; Koizumi,
M.; Yoshida, M.; Noyori, R. Org. Lett. 2000, 2, 1749.
(h) Morris, D. J.; Hayes, A. M.; Wills, M. J. Org. Chem.
2006, 71, 7035.
Entry
Ketone
Conv. (%)b
ee (%)c
44
1
2
3
4
5
6
7
8
89
>99
83
48
9
42
(3) (a) Wu, X.; Vinci, D.; Ikariya, T.; Xiao, J. Chem. Commun.
2005, 447. (b) Zaidlewicz, M.; Tafelska-Kaczmarek, A.;
Prewysz-Kwinto, A. Tetrahedron: Asymmetry 2005, 16,
3205.
(4) (a) Nichols, D. E.; Hoffman, A. J.; Oberlender, R. A.; Riggs,
R. M. J. Med. Chem. 1986, 29, 302. (b) Cho, C.-H.;
Neuenswander, B.; Lushington, G. H.; Larock, R. C.
J. Comb. Chem. 2008, 10, 941; and references therein.
(c) Nichols, D. E.; Snyder, S. E.; Oberlender, R.; Hohnson,
M. P.; Huang, Z. J. Med. Chem. 1991, 34, 276.
10
11
12
>99
>99
77
83
86
81
a Reactions were carried out using catalyst 6 (0.5 mol%) at 40 °C and
50 bar hydrogen, 1% KOt-Bu in i-PrOH (3 mL) for 16 h.
b Conversion determined against Et4Si as internal standard.
c Determined by HPLC (see experimental section), and assigned as R
configuration.
(d) Johansson, G.; Brisander, N.; Sundquist, S.; Hacksell, U.
Chirality 1998, 10, 813. (e) de Carvalho e Silveiria, G. P.;
Coelho, F. Tetrahedron Lett. 2005, 46, 6477. (f)Sun, L.-Q.;
Takaki, K.; Chen, J.; Bertenshaw, S.; Iben, L.; Mahle, C. D.;
Ryan, E.; Gao, Q.; Xu, C. Bioorg. Med. Chem. Lett. 2005,
15, 1345. (g) Vinh, T. K.; Lopez Delgado, P. O.; Fernandez-
Perez, S.; Walters, H. M.; Smith, H. J.; Nichols, P. J.;
Simons, C. Bioorg. Med. Chem. Lett. 1999, 9, 2105.
(5) (a) Brandt, P.; Roth, P.; Andersson, P. G. J. Org. Chem.
2004, 69, 4885. (b) Ohhuma, T.; Koizumi, M.; Ikehira, H.;
Yokozawa, T.; Noyori, R. Org. Lett. 2000, 2, 659.
(c) Sandoval, C. A.; Qixun, S.; Liu, S.; Noyori, R. Chem.
Asian J. 2010, 4, 1221.
(6) Maerten, E.; Agbossou-Niedercorn, F.; Castanet, Y.;
Mortreux, A. Tetrahedron 2008, 64, 8700.
(7) Gill, M. Tetrahedron 1984, 40, 621.
(8) An almost identical R-configured alcohol to 13 (fluoro rather
than chloro) gave opposite optical rotation to (S)-13, see:
Botta, M.; Summa, V.; Corelli, F.; Di Pietro, G.; Lombardi,
P. Tetrahedron: Asymmetry 1996, 7, 1263.
ue, is higher than observed in the reduction of the bench-
mark substrate acetophenone using this catalyst.
In conclusion, this study on the asymmetric reduction of
some benzofuranyl aryl ketones provides support for the
proposal that certain transfer hydrogenation catalysts
have a significant element of electronic control over the
selectivity, most likely as a result of favourable Ru–ArC–
H·Ar p interactions in the transition state. On the other
hand, the results are consistent with these pressure hydro-
genations being primarily under steric control. This study
also provides a convenient method to prepare secondary
alcohols flanked with benzofuranyl and aryl substituents
in good enantioselectivity.9
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(9) The catalysts used were formed from either
[RuCl2(benzene)]2, [RuCl2(p-cymene)]2 or [RhCl2Cp*]2 and
(S,S)-Ts-DPEN or (1R,2S)-(+)-cis-1-amino-2-indanol. Using
[RuCl2(R)-BINAP(R,R)-DPEN], alcohol 16 was assigned as
having R-configuration by Mosher analysis6,8 on the
mandelate ester (see the Supporting Information). A similar
analysis was carried out on alcohol 15. The other alcohols,
which show similar HPLC behaviour, are therefore proposed
to have the (R)-configuration. Transfer hydrogenation
reactions using [RuCl2(benzene)]2, [RuCl2(p-cymene)]2 or
[RhCl2Cp*]2 combined with (S,S)-Ts-DPEN or (1R,2S)-(+)-
cis-1-amino-2-indanol as catalyst, gave the opposite S-
configured alcohols in each case.
Acknowledgment
We thank the EPSRC for funding, Johnson Matthey for the loan of
certain precious metal salts and all the technical staff in the School
of Chemistry.
References and Notes
(1) (a) The comprehensive handbook of homogeneous
hydrogenation; Elsevier, C. J.; DeVries, J. N. H., Eds.;
Wiley-VCH: Weinheim, 2006. (b) Ikariya, T.; Blacker, A. J.
Acc. Chem. Res. 2007, 40, 1300. (c) Gladiali, S.; Alberico,
E. Chem. Soc. Rev. 2006, 35, 226. (d) Hashiguchi, S.; Fujii,
A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc.
1995, 117, 7562. (e) Ohhuma, T.; Ooka, H.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1995, 117, 10417.
2-(Trimethylsilyl)benzofuran:7 A solution of 2,3-benzo-
furan (5.1 mL, 46 mmol) in anhydrous THF (50 mL) was
cooled to –78 °C in a nitrogen atmosphere. n-BuLi (40 mL,
1.6 M in hexanes, 64 mmol) was then added slowly to the
solution. After stirring at –78 °C for 1 h, chlorotri-methyl-
silane (9.5 mL, 75 mmol) was added to the suspension. The
mixture was then allowed to stir at –78 °C for 1 h, then at r.t.
for a further 16 h. The reaction mixture was diluted with
hexanes, filtered, and evacuated in vacuo to give a crude
yellow oil (9.108 g). The crude product was purified by
column chromatography (silica, hexane), to give a colourless
oil (7.368 g, 39 mmol, 84%). 1H NMR (400 MHz, CDCl3):
d = 0.34 (s, 9 H, SiCH3), 6.84 (s, 1 H, CHCSiMe3), 7.13–7.29
(m, 2 H, 2 × ArH), 7.45–7.60 (s, 2 H, 2 × ArH); 13C NMR
(75 MHz, CDCl3): d = 0.1 [Si(CH3)3], 113.1 [CHC(SiMe3)],
(f) Takehara, J.; Hashiguchi, S.; Fujii, A.; Inoue, S.-I.;
Ikariya, T.; Noyori, R. Chem. Commun. 1996, 233.
(g) Blacker, A. J.; Mellor, B. J. WO9842643A1, Priority
date 26/3/1997 (Avecia), 1997. (h) Doucet, H.; Ohkuma, T.;
Murata, K.; Yokozawa, T.; Kazawa, M.; Katayama, E.;
England, A. F.; Ikariya, T.; Noyori, R. Angew. Chem. Int.
Ed. 1998, 37, 1703.
(2) (a) Noyori, R.; Ohkuma, T. Angew. Chem. Int. Ed. 2001, 40,
40. (b) Lennon, I. C.; Casy, G.; Johnson, N. B. Chem. Today
2003, 63. (c) Lennon, I. C.; Moran, P. H. Curr. Opin. Drug
Synlett 2011, No. 1, 65–68 © Thieme Stuttgart · New York

68
I. Carpenter, M. L. Clarke
LETTER
117.8 (ArCH), 122.8 (ArCH), 124.1 (ArCH), 126.1 (ArCH),
129.8 (ArC ipso-CH), 159.9 (CSiMe3), 165.3 (ArC ipso-
Oxygen); MS (ES+): m/z = 213.12 [M + Na]+.
was analysed by 1H NMR using tetraethylsilane as an internal
standard to calculate the conversion into product. In some
instances, the products were isolated using column
Acylation of 2-(trimethylsilyl)benzofuran; General
Procedure A: To a solution of an acid chloride (1.1 equiv) in
anhydrous CH2Cl2 under a nitrogen atmosphere, trimethyl-
silylbenzofuran (1.0 equiv) was added. The solution was
stirred vigorously at r.t., whilst TiCl4 (1.25 equiv) was added
dropwise. The resulting suspension was stirred at r.t. for 48 h,
followed by addition of water. The solution was extracted
with Et2O, dried, and concentrated in vaccuo to give the crude
product. The crude product was purified by column
chromatography (hexane–CH2Cl2).
chromatography, and the products were fully characterised.
Pressure Hydrogenation; General Procedure C: Under a
nitrogen atmosphere, the substrate, internal standard, 0.25
mol% metal complex and 0.5 mol% ligand were transferred
into a microwave vial and dissolved in anhydrous and
degassed solvent (3 mL) and stirred for 2 min. The vials were
then transferred to a steel autoclave and pressurised with H2
gas. The reaction was then heated and stirred for 16 h. The
autoclave was immersed in cold water and depressurised. The
crude reaction mixture was then analysed by 1H NMR using
tetraethylsilane as an internal standard to calculate the
conversion into product.
Using general Procedure A: Using
trimethylsilylbenzofuran (5.00 g, 26.3 mmol), 2-methoxy-
benzoyl chloride (4.39 g, 28.5 mmol), and TiCl4 (3.6 mL,
33.2 mmol) in CH2Cl2 (100 mL), ketone 10 was obtained as
a pale-yellow oil (4.10 g, 17.4 mmol, 66%). 1H NMR (400
MHz, CDCl3): d = 2.43 (s, 3 H, CH3), 7.26–7.33 (m, 4 H,
4 × ArH), 7.40–7.45 (m, 1 H, ArH), 7.46–7.51 (m, 1 H,
ArH), 7.56 (m, 1 H, ArH), 7.62 (d, 1 H, ArH), 7.60–7.64 (m,
1 H, ArH), 7.66–7.69 (m, 1 H, ArH); 13C NMR (75 MHz,
CDCl3): d = 20.2 (CH3), 113.2 (CHCC=O), 117.9 (ArCH),
123.9 (ArCH), 124.4 (ArCH), 125.7 (ArCH), 127.5 (ArC
ipso-CH), 128.9 (ArCH), 129.0 (ArCH), 131.4 (ArCH),
131.7 (ArCH), 137.8 (ArC), 153.1 (OCC=O), 156.7 (ArC
ipso-Oxygen), 187.4 (C=O); MS (ES+): m/z = 258.85 [M +
Na]+; HRMS: m/z calcd. for C16H12O2Na: 259.0735; found:
259.0732; IR: 3064, 1939, 1660, 1549,1445, 1328, 1219,
1186, 1114cm–1; Anal. Calcd for C16H12O2: C, 81.34; H, 5.12.
Found: C, 81.39; H, 5.05.
Transfer Hydrogenation; General Procedure B: Under a
nitrogen atmosphere, the substrate, internal standard, 0.25
mol% metal complex, 0.5 mol% ligand and t-BuOK (1 M in
t-BuOH) were transferred into a microwave vial and
dissolved in anhydrous and degassed solvent (3 mL) and
stirred for 2 min. The reaction was then heated and stirred
for16 h. The vials were cooled and the crude reaction mixture
(S)-o-Methylphenyl(benzofuran-2-yl)methanol (16):
Using general procedure B with substrate (58.3 mg, 0.23
mmol), [RhCp*Cl2]2 (0.25 mol%), and aminoindanol (0.5
mol%), a yellow semi-solid was obtained (69 mg,
0.228 mmol, 99%, >99% conversion, 74% ee [determined by
HPLC: OD-H (i-PrOH–hexane, 10:90; flow: 0.5 mL/min)]).
Comparison of the HPLC behaviour of this compound to an
analogous sample that had been treated with methoxyphenyl-
acetic acid and analysed by NMR, showed this sample to
have (S)-configuration. [a]D20 +28.2 (c = 2.2 g/100 mL,
CHCl3); 1H NMR (300 MHz, CDCl3): d = 2.28 (s, 3 H, CH3),
2.42 (br s, 1 H, OH), 6.07 (s, 1 H, CHOH), 6.34 (s, 1 H,
ArH), 7.08–7.24 (m, 5 H, 5 × ArH), 7.35–7.45 (m, 2 H,
2 × ArH), 7.46–7.53 (m, 1 H, ArH); 13C NMR (75 MHz,
CDCl3): d = 19.1 (CH3), 67.5 (CHOH), 104.6 (ArCH), 111.5
(CHCC=O), 121.3 (ArCH), 122.7 (ArCH), 124.5 (ArCH),
126.3 (ArCH), 128.4 (ArC ipso-CH), 128.7 (ArCH), 130.9
(ArCH), 136.0 (ArC), 138.7 (ArC), 156.0 (OCC=O), 159.2
(ArC ipso-oxygen); MS (ES+): m/z = 260.77 [M + Na]+.
For full experimental details, spectroscopic and analytical
data, along with a discussion on the assignment of the
configurations, see the Supporting Information.
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