Effective synthesis of 2,5-disubstituted tetrahydrofurans from glycerol by catalytic alkylation of ketones

Article abstract of DOI:10.1039/c1gc15764g

The [IrCl(cod)]₂ catalyzed α-alkylation of substituted acetophenones with solketal followed by reduction and iron mediated cyclization provides 2,5-disubstituted tetrahydrofurans.

Full text of DOI:10.1039/c1gc15764g

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COMMUNICATION
Effective synthesis of 2,5-disubstituted tetrahydrofurans from glycerol by
catalytic alkylation of ketones†
Magnus Rueping* and Vilas B. Phapale
Received 28th June 2011, Accepted 22nd September 2011
DOI: 10.1039/c1gc15764g
The [IrCl(cod)]2 catalyzed a-alkylation of substituted ace-
tophenones with solketal followed by reduction and iron
mediated cyclization provides 2,5-disubstituted tetrahydro-
furans.
A catalytic system based on a [Ir(cod)Cl]2–PPh3–KOH com-
bination was reported to be effective for the alkylation of
ketones with primary alcohols and diols in the absence of
solvent.11 Iridium was also found to be an efficient catalyst for
the a-alkylation of other functional groups such as nitriles or
acetates.12–14
The development of improved protocols and strategies for the
efficient construction of carbon-carbon bonds continues to be a
challenge in organic synthesis. Among the vast array of estab-
lished transformations, the a-alkylation of carbonyl compounds
emerged as a powerful method for C–C bond formation.1
Typically classical methods make use of electrophilic alkylating
agents like alkyl halides and result in the formation of undesired
salts as by-products.2 As a greener and more economical alterna-
tive, the metal catalyzed a-alkylation of carbonyl, and its related
compounds, with primary alcohols is attracting attention.3 This
method possesses significant advantages over conventional a-
alkylation methods as it proceeds through a hydrogen auto-
transfer process (“borrowing hydrogen”) in which water is the
only generated waste product.3 The overall process is a domino
reaction based on the alcohol dehydrogenation which yields an
aldehyde that undergoes aldol condensation with the existing
carbonyl compound – commonly a methyl ketone – to afford an
a,b-unsaturated carbonyl which is subsequently regioselectively
reduced at the C–C double bond. Full reduction may also take
place, affording a saturated secondary alcohol as the product.
In this context, Cho et al. described the ruthenium catalyzed a-
alkylation of ketones with primary alcohols leading to saturated
secondary alcohols as major products.4 In order to suppress
the reduction of the carbonyl group, the same reaction was
performed in the presence of 1-dodecene serving as a hydrogen
acceptor.5 Yus et al. reported the a-alkylation of ketones with
benzylic alcohols using [Ru(DMSO)4Cl2] as a phosphine free
catalyst.6 Heterogeneous palladium catalysts, such as palladium
on carbon,7 and palladium nanoparticles on a polymer8 or
entrapped in aluminium hydroxide [Pd/AlO(OH)]9 have also
been applied in these processes.10
Given the features of the described transformations, we
decided to investigate the possibility of integrating such a process
into a more elaborate sequential protocol which would allow the
synthesis of more complex structures in a sustainable manner.
Herein, we report our designed strategy and its successful ap-
plication in the diastereoselective synthesis of 2,5-disubstituted
tetrahydrofurans (Scheme 1).15
Scheme 1 Proposed sequential strategy for the synthesis of tetrahydro-
furan derivatives.
Due to its latent functionalization, solketal (2), which is read-
ily available through the protection of glycerol with acetone,16
was chosen as a hydrogen donor for the a-alkylation of
acetophenone. A large range of bases was evaluated in the
reaction of acetophenone (1a) with solketal (2) and the results
are summarized in Table 1.
In the presence of K2CO3, the reaction of acetophenone with
solketal proceeded with less than 10% conversion (Table 1, entry
1). Stronger bases like CsOH, NaOH and Ba(OH)2 afforded the
product in moderate yields (Table 1, entries 2–4). LiOH·H2O
(40 mol%) proved to be the most successful base affording the
desired product in 82% yield (Table 1, entry 7). In the presence
of triethylamine no alkylation product could be detected (Table
1, entry 8). The same result was observed when the reaction was
performed in the absence of a base.
With the optimized conditions for the alkylation reaction in
hand, the reaction of various acetophenones with solketal was
investigated using catalytic amounts of [Ir(cod)Cl]2 (Table 2).
Subsequent reduction with NaBH4 afforded the corresponding
secondary alcohols 4 in good to high yields. Acetal deprotection
and cyclization mediated by FeCl3 afforded 2,5-disubstituted
RWTH Aachen University, Institute of Organic Chemistry, Landoltweg
1, 52074, Aachen, Germany.
E-mail: Magnus.Rueping@RWTH-Aachen.de;
Fax: (+49)-(0)241-8092665; Tel: 49 241 8094710
† Electronic supplementary information (ESI) available: General pro-
cedures, characterization data, and copies of the NMR spectra of the
products are provided. See DOI: 10.1039/c1gc15764g
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Table 1 Catalytic a-alkylation of acetophenone with solketal using
tetrahydrofurans 5 bearing a primary alcohol functional group
in very good yields.17
[Ir(cod)Cl]2 and different basesa
Moderate trans/cis isomeric ratios were observed with ke-
tones bearing electron-withdrawing (Table 2, entries 2, 3) and
electron-donating groups (Table 2, entries 7, 8) on the aryl
substituent. Slightly better trans/cis selectivities were observed
with substrates bearing t-Bu and Me groups (Table 2, entries
5, 6). Improved diastereomeric ratios were obtained for the
substrates bearing biphenyl and naphthyl residues. (Table 2,
entries 4, 10). The heteroaryl derivative 1k afforded the desired
product 5k as a 1 : 1 diastereomeric mixture in good yields (Table
2, entry 11). Cyclic ketone 1l worked well in the alkylation and
reduction steps (4l 73% yield), however, the yield of the final step
was moderate and the product was obtained as a 1 : 1 ratio of
isomers (Scheme 2, 5l 46% yield).
Entry
Base
Yield (%)b
1
2
3
4
5
6
7c
8
9
K2CO3
CsOH
NaOH
Ba(OH)2
KOH
LiOH·H2O
LiOH·H2O
Et3N
8
25
48 (36 + 12)
53 (46 + 7)
61 (55 + 6)
68 (60 + 8)
82 (73 + 9)
0
—
0
a 1a (1 mmol) was reacted with solketal (2, 1.8 mmol) in the presence
of Ir complex (2 mol%) and base (10 mol%) in toluene (0.2 mL) at 110
◦C for 17 h. b Yield – numbers in the brackets represent the mixture
of a-alkylated ketone (major) and alcohol. c LiOH·H2O (40 mol%) was
used.
Scheme 2 Conversion of cyclic ketone 1l.
Table 2 Synthesis of 2,5-disubstituted tetrahydrofurans
Furthermore, a one-pot three-step procedure that does not re-
quire chromatographic purification of any of the intermediates,
proved to be feasible and the product 5a has been obtained in
an overall yield of 59%.
Subsequent derivatisation of the products is possible
through oxidation of the primary alcohol to afford 5-
phenyltetrahydrofuran-2-carbaldehydes whichcaneasily becon-
verted into the corresponding six-membered ring lactones 6
(Scheme 3).18
Entry 1, Ar
4, Yield (%)a,b 5, Yield (%)c (trans : cis)d,e
1
2
3
4
5
6
7
8
Ph
4-F–C6H4
3-CF3–C6H4
4-C6H5–C6H4
4-t-Bu–C6H4
3,4-CH3–C6H3
4-MeO–C6H4
80
87
82
93
85
88
86
91
5a, 86 (1.8 : 1)
5b, 88 (2.0 : 1)
5c, 81 (1.4 : 1)
5d, 89 (6.3 : 1)
5e, 91 (3.8 : 1)
5f, 92 (3.3 : 1)
5g, 90 (1.8 : 1)
5h, 89 (1.7 : 1)
Scheme 3 Functionalization of the tetrahydrofuran derivatives 5.
Regarding the reaction mechanism, it is assumed that the
alkylation reaction follows the same pathway as the previously
reported related transformations (Scheme 4).3 In the first step,
hydrogen transfer oxidation of the alcohol 2 gives aldehyde 7 and
an iridium hydride. Base-catalyzed aldol condensation between
aldehyde 7 and ketone 1 gives a,b-unsaturated ketone 8 which is
hydrogenated by the Ir-hydride complex generated in the course
of the reaction, to form the a-alkylated ketone 3.
9
86
84
5i, 88 (4.3 : 1)
5j, 83 (5.9 : 1)
10
11
77
5k, 74 (1 : 1)
a The reactions were carried out with 1 (1 mmol), solketal (2, 1.8 mmol)
in the presence of [Ir(cod)Cl]2 (2 mol%), PPh3 (6 mol%) and LiOH·H2O
(40 mol%) in toluene (0.2 mL) at 110 ◦C; solvent was removed and 3
was treated with 1 equiv. of NaBH4 in methanol at 10 ◦C for 2 h. b Yield
over two steps. c Alcohol 4 was treated with 1 equiv. of anhydrous FeCl3
in DCM at room temperature for 45 min. d Diastereomeric ratio was
determined by 1H NMR spectroscopy. e The trans stereochemistry for the
major diastereomer has been assigned according to the literature.17e,f,h
Scheme 4 Proposed mechanism for the a-alkylation of solketal.
56 | Green Chem., 2012, 14, 55–57
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In conclusion, a convenient and highly effective Ir-catalyzed
a-alkylation of ketones with subsequent reduction and deprotec-
tion/cyclization methodology for the synthesis of valuable 2,5-
disubstituted tetrahydrofurans was developed. Notably, com-
mercially available substituted acetophenones as well as solketal
a readily available derivative of the bulk chemical glycerol are
used in the atom-economic transfer hydrogen reaction, whereby
water is the only by-product. The subsequent reduction and de-
protection/cyclization proceed under mild reaction conditions
and afford 2,5-disubstituted tetrahydrofurans in good to high
overall yields. In addition, a more practical, one-pot three-step
procedure has been developed.
8 Y. M. A. Yamada and Y. Uozumi, Org. Lett., 2006, 8, 1375–1378.
9 M. S. Kwon, N. Kim, S. H. Seo, I. S. Park, R. K. Cheedrala and J.
Park, Angew. Chem., Int. Ed., 2005, 44, 6913–6915.
10 For the alkylation of methyl ketones with primary alcohols promoted
by Nickel nanoparticles (1 equiv), see: F. Alonso, P. Riente and M.
Yus, Synlett, 2007, 1877–1880.
11 (a) K. Taguchi, H. Nakagawa, T. Hirabayashi, S. Sakaguchi and
Y. Ishii, J. Am. Chem. Soc., 2004, 126, 72–73. For the reaction of
ketones with diols leading to diketones, see; (b) K. Maeda, Y. Obora,
S. Sakaguchi and Y. Ishii, Bull. Chem. Soc. Jpn., 2008, 81, 689–696.
12 Iridium catalyzed alkylation of nitriles: (a) C. Lo¨fberg, R. Grigg, M.
A. Whittaker, A. Keep and A. Derrick, J. Org. Chem., 2006, 71, 8023–
8027. Rhodium catalyzed alkylation of nitriles; (b) R. Grigg, T. R. B.
Mitchell, S. Sutthivaiyakit and N. Tongpenyai, Tetrahedron Lett.,
1981, 22, 4107–4110. Ruthenium catalyzed alkylation of nitriles;
(c) K. Motokura, D. Nishimura, K. Mori, T. Mizugaki, K. Ebitani
and K. Kaneda, J. Am. Chem. Soc., 2004, 126, 5662–5663.
Acknowledgements
13 Iridium catalyzed alkylation of acetates: Y. Iuchi, Y. Obora and Y.
Ishii, J. Am. Chem. Soc., 2010, 132, 2536–2537.
V.B.P. thanks the Alexander von Humboldt foundation for a
post-doctoral research fellowship.
14 For the Ir catalyzed alkylation of other substrates with alcohols (C–C
bond formation): (a) M. G. Edwards and J. M. J. Williams, Angew.
Chem., Int. Ed., 2002, 41, 4740–4743; (b) C. Lo¨fberg, R. Grigg, A.
Keep, A. Derrick, V. Sridharan and C. Kilner, Chem. Commun.,
2006, 5000–5002; (c) P. J. Black, G. Cami-Kobeci, M. G. Edwards,
P. A. Slatford, M. K. Whittlesey and J. M. J. Williams, Org. Biomol.
Chem., 2006, 4, 116–125; (d) M. Morita, Y. Obora and Y. Ishii, Chem.
Commun., 2007, 2850–2852; (e) S. Whitney, R. Grigg, A. Derrick and
A. Kepp, Org. Lett., 2007, 9, 3299–3302; (f) K.-I. Fujita, C. Asai, T.
Yamaguchi, F. Hanasaka and R. Yamaguchi, Org. Lett., 2005, 7,
4017–4019; (g) D. Gnanamgari, C. H. Leung, N. D. Schley, S. T.
Hilton and R. H. Crabtree, Org. Biomol. Chem., 2008, 6, 4442–4445.
15 For a recent review on the diastereoselective synthesis of 2,5-
disubstituted tetrahydrofuranes, see: G. Jalce, X. Franck and B.
Figade`re, Tetrahedron: Asymmetry, 2009, 20, 2537–2581.
Notes and references
1 (a) D. Caine, in Comprehensive Organic Synthesis, vol. 3, ed. B.
M. Trost and I. Fleming, Pergamon, Oxford, 1991, pp. 1–63; (b) S.
Carrettin, J. Guzman and A. Corma, Angew. Chem., Int. Ed., 2005,
44, 2242–2245; (c) Modern Carbonyl Chemistry, ed. J. Otera, Wiley-
VCH, Weinheim, 2000.
2 Handbook of Green Chemistry and Technology, ed. J. H. Clark and
D. J. Macquarrie, Blackwell, Oxford, 2002.
3 For recent reviews (a) G. Guillena, D. J. Ramo´n and M. Yus,
Angew. Chem., Int. Ed., 2007, 46, 2358–2364; (b) T. D. Nixon, M.
K. Whittlesey and J. M. J. Williams, Dalton Trans., 2009, 753–762;
(c) M. H. S. A. Hamid, P. A. Slatford and J. M. J. Williams, Adv.
Synth. Catal., 2007, 349, 1555–1575; (d) F. Alonso, F. Foubelo, J. C.
Gonza´les-Go´mez, R Mart´ınez, D. J. Ramo´n, P. Riente and M. Yus,
Mol. Diversity, 2010, 14, 411–424.
4 (a) C. S. Cho, B. T. Kim, T.-J. Kim and S. C. Shim, J. Org. Chem.,
2001, 66, 9020–9022. For a combined Ir–Ru catalytic system applied
in the asymmetric alkylation of ketones with alcohols affording
chiral secondary alcohols in good yields and excellent selectivities,
see: (b) G. Onodera, Y. Nishibayashi and S. Uemura, Angew. Chem.,
Int. Ed., 2006, 45, 3819–3822.
16 (a) C. X. A. da Silva, V. L. C. Goncalves and C. J. A. Mota,
Green Chem., 2009, 11, 38–41; (b) A. Behr, J. Eilting, K. Irawadi,
J. Leschinski and F. Lindner, Green Chem., 2008, 10, 13–30.
17 For alternative protocols, see: (a) S. Inoki and T. Mukaiyama, Chem.
Lett., 1990, 67–70; (b) J. Berninger, U. Koert, C. Eisenberg-Ho¨hl
and P. Knochel, Chem. Ber., 1995, 128, 1021–1028; (c) K. Miura,
T. Hondo, S. Okajima and A. Hosomi, Tetrahedron Lett., 1996, 37,
487–490; (d) K. Miura, T. Hondo, T. Takahashi and A. Hosomi,
Tetrahedron Lett., 2000, 41, 2129–2132; (e) K. Miura, S. Okajima, T.
Hondo, T. Nakagawa, T. Takahashi and A. Hosomi, J. Am. Chem.
Soc., 2000, 122, 11348–11357; (f) J. Hartung, S. Drees, M. Greb, P.
Schmidt, I. Svoboda, H. Fuess, A. Murso and D. Stalke, Eur. J. Org.
Chem., 2003, 2388–2408; (g) B. M. Pe´rez, D. Schuch and J. Hartung,
Org. Biomol. Chem., 2008, 6, 3532–3541; (h) C. Palmer, N. A. Morra,
A. C. Stevens, B. Bajtos, B. P. Machin and B. L. Pagenkopf, Org.
Lett., 2009, 11, 5614–5617.
5 C. S. Cho, B. T. Kim, T.-J. Kim and S. C. Shim, Tetrahedron Lett.,
2002, 43, 7987–7989.
6 (a) R. Mart´ınez, G. J. Brand, D. J. Ramo´n and M. Yus, Tetrahedron
Lett., 2005, 46, 3683–3686; (b) R. Mart´ınez, D. J. Ramo´n and M.
Yus, Tetrahedron, 2006, 62, 8988–9001.
7 C. S. Cho, J. Mol. Catal. A: Chem., 2005, 240, 55–60.
18 L. Wang, K. Thai and M. Gravel, Org. Lett., 2009, 11, 891–893.
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