Iridium catalyzed acceptor-less dehydrogenative coupling of alcohols and 4-hydroxy-6-methyl-2-pyrone under microwave conditions

Article abstract of DOI:10.1016/j.tetlet.2015.10.034

Iridium catalyzed acceptor-less dehydrogenative coupling of benzyl type alcohols and 4-hydroxy-6-methyl-2-pyrone under microwave conditions afforded 3,3′-(arylmethylene)bis(4-hydroxy-6-methyl-2H-pyran-2-ones) in good yields.

Full text of DOI:10.1016/j.tetlet.2015.10.034

Accepted Manuscript
Iridium catalyzed acceptor-less dehydrogenative coupling of alcohols and 4-
hydroxy-6-methyl-2-pyrone under microwave conditions
Mitchell Proud, Visuvanathar Sridharan
PII:
S0040-4039(15)30231-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.10.034
TETL 46863
Reference:
Tetrahedron Letters
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6 October 2015
8 October 2015
Please cite this article as: Proud, M., Sridharan, V., Iridium catalyzed acceptor-less dehydrogenative coupling of
alcohols and 4-hydroxy-6-methyl-2-pyrone under microwave conditions, Tetrahedron Letters (2015), doi: http://
dx.doi.org/10.1016/j.tetlet.2015.10.034
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Iridium catalyzed acceptor-less dehydrogenative coupling of alcohols and 4-
hydroxy-6-methyl-2-pyrone under microwave conditions.
Mitchell Proud and Visuvanathar Sridharan*

1
Tetrahedron Letters
Iridium catalyzed acceptor-less dehydrogenative coupling of alcohols and 4-hydroxy-
6-methyl-2-pyrone under microwave conditions.
Mitchell Proud and Visuvanathar Sridharan*
School of Chemistry, University of Leeds, LS2 9JT, UK
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Iridium catalysed acceptor-less dehydrogenative coupling of benzyl type alcohols and 4-
hydroxy-6-methyl-2-pyrone under microwave conditions afforded 3,3’-(arylmethylene)bis(4-
hydroxy-6-methyl-2H-pyran-2-ones) in good yields
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Iridium
Dehydrogenation
Catalysis
Microwave
Cascade
3,3’-(Aryl/alkylmethylene)bis(4-hydroxy-2H-pyran-2-ones
are important structural skeletons possessing a wide range of
medicinal properties including anti-inflammatory,1 and anti
coagulant2 activities (Figure. 1).
by iridium, rhodium and ruthenium complexes to form new C-N
and C-C bonds.4 Kempe et al. have reported new iridium
catalysts stabilized by P, N ligands for the synthesis of quinolines
and pyrroles via acceptor-less dehydrogenative condensation of
primary/secondary alcohols and 1,2- aminoalcohols.5,6
Benzimidazoles and quinoxalines were also synthesized from
aromatic diamines and alcohols via an iridium catalyzed
acceptor-less dehydrogenative alkylation.7 Milstein et al. have
reported the direct conversion of alcohols to amides using a
9
ruthenium pincer complex catalyst.8 Beller, and Saito10 have
also reported examples for the synthesis of unsymmetrically
substituted N-heterocyclic compounds via a ruthenium catalyzed
acceptor-less dehydrogenative coupling process. Recently we
have reported an iridium catalyzed chemoselective alkylation of
2’-aminoacetophenone with alcohols to form either new C-C or
C-N bonds under microwave irradiation (Scheme 1).11
Figure 1. Bioactive bis-pyrone compounds
To increase the molecular complexity of simple organic
substrates using efficient (high atom economy), selective, high
yielding, and environmentally benign methods is a significant
contemporary challenge for synthetic organic chemists. C-C and
C-N bond formations are pivotal methods for achieving this goal.
The indirect functionalisation of alcohols using catalytic amounts
of a metal complex and base which generates only water as a by-
product is an attractive green alternative to standard C-C and C-N
bond forming reactions. These cascades are termed as Redox –
neutral, hydrogen auto transfer or borrowing hydrogen
processes.3
Scheme 1
In this communication we report an iridium catalyzed
acceptor-less dehydrogenative coupling of alcohols and 4-
We and other groups have been involved in the alkylation of
amines and active methylene compounds with alcohols catalysed
hydroxy-6-methyl-2-pyrone
methylene)bis(4-hydroxy-6methyl-2H-pyran-2-ones)
microwave conditions (Scheme 2, Path A).
to
generate
3,3’-(aryl
under
* Cross ponding Author: V.Sridharan@leeds.ac.uk; Tel +44-1133436520

2
Tetrahedron
6
51
53
Scheme 2
7
We initially surveyed a range of catalysts and identified the
iridium chloro-bridged compound 1 [X = Cl, M = Ir (III)] (Fig. 2)
as an effective catalyst for this transformation (Scheme 2).11
8
9
70
70
64
Figure 2
Microwave irradiation has been reported to dramatically
accelerate a number of metal catalysed reactions.12 Further
optimisation showed that the reaction could be achieved under
microwave conditions (300W, temperature automatically
controlled by an IR sensor) and identified cesium carbonate as
the base of choice. Initially, we carried out the alkylation reaction
of 4-hydroxy-6-methyl-2-pyrone (1 mmol) using para-methoxy
benzyl alcohol (3 mmol), Cs2CO3 (20 mol%) and [Cp*IrCl2]2 (2.5
mol%) in toluene (3 mL) at 110 °C for 90 min under microwave
irradiation to cleanly afford the bis C-alkylated product 1 in 60%
yield (Table 1, entry 1).
10
Table 1. Iridium catalyzed dehydrogenative couplinga
Entry
1
Alcohol
Product
Yield (%)b
a
4-hydroxy-6-methyl-2-pyrone (1 mmol), alcohol (3 mmol), [IrCp*Cl2]2 (2.5
60
mol%), Cs2CO3 (20 mol%), 110 °C, 90 min, microwave irradiation. b Isolated
yield
In the above process, no product was isolated resulting from
the redox-neutral pathway (Scheme 2, Path B). No reaction took
place in the presence of Cs2CO3 alone, under essentially the same
microwave conditions as above, indicating that the combination
of the iridium complex and base was necessary for the reaction.
Lowering the temperature to 80 °C under microwave irradiation
(1 hr) afforded only 50% conversion to the product 1. We elected
to keep the temperature at 110 °C for the remainder of the series
of reactions.
70
2
3
Benzyl alcohols substituted with electron-withdrawing or
donating groups were readily alkylated to afford the
corresponding bis-pyrone products 2-11 in good yield (40-70%)
(Table 1, entries 2-10). The reaction was not significantly
affected by either the location or the electronic nature of the
substituents on the aryl ring. The heteroaromatic, thiophene-2-
methanol was alkylated to give the corresponding bis- pyrone
product 5 (Table 1 entry 5) in good yield. During all of these
reactions the dehydrogenative pathway (Scheme 2, Path A) was
observed with none of the mono alkylated derivatives (Scheme 2,
Path B) being observed. Traditionally 3,3’-(arylmethylene)bis(4-
40
60
4
5
hydroxy-2H-pyran-2-ones
are
synthesized
from
the
corresponding aldehydes and 4-hydroxy-6-methyl-2-pyrone.2, 13
The proposed mechanism for this transformation involves
dehydrogenation of the primary alcohol to generate an aldehyde
and metal hydride species. Knoevenagel type condensation
followed by a Michael addition process led to the 3,3’-
(arylmethylene)bis(4-hydroxy-2H-pyran-2-ones (Scheme 3, Path
A). However Knoevnagel type condensation followed by
65

3
6
Forberg, D.; Obenauf, J.; Friedrich, M.; Huehne, S. M.; Mader, W.;
Motz, G.; Kempe, R. Catal. Sci. Tech. 2014, 4, 4188-4192.
hydrogenation of the double bond by the in situ formed metal
hydride would give the C-3 alkylated product (Scheme 3, Path
B). In this case, the Michael addition competes with the reduction
process under the microwave conditions.
7
8
9
Hille, T.; Irrgang, T.; Kempe, R. Chem. Eur. J. 2014, 20, 5569-5572.
Gunanathan, C.; Ben-David, Y.; Milstein, D. Science, 2007, 317, 790.
Penalopez, H.; Neumann, M.; Beller, M. Chem. Eur. J. 2014, 20, 1818-
1824.
10 Lida, K.; Miura, T.; Ando, J.; Saito, S. Org. Lett. 2013, 15, 1436-1439.
11 Bhat, S. and Sridharan, V. Chem. Commun. 2012, 48, 4701-4703.
12 (a) Loefberg, C.; Grigg, R.; Whittaker, W. A.; Keep, A.; Derrick, A. J.
Org. Chem. 2006, 71, 8023-8027; (b) Watson, A.; Maxwell, A. C.;
Williams, J. M. J. J. Org. Chem. 2011, 76, 2328-2331.
13 Hisahiro, H.; Norikazu, F.; Toshio, S.; Masayoshi, A.
Heterocycles,2009, 53, 549-552
Scheme 3
In conclusion we have developed an iridium catalyzed
dehydrogenation/ Knoevenagel type condensation/ Michael
addition cascade to give 3,3’-bis arylmethenes (Scheme 2, Path
A) in good yields.
Acknowledgments
We thank Leeds University for support.
Notes and references
1
2
Rehse, K.; Schinkel, W. Archiv der Pharmazie. 1983, 316, 988-994.
Minassi, A.; Cicione, L.; Koberle, A.; Bauer, J.; Laufer, S.; Werz, O.;
Appendino, G. Eur. J. Org. Chem. 2012, 772-779.
3
Review articles on redox-neutral process: (a) Hamid, H. S. A.; Slatford,
J. M. J. Adv. Synth. Catal, 2007, 349, 1555-1575; (b) Nixon, T. D.;
Whittlesey, M. K.; Williams, J. M. J. Dalton Trans. 2009, 753-762; (c)
Guillena, G.; Ramon, D. J.; Yus, M. Chem. Rev. 2010, 110, 1611-
1641;(d) Baehn, S.; Imm, S.; Neubert, L.; Zhang, M.; Neumann, H.;
Beller, M. Chem. Cat. Chem. 2011, 3, 1853-1864; (e) Yang, Q.; Wang,
Q.; Yu, Z. Chem. Soc. Rev., 2015, 44, 2757-2785.
4
For selected key papers with regard to Ir catalyzed C-C couplings see:
(a) Edwards, M. G.; Williams, J. M. J. Angew. Chem.Int. Ed. 2002, 41,
4740-4743; (b) Tauchi, K.; Nakagawa, H.; Hirabayashi, T.; Sakuchi,
S.; Ishii, Y. J. Am. Chem. Soc. 2004, 126, 72-73; (c) Motokura, K.;
Nishimura, D.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. J. Am.
Chem.Soc. 2004, 126, 5662-5663; (d) Lofberg, C.; Grigg, R.; Derrick,
A.; Sridharan, V.; Kilner, C. Chem. Commun. 2006, 5000-5002; (e)
Shibahara, F.; Bower, J.F.; Krische, M. J. J. Am. Chem. Soc. 2008, 130,
6338-6339; (f) Bower, J. F.; Patman, R.L.; Krische, M.J. Org. Lett.
2008, 10, 1033-1035: (g) Bower, J. F.; Skucas, E.; Patman, R.L.;
Krische, M. J. J. Am. Chem. Soc. 2007, 129, 15134-15135; (h) Ngai,
M.Y.; Skucas, E.; Krische, M. J. Org.Lett. 2008, 10, 2705-2708: (i)
Patman, R.L.; Williams, V. M.; Bower, J.F.; Krische, M.J. Angew.
Chem. Int. Ed. 2008, 47, 1-5; (j) Patman, R.L.; Chaulagin, M.R,;
Williams, V.M.; Krische, M. J. J. Am. Chem.Soc. 2009, 131, 2066-
2067; (k) Grigg, R.; Lofberg, C.; Whitney, S.; Sridharan, V.; Keep, A.;
Derrick, A. Tetrahedron 2009, 65, 849-854; (l) Grigg, R.; Whitney, S.;
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(m) Ganamgari, D.; Sauer, E. L. O.; Schley, N. D.; Butler, C.;
Incarvito, C. D.; Crabtree, R. H. Organometallics 2009, 28, 321-325;
(n) Iuchi, Y.; Hyotanishi, M.; Miller, B. E.; Maede, K.; Obora, Y.;
Ishii, Y. J. Org. Chem. 2010, 75, 1803-1806; (m) Allen, L. J.;
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