Highly efficient cross-dehydrogenative-coupling between ethers and active methylene compounds

Article abstract of DOI:10.1002/anie.200503255

(Chemical Equation Presented) An unlikely couple: C-C bonds can be formed between ethers and methylene compounds by cross-dehydrogenative-coupling (see scheme; DDQ = 2,3-dichloro-5,6-dicyanobenzoquinone). This straightforward reaction employs mild conditi

Full text of DOI:10.1002/anie.200503255

Angewandte
Chemie
Synthetic Methods
DOI: 10.1002/anie.200503255
Highly Efficient Cross-Dehydrogenative-
Coupling between Ethers and Active Methylene
Compounds**
Yuhua Zhang and Chao-Jun Li*
À
Transition-metal-catalyzed C H bond activation and subse-
À
quent C C bond formation provide an alternative to tradi-
tional functional-group organic chemistry.[1] With the aim of
seeking novel and highly efficient synthetic approaches,[2] our
group recently focused on developing cross-dehydrogenative-
coupling (CDC) methodologies to construct molecules by
À
directly utilizing C H bonds. We recently reported three
types of CDC reactions (Scheme 1)[3] in which the presence of
Scheme 1. Cross-dehydrogenative-coupling (CDC)of amines to form
À
C C bonds.
an adjacent nitrogen atom was essential. However, the
synthesis of oxygen-containing compounds such as epoxides
and ethers are of great interest in industrial and academic
research, because these compounds are not only important
structural units in many natural products and biologically
active compounds,[4] but also highly versatile building blocks
in synthetic organic chemistry.[5] Therefore, in an effort to
À
functionalize the C H bond of ethers and related oxygen-
containing compounds directly,[6] we report herein a new type
of CDC reaction under mild conditions to construct b-diester
ethers catalyzed by a combination of indium[7] and copper[8]
catalysts in the presence of 2,3-dichloro-5,6-dicyanobenzo-
3
À
quinone (DDQ). This reaction combines a C(sp ) H bond
3
À
adjacent to an oxygen atom with a C(sp ) H bond in
pronucleophiles, leading to a new C C bond (Scheme 2).
À
[*] Dr. Y. Zhang
Department of Chemistry, Tulane University
6400 Freret St., New Orleans, LA 70118 (USA)
Prof. Dr. C.-J. Li
Department of Chemistry, McGill University
801 Sherbrooke St. West, Montreal, PQH3A2K6 (Canada)
Fax: (+1)514-398-3797
E-mail: cj.li@mcgill.ca
[**] We are grateful to the Canada Research Chair (Tier I)foundation (to
C.-J.L.), the NSERC, and the NSF-EPA joint program for a
Sustainable Environment for support of our research. Y.Z. thanks
McGill University for their hospitality during the aftermath of
Hurricane Katrina and Z. Li, L. Zhao, and X. Yao (at McGill
University)for their help with NMR spectroscopic and HRMS
analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2006, 45, 1949 –1952
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1949

Communications
benzyl methyl ether under the optimized reaction conditions
(Table 2). Isochroman and its derivatives were found to be
more reactive than phthalan and benzyl methyl ether. A large
amount of benzyl methyl ether remained unchanged after the
reaction. No desired product was isolated when benzyl phenyl
ether was treated with dimethyl malonate, which could be due
to the increased steric effect of the bulky phenyl group in the
ether. Notably, benzoylnitromethane was also reactive with
isochroman. 2,4-Pentanedione and b-ketone esters also
reacted effectively with isochroman; however, they generated
a rather complicated mixture that is still under investigation.
A likely mechanism of this CDC reaction is shown in
Scheme 3. The first step involves a hydride abstraction from
À
Scheme 2. Cross-dehydrogenative-coupling (CDC)of ethers to form C
C bonds. DDQ=2,3-dichloro-5,6-dicyanobenzoquinone; Tf=trifluoro-
methanesulfonyl.
Various transition metals were initially examined as
potential catalysts for the desired CDC reaction between
isochroman[9] and dimethyl malonate (Table 1). A combina-
Table 1: Optimization of reaction conditions.[a]
Entry
Catalyst
Solvent
Conversion
Yield
(1a)[%] [b]
(3a)[%] [b]
[c]
1
2
3
4
5
6
7
8
InCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
96
100
94
100
100
93
72
n.d.[d]
76
[c]
[c]
In(OAc)3
In(OTf)3
In(NO3)3
[c]
n.d.[d]
n.d.[d]
69
50
77
[c]
In(OH)3
Scheme 3. Possible mechanism for the CDC reaction of ether with
malonate.
[c]
Cu(OTf)2
Cu(OTf)[c]
94
92
InCl3/Cu(OTf)2
(5 mol%/5 mol%)
InCl3/Cu(OTf)2
(10 mol%/5 mol%)
InCl3/Cu(OTf)2
(5 mol%/10 mol%)
InCl3/Cu(OTf)[e]
InCl3/Cu(OTf)2
InCl3/Cu(OTf)2
InCl3/Cu(OTf)2
InCl3/Cu(OTf)2
9
CH2Cl2
CH2Cl2
95
95
74
77
the benzylic position of isochroman to generate a cationic
species.[10] The malonate is activated by the In/Cu catalyst.[11]
Subsequently, the coupling of the two intermediates results in
the desired product and regenerates the catalyst. However, it
is also possible that the lactol compound is involved as an
intermediate and is further converted into the corresponding
cross-coupling product. Alternatively, InIII may activate DDQ
through coordination with its carbonyl oxygen atom, which
increases the oxidizing power of DDQ.[12]
10
11
12
13
14
15
16
17
CH2Cl2
DCE
MeNO2
THF
H2O
PhMe
MeCN
96
96
82
0
68
80
68
71
76
66
[e]
[e]
n.d.[d]
n.d.[d]
43
[e]
[e]
[e]
InCl3/Cu(OTf)2
InCl3/Cu(OTf)2
[e]
44
In summary, the first highly efficient cross-dehydrogen-
3
[a] Isochroman (0.5 mmol), dimethyl malonate (0.6 mmol), DDQ
(0.6 mmol), solvent (2–3 mL). [b] Determined by 1H NMR spectroscopy
using an internal standard. [c] Catalyst: 10 mol%. [d] Not detected by
1H NMR spectroscopy. [e] In/Cu (5 mol%/5 mol%).
À
ative-coupling reaction between a C(sp ) H bond adjacent to
3
À
an oxygen atom and a C(sp ) H bond of a pronucleophile,
À
catalyzed by In/Cu, has been developed to generate a C C
bond. This methodology not only provides the simplest way to
construct isochroman derivatives and b-ether diesters, but
also opens a new way to build and study more complex
oxygen-containing natural products. The advantages of this
method include: 1) relatively mild reaction conditions; 2) tol-
erance of various functional groups; 3) direct use of simple
ethers as starting materials; 4) high regioselectivity; and
5) direct use of relatively cheap metals, indium and copper,
as catalysts. The scope, mechanism, and synthetic application
of this reaction are currently under investigation.
tion of InCl3 and Cu(OTf)2 provided the best results. No
desired product was observed without these catalysts. To
improve the yield, we examined various ratios of isochroman,
dimethyl malonate, and DDQ. The best yield was obtained
when isochroman/malonate/DDQ = 1:1.2:1–1.2. When the
amount of DDQ was increased to more than 1.5 equivalents,
the yield decreased dramatically. The reaction did not
proceed in the absence of DDQ. It was also found that the
suitable solvents for this reaction are CH2Cl2, 1,2-dichloro-
ethane (DCE), and MeNO2. The desired product was not
detected when the reaction was performed in THF or H2O.
There was no evident difference when the reaction was
performed in dry CH2Cl2 or CH2Cl2 without drying.
Received: September 13, 2005
Published online: February 15, 2006
À
À
Several active methylene compounds were then used in
the reaction with isochroman derivatives, phthalan, and
Keywords: C C coupling · C H activation · copper ·
homogeneous catalysis · indium
.
1950
www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 1949 –1952

Angewandte
Chemie
Table 2: CDC reaction of ethers with active methylene compounds.[a]
Entry
1
2
Product
Yield Entry
[%][b]
1
2
Product
Yield
[%][b]
1
71
9
1a
65
2
3
1a
1a
66
63
10
11
2a
2b
60
57
1b
1b
1b
4
1a
decomp.
12
2g
40
5
6
1a
1a
65
53
13
2h
2a
65
48
14[c]
7
1a
64
15[d]
1c
2b
8
1a
72
16
2a
17
[a] Diethyl ether (0.5 mmol), active methylene compound (0.6 mmol), InCl3/Cu(OTf)2 (5 mol%/5 mol%), DDQ (0.6 mmol); all reactions were run for 24–
36 h. [b] Yields of isolated products based on ethers. [c] Phthalan (0.2 mmol), dimethyl malonate (0.4 mmol), DDQ (0.2 mmol). [d] Phthalan (0.2 mmol),
diethyl malonate (0.4 mmol), DDQ (0.24 mmol).
2004, 689, 4083 – 4091; j) C. Jia, T. Kitamura, Y. Fujiwara, Acc.
Chem. Res. 2001, 34, 633 – 639.
[1] For reviews, see: a) V. Ritleng, C. Sirlin, M. Pfeffer, Chem. Rev.
2002, 102, 1731 – 1769; b) G. Dyker, Angew. Chem. 1999, 111,
1808 – 1822; Angew. Chem. Int. Ed. 1999, 38, 1698 – 1712; c) T.
Naota, H. Takaya, S. I. Murahashi, Chem. Rev. 1998, 98, 2599 –
2660; for some recent examples, see: d) N. Chatani, T. Asaumi, S.
Yorimitsu, T. Ikeda, F. Kakiuchi, S. Murai, J. Am. Chem. Soc.
2001, 123, 10935 – 10941; e) L. J. Gooßen, Angew. Chem. 2001,
113, 3929 – 3932; Angew. Chem. Int. Ed. 2002, 41, 3775 – 3778;
f) B. A. Arndtsen, R. G. Bergman, T. A. Mobley, T. H. Peterson,
Acc. Chem. Res. 1995, 28, 154 – 162; g) H. Chen, S. Schlecht, T. C.
Semple, J. F. Hartwig, Science 2000, 287, 1995; h) A. S. Goldman,
Nature 1993, 366, 514; i) R. H. Crabtree, J. Organomet. Chem.
[2] a) C.-J. Li, Acc. Chem. Res. 2002, 35, 533 – 538; b) C.-J. Li, Chem.
Rev. 2005, 105, 3095 – 3166; c) C. Wei, Z. Li, C.-J. Li, Synlett 2004,
1472 – 1483; d) C.-J. Li, Chem. Rev. 1993, 93, 2023 – 2035.
[3] a) Z. Li, C.-J. Li, J. Am. Chem. Soc. 2005, 127, 6968 – 6969; b) Z.
Li, C.-J. Li, J. Am. Chem. Soc. 2005, 127, 3672 – 3673; c) Z. Li,
C.-J. Li, Org. Lett. 2004, 6, 4997 – 4999; d) Z. Li, C.-J. Li, J. Am.
Chem. Soc. 2004, 126, 11810 – 11811; e) Z. Li, C.-J. Li, Eur. J.
Org. Chem. 2005, 3173 – 3176; see also: f) S.-I. Murahashi, N.
Komiya, H. Terai, T. Nakae, J. Am. Chem. Soc. 2003, 125,
15312 – 15313; g) Y. Hatamoto, S. Sakaguchi, Y. Ishii, Org. Lett.
2004, 6, 4623 – 4625; h) T. Yokota, M. Tani, S. Sakaguchi, Y. Ishii,
Angew. Chem. Int. Ed. 2006, 45, 1949 –1952
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1951

Communications
J. Am. Chem. Soc. 2003, 125, 1476 – 1477; i) J. Tsuji, H.
Nagashima, Tetrahedron 1984, 40, 2699 – 2702; j) B. DeBoef,
S. J. Pastine, D. Sames, J. Am. Chem. Soc. 2004, 126, 6556 – 6557;
k) K. C. Nicolaou, R. E. Zipkin, N. A. Petasis, J. Am. Chem. Soc.
1982, 104, 5558 – 5560; l) Z. Li, C.-J. Li, J. Am. Chem. Soc. 2006,
128, 56 – 57.
[4] a) J. W. Blunt, B. R. Copp, M. H. G. Munro, P. T. Northcote,
M. R. Prinsep, Nat. Prod. Rep. 2005, 22, 15 – 61; b) V. M.
Dembitsky, T. A. Gloriozova, V. V. Poroikov, Mini-Rev. Med.
Chem. 2005, 5, 319 – 336; c) T. L. Simmons, E. Andrianasolo, K.
McPhail, P. Flatt, W. H. Gerwick, Mol. Cancer Ther. 2005, 4,
333 – 342; d) D. J. Newman, G. M. Cragg, J. Nat. Prod. 2004, 67,
1216 – 1238; e) L. Bongiorni, F. Pietra, Chem. Ind. 1996, (2), 54 –
58.
[5] a) I. Kadota, Y. Yamamoto, Acc. Chem. Res. 2005, 38, 423 – 432;
b) M. Sasaki, H. Fuwa, Synlett 2004, 1851 – 1874; c) L. F. Tietze,
N. Rackelmann, Pure Appl. Chem. 2004, 76, 1967 – 1983; d) E.
Lee, Pure Appl. Chem. 1996, 68, 631 – 634; e) G. M. Nicholas,
A. J. Phillips, Nat. Prod. Rep. 2005, 22, 144 – 161.
[6] For our early workon an ether-functionalization reaction, see: Y.
Zhang, C.-J. Li, Tetrahedron Lett. 2004, 45, 7581 – 7584.
[7] For representative reviews on indium catalyzed reactions, see:
a) P. Cintas, Synlett 1995, 1087 – 1096; b) C.-J. Li, Tetrahedron
1996, 52, 5643 – 5668; c) J. A. Marshall, Chemtracts: Org. Chem.
1997, 10, 481; d) I. Coldham, J. Chem. Soc. Perkin Trans. 1 1998,
1343 – 1364; e) C.-J. Li, T.-H. Chan, Tetrahedron 1999, 55,
11149 – 11176; f) K. K. Chauhan, C. G. Frost, J. Chem. Soc.
Perkin Trans. 1 2000, 3015 – 3019; g) B. C. Ranu, Eur. J. Org.
Chem. 2000, 55, 2347 – 2356; h) G. Babu, P. T. Perumal, Aldri-
chimica Acta 2000, 33, 16; i) J. A. Marshall, Chem. Rev. 1996, 96,
31 – 48.
[8] For recent reviews on copper-catalyzed reactions, see: a) I. P.
Beletskaya, A. V. Cheprakov, Coord. Chem. Rev. 2004, 248,
2337 – 2364; b) T. D. Nelson, R. D. Crouch, Org. React. 2004, 63,
265 – 555; c) K. Kunz, U. Scholz, D. Ganzer, Synlett 2003, 2428 –
2439; d) S. V. Ley, A. W. Thomas, Angew. Chem. 2003, 115,
5558 – 5607; Angew. Chem. Int. Ed. 2003, 42, 5400 – 5449; e) B. L.
Feringa, R. Naasz, R. Imbos, L. A. Arnold in Modern Organo-
copper Chemistry (Ed.: N. Krause), Wiley-VCH, Weinheim,
2002, pp. 224 – 258; f) J. Hassan, M. Sevignon, C. Gozzi, E.
Schulz, M. Lemaire, Chem. Rev. 2002, 102, 1359 – 1470; g) C.
Hertweck, J. Prakt. Chem. 2000, 342, 316 – 321.
[9] Such compounds exhibit a wide range of biological activities; for
examples, see: a) R. E. Ziegert, J. Toraeng, K. Knepper, S. Bräse,
J. Comb. Chem. 2005, 7, 147 – 169; b) J. D. Hepworth, B. M.
Heron, Prog. Heterocycl. Chem. 2003, 15, 360.
[10] D. Hermeling, Ger. Offen. DE 4201544, A1 19930729, 1993, p. 5.
[11] a) M. Nakamura, K. Endo, E. Nakamura, J. Am. Chem. Soc.
2003, 125, 13002 – 13003; b) T. Pei, X. Wang, R. A. Widenhoe-
fer, J. Am. Chem. Soc. 2003, 125, 648 – 649; c) D. Yang, J. H. Li,
Q. Gao, Y. L. Yan, Org. Lett. 2003, 5, 2869 – 2871; d) J. J.
Kennedy-Smith, S. T. Staben, F. D. Toste, J. Am. Chem. Soc.
2004, 126, 4526 – 4527; e) X. Yao, C.-J. Li, J. Am. Chem. Soc.
2004, 126, 6884 – 6885; f) R.-V. Nguyen, X. Yao, D. S. Bohle, C.-J.
Li, Org. Lett. 2005, 7, 673 – 675.
[12] H.-B. Zhang, L. Liu, Y.-J. Chen, D. Wang, C.-J. Li, Adv. Synth.
Catal. 2006, 348, 229 – 235.
1952
www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 1949 –1952