Alkynylboronic esters as efficient dienophiles in cobalt-catalyzed Diels-Alder reactions

Article abstract of DOI:10.1002/anie.200351404

Versatile building blocks with a dihydroaromatic vinylic boron substructure can be generated efficiently by cobalt-catalyzed Diels-Alder reactions and used in Suzuki coupling reactions for the synthesis of functionalized polycyclic compounds (see scheme).

Full text of DOI:10.1002/anie.200351404

Angewandte
Chemie
organic synthesis.[1] The synthesis of vinylic boron compounds
by thermal Diels–Alder reactions is rare, since the low
reactivity of alkynylboronic esters[2] and the instability of 2-
boron-functionalized 1,3-dienes[3] prohibit the efficient use of
these materials in these reactions.
In contrast to the thermal Diels–Alder reactions with
alkynylboronic esters, the cobalt(i)-catalyzed cycloaddition[4]
of alkynylboron compounds 1 with the acyclic 1,3-dienes 2
proceeds under very mild conditions to generate the corre-
sponding dihydroaromatic vinylboron compounds 3 in good
yield (Scheme 1).[5] Acatalyst system consisting of
[CoBr2(dppe)]
(dppe = bis(diphenylphosphanyl)ethane),
ZnI2, and Zn powder has proven to be very effective for the
reaction of the alkynylboron compounds.
Scheme 1. Regioselective cobalt(i)-catalyzed Diels–Alder reaction of
alkynylboronic esters with 1,3-dienes.
Alkynyl pinacol boronic esters, alkynyl diisopropylbor-
onic esters, and alkynyl-9-BBN boranes can all be used as the
dienophilic alkyne component. The latter cycloadducts are
much more difficult to isolate than the pinacol derivatives,
which can be purified by regular column chromatography on
silica gel.
The reaction of the alkynylboron compounds with iso-
prene generates predominantly the regioisomer in which the
methyl group of the diene and the boronic ester functionality
have a meta relationship. Both the regioselectivity and the
stability of the adducts increased on going from the 9-BBN
derivatives to the isopropyl boronic esters to the pinacol
boronic esters (Table 1). For the latter adducts the regiose-
lectivity is generally very good (> 95: < 5).[6] In most cases the
other regioisomer could only be detected in traces.[7]
Catalytic Diels–Alder Reactions
Alkynylboronic Esters as Efficient Dienophiles in
Cobalt-Catalyzed Diels–Alder Reactions
Based on the effective control of the regiochemistry, the
mild reaction conditions, and the good yields of the sensitive
dihydroaromatic products, we investigated the subsequent
reactions of the cycloadducts as a platform for the efficient
synthesis of more complex products. The complexity of the
products could be increased significantly by palladium-
catalyzed Suzuki coupling reactions (Scheme 2). The reaction
sequence consisting of the cobalt-catalyzed Diels–Alder
reaction, Suzuki coupling giving 4, and mild oxidation with
DDQ to yield 5 can be performed as a one-pot operation
without isolation of the intermediates. The dihydroaromatic
vinylic boron compounds 3 can be used in sp2/sp2 and sp2/sp
coupling reactions with the corresponding halides to generate
intermediates 4. Thus building blocks can be connected to
give more complex polyfunctionalized structures (Table 2).
Gerhard Hilt* and Konstantin I. Smolko
In memory of Konstantin Smolko
The palladium-catalyzed Suzuki coupling of boron-function-
alized aromatic and vinylic building blocks has been estab-
lished as a useful tool for carbon–carbon bond formation in
[*] Prof. Dr. G. Hilt, K. I. Smolko
Fachbereich Chemie
Philipps-Universität Marburg
Hans-Meerwein-Strasse, 35043 Marburg (Germany)
Fax : (+49)6421-282-5677
E-mail: hilt@chemie.uni-marburg.de
Angew. Chem. Int. Ed. 2003, 42, 2795 – 2797
DOI: 10.1002/anie.200351404
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2795

Communications
Table 1: Results of the cobalt(i)-catalyzed Diels–Alder reaction with
alkynylboronic esters.
Table 2: Results of the reaction sequence consisting of Diels–Alder
reaction, Suzuki coupling, and DDQ oxidation.
Entry
R1
Diene
Product
Yield [%]
Entry
3
R-Hal
5
Yield [%][a]
83
1
Ph
85
1
2
3
Ph
Ph
76
71
2
3
4
89
85
85
4
Ph
68
5
6
Ph
61
85
SiMe3
5
6
73
83
7
8
9
91
63
76
7
8
68
75
9
63
[a] Yield over three steps.
Tricyclic compounds can be prepared efficiently when the
Suzuki coupling of the isopropenyl substituents building
block 6 with alkoxy-functionalized aromatic halides is fol-
lowed by oxidation with DDQ and cleavage of the ether with
trimethylsilyl iodide (Scheme 3). Spontaneous cyclization[8]
gives the framework of the family of cannabinoid natural
products 7. Structural variations are easily accessible by this
Scheme 2. Suzuki coupling of the dihydroaromatic boron derivatives
and subsequent oxidation. dppf=bis(diphenylphosphanyl)ferrocene,
DDQ=dichlorodicyanobenzoquinone.
Scheme 3. Synthesis of heterocyclic compounds from polyfunctionalized dihydroaromatic boron compounds. TMSI=trimethylsilyl iodide.
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modular approach. For example, the Suzuki coupling of 2-
iodobenzylic alcohol and the following acid-catalyzed cycli-
zation generates the structurally related product 8 in good
yield. These and other reactions of dihydroaromatic boron
compounds give an indication of the synthetic potential of this
new class of compounds, which we are currently investigating.
Keywords: alkynes · boron compounds · Diels–Alder reactions ·
dihydroaromatic compounds · Suzuki reaction
.
[1] A. Suzuki, Pure Appl. Chem. 1994, 66, 213; A. Suzuki in Metal-
Catalyzed Cross-Coupling Reactions (Eds.: F. Diederich, P. J.
Stang), Wiley-VCH, Weinheim, 1998, chapt. 2, p. 49.
[2] D. S. Matteson, J. O. Wasserbillig, J. Org. Chem. 1963, 28, 366;
M. A. Silva, S. C. Pellegrinet, J. M. Goodman, J. Org. Chem. 2002,
67, 8203; D. A. Singleton, S.-W. Leung, J. Org. Chem. 1992, 57,
4796; S.-W. Leung, D. A. Singleton, J. Org. Chem. 1997, 62, 1955;
D. A. Singleton, S.-H. Leing, J. Organomet. Chem. 1997, 544, 157;
for an application in the Dötz reaction see: M. W. Davies, C. N.
Johnson, J. P. A. Harrity, J. Org. Chem. 2001, 66, 3525; for an
application in [3þ2]-cycloadditions see: W. M. Davies, R. A. J.
Wybrow, C. N. Johnson, J. P. A. Harrity, Chem. Commun. 2001,
1558; for the synthesis of the alkynylboron derivatives see: H. C.
Brown, N. G. Bhat, M. Srebnik, Tetrahedron Lett. 1988, 29, 2631.
[3] N. Guennouni, C. Rasset-Deloge, B. Carboni, M. Vaultier, Synlett
1992, 581; A. Kamabuchi, N. Miyaura, A. Suzuki, Tetrahedron
Lett. 1993, 34, 4827; M. Shimizu, T. Kurahashi, T. Hiyama, Synlett
2001, 1006; J. Renoud, C.-D. Graf, L. Oberer, Angew. Chem. 2000,
112, 3231; Angew. Chem. Int. Ed. 2000, 39, 3101; F. Carreaux, F.
Posseme, B. Carboni, A. Arrieta, B. Lecea, F. P. Cossio, J. Org.
Chem. 2002, 67, 9153.
[4] For previous reports on cobalt-catalyzed reactions see: G. Hilt, F.-
X. du Mesnil, S. Lꢀers, Angew. Chem. 2001, 113, 408; Angew.
Chem. Int. Ed. 2001, 40, 387; G. Hilt, K. I. Smolko, Synlett 2002,
1081.
[5] When Bu4NBH4 was used as reducing agent for the generation of
the active cobalt(i) catalyst, side reactions such as the reduction of
the triple bond were observed.
[6] The regioselectivity can be explained by steric effects as well as by
an insertion of the alkynylboron derivative into the intermediate
cobaltacycle in terms of a Michael addition.
[7] Traces of a side product could be detected by GC and GCMS,
which could be either a regioisomer or a double-bond isomer (1,3-
cyclohexadiene derivative).
Experimental Section
Synthesis of 2-(5-methyl-2-thiophen-2-yl-phenyl)pyridine (Table 2,
entry 9): A10-mL Schlenk flask was charged with [CoBr 2(dppe)]
(31 mg, 0.05 mmol, 5 mol%), ZnI2 (100 mg, 0.31 mmol, 31 mol%),
and zinc dust (22 mg, 0.3 mmol, 30 mol%) in dry dichloromethane
under a nitrogen atmosphere. After addition of 4,4,5,5-tetramethyl-
(2-thiophen-2-yl-ethynyl)-1,3,2-dioxaborolane (234 mg, 1.0 mmol)
and isoprene (82 mg, 1.2 mmol) the mixture was stirred for 16 h at
ambient temperature (GC, GCMS monitoring). The solvents were
removed, and the residue was dissolved in THF (5 mL) and aqueous
NaOH solution (10%, 2 mL). Then 2-bromopyridine (170 mg,
1.1 mmol) and [PdCl2(dppf)] (70 mg, 0.1 mmol, 10 mol%) were
added. The solution was stirred over night at ambient temperature
then diluted with water (20 mL) and diethyl ether (30 mL). The
aqueous phase was extracted with diethyl ether (2 ” 20 mL), washed
with brine, and dried over Na2SO4. After the solvent was removed,
the residue was dissolved in benzene (10 mL) and DDQ (300 mg,
1.32 mmol) was added in one portion. After 10 min basic Na2S2O3
solution (10% Na2S2O3 and 10% NaOH, 20 mL) was added and the
mixture was stirred for another 5 min. The aqueous phase was
extracted with diethyl ether (2 ” 20 mL), washed with brine, and dried
over Na2SO4. The crude product was purified by column chromatog-
raphy on silica gel, eluting with pentane/diethyl ether (10:1), and the
product was obtained as an oily mass (158 mg, 0.63 mmol, 63%).
1H NMR (C6D6, 300 MHz): d = 2.33 (s, 3H), 6.57 (dd, 1H, J = 3.5 Hz,
1.2 Hz), 6.77 (dd, 1H, J = 3.6 Hz, 5.2 Hz), 6.97–7.20 (m, 4H), 7.33–
7.47 (m, 2H), 7.41 ppm (dd, J = 1.9 Hz, 7.7 Hz); 13C NMR (C6D6,
75 MHz): d = 21.0, 121.6, 124.9, 125.3, 126.7, 127.0, 129.2, 130.2, 130.6,
131.1, 135.4, 137.9, 139.6, 142.9, 149.3, 159.3 ppm; IR (KBr): n˜ = 3066
(m), 2919 (m), 1587 (s), 1562 (s), 1464 (s), 1429 (s), 818 (s), 789(s), 747
(s), 698 cmꢀ1 (s); MS (EI): m/z (%): 250 (M+ꢀ1, 100), 235 (7), 218
(13), 194 (22), 180 (4), 118 (5), 108 (5), 95 (3); HRMS: calcd for
C16H12NS (M+ꢀH): 250.0690, found: 250.0669.
[8] Traces of water should be present so the reaction can reach
completion within 5 minutes.
Received: March 14, 2003 [Z51404]
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