Pd(0)-catalyzed cross-coupling reactions of boron derivatives with a lactam-derived N-Boc enol triflate

Article abstract of DOI:10.1021/ol005759u

(equation presented) The cross-coupling reaction of 2-(1-alkenyl)-1,3,2-benzodioxaboroles, obtained from alkynes and catecholborane, and other boron derivatives with a lactam-derived N-Boc enol triflate occurred under very mild conditions in a THF-water m

Full text of DOI:10.1021/ol005759u

ORGANIC
LETTERS
2000
Vol. 2, No. 9
1241-1242
Pd(0)-Catalyzed Cross-Coupling
Reactions of Boron Derivatives with a
Lactam-Derived N-Boc Enol Triflate
Ernesto G. Occhiato,* Andrea Trabocchi, and Antonio Guarna
Dipartimento di Chimica Organica “U. Schiff” and Centro di Studio sulla Chimica e
la Struttura dei Composti Eterociclici e loro Applicazioni, C.N.R.; UniVersita` di
Firenze, Via G. Capponi 9, I-50121 Firenze, Italy
labgua@chimorg.unifi.it
Received March 6, 2000
ABSTRACT
The cross-coupling reaction of 2-(1-alkenyl)-1,3,2-benzodioxaboroles, obtained from alkynes and catecholborane, and other boron derivatives
with a lactam-derived N-Boc enol triflate occurred under very mild conditions in a THF−water medium employing (Ph3P)2PdCl2 as a catalyst,
providing the corresponding 6-substituted N-Boc 3,4-dihydro-2H-pyridines in high yields.
In recent years, lactam-derived enol triflates have gained
importance as intermediates in the synthesis of heterocyclic
compounds. Hiemstra and Speckamp1 have shown that these
compounds can undergo palladium-mediated displacement
of the triflate group with nucleophiles such as organotin and
organozinc derivatives, as well as methoxycarbonylation
reactions. Comins2 and other authors3,4 have reported cou-
pling reactions with organocuprates and organotin com-
pounds, while Sonogashira-type cross-coupling reactions with
monosubstituted acetylenes have been described by Isobe5
and, more recently, by Cha.6 Surprisingly, no examples of
Suzuki-type reactions of lactam-derived enol triflates have
been yet described, although the use of organoboron com-
pounds as nucleophiles in Pd-catalyzed cross-coupling reac-
tions with vinyl and aryl triflates or halides is a powerful
methodology in organic synthesis.7
dioxaboroles and other boron derivatives with six-membered
enol triflates such as 2 (Scheme 1), bearing a N-Boc
protecting group, would certainly extend the utility and scope
of this class of compounds8 in the preparation, and the further
synthetic elaboration, of heterocyclic compounds.1,2,9 More-
over, the N-Boc protection provides a possible alternative
Scheme 1
The possibility of forming new C-C bonds by Pd(0)-
catalyzed coupling reactions of 2-(1-alkenyl)-1,3,2-benzo-
(1) (a) Luker, T.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1997,
62, 8131-8140. (b) Luker, T.; Hiemstra, H.; Speckamp, W. N. Tetrahedron
Lett. 1996, 37, 8257-8260. (c) Bernabe´, P.; Rutjes, F. P. J. T.; Hiemstra,
H.; Speckamp, W. N. Tetrahedron Lett. 1996, 37, 3561-3564.
(2) Foti, C. J.; Comins, D. L. J. Org. Chem. 1995, 60, 2656-2657.
(3) Tsushima, K.; Hirade, T.; Hasegawa, H.; Murai, A. Chem. Lett. 1995,
9, 801-802.
(4) Beccalli, E. M.; Marchesini, A. Tetrahedron 1995, 51, 2353-2362.
(5) Okita, T.; Isobe, M. Tetrahedron 1995, 51, 3737-3744.
(6) Ha, J. D.; Lee, D.; Cha, J. K. J. Org. Chem. 1997, 62, 4550-4551.
(7) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
10.1021/ol005759u CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/06/2000

to other electron-withdrawing protecting groups such as
N-tosyl,1 N-Bz,2,3 or N-Cbz,2,9 since it is removable under
different conditions.
product, which we observed when performing the reaction
under the usual conditions.
N-Boc-protected compounds 4a-c are potential dienes for
Diels-Alder reactions, as reported for closely related
compounds in which the N atom bore a tosyl1a or a Cbz
group.9 We carried out the cycloaddition between 4a and
4b and N-phenylmaleimide 9 (2.5 equiv) (Scheme 3) in
N-Boc enol triflate 2 was prepared in 75% yield by
treatment of N-Boc lactam 1 with LiHMDS and N-phenyl-
triflimide, in the presence of HMPA.3 The reaction of 2 with
2-[(E)-1-hexenyl]-1,3,2-benzodioxaborole 3a10 (Scheme 1)
was first attempted under the classical conditions reported
for the reaction of enol triflates with alkenylboronate, i.e.,
using (Ph3P)4Pd catalyst in dioxane at 85 °C and K3PO4 as
a base.11 However, the reaction did not occur at all,
recovering after 5 h the unreacted starting material 2. Instead,
when we used (Ph3P)2PdCl2 as a catalyst (5% mol) in a
THF-water mixture and in the presence of Na2CO3 as a
base (Scheme 1), the reaction proceeded very fast at 80 °C,
affording 4a12 after 2 h in 81% yield and with maintenance
of the double bond geometry; the reaction rate was slightly
slower at 40 °C (82% yield after 6 h), while at room
temperature it reached completion (82% yield) after 16 h.
We tested also the more hindered (o-tol3P)2PdCl2 for the
reaction of 2 with 3a, but the reaction was slower, furnishing
4a in 16% yield after 48 h at room temperature.
Two other alkenylboronates, 3b,c, prepared from the
corresponding alkynes and catecholborane as reported,10 were
used as nucleophiles (Scheme 1). The reactions, always
carried out with (Ph3P)2PdCl2, were successful in providing
the corresponding products 4b,c. After 6 h at 40 °C, the
conversion was complete in both cases. Compound 4b,
obtained in 76% yield, maintained the E geometry of the
double bond. This compound in particular was quite acid
sensitive, and even when left in CDCl3 solution it underwent
ring opening to give 5 in a 6:1 ratio with 4b after 48 h
(Scheme 1).
Scheme 3
refluxing benzene obtaining, after 2 h, endo-cycloadducts
10 (74%) and 11 (71%) in which migration of the double
bond to the more substituted position occurred.9 The endo
stereochemistry, easily assignable by the 1H NMR coupling
constant value of about 4.0 Hz between protons Ha and Hb
(in cis relationship), is in accordance with the results obtained
by Cha in the cycloaddition of N-phenylmaleimide with a
similar N-Cbz-protected substrate.9
In conclusion, we have shown that the coupling reaction
of alkenylboronates and other boron derivatives with six-
membered lactam-derived N-Boc enol triflates is feasible
under very mild conditions in THF-water employing
(Ph3P)2PdCl2 as a catalyst, which provides in high yields the
corresponding 6-(1-alkenyl)- and 6-aryl-substituted N-Boc
3,4-dihydro-2H-pyridines. The former are useful dienes for
Diels-Alder reactions in the construction of more complex
heterocyclic structures.
For the introduction of an aryl group, we found convenient
the use of aryldiethylboranes, 2-aryl-1,3,2-dioxaborinanes,
and arylboronic acids, such as commercially available
compounds 6a-c (Scheme 2). Diethyl(3-pyridyl)borane 6a
Acknowledgment. We thank MURST, the University of
Florence (COFIN 1998-2000), and Consiglio Nazionale
delle Ricerche (CNR) for financial support. Dr. Dina Scarpi
and Dr. Fabrizio Machetti are acknowledged for carrying
out some preliminary experiments. Mr. Sandro Papaleo and
Mrs. Brunella Innocenti are acknowledged for their technical
support.
Scheme 2
Supporting Information Available: Experimental pro-
cedures and characterization of compounds 4a-c, 7-8, 10,
and 11. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL005759U
(8) The extension of the methodology to five-membered enol triflates
from N-acylpyrrolidin-2-ones is not immediate due to the high instability
and difficulty in the isolation of these compounds (see refs 1a,b and 2).
(9) Ha, J. D.; Kang, C. H.; Belmore, K. A.; Cha, J. K. J. Org. Chem.
1998, 63, 3810-3811.
(10) (a) Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1975, 97, 5249-
5255. (b) Miyaura, N.; Suzuki, A. Org. Synth. 1990, 68, 130-136.
(11) Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201-
2208.
reacted fast with 2 under the usual conditions at 80 °C,
providing 7 in 91% yield after 2 h. The reaction of boron
derivative 6b with 2 was complete after 3 h at 40 °C,
affording 6-phenyl-substituted N-Boc 3,4-dihydro-2H-pyri-
dine 8 in 85% yield. The same compound was obtained in
87% yield after 2 h at 40 °C using phenylboronic acid 6c.
In this case, we increased the volume of the aqueous 2 M
Na2CO3 solution to avoid a possible ring opening of the
(12) All new compounds were fully characterized and gave satisfactory
elemental analysis.
1242
Org. Lett., Vol. 2, No. 9, 2000