Synthesis of α-acyl-functionalized azacycles by Pd-catalyzed cross-coupling reactions of α-alkoxyboronates with lactam-derived vinyl triflates

Article abstract of DOI:10.1021/jo025930a

Alkoxydienyl- and alkoxystyrylboronates were used for Pd-catalyzed cross-coupling reactions with lactam-derived vinyl triflates. The hydrolysis of the coupling products with alkoxystyrylboronates provided the corresponding α-acyl-substituted 3,4-dihydro-(2H)-pyridines and 2,3,4,5-tetrahydroazepines in good to high yields. The hydrolysis of the coupling products with alkoxydienylboronates, performed in the presence of Amberlyst 15, resulted in a Nazarov-type cyclization that afforded hexahydro[1]pyrindin-7-ones and 3,4,5,6,7,8-hexahydro-(2H)-cyclopenta[b]azepin-8-ones. This methodology represents a novel and efficient procedure for the preparation of these classes of azacyclic compounds.

Full text of DOI:10.1021/jo025930a

this methodology we were able to introduce alkyl, alkenyl,
allyl, aryl, and heteroaryl groups. To functionalize those
heterocycles with various acyl groups,5 we decided to
exploit a new class of readily accessible alkoxyboronates6
which appeared suitable for transferring masked acyl
moieties by a Suzuki-Miyaura cross-coupling reaction.
Subsequent hydrolysis would then furnish the corre-
sponding 6-acyl-3,4-dihydro-(2H)-pyridines and 7-acyl-
2,3,4,5-tetrahydroazepines. Alkoxystannanes have indeed
been employed for this reason but their use has been
limited to one example only.2b In any case the use of
boronates, where possible, is preferable because of their
low toxicity and environmental impact.
We have coupled two different classes of alkoxybor-
onates with N-alkoxycarbonyl triflates 1a ,b and 10
(Schemes 1 and 3). Alkoxydienylboronates 2 and 3 allow
the incorporation of R,â-unsaturated acyl moieties, and
alkoxystyrylboronates 14 and 15 permit the introduction
of aryl-substituted R-acyl groups. These alkoxyboronates
were prepared in high yields according to the reported
procedure.6 As for the triflates, besides the N-Cbz protec-
tion utilized in 1a and 10, we also employed the N-
methoxycarbonyl group (in 1b)7 to have an alternative
protecting group for synthetic purposes. Moreover it
should guarantee a higher stability in the presence of
acids than the N-Boc protection, which we have employed
in our previous studies.4a,b
The reaction between 1a and boronate 2 was carried
out in THF at 50 °C, in the presence of 5% (Ph3P)2PdCl2
as a catalyst and aqueous 2 M Na2CO3 as a base (Scheme
1). It was complete after 3 h, affording ethoxybutadienyl
tetrahydropyridine 4 in 77% yield after chromatographic
purification. Coupling of 1a with the methyl-substituted
ethoxydienylboronate 3 furnished, under the same condi-
tions, product 5 in 78% yield.
Hydrolysis of 4 was first carried out by dissolving the
starting material in CHCl3 in the presence of the acidic
Amberlyst 15 resin at room temperature.8 After 2.5 h the
TLC showed the complete conversion of 4 into a more
polar product that was purified and fully characterized:
to our surprise its structure corresponded to that of
hexahydro[1]pyrindin-7-one compound 8 (obtained in
73% yield after chromatography).9 An analogous result
Syn th esis of r-Acyl-F u n ction a lized
Aza cycles by P d -Ca ta lyzed Cr oss-Cou p lin g
Rea ction s of r-Alk oxybor on a tes w ith
La cta m -Der ived Vin yl Tr ifla tes
Ernesto G. Occhiato,*,† Cristina Prandi,*,‡
Alessandro Ferrali,† Antonio Guarna,†
Annamaria Deagostino,§ and Paolo Venturello§
Dipartimento di Chimica Organica “U. Schiff”, and ICCOM,
Universita` di Firenze, Via della Lastruccia 13, I-50019
Sesto Fiorentino, Italy, Dipartimento di Scienze e Tecnologie
Avanzate, Universita` del Piemonte Orientale, Spalto
Marengo 33, 15100 Alessandria, Italy, and Dipartimento di
Chimica Generale ed Organica Applicata, Universita` di
Torino, Corso Massimo D’Azeglio, 48, I-10125 Torino, Italy
ernesto.occhiato@unifi.it; cristina.prandi@unito.it
Received May 13, 2002
Abstr a ct: Alkoxydienyl- and alkoxystyrylboronates were
used for Pd-catalyzed cross-coupling reactions with lactam-
derived vinyl triflates. The hydrolysis of the coupling
products with alkoxystyrylboronates provided the corre-
sponding R-acyl-substituted 3,4-dihydro-(2H)-pyridines and
2,3,4,5-tetrahydroazepines in good to high yields. The hy-
drolysis of the coupling products with alkoxydienylboronates,
performed in the presence of Amberlyst 15, resulted in a
Nazarov-type cyclization that afforded hexahydro[1]pyrindin-
7-ones and 3,4,5,6,7,8-hexahydro-(2H)-cyclopenta[b]azepin-
8-ones. This methodology represents a novel and efficient
procedure for the preparation of these classes of azacyclic
compounds.
Since it was first reported by Isobe,1 the Pd-catalyzed
functionalization of lactam-derived vinyl triflates2 and
vinyl phosphates3 has become an important tool for the
synthesis of nitrogen-containing heterocycles. We have
recently shown that structurally diverse boronic acids
and esters efficiently couple with vinyl triflates derived
from six- and seven-membered N-alkoxycarbonyl lactams
to give the corresponding 6- and 7-subsituted 3,4-dihydro-
(2H)-pyridines and 2,3,4,5-tetrahydroazepines.4 Using
* Address correspondence to these authors. E.G.O.: Universita` di
Firenze; phone +39-055-4573480; fax +39-055-4573531. C.P.: Uni-
versita` del Piemonte Orientale; phone +39-011-6707647; fax: +39-
0131-287416.
(4) (a) Occhiato, E. G.; Trabocchi, A.; Guarna, A. J . Org. Chem. 2001,
66, 2459-2465. (b) Occhiato, E. G.; Trabocchi, A.; Guarna, A. Org. Lett.
2000, 2, 1241-1242.
(5) Pd-catalyzed carbonylation of lactam-derived triflates might
represent a general route (yet to be explored) for the incorporation of
an acyl moiety. So far, Pd-catalyzed carbonylation has been applied
to these systems only for the introduction of ester and amide groups
(see ref 2b and references therein).
(6) Balma Tivola, P.; Deagostino, A.; Prandi, C.; Venturello, P. Org.
Lett. 2002, 4, 1275-1277.
(7) Compound 1b was prepared in 89% yield from the corresponding
N-CO2Me protected δ-valerolactam according to the procedure reported
for 1a in ref 4a. 1H NMR (CDCl3) δ 5.30 (t, J ) 3.5 Hz, 1 H), 3.78 (s,
3 H), 3.65 (m, 2 H), 2.26 (m, 2 H), 1.78 (m, 2 H).
(8) Prandi, C.; Venturello, P. J . Org. Chem. 1994, 59, 5458-5462.
(9) The structure of this compound was easily assigned by 1H and
13C NMR analysis: in the proton spectrum, the protons on C6 form
an AX system with geminal coupling J ) 15.8 Hz. Only one of the two
protons couples significantly with 5-H (J ) 6.6 Hz). The methyl group
at position 5 resonates as a doublet (J ) 7.0 Hz) due to the coupling
with 5-H. In the carbon spectrum, a triplet at 42.8 ppm and a doublet
at 33.4 are attributable to C6 and C5, respectively.
† Universita` di Firenze.
‡ Universita` del Piemonte Orientale.
§ Universita` di Torino.
(1) (a) Okita, T.; Isobe, M. Tetrahedron 1995, 51, 3737-3744. (b)
Okita, T.; Isobe, M. Synlett 1994, 589-590.
(2) (a) Toyooka, N.; Okumura, M.; Takahata, H. J . Org. Chem. 1999,
64, 2182-2183. (b) Luker, T.; Hiemstra, H.; Speckamp, W. N. J . Org.
Chem. 1997, 62, 8131-8140. (c) Luker, T.; Hiemstra, H.; Speckamp,
W. N. J . Org. Chem. 1997, 62, 3592-3596. (d) Luker, T.; Hiemstra,
H.; Speckamp, W. N. Tetrahedron Lett. 1996, 37, 8257-8260. (e)
Bernabe´, P.; Rutjes, F. P. J . T.; Hiemstra, H.; Speckamp, W. N.
Tetrahedron Lett. 1996, 37, 3561-3564. (f) Foti, C. J .; Comins, D. L.
J . Org. Chem. 1995, 60, 2656-2657. (g) Tsushima, K.; Hirade, T.;
Hasegawa, H.; Murai, A. Chem. Lett. 1995, 9, 801-802. (h) Beccalli,
E. M.; Marchesini, A. Tetrahedron 1995, 51, 2353-2362. (i) Ha, J . D.;
Lee, D.; Cha, J . K. J . Org. Chem. 1997, 62, 4550-4551.
(3) (a) Lepifre, F.; Clavier, S.; Bouyssou, P.; Coudert, G. Tetrahedron
2001, 57, 6969-6975. (b) J iang, J .; De Vita, R. J .; Doss, G. A.; Goulet,
M. T.; Wyvratt, M. J . J . Am. Chem. Soc. 1999, 121, 593-594.
10.1021/jo025930a CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/29/2002
7144
J . Org. Chem. 2002, 67, 7144-7146

SCHEME 1a
aprotic media or â-silyl- or â-stannyl-substituted dienones
are used to perform the reaction.13,14 In our case the
reaction proceeds smoothly at room temperature presum-
ably due to the facile loss of the bridgehead proton from
the intermediate cation.11c Although unsaturated ketone
6 could be invoked as an intermediate in a Nazarov-type
process leading to 8, when pure 6 was dissolved in CHCl3
with Amberlyst 15 it did not give rise to 8. Our mild
procedure to form compounds 8 and 9, which formally
derive from the Nazarov cyclization of R,â-unsaturated
dienones 6 and 7, could therefore be conveniently used
for the preparation of compounds containing the hexahy-
dro[1]pyrindin-7-one structure, a useful intermediate in
natural product synthesis.15 The above synthetic se-
quence was also applied to the synthesis of the larger
3,4,5,6,7,8-hexahydro-(2H)-cyclopenta[b]azepin-8-one 12
(Scheme 1). Coupling of caprolactam-derived vinyl triflate
104a with 2 (Scheme 1) afforded azepine derivative 11 in
45% yield after chromatography. As already observed for
this triflate,4a the coupling yield was lower compared to
that obtained with the corresponding six-membered
triflate 1a due to its partial decomposition during the
course of the reaction. Subsequent hydrolysis over Am-
berlyst 15 gave the Nazarov product 12 in 41% yield after
chromatography together with a smaller amount of R,â-
unsaturated ketone 13 (13%).
a
Conditions: (a) (Ph3P)2PdCl2 (5%), THF, 2 M Na2CO3, 50 °C;
(b) Amberlyst 15, CHCl3, 25 °C; (c) 0.02 M HCl, MeOH, 25 °C; (d)
(Ph3P)4Pd (3%), toluene, EtOH, 2 M K2CO3, 25 °C.
The incorporation of aryl-substituted R-acyl moieties
was realized by coupling the suitable alkoxystyrylbor-
onates 14 and 15 with triflates 1a ,b and 10 (Scheme 3).
The reaction between 1a and 14, carried out in THF in
the presence of 5% (Ph3P)2PdCl2 and 2 M Na2CO3,
smoothly gave product 16 in 81% yield after 3 h at 50
°C. When 2-methyl-substituted styryl boronate 15 was
used as the coupling partner with 1a and 1b, the reaction
rate apparently decreased dramatically, the conversions
to 17 and 18 being about 5 and 30%, respectively, after
4 h at 60 °C. The increased steric hindrance due to the
further degree of substitution at the C-C double bond
in 15 could be a reason for the low conversion observed.16
The coupling yields were greatly improved when the
reactions between 15 and triflates 1a and 1b were
conducted in toluene in the presence of (Ph3P)4Pd (3%)
as a catalyst, aqueous 2 M K2CO3, and with EtOH as a
cosolvent. GC monitoring revealed the disappearance of
the reagents after 4 h at room temperature in the case
of triflate 1b. The reaction of N-Cbz-protected triflate 1a
was slower, being complete after 16 h at 25 °C and 2 h
SCHEME 2
was obtained when 5 was subjected to the same condi-
tions, affording pure 9 in 71% yield after chromatogra-
phy. In this case a very small amount (about 5% yield)
of R,â-unsaturated ketone 7 was obtained from the
chromatography of the crude reaction mixture.
R,â-Unsaturated ketone 6 was isolated from a mixture
containing product 8 when the hydrolysis of 4 was carried
out under aqueous acidic conditions, i.e., dissolving 4 in
a dilute HCl solution in MeOH and stirring at room
temperature. After 2 h the reaction was complete (by
1
TLC) and H NMR analysis of the crude reaction mixture
revealed the presence of two major products in a 1:1 ratio.
After chromatographic separation, 6 and 8 were obtained
in moderate yields (35 and 31%, respectively).
The formation of product 8 (and 9) can be accounted
for by the initial protonation of the distal double bond10
followed by an immediate Nazarov-type electrocyclization
(Scheme 2). The Nazarov cyclization11 usually occurs
under quite drastic conditions (concentrated protic acids
and high temperature)12 unless either Lewis acids in
(12) For example, the cyclization of 2-(3-methylbut-2-enoyl)indoles
to give the corresponding cyclopenta[b]indolones occurred by heating
at 110 °C with polyphosphoric acid: Bergman, J .; Venemalm, L.;
Gogoll, A. Tetrahedron 1990, 46, 6067-6084.
(13) (a) Cooke, F.; Moerck, R.; Schwindeman, J .; Magnus, P. J . Org.
Chem. 1980, 45, 1046-1045. (b) Paquette, L. A.; Fristad, W. E.; Dime,
D. S.; Bailey, T. R. J . Org. Chem. 1980, 45, 3017-3028. (c) J ones, T.
K.; Denmark, S. E. J . Am. Chem. Soc. 1982, 104, 2642-2645. (b) Peel,
M. R.; J ohnson, C. R. Tetrahedron Lett. 1986, 27, 5947-5950.
(14) The Nazarov reaction carried out on compounds closely related
to those reported in ref 12 occurred after heating for 2 h in the presence
of BF3: Miki, Y.; Hachiken, H.; Sugimoto, Y.; Yanase, N. Heterocycles
1997, 45, 1759-1766.
(15) For example see: Heathcock, C. H.; Norman, M. H.; Dickman,
D. A. J . Org. Chem. 1990, 55, 798-811.
(16) Progressive degradation of boronate 15 during the course of the
reaction also has been observed. We isolated by chromatography a
product having the following structure: Ph(Me)CdC(OMe)H. In the
1H NMR spectrum of the reaction mixtures, the dCH signal at 6.38
ppm of this olefin was diagnostic.
(10) The initial double bond protonation that takes place in the
formation of 8 is consistent with the proposed mechanism of γ-pyranone
ring closure observed when substrates containing the same alkoxydi-
enyl moiety were hydrolyzed. Prandi, C.; Venturello, P. J . Org. Chem.
1994, 54, 3494-3496.
(11) (a) Nazarov, I. N.; Torgov, I. B.; Terekhova, L. N. Izv. Akad.
Nauk SSSR Otd. Khim. Nauk 1942, 200. (b) Braude, E. A.; Forbes,
W. F. J . Chem. Soc. 1953, 2208-2216. (c) Giese, S.; West, F. G.
Tetrahedron 2000, 56, 10221-10228 and references therein.
J . Org. Chem, Vol. 67, No. 20, 2002 7145

SCHEME 3a
thetically, therefore, the use of the N-CO2Me group is
preferable to N-Cbz protection in our methodology since
the formation of a methyl cation through the mechanism
reported in Scheme 3 is disfavored. Finally, coupling of
caprolactam-derived vinyl triflate 10 with 14 (Scheme 3)
gave 22 in inferior yield (50%) than the coupling of 14
with 1a . Hydrolysis under the usual conditions afforded
R-acyl azepine 23 in 54% yield.
In conclusion we have successfully used alkoxydienyl-
and alkoxystyrylboronates for Pd-catalyzed cross-cou-
pling reactions with lactam-derived vinyl triflates. The
hydrolysis of the coupling products with alkoxystyryl-
boronates provided the corresponding R-acyl-substituted
3,4-dihydro-(2H)-pyridines and 2,3,4,5-tetrahydroazepines
in good to high yields. The hydrolysis of the coupling
products with alkoxydienylboronates, performed with
Amberlyst 15, resulted instead in a Nazarov-type cy-
clization that afforded hexahydro[1]pyrindin-7-ones and
3,4,5,6,7,8-hexahydro-(2H)-cyclopenta[b]azepin-8-ones. This
methodology represents a novel and efficient procedure
for the preparation of these classes of azacyclic com-
pounds. The extension of the methodology to the synthe-
sis of more complex heterocyclic structures is currently
under study.
Ack n ow led gm en t. We thank MIUR and University
of Florence (COFIN 2000-2002) for financial support.
Mr. Sandro Papaleo and Mrs. Brunella Innocenti are
acknowledged for their technical support.
a
Conditions: (a) (Ph3P)2PdCl2 (5%), THF, 2 M Na2CO3, 50 °C;
(b) (Ph3P)4Pd (3%), toluene, EtOH, 2 M K2CO3, 25 °C; (c) Amberlyst
15, CHCl3, 25 °C; (d) 0.5 M HCl, MeOH, 25 °C, 16 h.
at 40 °C. Chromatographic purifications afforded 17 and
18 in 68% and 64% yield, respectively.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and full characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The hydrolysis of 16 in the presence of Amberlyst 15
in CHCl3 was quite slow compared with that of 4 and 5,
but provided the corresponding R-aryl ketone 19 in 71%
yield after 8 h at room temperature. The N-CO2Me
protection in compound 17 was stable under the same
hydrolysis conditions since compound 20 was obtained
in 93% yield after 12 h at room temperature.
When the same reaction was performed on N-Cbz-
protected compound 18, oxazolidinone 21 was obtained
as the only product after 20 h at room temperature (74%
yield after chromatography). The formation of 21 can be
explained, as depicted in Scheme 3, by attack of the
carbamate CdO group on the carbocation formed after
initial protonation of the double bond. The process is
favored by the loss of the benzyl cation.17,18 Hydrolysis
of 18 in a diluted methanolic HCl solution confirmed this
experimental result, since it afforded 21 as the only
detectable product (78% after chromatography).19,20 Syn-
J O025930A
(17) In the hydrolysis of 16, about 10% of the crude reaction mixture
(from 1H NMR analysis) was attributable to the corresponding cyclic
carbamate, but this was not isolated.
(18) In the 1H NMR spectrum of 21 the proton on C5 resonates at
4.83 ppm (shielded due to the lack of conjugation with the CdO) and
the OMe group resonates at 3.25 ppm as a singlet. In the 13C NMR
spectrum, C5 resonates at 98.0 ppm (usually at about 120 ppm in
compounds such as 19 and 20) and the OMe as a quartet at 48.2 ppm.
The quaternary acetal C atom resonates at 108.6 ppm as a singlet and
the CdO group at 153.6 ppm. In the IR spectrum this has a strong
absorption at 1759 cm-1
.
(19) Product 21 was also recovered during an attempt at purification
of compound 18 on silica gel without the addition of Et3N to the eluant.
(20) A similar process has been reported very recently by Comins,
although in that case the cyclization, which took place after addition
of I2 to a double bond, gave rise to a six-membered cyclic carbamate:
Williams, A. L.; Grillo, T. A.; Comins, D. L. J . Org. Chem. 2002, 67,
1972-1973.
7146 J . Org. Chem., Vol. 67, No. 20, 2002