Synthesis of functionalized spiroheterocycles by sequential multicomponent reaction/metal-catalyzed carbocylizations from simple β-ketoesters and amides

Article abstract of DOI:10.1055/s-2007-973896

A new strategy from simple cyclic β-ketoesters or amides involving a selective three-component reaction and a ring-closing metathesis or a palladium-catalyzed carbocyclization in a sequential fashion to access spiroheterocycles is reported. This expedient

Full text of DOI:10.1055/s-2007-973896

LETTER
1037
Synthesis of Functionalized Spiroheterocycles by Sequential Multicomponent
Reaction/Metal-Catalyzed Carbocylizations from Simple b-Ketoesters and
Amides
S
ynthesis of Funct
a
ionalized S
d
piroheterocy
j
cles ira Habib-Zahmani,a Jacques Viala,*b Salih Hacini,a Jean Rodriguez*b
a
Laboratoire de Synthèse Organique, Institut de Chimie, Université d’Oran-Es-Sénia, BP-1524, 31000 Oran, Algérie
b
Faculté des Sciences et Techniques, Université Paul Cézanne (Aix-Marseille III), UMR CNRS 6178 SYMBIO,
Boîte 531, 13397 Marseille Cedex 20, France
Fax +33(4)91289187; E-mail: jean.rodriguez@univ-cezanne.fr
Received 12 February 2007
and specialized heterocyclic scaffolds.8 As part of our ef-
forts to develop new routes to construct novel heterocyclic
structures with high synthetic and biological potential, we
have recently reported efficient MCRs from 1,3-dicarbo-
Abstract: A new strategy from simple cyclic b-ketoesters or
amides involving a selective three-component reaction and a ring-
closing metathesis or a palladium-catalyzed carbocyclization in a
sequential fashion to access spiroheterocycles is reported. This
expedient two-step sequence generates compounds of significant nyl compounds9 including b-ketoesters and b-keto-
amides.10 In this communication we report on our efforts
molecular complexity and high synthetic and biological relevance
from simple and readily available starting materials.
on extensions and postmodifications of our previously
Key words: multicomponent reactions, ring-closing metathesis,
Heck reaction, spiroheterocycles, 1,3-dicarbonyl compounds
developed three-component a,g-difunctionalization of b-
ketoesters and amides10b using either a ring-closing meta-
thesis (RCM) or a palladium-catalyzed carbocyclization
as ultimate step in the sequence for the selective elabora-
Multicomponent reactions (MCRs),1 combining at least tion of spiroheterocycles (Scheme 1).
three different substrates in a one-pot operation, constitute
Although spirobicyclic rings are less represented in nature
nowadays a central academic and industrial investigation
domain2 in diversity-oriented synthesis3 of functionalized
heterocycles. These very efficient atom-4 and step-
economic5 transformations also combine increase in
molecular and functional complexity with practical and
environmental concerns,6 approaching quite closely the
concept of an ideal synthesis.7 In recent years, some of
these transformations involving isocyanides have been
combined with specific chemical post-condensation mod-
ifications that allow access to even more functionalized
compared to other fused systems, they occur widely
through terrestrial plants, marine organisms or fungi and
therefore have attracted considerable interest from both
theoretical and synthetic points of view.11 More particu-
larly, the spiroheterocyclic nucleus is present in a variety
of natural products and biologically active compounds
and can be of importance in the development of new
medicinally relevant heterocyclic scaffolds. For example,
a new class of marine toxins isolated from shellfish and
dinoflagellate, such as pinnatoxins12 and pteriatoxin,13
O
RCM
Ar
YR = N(allyl)Me
Y
X
O
O
= O(allyl)
O
R
Y
O
O
X
( )n
DBU
THF–MeOH
+
z
Heck
Ar
Ar
Y
R
N
N
YR = N(allyl)Me
X
X
( )n
Br
O
O
z
+
O
Buchwald
ArCHO
Ph
Ar
YR = NHPh
X
( )n
O
Scheme 1 General method for spiroheterocycles
SYNLETT 2007, No. 7, pp 1037–1042
2
4.
0
4.
2
0
0
7
Advanced online publication: 13.04.2007
DOI: 10.1055/s-2007-973896; Art ID: G05207ST
© Georg Thieme Verlag Stuttgart · New York

1038
H. Habib-Zahmani et al.
LETTER
1a: n = 0 R1 = allyl
b: n = 0 R1 = allyl,
c: n = 0 R1 = N(allyl)Me Y = CH2
d: n = 0 R1 = N(allyl)Me Y = S
Y = CH2
Y = S
O
COR1
Y
( )n
e: n = 0
R
1 = NHPh
Y = CH2
Y = CH2
O
f : n = 1 R1 = NHPh
R3
COR1
R2
DBU
+
Y
THF–MeOH
O
2a: R2 = Ph
b: R2 = 2-furyl
( )n
R2
H
4a–i
+
3a: R3 = allyl
b: R3 = 2-bromopropenyl
c: R3 = pent-2-ynyl
R3 Br
Scheme 2 MCRs with cyclic b-ketoesters and amides
exhibits an azaspiro[6,5] system responsible for the bio- The success of our methodology rests upon the functional
logical activity. Therefore, targeting these heterocyclic tolerance of the MCR both in the carbocyclic and in the
cores has long been an area of intense development and heterocyclic series. Therefore, the new properly function-
still constitutes an active domain. Although numerous alized precursors for the carbocyclizations, bearing the
methods have been reported for the synthesis of function- required quaternary carbon atom, were readily obtained
alized spiroheterocyclic compounds, our approach consti- by varying the 1,3-dicarbonyl compound 1, the aldehyde
tutes the first implication of a totally chemo-, regio-, and 2 and the electrophile 3 components (Scheme 2).
stereoselective MCR coupled with specific post-conden-
sations and using simple and readily available cyclic b-ke-
toesters and amides.14
Table 1 MCRs Leading to Spiroheterocyclic Precursorsa
Entry
Ketoester Aldehyde R2 Halide R3
Time (h)
24c
Product
Yield (%)b
72
O
1
1a
1b
1d
2-furyl
2-furyl
2-furyl
allyl
allyl
allyl
4a10c
O
O
O
O
O
12d
48
4b
68
48
O
O
2
3
O
N
S
S
O
O
4c
O
4
1c
2-furyl
pent-2-ynyl
48
4d
38
O
N
O
O
5
6
1d
1c
2-furyl
pent-2-ynyl
48
48
4e
4f
46
34
O
N
S
O
O
Br
Ph
2-bromopropenyl
Ph
N
O
Synlett 2007, No. 7, 1037–1042 © Thieme Stuttgart · New York

LETTER
Synthesis of Functionalized Spiroheterocycles
1039
Table 1 MCRs Leading to Spiroheterocyclic Precursorsa (continued)
Entry
Ketoester Aldehyde R2 Halide R3
Time (h)
Product
Yield (%)b
41
O
Br
7
1d
1e
1f
Ph
2-bromopropenyl
2-bromopropenyl
2-bromopropenyl
48
4g
4h
4i
Ph
N
S
O
O
Br
O
8
9
2-furyl
Ph
24
24
90
39
Ph
N
H
O
O
Br
Ph
Ph
N
H
O
a Unless otherwise specified, the reactions were conducted in MeOH at reflux.
b Isolated yield.
c The reaction was run in THF containing 10% MeOH at r.t.
d The reaction was performed at 0 °C to prevent transesterification.
Under general experimental conditions (Table 1) consist-
Mes
P(Cy)3
N
N
Mes
Ph
ing in the utilization of DBU as base in MeOH, both b-ke-
toesters (entries 1 and 2), tertiary b-ketoamides (entries 3–
7), and secondary b-ketoamides (entries 8 and 9) includ-
ing the thioheterocyclic series gave good to excellent re-
sults.15 The reaction proceeded smoothly either with allyl
bromide (3a), 2-bromopropenyl bromide (3b) or pent-2-
ynyl bromide (3c) as electrophiles allowing the selective
and modular preparation of RCM precursors 4a–e and
vinylic bromides 4f–i required for the palladium carbo-
cyclizations (Table 1). Compounds 4a–h exhibit the E-
configuration of the double bond as we have shown in our
previous paper.10b
Cl
Cl
Cl
Ru
Ru
Ph
Cl
P(Cy)3
P(Cy)3
5a
5b
Figure 1 Grubbs’ first- and second-generation catalysts
4d,e also proceeded smoothly to give the expected spiro-
structures 6d,e bearing a synthetically valuable 1,3-diene,
with acceptable yields (entries 4 and 5).
Alternatively, compounds 4f–i were properly functional-
ized to be involved in intramolecular palladium-catalyzed
carbocyclizations such as Heck18 reaction and Buchwald19
amidation. To this end, compounds 4f,g were easily
cyclized with a comparable efficiency under standard
conditions using Pd(OAc)2 and PPh3 in the presence of
Et3N in refluxing MeCN (entries 6, 7).20 The expected
spiro[6,4]lactams 7a,b conserved the feature of a synthet-
ically useful exocyclic cis-fixed 1,3-diene which reacted
with dimethyl acetylenedicarboxylate (DMAD) in reflux-
ing benzene to give the tricyclic skeleton 8 with 93% yield
(Scheme 3).
With this selection of new, highly functionalized precur-
sors in hand we started to explore their chemistry taking
advantage of the presence of a quaternary center for the
construction of diverse spirostructures 6 and 7 (Table 2).
We looked first at the RCM starting with diallyl ketoester
4a which we found not to be trivial. Indeed, the RCM
turned out to be highly catalyst-dependent, since only
degradation was observed or no conversion was reached
with up to 20 mol% of the first-generation Grubbs’ cata-
lyst 5a (Figure 1), regardless of the reaction conditions or
adding various amounts of Ti(Oi-Pr)4 in order to prevent
the deactivation of the catalyst.16 Alternatively, a substan-
tial yield of 59% was achieved for spiro[6,4]lactone 6a
when 20 mol% of the more active second-generation
Grubbs’ catalyst 5b was used in refluxing CH2Cl2 for 30
hours (Table 2, entry 1).17
Finally, bromoolefins 4h,i were subjected to the standard
catalytic amidation conditions involving the Pd(OAc)2–
DPEphos [bis(2-diphenylphosphinophenyl)ether] system
to
give
the
exo-methylene
spiro[4,4]-
and
spiro[5,4]amides 7c and 7d with 66% and 40% yields,
On the basis of the success of this model system, the cor-
responding sulfur-containing spirolactone 6b and spiro-
lactam 6c were obtained in 56% and 70% yields,
respectively (entries 2 and 3) with a surprisingly much
lower catalyst loading despite the presence of the sulfur
atom. On the other hand, the enyne-RCM of precursors
respectively (entries 8 and 9).
In conclusion, we have shown that the combination of the
three-component a,g-difunctionalization of 1,3-dicarbon-
yl compounds with diene- and enyne-RCM or palladium-
catalyzed carbocyclizations constitutes a new, easy and
modular access to a variety of functionalized spirohetero-
Synlett 2007, No. 7, 1037–1042 © Thieme Stuttgart · New York

1040
H. Habib-Zahmani et al.
LETTER
Table 2 Spiroheterocycles from Compounds 4
Entry
1
MCR
Conditions
Product
Yield (%)a
59
O
O
O
O
4a
20 mol%, 30 hb
6a
6b
6c
O
O
N
O
O
O
O
O
2
3
4b
4c
10 mol%, 10 hb
5 mol%, 4 hb
56
70
S
S
O
4
5
4d
10 mol%, 12 hb
6d
59
O
N
O
O
4e
4f
5 mol%, 7 hb
6e
7a
62
73
O
N
S
O
O
6
7
8
PPh3, Et3N, 17 hc
N
O
O
4g
4h
4i
PPh3, Et3N, 17 hc
K2CO3, 24 hd
K2CO3, 24 hd
7b
7c
7d
72
66
40
N
S
O
O
O
N
O
O
O
N
9
a Isolated yield.
b All RCM were performed in anhyd CH2Cl2 at reflux using catalyst 5b.
c Heck reactions were performed in refluxing anhyd MeCN using Pd(OAc)2 (5 mol%) as catalyst.
d Buchwald amidations were performed in refluxing toluene using the Pd(OAc)2–DPEphos (10:15; mol%) system as catalyst.
cycles including [4,4]-, [5,4]- and [6,4]-lactone and
lactam systems as potential synthetic scaffolds for the
discovery of novel lead structures.
Acknowledgment
We thank Dr. Robert Faure for helpful assistance with NMR struc-
ture determinations, the French Research Ministry, the CNRS and
the Université Paul Cézanne (UMR 6178) for financial support.
Synlett 2007, No. 7, 1037–1042 © Thieme Stuttgart · New York

LETTER
Synthesis of Functionalized Spiroheterocycles
1041
O
CO2Me
CO2Me
N
O
O
PhH, reflux
93%
7a
N
CO2Me
O
8
+
CO2Me
Scheme 3 Diels–Alder reaction on spirolactam 7a
(11) (a) Sannigrahi, M. Tetrahedron 1999, 55, 9007. (b) Martin,
J. D. In Studies in Natural Products Chemistry, Vol. 6;
Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1990, 59.
(c) El Bialy, S. A. A.; Braun, H.; Tietze, L. F. Synthesis
2004, 2249.
(12) Takada, N.; Umemura, N.; Suenaga, K.; Chou, T.; Nagatsu,
A.; Haino, T.; Yamada, K.; Uemura, D. Tetrahedron Lett.
2001, 42, 3491.
(13) Takada, N.; Umemura, N.; Suenaga, K.; Uemura, D.
Tetrahedron Lett. 2001, 42, 3495.
(14) (a) See ref. 10b. (b) Charonnet, E.; Filippini, M. H.;
Rodriguez, J. Synthesis 2001, 788.
(15) General Procedure for MCRs: To a solution of ketoester or
ketoamide 1 (1 mmol) and DBU (3 mmol) in appropriate
solvent (4 mL, Table 1) was added the corresponding
aldehyde 2 (1.1 mmol) and halide 3 (2 mmol). The resulting
solution was stirred for the indicated time and at the
indicated temperature (Table 1). After completion of the
reaction and evaporation of most of the solvent under
reduced pressure, 1 N solution of HCl (30 mL) was added to
the oily residue. Extraction with Et2O (3 × 40 mL) followed
by successive washing with distilled H2O (2 × 20 mL) and
brine (20 mL) gave, after drying (MgSO4) and evaporation
of the solvent, the crude compounds which were purified by
flash chromatography on silica gel.
References and Notes
(1) (a) For a recent monograph, see: Multicomponent
Reactions; Zhu, J.; Bienaymé, H., Eds.; Wiley-VCH:
Weinheim, 2005. For some recent reviews on MCRs, see:
(b) Dömling, A. Chem. Rev. 2006, 106, 17; and references
cited therein. (c) Bienaymé, H.; Hulme, C.; Oddon, G.;
Schmitt, P. Chem. Eur. J. 2000, 6, 3321. (d) Dömling, A.;
Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168. (e) Zhu, J.
Eur. J. Org. Chem. 2003, 1133. (f) Orru, R. V.; de Greef, M.
Synthesis 2003, 1471. (g) Ramon, D. J.; Yus, M. Angew.
Chem. Int. Ed. 2005, 44, 1602. For representative reviews,
see: (h) Tietze, L. F. Chem. Rev. 1996, 96, 115. (i) Tietze,
L. F.; Lieb, M. E. Curr. Opin. Chem. Biol. 1998, 2, 363.
(j) Rodriguez, J. Synlett 1999, 505. (k) Tietze, L. F.;
Brasche, G.; Gericke, K. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, 2006.
(2) Weber, L.; Illgen, M.; Almstetter, M. Synlett 1999, 366.
(3) Schreiber, S. L. Science 2000, 287, 1964.
(4) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M.
Angew. Chem. Int. Ed. 1995, 34, 258. (c) Trost, B. M. Acc.
Chem. Res. 2002, 35, 695.
(5) (a) Wender, P. A.; Bi, F. C.; Gamber, G. G.; Gosselin, F.;
Hubbard, R. D.; Scanio, M. J. C.; Sun, R.; Williams, T. J.;
Zhang, L. Pure Appl. Chem. 2002, 74, 25. (b) Wender, P.
A.; Baryza, J. L.; Brenner, S. E.; Clarke, M. O.; Gamber, G.
G.; Horan, J. C.; Jessop, T. C.; Kan, C.; Pattabiraman, K.;
Williams, T. J. Pure Appl. Chem. 2003, 75, 143.
(c) Wender, P. A.; Baryza, J. L.; Brenner, S. E.; Clarke, M.
O.; Craske, M. L.; Horan, J. C.; Meyer, T. Curr. Drug
Discov. Technol. 2004, 1, 1. (d) Wender, P. A.; Gamber, G.
G.; Hubbard, R. D.; Pham, S. M.; Zhang, L. J. Am. Chem.
Soc. 2005, 127, 2836.
(6) For a special issue in environmental chemistry, see:
Grissom, C. B. Chem. Rev. 1995, 95, 3.
(7) Wender, P. A.; Handy, S. T.; Wright, D. L. Chem. Ind.
(London) 1997, 765.
(8) (a) See refs 1a and 1b. (b) Gracias, V.; Gasiecki, A. F.;
Djuric, S. W. Org. Lett. 2005, 7, 3183.
(9) For recent reviews, see: (a) Simon C., Constantieux T.,
Rodriguez J.; Eur. J. Org. Chem.; 2004, 4957.
Physical Data for Compound 4b: yellow oil; Rf [Et2O–PE
(50:50)] 0.79. IR (liquid film): 2942, 1740, 1678, 1588,
1472, 1208, 1133, 927 cm–1. MS: m/z (%) = 305 (100) [M +
H+], 264 (13), 247 (36), 219 (12), 206 (8). 1H NMR (300.13
MHz, CDCl3): d = 7.50 (d, J = 1.5 Hz, 1 H), 7.35 (s, 1 H),
6.72 (d, J = 3.5 Hz, 1 H), 6.53 (dd, J = 1.5, 3.5 Hz, 1 H),
5.65–5.92 (m, 2 H), 5.13–5.32 (m, 4 H), 4.63 (dd, J = 1.0, 5.6
Hz, 2 H), 3.71 (d, J = 11.2 Hz, 1 H), 3.15 (d, J = 11.2 Hz, 1
H), 2.84 (dd, J = 7.1, 13.8 Hz, 1 H), 2.58 (dd, J = 7.6, 13.8
Hz, 1 H). 13C NMR (75.47 MHz, CDCl3): d = 197.3, 168.9,
151.6, 144.7, 131.3, 132.0, 128.2, 118.8, 115.9, 120.1,
112.9, 115.5, 66.6, 60.4, 38.6, 32.7.
(16) (a) Fürstner, A.; Langemann, K. J. Am. Chem. Soc. 1997,
119, 9130. (b) Cossy, J.; Bauer, D.; Bellosta, V.
Tetrahedron Lett. 1999, 40, 4187. (c) Ghosh, A. K.;
Cappiello, J.; Shin, D. Tetrahedron Lett. 1998, 39, 4651.
(d) Fürstner, A.; Langemann, K. J. Am. Chem. Soc. 1997,
119, 9130.
(b) Constantieux, T.; Rodriguez, J. In Targets in
Heterocyclic Systems, Vol 9; Attanasi, O. A.; Spinelli, D.,
Eds.; Società Chimica Italiana: Rome, 2005. (c) Liéby-
Muller, F.; Simon, C.; Constantieux, T.; Rodriguez, J. QSAR
Comb. Sci. 2006, 25, 432.
(17) General Procedure for RCMs: To a 6 × 10–3 M solution of
spiroheterocyclic precursors 4a–e in anhyd CH2Cl2, under
an atmosphere of argon, Grubbs’ catalyst 5b was introduced
in several portions of 2% every 2 h. The mixture was stirred
at reflux and completion of reaction was checked by TLC.
The mixture was filtered through a pad of silica gel and celite
and the crude material was purified by flash chromatography
on silica gel.
(10) (a) Liéby-Muller, F.; Simon, C.; Imhof, K.; Constantieux,
T.; Rodriguez, J. Synlett 2006, 1671. (b) Liéby-Muller, F.;
Constantieux, T.; Rodriguez, J. J. Am. Chem. Soc. 2005, 127,
17176. (c) Habib-Zahmani, H.; Hacini, S.; Charonnet, E.;
Rodriguez, J. Synlett 2002, 1827.
Synlett 2007, No. 7, 1037–1042 © Thieme Stuttgart · New York

1042
H. Habib-Zahmani et al.
LETTER
Physical Data for Compound 6c: yellow solid; mp 104–
106 °C. IR (liquid film): 2960, 1708, 1620, 1460, 1201, 1030
cm–1. MS: m/z (%) = 290 (100) [M + H+], 233 (17), 190 (5).
1H NMR (300.13 MHz, CDCl3): d = 7.53 (d, J = 1.7 Hz, 1
H), 7.32 (s, 1 H), 6.67 (d, J = 3.3 Hz, 1 H), 6.49 (dd, J = 1.7,
3.3 Hz, 1 H), 5.75–5.85 (m, 2 H), 3.90–4.18 (m, 2 H), 3.81
(d, J = 11.7 Hz, 1 H), 3.03 (s, 3 H), 3.00 (d, J = 11.7 Hz, 1
H), 2.89–2.98 (m, 1 H), 2.26–2.35 (m, 1 H). 13C NMR (75.47
MHz, CDCl3): d = 198.6, 170.2, 151.8, 144.4, 127.7, 125.8,
128.4, 112.8, 115.5, 115.0, 60.4, 49.8, 38.9, 35.1, 31.9.
(20) General Procedure for Heck Reaction: To a 4 × 10–2
M
solution of spiroheterocyclic precursors 4f and 4g in anhyd
MeCN, under an atmosphere of argon, palladium acetate (4
equiv) and PPh3 (8 equiv) were added, followed by Et3N (1.2
equiv). The mixture was stirred at reflux and the completion
of reaction was checked by TLC. The mixture was filtered
through a pad of celite and the crude material was purified
by flash chromatography on silica gel.
Physical Data for Compound 7b: yellow powder; mp 169–
171 °C. IR (liquid film): 2926, 1719, 1626, 1444, 1337,
1256, 940 cm–1. MS: m/z (%) = 326 (100) [M + H+], 295 (3),
255 (3), 201 (3), 164 (16). 1H NMR (300.13 MHz, CDCl3):
d = 7.34–7.64 (m, 6 H), 5.41 (d, J = 0.9, 16.6 Hz, 2 H), 5.02
(d, J = 9.3 Hz, 1 H), 4.72 (dd, J = 1.1, 15.1 Hz, 2 H), 4.04
(dd, J = 0.9, 11.3 Hz, 1 H), 3.57 (d, J = 15.3 Hz, 1 H), 3.07
(d, J = 11.2 Hz, 1 H), 3.03 (s, 3 H), 2.98 (d, J = 14.4 Hz, 1
H), 2.56 (d, J = 14.4 Hz, 1 H). 13C NMR (75.47 MHz,
CDCl3): d = 200.9, 169.0, 143.5, 141.8, 135.0, 130.5, 129.6,
129.5, 129.2, 128.8, 115.3, 112.8, 61.4, 54.2, 39.4, 37.1,
31.1.
(18) Heck, R. F. Vinyl Substitution with Organopalladium
Intermediates, In Comprehensive Organic Synthesis, Vol. 4;
Pergamon: Oxford, 1991.
(19) (a) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem.
Soc. 1996, 118, 7215. (b) Yang, B. H.; Buchwald, S. L. Org.
Lett. 1999, 1, 35.
Synlett 2007, No. 7, 1037–1042 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.