The Lewis acid-catalyzed Nazarov reaction of 2-(N-methoxycarbonylamino)-1, 4-pentadien-3-ones

Article abstract of DOI:10.1021/ol053071h

A highly efficient carbonylative Suzuki-Miyaura coupling reaction of lactam-derived vinyl triflates and alkenylboronic acids afforded 2-(N-methoxycarbonylamino)-1,4-pentadien-3-ones as suitable substrates for the Nazarov reaction. The most competent Lewis

Full text of DOI:10.1021/ol053071h

ORGANIC
LETTERS
2
006
Vol. 8, No. 4
81-784
The Lewis Acid-Catalyzed Nazarov
Reaction of 2-(N-Methoxycarbonyl-
amino)-1,4-pentadien-3-ones
7
Paolo Larini, Antonio Guarna, and Ernesto G. Occhiato*
Dipartimento di Chimica Organica “U. Schiff”, UniVersit a` di Firenze, Via della
Lastruccia 13, I-50019 Sesto Fiorentino, Italy
ernesto.occhiato@unifi.it
Received December 19, 2005
ABSTRACT
A highly efficient carbonylative Suzuki
methoxycarbonylamino)-1,4-pentadien-3-ones as suitable substrates for the Nazarov reaction. The most competent Lewis acids for the Nazarov
reaction were Cu(OTf) (2 mol %) and Sc(OTf) (3 mol %) in DCE, which provided the Nazarov products in excellent yield. As both the carbonylative
−Miyaura coupling reaction of lactam-derived vinyl triflates and alkenylboronic acids afforded 2-(N-
2
3
coupling and the subsequent Nazarov reaction were high yielding, the overall methodology is a concise and efficient route to [1]pyrindine
systems.
The acid-catalyzed cyclization of a doubly R,â-unsaturated
ketone (Scheme 1), referred to as the Nazarov reaction, with
by the 4p-electron pentadienyl cation formed, in the original
version of the Nazarov reaction, upon treatment of the divinyl
ketone with either a mineral or a Lewis acid. Very recently,
1
its large number of variants, is a powerful method for the
2
construction of five-membered carbocycles. The Nazarov
reaction has most recently been exploited for the partial or
3
total synthesis of natural products such as terpestacin,
Scheme 1. The Lewis Acid-Catalyzed Nazarov Reaction
4
5
6
7
roseophilin, guanacastepene A, havanensin, cephalotaxine,
8
1,2
cucumin H, and others. The ring closure (Scheme 1)
occurs through a conrotatory electrocyclic process undergone
(
1) (a) Nazarov, I. N.; Torgov, I. B.; Terekhova, L. N. IzV. Akad. Nauk.
SSSR Khim. Nauk. 1942, 200. (b) Denmark, S. E. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, UK,
1
991; Vol. 5, pp 751-784. (c) Habermas, K. L.; Denmark, S. E.; Jones, T.
D. Org. React. 1994, 45, 1-158.
2) Most recent reviews: (a) Tius, M. A. Eur. J. Org. Chem. 2005, 2193-
206. (b) Pellissier, H. Tetrahedron 2005, 61, 6479-6517. (c) Frontier, A.
(
2
J.; Collison, C. Tetrahedron 2005, 61, 7577-7606.
a true catalytic variant of the original Nazarov reaction
(
3) Berger, G. O.; Tius, M. A. Org. Lett. 2005, 7, 5011-5013.
9
(
4) (a) Occhiato, E. G.; Prandi, C.; Ferrali, A.; Guarna, A. J. Org. Chem.
promoted by Lewis acids has been disclosed by Frontier
(
2
005, 70, 4542-4545. (b) Harrington, P. E.; Tius, M. A. J. Am. Chem.
Soc. 2001, 123, 8509-8514.
5) (a) Nakazaki, A.; Sharma, U.; Tius, M. A. Org. Lett. 2002, 4, 3363-
366. (b) Chiu, P.; Li, S. Org. Lett. 2004, 6, 613-616.
6) Fernandez Mateos, A.; Mateos Buron, L.; Martin de la Nava, E. M.;
Rubio Gonzales, R. J. Org. Chem. 2003, 68, 3585-3592.
7) (a) Kim, S.-H.; Cha, J. K. Synthesis 2000, 2113-2116. (b) Li, W.-D.;
Wang, Y.-Q. Org. Lett. 2003, 5, 2931-2934.
8) Srikrishna, A.; Dethe, D. H. Org. Lett. 2003, 5, 2295-2298.
10
Scheme 2, eq 1) and Trauner (eq 2), who employed less
(
3
(9) (a) He, W.; Sun, X.; Frontier, A. J. J. Am. Chem. Soc. 2003, 125,
(
14278-14279. (b) Janka, M.; He, W.; Frontier, A. J.; Eisenberg, R. J. Am.
Chem. Soc. 2004, 126, 6864-6865. (c) Janka, M.; He, M.; Frontier, A. J.;
Flaschenriem, C.; Eisenberg, R. Tetrahedron 2005, 61, 6193-6206.
(10) Liang, G.; Gradl, S. N.; Trauner, D. Org. Lett. 2003, 5, 4931-
4934.
(
(
1
0.1021/ol053071h CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/27/2006

process.17 The presence of the electron-withdrawing N-
protecting group is expected to lower the reactivity of these
systems compared to the pyrane derivatives, but we know
that such a protected N atom is still capable of stabilizing a
Scheme 2. Lewis Acid-Catalyzed Nazarov Reactions
1
4b,c
positive charge in closely related substrates.
Moreover,
the N-protecting group can have a role in coordinating the
Lewis acid. The methoxycarbonyl group was chosen as the
N-protecting group owing to its greater stability to mineral
and Lewis acids than N-Boc and N-Cbz protections.18
For the synthesis of the N-protected 2-amino-1,4-penta-
dien-3-ones 3 we relied on our experience on the coupling
reactions of lactam-derived vinyl triflates 1 (Scheme 3).19
Scheme 3. Carbonylative Stille Coupling
than 10 mol % of the catalyst [Cu(OTf)
2
or an Ir(III) catalyst,
11
and AlCl , respectively] to perform the reaction.
3
The use of chiral Lewis acids in a catalytic amount (10
mol % of a Sc-pybox) for the enantioselective Nazarov
In particular, for the rapid assembly of a model Nazarov
20
21
substrate (3a) both Stille and Suzuki-Miyaura carbony-
lative couplings were for the first time attempted with these
triflates.
1
2
reaction has been so far reported only by Trauner (eq 2),
1
3
as Aggarwal used 50-100 mol % of a Cu-pybox Lewis
acid to efficiently promote the reaction.
The carbonylative Stille coupling reaction of 1 with
With the pyrane derivatives (eqs 1-2), because of the
presence of the oxygen atom in the ring, the Lewis acid is
presumably bound in a bidentate fashion to the substrate,
which is reputed to allow the two vinyl moieties to adopt
the proper orientation for the cyclization,9b as well as to
amplify the degree of stereocontrol in the final product
formation.12 Moreover it is also likely that the heterocycle
oxygen atom accelerates the overall process by stabilizing
2
2
1
-hexenylstannane 2 provided in our case the target
compound 3a (Scheme 3) in acceptable yield (67%) only at
high CO pressure (50 atm) and temperature (60 °C), in the
presence of (Ph P) Pd (3%) as the catalyst. The same reaction
3 4
(16) For example: streptazolin, streptazon C, and streptazon A, isolated
from Streptomyces Viridochromogenes, Streptomyces luteogriseus, and
FORM5, Strain A1. See: (a) Drautz, H.; Z a¨ hner, H.; Kupfer, E.; Keller-
Schierlein, W. HelV. Chim. Acta 1981, 64, 1752-1768. (b) Grabley, S.;
Kluge, H.; Hoppe, H.-U. Angew. Chem., Int. Ed. 1987, 26, 664-665. (c)
Grabley, S.; Hammann, P.; Kluge, H.; Wink, J.; Kricke, P.; Zeeck, A. J.
Antibiot. 1991, 44, 797-800. (d) Puder, C.; Krastel, P.; Zeeck, A. J. Nat.
Prod. 2000, 63, 1258-1260. (e) Puder, C.; Loya, S.; Hizi, A.; Zeeck, A. J.
Nat. Prod. 2001, 64, 42-45. For the synthesis of streptazolin and related
natural products see: (f) Trost, B. M.; Chung, C. K.; Pinkerton, A. B. Angew.
Chem., Int. Ed. 2004, 43, 4327-4329 and references therein. Pyrindicin,
isolated from Streptomyces sp. SCC 2313. See: (g) Omura, S.; Tanaka,
H.; Awaya, J.; Narimatsu, Y.; Konda, Y.; Hata, T. Agric. Biol. Chim. 1974,
14a
the positive charge in the oxyallyl intermediate, as also
reported with closely related substrates.1
4b,c
Due to our interest in the Nazarov reaction involving
4a,14,15
heterocyclic systems,
we wanted to investigate if the
reaction conditions of eqs 1 and 2 could be extended to the
corresponding 2-amino-1,4-pentadien-3-ones (eq 3). This
would certainly expand the scope of the Lewis acid-catalyzed
Nazarov reaction, as the [1]pyrindine system that is formed
3
8, 899-906. Abikoviromycin, isolated from Streptomyces abikoensis.
See: (h) Gurevich, A. I.; Kolosov, M. N.; Korobko, V. G.; Onoprienko, V.
V. Tetrahedron Lett. 1968, 9, 2209-2212. Proline-specific Maillard
compounds: Chen, C.-W. Lu, G.; Ho, C.-T. J. Agric. Food Chem. 1997,
1
6
is contained in a number of natural compounds, and lay
the basis for developing an enantioselective version of the
4
5, 2996-2999.
(
17) We have already shown that with suitably substituted N-heterocycle
(
11) PdCl2(CN)2 is also effective a 1-10 mol %, but the cyclization
derivatives there is an elevated control of the stereochemistry at C5.
However, the possibility of organizing the absolute stereochemistry at this
carbon atom by an external control is doubtlessly more attractive and general
in scope. See refs 4a and 14b,c.
occurs through a mechanism different from the one reported in Scheme 1.
a) Bee, C.; Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 4927-4930.
Examples of Lewis acid catalysis have been reported by West in interrupted
(
Nazarov reactions. (b) Giese, S.; West, F. G. Tetrahedron Lett. 1998, 39,
(18) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
8
393-8396. (c) Giese, S.; West, F. G. Tetrahedron 2000, 56, 10221-10228.
Synthesis; John Wiley & Sons: New York, 1999.
(d) Wang, Y.; Arif, A. M.; West, F. G. J. Am. Chem. Soc. 1999, 121, 876-
(19) (a) Occhiato, E. G.; Trabocchi, A.; Guarna, A. J. Org. Chem. 2001,
66, 2459-2465. (b) Occhiato, E. G. Mini-ReV. Org. Chem. 2004, 1, 149-
162 (c) Occhiato, E. G.; Lo Galbo, F.; Guarna, A. J. Org. Chem. 2005, 70,
7324-7330.
(20) Crisp, G. T.; Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1984,
106, 7500-7506.
(21) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(22) (E)-Tributyl-1-hexenylstannane 2 was prepared in good yield (82-
86%) by Pd-catalyzed hydrostannation of 1-bromohexyne according to two
different procedures: (a) Zhang, H. X.; Guib e´ , F.; Balavoine, G. J. Org.
Chem. 1990, 55, 1857-1867. (b) Shen, R.; Lin, C. T.; Porco, J. A., Jr. J.
Am. Chem. Soc. 2002, 124, 5650-5651.
8
77. (e) Wang, Y.; Schill, B. D.; Arif, A. M.; West, F. G. Org. Lett. 2003,
5
, 2747-2750.
(
(
(
12) Liang, G.; Trauner, D. J. Am. Chem. Soc. 2004, 126, 9544-9545.
13) Aggarwal, V. K.; Belfield, A. J. Org. Lett. 2003, 5, 5075-5078.
14) (a) Cavalli, A.; Masetti, M.; Recanatini, M.; Prandi, C.; Guarna,
A.; Occhiato, E. G. Chem. Eur. J. 2006, in press. (b) Occhiato, E. G.; Prandi,
C.; Ferrali, A.; Guarna, A.; Venturello, P. J. Org. Chem. 2003, 68, 9728-
9
741. (c) Prandi, C.; Ferrali, A.; Guarna, A.; Venturello, P.; Occhiato, E.
G. J. Org. Chem. 2004, 69, 7705-7709.
15) Prandi, C.; Deagostino, A.; Venturello, P.; Occhiato, E. G. Org.
Lett. 2005, 7, 4345-4348.
(
782
Org. Lett., Vol. 8, No. 4, 2006

conducted at 1 atm, with or without CuI as cocatalyst,23 or
with a different catalyst such as Pd(OAc) /Ph P, failed in
providing higher yields, sometimes resulting either in
degradation of the starting material or in the formation of
the Stille product as the major component of the reaction
mixture.
2
3
Table 1. The Nazarov Reaction of Dienones 3a-da
To the best of our knowledge, the carbonylative Suzuki-
Miyaura coupling of vinyl triflates with alkenylboronic acids
24
has never been reported. We employed 1-pentenylboronic
acid (2 equiv) and were lucky to observe the rapid formation
of the desired product 3b (R ) n-Pr, Scheme 4) at our first
conc
(M)
T
(°C)
time
(h)
conv
(%)
2
b,c
entry
3
acid
TFA
TFMSA
BF3.Et2O
Et2AlCl
SnCl4
TiCl4
FeCl3
AlCl3
FeCl3
equiv
1
2
3
4
5
6
7
8
9
a
a
a
b
b
b
a
a
b
b
b
b
b
a
c
neat
3
1.5
0.7
0.7
0.7
0.7
0.7
0.1
0
0
0
0
0
0
0
0
20
20
55
55
55
55
55
55
2.5 100
0.06
0.02
0.02
0.02
0.02
0.02
0.02
0.2
0.15
0.2
0.2
0.2
0.2
5
18
18
3.5 50
3
2.5 88 (75)
7.5 82
23
18
8
7
100 (83)
55
30
Scheme 4. Carbonylative Suzuki-Miyaura Coupling
55 (22)
74 (58)
11
92 (75)
41
100 (86)
15
1
1
1
1
1
1
1
0
1
2
3
4
5
6
AlCl3
0.1
Cu(OTf)2
Zn(OTf)2
Sc(OTf)3
Yb(OTf)3
Sc(OTf)3
Sc(OTf)3
0.02
0.02
0.03
0.02
0.03
0.03
3
3
0.2
0.2
2.5 100 (83)
4 95 (72)
d
attempt at atmospheric pressure of CO, in the presence of
a
Reaction carried out on 0.2-0.3 mmol of substrates in CH2Cl2 (entries
2 3
5% Pd(OAc) /10% Ph P as the catalyst, and CsF (3 equiv)
b
1
2
-9), MeCN (entry 10), or Cl(CH2)2Cl (entries 11-16). From the H
for the boron quaternization, in THF at 60 °C. The best
results were achieved by carrying out the reaction at room
temperature, which avoided some degradation of the starting
material (78% yield after 3 h). As expected, changing from
cesium to cheaper potassium fluoride (4 equiv) decreased
c
NMR analysis of the crude reaction mixture. The yield after chromatog-
raphy is given in parentheses.
5
a. In both cases the yield was much higher than with the
corresponding pyrrolidinone-derived dienones
the relative stability of the azabicyclic [4.3.0]nonenyl and
3.3.0]octenyl cationic intermediates. Catalytic amounts of
Brønsted acids, as the Amberlyst 15 resin in chloroform,
failed to give the cyclization product in accordance with our
4a,14b
reflecting
25
the yield (46% after 4 h). Also, freshly prepared 1-hex-
enylboronic acid 4a26 was superior to the commercial
[
27
product, perhaps because of its lower content of water. The
best conditions were then extended to a short series of
alkenylboronic acids as reported in Scheme 4. With com-
mercial p-fluorostyrylboronic acid 4d the results of the
carbonylative coupling were poorer, but they were greatly
improved by slightly changing the reaction conditions (70%
after chromatography, see the Supporting Information).
The results of the Lewis acid-catalyzed Nazarov reaction
of compounds 3a-d are reported in Table 1.
1
4b
earlier observations.
A first screening of Lewis acids (entry 3-8) was carried
out with 70 mol % of the catalyst but at high dilution (0.02
M) and at 0 °C. In all cases, reactions were monitored by
TLC and stopped when no more conversion was observed.
With the exception of the reactions carried out with FeCl
entry 7) and AlCl (entry 8) in no cases was the conversion
appreciably higher than 50%. This could be due to degrada-
tion of the Lewis acid because of the presence of adventitious
water, but a slow product-to-substrate Lewis acid exchange
as the concentration of the product increases cannot be ruled
out. In all cases, the N-protection was maintained in the final
product. The most promising Lewis acid was FeCl , which
3
provided in 2.5 h the Nazarov product 5a in 75% yield (after
chromatography) (entry 7). The same reaction was carried
out with 10 mol % of FeCl at low (0.04 M) and high (0.2
3
M) concentration at 20 °C. In the latter case the reaction did
not proceed further after 23 h (74% conversion) and the
product was obtained in 58% yield (entry 9). We wanted to
3
in 10 mol % which was the best catalyst with
-alkoxy-1,4-pentadien-3-ones as 6 (Figure 1; this gave the
3
(
3
We started our study by evaluating some Brønsted acids
(entries 1 and 2). Both neat TFA and triflic acid (3 equiv, in
DCM) quantitatively converted 3a into the Nazarov product
(
23) Mazzola, R. D., Jr.; Giese, S.; Benson, C. L.; West, F. G. J. Org.
Chem. 2004, 69, 220-223.
24) Actually, we are aware of no examples of carbonylative Suzuki-
(
Miyaura couplings of alkenylboronic acids, with the exception of a
carbonylative reaction of a styrylboronic acid with a diazonium salt. The
carbonylative coupling of 9-alkyl-9-BBN, arylboronic acids, and heteroaryl-
boronic acids is instead well-known, and usually requires high temperature
and CO pressure. (a) Andrus, M. B.; Ma, Y.; Zang, Y.; Song, C. Tetrahedron
Lett. 2002, 43, 9137-9140 and references therein. (b) See ref 21.
(
25) Wright, S. W.; Hageman, D. L.; McClure, L. D. J. Org. Chem.
994, 59, 6095-6097.
26) Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1975, 97, 5249-
255.
27) The water present in mixture with trans-1-hexenylboronic acid can
1
(
5
try also AlCl
2
(
interfere with the catalytic cycle by hydrolyzing the acyl-palladium
intermediate complex.
1
0
Nazarov product in 92% after 50 min), but to our surprise
Org. Lett., Vol. 8, No. 4, 2006
783

Finally the best conditions [Sc(OTf)
applied to substrates 3c,d possessing a distal aromatic moiety
entries 15 and 16). Notwithstanding the presence of the
3
(3 mol %)] were
(
aromatic ring that could stabilize the positive charge of the
pentadienyl cation, with 3c the reaction was as fast as that
with 3b. Also, the p-F group in 3d had no particular effect
on the rate of the process (reaction almost complete in 4 h,
entry 16). Under these reaction conditions, therefore, there
seems not to be dependence of the reaction rate on the
electrocyclization step, as was also recently observed by
Figure 1. 2-Alkoxy-1,4-pentadien-3-ones.
3+
9c
AlCl
3
gave very poor results (entry 10). Al is a harder
Frontier.
3
+
cation than Fe , which could result in a stronger O-Al
bond in the Nazarov product and thus in a slower turnover.
The presence of the N-CO Me protecting group could further
favor the Al coordination in the final product, which could
contribute to the sensible difference in reactivity between
In conclusion, we have for the first time carried out a very
efficient carbonylative Suzuki-Miyaura coupling reaction
using alkenylboronic acids as the nucleophiles, which
provided 2-(N-methoxycarbonylamino)-1,4-pentadien-3-ones
as useful substrates for the Lewis acid-catalyzed Nazarov
reaction. To this aim, the most competent Lewis acids were
2
8
2
3+
3
b and 6 under the same conditions.
,4-Pentadien-3-ones 7 and 8 (Figure 1) have been reported
to react successfully to form the corresponding Nazarov
products in the presence of 2 mol % of Cu(OTf) in DCE at
Because of the presence of the 2-oxygen atom,
dienone 7 was more reactive than 8 under these conditions
60% yield after 0.5 h, and 37% yield after 4 h, respectively).
1
2 3
Cu(OTf) (2 mol %) and Sc(OTf) (3 mol %) in DCE, which
provided the Nazarov product in high yield. Despite the
electron withdrawing N-protecting group, the reactivity of
2-amino-1,4-pentadien-3-ones was comparable or just slightly
lower than that of the corresponding 2-alkoxy-1,4-pentadien-
3-ones. As both the carbonylative coupling and the subse-
quent Nazarov reaction were high yielding, the overall
methodology is a concise and efficient route to cyclopenta-
fused N-heterocycles. The use of chiral Lewis acids for the
enantioselective Nazarov reaction of 2-(N-methoxycarbony-
lamino)-1,4-pentadien-3-ones is currently being investigated
in our laboratory.
2
9
a,b
55 °C.
(
Based on our reasoning on the effect of N-protection we
expected something between these results with substrate 3b.
In fact, after 4 h the conversion into 5b was higher than
50% and after 8 h the reaction was almost complete (92%
conversion, 75% yield after chromatography, entry 11). Of
the fourth period transition metal Lewis acids, however, Sc-
3
(OTf) (3 mol %) was the best one (entry 13), as the substrate
was quantitatively converted into 5b after 3 h at 55 °C (86%
yield after chromatography).
Acknowledgment. We thank MIUR and University of
Florence for financial support, Cassa di Risparmio di Firenze
for granting a 400 MHz NMR spectrometer, and Maurizio
Passaponti and Brunella Innocenti for technical support.
Of the lanthanide Lewis acids we tried the Yb(OTf)
3
(2
mol %), as Yb3 is the smallest and the hardest cation of
+
the series, and therefore the closest to the highly efficient
Sc . However, the results were poor, as after 3 h at 55 °C
the conversion was only 15% (entry 14), which could simply
3+ 29
Supporting Information Available: Full experimental
details and spectroscopic data; H NMR spectra of com-
pounds 3a-d and 5a-d. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
3
reflect the lower Lewis acidity of Yb(OTf) compared to Sc-
3
0
3
(OTf) .
OL053071H
(
28) Kerr, J. A. In CRC Handbook of Chemistry and Physics 1999-
2
000, A Ready-Reference Book of Chemical and Physical Data, 81st ed.;
Lide, D. R., Ed.; CRC Press: Boca Raton, FL 2000.
29) Boehme, C.; Wipff, G. Chem. Eur. J. 2001, 7, 1398-1407.
(30) Kobayashi, S.; Manabe, K. Pure Appl. Chem. 2000, 72, 1373-
1380.
(
784
Org. Lett., Vol. 8, No. 4, 2006