Intramolecular nitroalkene diels-alder reaction catalyzed by br?nsted acids

Article abstract of DOI:10.1055/s-0030-1260542

Br?nsted acid catalysis of intramolecular Diels-Alder cyclizations of (E)-1-nitro-1,6,8-nonatrienes and (E)-1-nitro-1,7,9-decatrienes was investigated. Catalyzed reactions showed significantly higher endo selectivities than the corresponding thermal react

Full text of DOI:10.1055/s-0030-1260542

CLUSTER
1259
Intramolecular Nitroalkene Diels–Alder Reaction Catalyzed by Brønsted
Acids
Intramolecular
Nit
n
roalkene
D
ie
d
ls–Alder
R
ea
r
ction eina Aguado, Norito Takenaka*
Department of Chemistry, University of Miami, 1301 Memorial Drive, Coral Gables, FL 33146-0431, USA
Fax +1(305)2844571; E-mail: n.takenaka@miami.edu
Received 31 January 2011
H2N
Abstract: Brønsted acid catalysis of intramolecular Diels–Alder
cyclizations of (E)-1-nitro-1,6,8-nonatrienes and (E)-1-nitro-1,7,9-
decatrienes was investigated. Catalyzed reactions showed signifi-
cantly higher endo selectivities than the corresponding thermal re-
actions. To our knowledge, this is the first example of catalysis
H
reduction
hydrolysis
R
R
H
H
(substoichiometric amount of catalysts) of the intramolecular ni-
troalkene Diels–Alder reaction.
O2N
O2N
O
H
H
H
R
R
Key words: Brønsted acid catalysis, intramolecular Diels–Alder
cyclizations, catalysis
H
H
radical hydro-
denitration
The importance of the intramolecular Diels–Alder reac-
tion can hardly be exaggerated. Its many features have
been widely discussed (e.g., two new carbon–carbon
bonds, two rings and up to four stereocenters can be made
in a single step).1 In particular, its strategic uses have sig-
nificantly advanced the synthesis of complex natural
products. Its nitroalkene variant2 offers unique advantages
due to the synthetic versatility of the nitro group,3 which
allows ready access to bicyclic motifs that are otherwise
difficult to obtain (Scheme 1). Therefore, this process is
highly complementary to that of carbonyl-based sub-
strates. In this respect, Kurth and co-workers investigated
the thermal cyclizations of 1-nitro-1,6,8-nonatrienes for
the synthesis of perhydroindenes.2g The merits of the in-
tramolecular nitroalkene Diels–Alder reaction were clear-
ly demonstrated by the elegant synthesis of the AB ring
system of the zoanthamine alkaloids reported by Williams
and co-workers.2b It should be mentioned that the in-
tramolecular inverse electron-demand hetero Diels–Alder
reaction of nitroalkenes, which provide nitronate inter-
mediates, was systematically studied by Denmark and co-
workers.4
R
H
Scheme 1 Intramolecular nitroalkene Diels–Alder reaction
with Lewis acids were also reported by Guy and co-work-
ers.2d These pioneering studies proved that catalysis of the
intramolecular nitroalkene Diels–Alder reaction is ex-
tremely challenging. In light of our own findings7 that
Brønsted acids periselectively catalyzed the intermolecu-
lar nitroalkene Diels–Alder reactions despite the inherent
preference of nitroalkenes to undergo the inverse elec-
tron-demand hetero Diels–Alder reaction with Lewis ac-
ids, we were interested in investigating the effects of
Brønsted acids on the intramolecular variant. Herein we
report that pyridinium salt 1 (Table 1), NaBArF24·2.5H2O
{BArF24 = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate}8
and NaBArF24·(H2O)x(PhOH)y9 are efficient catalysts for
the cyclizations of (E)-1-nitro-1,6,8-nonatrienes, and (E)-
1-nitro-1,7,9-decatrienes.
The substrates for the intramolecular Diels–Alder reac-
tions were synthesized readily using well-known method-
ologies as illustrated in Scheme 2. Negishi coupling of
vinyl iodide 210 with either vinylzinc 3a11 or 3b12 provided
dienes 4a or 4b, respectively. The removal of TBS group,
followed by Swern oxidation afforded aldehydes 6a and
The use of Lewis acid catalysis is a powerful method of
increasing the rate and diastereoselectivity of many in-
tramolecular Diels–Alder reactions of carbonyl-based
substrates, and thus has had an enormous impact on chem-
ical synthesis.1c,5,6 Presumably due to the lack of its catal-
ysis method, examples of the nitroalkene variant in the
literature are remarkably rare.2 To this end, Williams and
co-workers examined a variety of Lewis acids to catalyze
the cyclization of several (E)-1-nitro-1,7,9-decatrienes.2b
Their attempts to enhance the endo selectivity through
Lewis acid activation proved difficult. Similar problems
6b.13
A
sequence of Henry reaction14 and the
dehydration15 of the corresponding b-hydroxy nitroal-
kanes 7a and 7b gave (E)-1-nitro-1,6,8-nonatrienes 8a
and 8b. (E)-1-Nitro-1,7,9-decatrienes 12a and 12b were
synthesized analogously from one-carbon elongated
aldehydes16 10a and 10b. It should be mentioned that the
dehydration reactions led to exclusive formation of the
E-olefins (1H NMR analysis of crude products), and these
SYNLETT 2011, No. 9, pp 1259–1261
x
x.
x
x.
2
0
1
1
Advanced online publication: 20.04.2011
DOI: 10.1055/s-0030-1260542; Art ID: Y03311ST
© Georg Thieme Verlag Stuttgart · New York

1260
A. Aguado, N. Takenaka
CLUSTER
PdCl2(PPh3)2
THF, r.t.
TBSO
O
TBSO
R
+
I
ZnCl
3a: R = Me
3b: R = Ph
R
2
4a: R = Me, (N/A)
4b: R = Ph, 82%
Bu4N+F–
HO
THF, r.t.
Swern ox.
R
R
6a: R = Me, 90%
6b: R = Ph, 91%
5a: R = Me, 75% (2 steps)
5b: R = Ph, 91%
(CF3
CO)2O, Et3N
MeNO2, KF
i-PrOH, r.t.
O2N
R
O2N
R
R
CH2Cl2, –10 °C
OH
7a: R = Me, 70%
7b: R = Ph, 76%
8a: R = Me, 74%
8b: R = Ph, 58%
Ph3P+CH2OMeCl–
t-BuOK, THF, r.t.
Hg(OAc)2
THF–H2O
6a or 6b
MeO
R
O
9a: R = Me, 79%
9b: R = Ph, 93%
10a: R = Me, 80%
10b: R = Ph, 64%
(10:1), 0 °C
OH
(CF3CO)2O, Et3N
CH2Cl2, –10 °C
MeNO2, KF
i-PrOH, r.t.
O2N
O2N
R
R
11a: R = Me, 85%
11b: R = Ph, 80%
12a: R = Me, 72%
12b: R = Ph, 65%
Scheme 2 Synthesis of nona- and decatrienes
tion cleanly and afforded the product in high yield with
excellent endo selectivity (Table 1, entry 5).
Table 1 Intramolecular Diels–Alder Reaction of (E)-1-Nitro-1,6,8-
nonatrienes
(E)-1-Nitro-1,7,9-decatrienes were evaluated next
(Table 2). Aliphatic substrate 12a (R = Me) was reported
to provide a 2.3:1 endo:exo ratio of products under ther-
mal conditions.2b To our delight, however, the catalyzed
reaction provided the product with high endo selectivity
(Table 2, entry 1). An attempt to increase the selectivity
by conducting the reaction at a lower temperature led only
to decreased yield (Table 2, entry 2). NaBArF24·2.5H2O
turned out to be less effective in terms of selectivity
O2N
BArF24
H
H
O2N
R
catalyst
R
CH2Cl2, r.t.
20 h
N
N
H
H
endo
catalyst 1
Entry
R
Catalyst (mol%)
1 (10)
Yield (%) endo:exo
1
2
3
4
5
Me
Me
Me
Me
Ph
47
91
87
85
86
>30:1
>30:1
>30:1
>30:1
>30:1
(Table 2,
entries
3
and
4).
Interestingly,
1 (20)
NaBArF24·(H2O)x(PhOH)y provided better yield and se-
lectivity than NaBArF24·2.5H2O did (Table 2, entry 5).
This may be attributable to the expected higher acidity of
the former complex. Aromatic substrate 12b (R = Ph) also
NaBArF24·2.5H2O (10)
NaBArF24·2.5H2O (20)
1 (20)
Table 2 Intramolecular Diels–Alder Reaction of (E)-1-Nitro-1,7,9-
decatrienes
nitroalkenes were stable to procedures of flash silica gel
chromatography.2b,17
O2N
NO2
H
R
We set out to investigate the cyclization of (E)-1-nitro-
1,6,8-nonatriene 8a (R = Me) with catalyst 1, which was
found to be optimal in our previous study of intermolecu-
lar nitroalkene Diels–Alder reaction.7 To our delight, it
cleanly catalyzed the reaction and provided the product in
good yield with excellent endo selectivity (Table 1, entry
1) while a 8.1:1 endo:exo ratio was reported for the corre-
sponding thermal reaction.2g The increase in catalyst load-
ing (20 mol%) led to the excellent yield (Table 1, entry 2).
Inspired by the Lewis acid assisted Brønsted acids devel-
oped by Yamamoto and co-workers,18 we tested
NaBArF24·2.5H2O, and found that it is a competent cata-
lyst for the present reaction. However, unlike a pyridini-
um salt, increased catalyst loading did not show a
beneficial effect on the yield (Table 1, entries 3 and 4).
Aromatic substrate 8b (R = Ph) also underwent the reac-
catalyst
R
CH2Cl2, 20 h
H
endo
Entry R Catalyst (mol%)
Temp Yield endo:exo
(°C) (%)
1
2
3
4
5
6
Me 1 (20)
25
0
77
44
88
27
93
71
14:1
13:1
8:1
Me 1 (20)
Me NaBArF24·2.5H2O (10)
Me NaBArF24·2.5H2O (10)
25
0
8:1
Me NaBArF24·(H2O)x(PhOH)y (10) 25
Ph 1 (20) 25
13:1
11:1
Synlett 2011, No. 9, 1259–1261 © Thieme Stuttgart · New York

CLUSTER
Intramolecular Nitroalkene Diels–Alder Reaction
1261
1985, 50, 2626.
underwent the reaction cleanly and afforded the product in
good yield, but with slightly decreased endo selectivity
(Table 2, entry 6).
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New York, 2001.
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In summary, we have evaluated the Brønsted acid cataly-
sis of intramolecular Diels–Alder cyclizations of (E)-1-ni-
tro-1,6,8-nonatrienes and (E)-1-nitro-1,7,9-decatrienes.
The present study demonstrated that the Brønsted acid ca-
talysis is an effective strategy for increasing the rate and
diastereoselectivity of this class of intramolecular Diels–
Alder reactions for which Lewis acid catalysis has proved
difficult.
Typical Experimental Procedure for the Brønsted Acid Cata-
lyzed Intramolecular Nitroalkene Diels–Alder Reaction
To a solution of triene 12a (12 mg, 0.063 mmol) in CH2Cl2 (125 mL)
cooled to 0 °C was added catalyst 1 (13 mg, 0.013 mmol) in one
portion under an atmosphere of dry argon. After stirring for 5 min
at 0 °C, the reaction mixture was allowed to warm to 25 °C. After
20 h, the reaction mixture was diluted with CH2Cl2, followed by the
addition of 50 mL of MeOH–hydrazine monohydrate solution (a
50:50 mixture by volume). The resulting solution was stirred for 5
min, diluted with H2O, extracted three times with CH2Cl2. The com-
bined organic layers were washed with brine, dried over Na2SO4,
and concentrated in vacuo. The ratio of diastereomers was deter-
mined by 1H NMR analysis of the crude reaction mixture
(endo:exo = 14:1), which was purified by flash chromatography on
silica gel (1.5% EtOAc in hexanes) to provide the product (9.4 mg,
77%).
(8) Selected references: (a) Liao, B.-S.; Chen, J.-T.; Liu, S.-T.
Synthesis 2007, 3125. (b) Chang, C.-T.; Chen, C.-L.; Liu,
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mixture of NaBArF24·2.5H2O and PhOH (2.5 equiv) in
toluene, followed by removal of toluene.
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References and Notes
(1) Selected reviews: (a) Juhl, M.; Tanner, D. Chem. Soc. Rev.
2009, 38, 2983. (b) Takao, K.; Munakata, R.; Tadano, K.
Chem. Rev. 2005, 105, 4779. (c) Roush, W. R. In
Comprehensive Organic Synthesis, Vol. 5; Trost, B. M.;
Fleming, I., Eds.; Pergamon Press: Oxford, 1991, 513–550.
(2) (a) Mahmood, S. Y.; Lallemand, M.-C.; Sader-Bakaouni, L.;
Charton, O.; Vérité, P.; Dufat, H.; Tillequin, F. Tetrahedron
2004, 60, 5105. (b) Williams, D. R.; Brugel, T. A. Org. Lett.
2000, 2, 1023. (c) Sader-Bakaouni, L.; Charton, O.;
(17) Knochel and co-workers reported that silica gel promoted
the cyclization of (1E,6E,8E)-1-nitro-1,6,8-nonatriene in
hexane. See ref. 2e.
(18) Yamamoto, H.; Futatsugi, K. Angew. Chem. Int. Ed. 2005,
44, 1924.
Kunesch, N.; Tillequin, F. Tetrahedron 1998, 54, 1773.
(d) Guy, A.; Serva, L. Synlett 1994, 647. (e) Jubert, C.;
Knochel, P. J. Org. Chem. 1992, 57, 5431. (f) Retherford,
C.; Knochel, P. Tetrahedron Lett. 1991, 32, 441. (g) Kurth,
M. J.; O’Brien, M. J.; Hope, H.; Yanuck, M. J. Org. Chem.
Synlett 2011, No. 9, 1259–1261 © Thieme Stuttgart · New York