Direct aza-Diels-Alder reaction in water catalyzed by layered α-zirconium hydrogen phosphate and sodium dodecyl sulfate

Article abstract of DOI:10.1002/ejoc.200801132

The direct aza-Diels-Alder reaction between 2-cyclohexen-1-one (1) and benzaldimines 2 in water is reported for the first time. The reaction occurs at 30°C, is catalyzed by layered α-zirconium hydrogen phosphate (α-ZrP) and requires the presence of sodium dodecyl sulfate (SDS). The reaction yield is excellent, the reaction is faster and the exo diastereo-selectivity is higher than when organic solvent is used. The one-pot, three-component version of the reaction and the recycling of both the catalyst and the aqueous mother liquor in toto (water, α-ZrP and SDS) have also been investigated. Wiley-VCH Verlag GmbH & Co. KGaA, 2009.

Full text of DOI:10.1002/ejoc.200801132

FULL PAPER
DOI: 10.1002/ejoc.200801132
Direct Aza-Diels–Alder Reaction in Water Catalyzed by Layered α-Zirconium
Hydrogen Phosphate and Sodium Dodecyl Sulfate
[
a]
[a]
[a]
[a]
Umberto Costantino, Francesco Fringuelli, Mara Orrù, Morena Nocchetti,
[a]
[a]
Oriana Piermatti,* and Ferdinando Pizzo
Keywords: Heterogeneous catalysis / Layered compounds / Green chemistry / Multicomponent reactions / Azo compounds
The direct aza-Diels–Alder reaction between 2-cyclohexen-
-one (1) and benzaldimines 2 in water is reported for the
selectivity is higher than when organic solvent is used. The
one-pot, three-component version of the reaction and the re-
1
first time. The reaction occurs at 30 °C, is catalyzed by lay- cycling of both the catalyst and the aqueous mother liquor in
ered α-zirconium hydrogen phosphate (α-ZrP) and requires
toto (water, α-ZrP and SDS) have also been investigated.
the presence of sodium dodecyl sulfate (SDS). The reaction
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
yield is excellent, the reaction is faster and the exo diastereo- Germany, 2009)
Introduction
The aza-Diels–Alder reaction is one of the best-known
processes in organic chemistry for the synthesis of six-mem-
bered, nitrogen-containing, heterocyclic compounds, which
are precursors of important biological compounds such as
alkaloids, peptides and aza-sugars.[1] While the reaction be-
tween preformed dienes and imines or enol ethers is well-
[
2]
known, fewer studies have investigated the aza-Diels–
Alder reaction that does not use preformed dienes (namely
the direct Diels–Alder reaction), and these reactions were
always carried out in organic solvents (CH CN, DMSO,
3
DMF, PhMe, NPM or DCM).[
3]
Scheme 1. Direct Brønsted acid-catalyzed aza-Diels–Alder reaction
of cyclohexenone 1 with aldimines 2.
A typical example of a direct aza-Diels–Alder process is
the reaction between 2-cyclohexen-1-one (1) and an ald-
imine 2 in the presence of a Brønsted acid (BH), which
activates both reagents. The α,β-unsaturated ketone 1, un-
der acidic conditions, is enolized to 5, which then undergoes based catalytic species, generally expensive, and the problem
a Mannich reaction with the protonated imine 6, followed of leaching of the metal, often toxic, into the products. The
by an intramolecular aza-Michael reaction to give the endo class of phosphates and phosphonates of the tetravalent
IV
and exo isoquinuclidines 3 and 4, regenerating the acid cat- metals (mainly Zr ) with a layered structure is attracting
alyst; this process is formally known as a hetero Diels– the attention of researchers because of their physical-chemi-
[
5]
Alder reaction (Scheme 1). The success of the reaction cal properties (chemical and thermal stability and high
[
5,6]
depends on the proton-donating capacity of the catalyst specific surface area) and high versatility;
acidity) and on the experimental conditions, particularly organic backbone of these compounds may be considered
the reaction medium.
a hook onto which organic groups with different function-
Brønsted-acid catalysis is a rapidly growing area of or- ality may be attached, allowing for the control of both the
the layered in-
(
[
3c–3e,4]
ganocatalysis.
The application of achiral and chiral reactivity and selectivity of the organic process. In addition,
Brønsted acids in organic synthesis avoids the use of metal- since they are insoluble in water and organic solvents, it is
easy to recover them by simple filtration or centrifugation
and reused.
[
a] Dipartimento di Chimica, Università di Perugia,
Via Elce di Sotto 8, 06123 Perugia, Italy
Fax: +39-075-5855560
The α-zirconium hydrogen phosphate α-Zr(HPO
α-ZrP), and α-zirconium sulfophenylphosphonate methan-
phosphonate α-Zr(O PCH ) (O PC H SO H) (α-ZrPS-
) ·H O
4 2 2
(
E-mail: oriana@unipg.it
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
3
3 1.2
3
6
4
3
0.8
O H) have very different acidities; the former is a weakly
3
1214
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1214–1220

Direct Aza-Diels–Alder Reaction in Water
acidic solid (pK = 2.0–3.0) with regularly spaced P-OH Table 1. Direct aza-Diels–Alder reaction of 2-cyclohexen-1-one (1)
a
with N-PMP-p-chlorobenzaldimine (2a).
groups, while the latter is a strong acid (acid strength, H
0
[
5c]
=
–5.6, –8.2).
Water plays an important role in the development of new
synthetic processes both by improving the chemical effi-
ciency and reducing the environmental impact.[ Our re-
search is always aimed at defining new, efficient, synthetic
7]
[
7c,7d,7f,8]
procedures by using water as a reaction medium,
Entry[a]
Catalyst
Medium
Additive
equiv.)
Conv. [%][b] 3a/4a
and in this context, we have also investigated, inter alia, the
(
Diels–Alder reaction and its aza version by using preformed
[
7d,8b–8e,8i,9]
1
2
3
4
5
6
7
α-ZrP
α-ZrP
α-ZrP
CH Cl2
–
–
–
–
–
0
0
0
–
–
–
2
dienes.
2
H O
To contribute to the development of the direct Diels–
Alder reaction we have focused our research on the use of
water as a reaction medium, which has not previously inves-
–
[c]
[d]
α-ZrP
2
H O
10
63:37
–
[
c]
[d]
α-ZrP
–
Ͻ1
[
e]
α-ZrP
–
α-ZrP
α-ZrP
AcOH
AcOH
2
H O
SDS (0.4)
SDS (0.4)
SDS (0.4)
SDS (0.2)
–
SDS (0.4)
–
SDS (0.4)
–
93
54:46
54:46
52:48
49:51
–
tigated, and on the use of layered α-ZrP and α-ZrPSO H as
3
2
H O
5
recyclable Brønsted-acid catalysts. In this context, we have
studied the reaction of 2-cyclohexen-1-one (1) with benzald-
[
f]
8
2
H O
73
64
0
9
10
11
H
H O
2
2
O
1
2
imines 2 [R = C H -R, R = C H -pOMe (PMP)], an effec-
6
4
6
4
tive route to isoquinuclidines 3 and 4 (azabicyclo[2.2.2]oc-
tanes), which are the structural elements of numerous natu-
rally occurring alkaloids with interesting biological proper-
ties.[
2
H O
48
51:49
54:46
50:50
–
48:52
–
[g]
1
2
α-ZrPSO
α-ZrPSO
3
H
H
H
2
O
O
O
O
O
O
11
[
g]
1
3
3
®
H
H
2
82
[g]
1
4
Amberlist 15
2
0
39
0
10]
®
[g]
1
5
Amberlist 15
H
H
2
SDS (0.4)
CTAB (0.4)
–
1
6
α-ZrP
DBSA
2
[
g]
17
H
2
30
50:50
[
a] Reaction conditions: imine 2a, cyclohexenone (1, 10 equiv.), cat-
Results and Discussion
alyst (20 mol-%) at 30 °C for 24 h, unless specified otherwise. [b]
The complement to 100% is unreacted 2a unless specified other-
wise. [c] Catalyst (100 mol-%). [d] Reaction time: 4 d. [e] Yield of
isolated products: 84%. [f] Cyclohexenone (1, 5 equiv.) [g] The com-
plement to 100% is unreacted 2a and p-chlorobenzaldehyde from
the hydrolysis of 2a.
We started with the optimisation of the process in water
for which N-PMP-p-chlorobenzaldimine (2a) was used
along with different proton sources as Brønsted acids (2a/1
=
1:10). The results are illustrated in Table 1.
In DCM, water or in the absence of a reaction medium
and in the presence of 20 mol-% of α-ZrP (with respect to
the imine), we did not detect the cycloadducts 3a and 4a Mannich reaction and provides 82% of 3a and 4a (Table 1,
®
after 24 h at 30 °C (Table 1, Entries 1–3). When we in- Entry 13). Amberlist 15, a highly acidic macromolecular
creased the amount of α-ZrP to 100 mol-%, we observed resin with sulfonic acid functionality, greatly favours the hy-
adducts 3a and 4a in small amounts and an endo/exo ratio drolysis of the imine (Table 1, Entries 14 and 15). A weak
of 63:37 after 4 d (Table 1, Entry 4); under the same reac- layered acid like α-ZrP coupled with the anionic surfactant
tion conditions, we observed no products when the reaction SDS is required for the success of the direct Diels–Alder
was carried out in the absence of solvent (Table 1, Entry 5). reaction in an aqueous medium. We isolated the iso-
It is well known that the combination of Brønsted acids quinuclidines 3a and 4a with excellent yield. The reaction
and surfactants catalyzes the Mannich-type reaction in time was six times shorter, and the exo adduct 4a was 2.5
[
4b,11]
water.
sulfate (SDS) to the reaction performed in water gave the toluene.
desired adducts 3a and 4a after 24 h in a conversion of 93% To evaluate the importance of the nature of the surfac-
84% isolated yield) and with a 54:46 endo/exo ratio tant, we studied the reaction with α-ZrP in the presence of
Table 1, Entry 6). The reaction performed in water in the 0.4 equiv. of cetyl trimethyl ammonium bromide (CTAB), a
The addition of 0.4 equiv. of sodium dodecyl times more abundant than in the reaction carried out in
[
3d]
(
(
presence of only SDS yielded only 5% of the desired ad- cationic surfactant, or by using only dodecylbenzenesul-
[
12]
ducts (Table 1, Entry 7).
fonic acid (DBSA), which works as a Brønsted acid and
When the amount of cyclohexenone 1 (5 equiv.) and SDS a surfactant. In the first case, we observed no reaction,
(0.2 equiv.) was reduced by half, the reaction conversion de- while in the second, we saw the competitive hydrolysis of
creased to 73% and 64%, respectively (Table 1, Entries 8 imine (Table 1, Entries 16 and 17).
and 9). The simple use of a weak organic acid such as acetic
A more in-depth investigation is necessary to understand
acid did not catalyze the reaction, and we obtained only the intriguing role played by SDS. At present, we hypothe-
4
8% product in the presence of SDS (Table 1, Entries 10 size that in an aqueous medium, SDS favours, very likely
+
+
[13]
and 11). α-ZrPSO H seemed to be more efficacious than through Na /H surface exchange, proton transfer from
3
did α-ZrP but its stronger acidity favoured the hydrolysis of the P-OH groups of the heterogeneous α-ZrP to the rea-
the imine, as seen by the production of p-chlorobenzalde- gents, particularly the imine. Moreover, since it is known
hyde (Table 1, Entry 12). The presence of SDS favours the that the endo/exo diastereoselectivity of the Diels–Alder re-
Eur. J. Org. Chem. 2009, 1214–1220
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1215

O. Piermatti et al.
FULL PAPER
action is affected by the use of surfactant,[9b] the interaction
of the protonated imine on the Stern layer of the micellar
aggregate could also explain the observed increase of exo
adduct 4a. The experiment with CTAB (Table 1, Entry 16)
1
2
and the good solubility of 5 and 6 (R = C H -p-Cl, R =
6
4
PMP) in the aqueous medium does not give much support
to a solubility effect due to SDS.
In order to extend the scope of this study and to confirm
the efficiency of the α-ZrP/SDS system in an aqueous me-
dium, we also considered the aza-Diels–Alder reaction of
cyclohexenone (1) with typical imines 2b–k, performed un-
der the previously found best conditions: α-ZrP (20 mol-
%) and SDS (0.4 equiv.) in water at 30 °C. The results are
illustrated in Table 2.
Scheme 2. One-pot, three-component, direct aza-Diels–Alder reac-
tion in water.
Table 2. Direct aza-Diels–Alder reaction in water of cyclohexenone
(
1) with N-PMP-benzaldimines 2 catalyzed by the heterogeneous
Brønsted acid α-ZrP and SDS.
washed it with water and reused it twice without observing
any decrease in reactivity or stereoselectivity (Table 3, En-
tries 1–3).
Table 3. Recycling of heterogeneous Brønsted acids α-ZrP in the
aza-Diels–Alder reaction of 2-cyclohexen-1-one (1) with N-PMP-
p-chlorbenzaldimine (2a).
Entry[a]
Imine 2 (Ar)
2a: pCl-C
2b: mCl-C
2c: oCl-C
2d: C
2e: pBr-C
2f: pF-C
2g: pO N-C
2h: pH CS-C
2i: pH CO-C
2j: pH C-C
2k: pNC-C
t [h]
Conv. [%][b] Yield [%][c]
3/4
Entry[a]
Run
Conversion [%]
3a/4a
1
2
3
4
5
6
7
8
9
6
H
H
6 4
H
6 4
H
5
H
6 4
H
4
H
6 4
6 4
H
6
H
4
24
24
72
24
72
24
72
24
24
24
24
93
88
83
92
93
95
78
94
88
89
90
84
79
74
83
83
84
70
82
79
80
80
54:46
54:46
51:49
54:46
50:50
56:44
50:50
43:57
42:58
48:52
55:45
1
2
3
Cycle 1
Cycle 2
Cycle 3
93
93
89
54:46
54:46
55:45
[
[
b]
b]
6
4
Cycle 1
Cycle 2
Cycle 3
93
90
91
54:46
54:46
54:46
6
[
[
c]
5
6
2
c]
3
3
4
[a] Reaction conditions: imine 2a, cyclohexenone 1 (10 equiv.), α-
ZrP (20 mol-%), SDS (0.4 equiv.) in water at 30 °C for 24 h. [b] The
recovered solid α-ZrP was washed with water, and reused in a new
reaction. [c] All of the reaction medium (water, α-ZrP and SDS)
was recovered and reused.
1
0
3
6 4
H
H
6 4
11
[
a] Reaction conditions: imine 2, cyclohexenone 1 (10 equiv.), α-
ZrP (20 mol-%), SDS (0.4 equiv.) in water 30 °C. [b] The comple-
ment to 100% is unreacted imine 2. [c] Yield of isolated products
(
For a reaction carried out in water, it is also important
to recover the aqueous medium in toto so that the protocol
3 + 4).
The reaction yields of isolated products were excellent is environmentally friendly. The aqueous mother liquor of
(
70–84%), and with respect to the reactions performed in the reaction of 1 with 2a (water, α-ZrP and SDS), after the
[
3d]
toluene,
the reaction times were 3–6 times shorter, and extraction of 3a and 4a, was recycled twice; we obtained
the exo adducts were ≈ 2.5–3 times more abundant. The the same conversion and endo/exo ratio of products as we
presence of hydrophobic groups such as SMe, OMe and had with unused reagents (Table 3, Entries 4–6).
Me increased the exo adduct percentage (52–58%, Table 2,
Entries 8–10). This finding is in agreement with the hypoth-
esis of an increased interaction of the aryl group of the
protonated imines with micellar aggregates of SDS.
Conclusions
Finally, we investigated the one-pot, three–component,
direct, aza-Diels–Alder reaction in water and the recovery Diels–Alder reaction between 2-cyclohexen-1-one (1) and
of the catalyst. mixture of p-chlorobenzaldehyde benzaldimines 2 carried out in water as a reaction medium.
1 equiv.), p-methoxyaniline (1 equiv.) and cyclohexen-2- The reaction is catalysed by layered α-ZrP and required the
In conclusion, we report for the first time the direct aza-
A
(
one (1, 10 equiv.) in the presence of α-ZrP (20 mol-%) and presence of a catalytic amount of SDS. Under these condi-
SDS (0.4 equiv.) in water, at 30 °C for 24 h, gave the cy- tions, the reaction was faster and the exo diastereoselecti-
cloadducts 3a and 4a with a 78% isolated yield and an vity was higher than that observed when the reaction was
endo/exo ratio of 56:44 (Scheme 2).
performed in toluene; the yield was excellent. The one-pot,
When solid Brønsted-acid catalysts are used, their ac- three-component version of the reaction and the recycling
tivity after being recovered becomes an important issue. We of both the catalyst and the aqueous mother liquor in toto
recovered the α-ZrP used in the reaction of 1 with 2a, gave very satisfactory results.
1216
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1214–1220

Direct Aza-Diels–Alder Reaction in Water
NMR (100.6 MHz, CDCl
5
1
3
): δ = 22.25, 22.61, 46.12, 49.51, 52.07,
5.65, 65.77, 114.77 (2 C), 114.81 (2 C), 123.92, 126.00, 127.80,
30.26, 134.91, 142.14, 144.53, 152.36, 211.46 ppm. IR (CHCl ): ν˜
Experimental Section
General: All chemicals were purchased and used without further
3
1
13
purification. H and C NMR spectra were recorded at 400 MHz
and 100.6 MHz, respectively, in CDCl solution. IR spectra were
recorded with a FT-IR instrument with CHCl as the solvent. GC
–1
=
1730.5, 1511.0, 1251.6, 1040.2, 818.9 cm .
rel-(1S,3S,4S)-3-(3-Chlorophenyl)-2-(4-methoxyphenyl)-2-azabicyclo-
2.2.2]octan-5-one (exo 4b): Yield 24.8 mg (36%), pale brown crys-
3
3
[
analyses were performed with a DB35H fused-silica capillary col-
umn (30 m, 0.53 mm diameter) with a split/split-less injector with
a FID detector with hydrogen as the gas carrier. Centrifugation
were performed at 12,000 rpm for 10 min. Thin Layered
Chromatography analyses were performed on silica gel on alumin-
ium plates. Column chromatography was performed with silica gel
1
tals; m.p. 143–145 °C. H NMR (400 MHz, CDCl
3
): δ = 1.70 (m,
2
H), 1.91 (m, 1 H), 2.26 (m, 1 H), 2.39 (dd, J = 18.8, 1.8 Hz, 1
H), 2.65 (dd, J = 5.8, 2.9 Hz, 1 H), 2.76 (dt, J = 18.8, 3.0 Hz, 1
H), 3.72 (s, 3 H), 4.44 (m, 1 H), 4.68 (d, J = 2.5 Hz, 1 H), 6.55 (m, 2
1
3
H), 6.76 (m, 2 H), 7.27–7.45 (m, 4 H) ppm. C NMR (100.6 MHz,
CDCl ): δ = 16.30, 26.29, 41.85, 48.92, 50.76, 55.66, 62.35, 114.42
2 C), 114.92 (2 C), 124.45, 126.42, 127.68, 130.13, 134.93, 142.36,
3
(230–400 mesh) eluting with petroleum ether/ethyl acetate, 80:20.
(
The recrystallization of adducts 3 and 4 was performed in n-hex-
ane/ethyl acetate. Melting points are uncorrected. α-Zirconium hy-
drogen phosphate (α-ZrP) was prepared as reported in the litera-
1
1
42.94, 152.28, 213.33 ppm. IR (CHCl
246.2, 1041.0, 816.0 cm . C20H20ClNO (341.83): calcd. C 70.27,
3
): ν˜ = 1725.3, 1509.0,
–
1
2
H 5.90, N 4.10; found C 70.39, H 5.82, N 4.25.
[
14]
ture.
prepared as reported in the literature. The endo adducts 3a–f and
j–k and the exo adducts 4a and 4d are known compounds;[3a,3b,3d]
The benzaldimines 2a–k are known compounds and were
[
15]
rel-(1S,3R,4S)-3-(2-Chlorophenyl)-2-(4-methoxyphenyl)-2-azabicyclo-
[3d]
3
[2.2.2]octan-5-one (endo 3c):
Yield 25.8 mg (38%), yellow crys-
1
the endo adducts 3g–i and the exo adducts 4b,c,e–k are new com-
pounds. For all the adducts, complete characterization has been
reported below.
tals; m.p. 134–136 °C. H NMR (400 MHz, CDCl ): δ = 1.80 (m,
3
1 H), 2.02 (m, 1 H), 2.23 (m, 2 H), 2.52 (dd, J = 18.8, 2.3 Hz, 1
H), 2.84 (ddd, J = 18.8, 3.7, 2.2 Hz, 1 H), 2.88 (dd, J = 5.2, 2.8 Hz,
1
H), 3.72 (s, 3 H), 4.47 (m, 1 H), 4.96 (d, J = 2.1 Hz, 1 H), 6.58
General Procedure for Aza-Diels–Alder Reaction: Imine
2
13
(
m, 2 H), 6.77 (m, 2 H), 7.18 (m, 2 H), 7.38 (m, 2 H) ppm.
C
(0.2 mmol), cyclohexenone 1 (2 mmol, 10 equiv.), catalyst α-ZrP
(0.04 mmol, 20 mol-%), SDS (0.08 mmol, 0.4 equiv.) and H
(1 mL) were added to a 2 mL vial. The mixture was stirred at 30 °C
NMR (100.6 MHz, CDCl
3
): δ = 22.22, 22.52, 45.89, 49.13, 50.22,
2
O
55.58, 62.88, 114.74 (2 C), 115.04 (2 C), 127.42, 127.50, 128.76,
130.07, 131.81, 138.67, 141.77, 152.41, 211.98 ppm. IR (CHCl ): ν˜
3
for 24–72 h (see Table 1–Table 2). The reaction mixture was ex-
tracted with ethyl acetate (3ϫ2 mL). The organic phase was sepa-
rated from the aqueous medium by centrifugation, and the com-
–1
=
1731.5, 1511.4, 1251.6, 1038.3, 819.3 cm .
rel-(1S,3S,4S)-3-(2-Chlorophenyl)-2-(4-methoxyphenyl)-2-azabicyclo-
2.2.2]octan-5-one (exo 4c): Yield 24.7 mg (36%), pale yellow crys-
[
2 4
bined organic layers were dried (Na SO ) and concentrated under
1
tals; m.p. 104–106 °C. H NMR (400 MHz, CDCl
2
H), 2.78 (dt, J = 18.7, 3.0 Hz, 1 H), 2.89 (dd, J = 5.5, 2.8 Hz, 1
H), 3.70 (s, 3 H), 4.47 (m, 1 H), 5.06 (d, J = 1.8 Hz, 1 H), 6.52 (m,
2
3
): δ = 1.72 (m,
reduced pressure. The crude endo/exo mixture of products (3 and 4)
were purified by column chromatography, and the separated endo-3
and exo-4 products were recrystallized.
H), 1.91 (m, 1 H), 2.33 (m, 1 H), 2.40 (dd, J = 18.7, 2.0 Hz, 1
rel-(1S,3R,4S)-3-(4-Chlorophenyl)-2-(4-methoxyphenyl)-2-azabicyclo-
H), 6.75 (m, 2 H), 7.25 (m, 2 H), 7.43 (m, 1 H), 7.67 (m, 1 H)
[
3d]
[
2.2.2]octan-5-one (endo 3a): Yield 31.0 mg (45%), white crystals;
13
ppm. C NMR (100.6 MHz, CDCl
3
): δ = 16.74, 26.29, 42.32,
7.01, 49.52, 55.59, 59.99, 114.50 (2 C), 14.85 (2 C), 127.00, 128.62,
28.77, 130.30, 132.19, 136.83, 142.12, 152.26, 213.21 ppm. IR
1
m.p. 170–172 °C. H NMR (400 MHz, CDCl
3
): δ = 1.75 (m, 1 H),
4
1
2
2
3
.0 (m, 1 H), 2.14 (m, 1 H), 2.26 (m, 1 H), 2.48 (dd, J = 18.8,
.4 Hz, 1 H), 2.71 (dd, J = 5.6, 2.7 Hz, 1 H), 2.75 (dt, J = 18.8,
.1 Hz, 1 H), 3.73 (s, 3 H), 4.43 (m, 1 H), 4.56 (d, J = 2.3 Hz, 1
–1
(
CHCl
3
): ν˜ = 1726.2, 1510.8, 1246.6, 1036.9, 798.3 cm
.
C
20
H
20ClNO (341.83): calcd. C 70.27, H 5.90, N 4.10; found C
2
13
H), 6.61 (m, 2 H), 6.78 (m, 2 H), 7.27 (m, 4 H) ppm. C NMR
100.6 MHz, CDCl ): δ = 22.25, 22.46, 46.06, 49.51, 52.09, 55.59,
5.51, 114.71 (2 C), 114.73 (2 C), 127.12 (2 C), 129.07 (2 C), 133.12,
40.74,142.08, 152.27, 211.50 ppm. IR (CHCl ): ν˜ = 1731.3, 1510.6,
70.33, H 5.96, N 4.19.
(
3
rel-(1S,3R,4S)-2-(4-Methoxyphenyl)-3-phenyl-2-azabicyclo[2.2.2]-
6
1
1
octan-5-one[
tals; m.p. 201–203 °C. H NMR (400 MHz, CDCl
H), 2.04 (m, 1 H), 2.15 (m, 1 H), 2.28 (m, 1 H), 2.48 (dd, J =
3b,d]
(endo 3d): Yield 27.5 mg (45%), pale yellow crys-
3
1
–1
3
): δ = 1.75 (m,
252.6, 1040.1, 817.1 cm .
1
rel-(1S,3S,4S)-3-(4-Chlorophenyl)-2-(4-methoxyphenyl)-2-azabicyclo- 18.8, 2.6 Hz, 1 H), 2.76 (dd, J = 5.7, 2.9 Hz, 1 H), 2.79 (dt, J =
[
3b]
[
2.2.2]octan-5-one (exo 4a):
Yield 24.6 mg (39%), pale yellow
crystals; m.p. 60–62 °C. H NMR (400 MHz, CDCl ): δ = 1.63–
.76 (m, 2 H), 1.90 (m, 1 H), 2.24 (m, 1 H), 2.39 (dd, J = 18.8,
.8 Hz, 1 H), 2.63 (dd, J = 5.8, 2.8 Hz, 1 H), 2.76 (dt, J = 18.8, 55.61, 66.18, 114.54 (2 C), 114.71 (2 C), 125.64 (2 C), 127.44,
.0 Hz, 1 H), 3.72 (s, 3 H), 4.43 (m, 1 H), 4.68 (d, J = 2.4 Hz, 1
128.86 (2 C), 142.15, 142.44, 152.04, 211.88 ppm. IR (CHCl ): ν =
18.8, 3.1 Hz, 1 H), 3.73 (s, 3 H), 4.45 (m, 1 H), 4.60 (d, J = 2.6 Hz,
1
13
3
1 H), 6.64 (m, 2 H), 6.78 (m, 2 H), 7.22–7.35 (m, 5 H) ppm.
C
1
1
3
NMR (100.6 MHz, CDCl ): δ = 22.29, 22.64, 46.07, 49.30, 52.21,
3
3
˜
13
–1
H), 6.54 (m, 2 H), 6.76 (m, 2 H), 7.37 (m, 4 H) ppm. C NMR 1726.6, 1510.8, 1252.1, 1040.6, 818.8 cm .
(
100.6 MHz, CDCl
3
): δ = 16.23, 26.29, 41.88, 48.95, 50.84, 55.63,
2.08, 114.35 (2 C), 114.87 (2 C), 127.66 (2 C), 128.98 (2 C), 133.07,
39.02,142.32, 152.21, 213.40 ppm. IR (CHCl ): ν˜ = 1725.7, 1511.0,
rel-(1S,3S,4S)-2-(4-Methoxyphenyl)-3-phenyl-2-azabicyclo[2.2.2]-
6
1
1
octan-5-one[ (exo 4d): Yield 23.5 mg (38%), pale yellow crystals;
3b]
3
1
m.p. 111–112 °C. H NMR (400 MHz, CDCl
3
): δ = 1.65 (m, 1 H),
–1
246.6, 1040.1, 817.4 cm .
1.75 (m, 1 H), 1.90 (m, 1 H), 2.28 (m, 1 H), 2.40 (dd, J = 18.7,
rel-(1S,3R,4S)-3-(3-Chlorophenyl)-2-(4-methoxyphenyl)-2-azabicyclo- 1.8 Hz, 1 H), 2.68 (dd, J = 5.8, 2.9 Hz, 1 H), 2.75 (dt, J = 18.7,
[
3d]
[
2.2.2]octan-5-one (endo 3b):
Yield 29.2 mg, (43%), yellow crys-
tals; m.p. 125–127 °C. H NMR (400 MHz, CDCl ): δ = 1.75 (m,
H), 2.04 (m, 1 H), 2.13 (m, 1 H), 2.26 (m, 1 H), 2.49 (dd, J =
8.8, 2.5 Hz, 1 H), 2.72 (dd, J = 5.7, 2.8 Hz, 1 H), 2.77 (dt, J = 55.65, 62.64, 114.26 (2 C), 114.84 (2 C), 126.23 (2 C) 127.35, 128.77
3.0 Hz, 1 H), 3.71 (s, 3 H), 4.45 (m, 1 H), 4.72 (d, J = 2.0 Hz, 1
1
13
3
H), 6.57 (m, 2 H), 6.75 (m, 2 H), 7.28–7.46 (m, 5 H) ppm.
C
1
1
1
1
NMR (100.6 MHz, CDCl ): δ = 16.31, 26.29, 41.93, 48.85, 51.04,
3
8.8, 3.0 Hz, 1 H), 3.74 (s, 3 H), 4.44 (m, 1 H), 4.56 (d, J = 2.5 Hz, (2 C), 140.42, 142.65, 152.01, 213.92 ppm. IR (CHCl
H), 6.61 (m, 2 H), 6.79 (m, 2 H), 7.18–7.31 (m, 4 H) ppm.
3
): ν˜ = 1723.1,
1
3
–1
C
1510.6, 1246.0, 1041.3, 814.5 cm .
Eur. J. Org. Chem. 2009, 1214–1220
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1217

O. Piermatti et al.
rel-(1S,3R,4S)-3-(4-Bromophenyl)-2-(4-methoxyphenyl)-2-azabicyclo- rel-(1S,3S,4S)-2-(4-Methoxyphenyl)-3-(4-nitrophenyl)-2-azabicyclo-
FULL PAPER
[
3d]
[
2.2.2]octan-5-one (endo 3e):
Yield 32.1 mg (42%), yellow crys-
tals; m.p. 201–203 °C. H NMR (400 MHz, CDCl ): δ = 1.75 (m,
H), 2.03 (m, 1 H), 2.13 (m, 1 H), 2.25 (m, 1 H), 2.47 (dd, J =
[2.2.2]octan-5-one (exo 4g): Yield 24.7 mg (35 %), yellow-orange
1
1
3
crystals; m.p. 127–129 °C. H NMR (400 MHz, CDCl
3
): δ = 1.58–
1
1
1
1
1.75 (m, 2 H), 1.95 (m, 1 H), 2.26 (m, 1 H), 2.42 (dd, J = 18.8,
8.8, 2.4 Hz, 1 H), 2.70 (dd, J = 5.6, 2.8 Hz, 1 H), 2.74 (dt, J = 1.9 Hz, 1 H), 2.70 (dd, J = 5.8, 2.9 Hz, 1 H), 2.79 (dt, J = 18.8,
8.3, 3.1 Hz, 1 H), 3.73 (s, 3 H), 4.43 (m, 1 H), 4.54 (d, J = 2.1 Hz, 3.0 Hz, 1 H), 3.71 (s, 3 H), 4.46 (m, 1 H), 4.80 (d, J = 2.4 Hz, 1
H), 6.60 (m, 2 H), 6.80 (m, 2 H), 7.19 (m, 2 H), 7.44 (m, 2 H) H), 6.52 (m, 2 H), 6.76 (m, 2 H), 7.63 (m, 2 H), 8.25 (m, 2 H) ppm.
ppm. C NMR (100.6 MHz, CDCl
9.51, 52.01, 55.58, 65.53, 114.72 (4 C), 121.26, 127.48 (2 C), 131.98
2 C), 141.28, 142.04, 152.26, 211.49 ppm. IR (CHCl ): ν˜ = 1731.4, (2 C), 141.80, 147.43, 148.37, 152.52, 212.39 ppm. IR (CHCl
1
3
13
3
): δ = 22.22, 22.44, 46.04,
C NMR (100.6 MHz, CDCl
50.44, 55.59, 62.21, 114.51 (2 C), 114.94 (2 C), 124.11 (2 C), 127.23
): ν˜
3
): δ = 16.28, 26.29, 41.90, 49.17,
4
(
1
3
3
–1
–1
510.5, 1251.9, 1040.1, 816.9 cm .
= 1726.6, 1513.8, 1347.9, 1247.1, 1182.4, 1040.8, 817.6 cm
(352.32): calcd. C 68.17, H 5.72, N 7.95; found C
8.30, H 5.81, N 8.07.
.
20 20 2 4
C H N O
rel-(1S,3S,4S)-3-(4-Bromophenyl)-2-(4-methoxyphenyl)-2-azabicyclo-
2.2.2]octan-5-one (exo 4e): Yield 32.0 mg (41%), pale brown crys-
tals; m.p. 108–110 °C. H NMR (400 MHz, CDCl
6
[
1
rel-(1S,3R,4S)-2-(4-Methoxyphenyl)-3-[(4-methylthio)phenyl]-2-aza-
3
): δ = 1.68 (m,
bicyclo[2.2.2]octan-5-one (endo 3h): Yield 25.0 mg (35 %), white
2
H), 1.90 (m, 1 H), 2.24 (m, 1 H), 2.39 (dd, J = 18.8, 2.8 Hz, 1
1
crystals; m.p. 155–157 °C. H NMR (400 MHz, CDCl
3
): δ = 1.74
H), 2.63 (dd, J = 5.7, 2.8 Hz, 1 H), 2.76 (dt, J = 18.8, 3.0 Hz, 1
H), 3.71 (s, 3 H), 4.43 (m, 1 H), 4.66 (d, J = 2.3 Hz, 1 H), 6.54 (m,
(
m, 1 H), 2.02 (m, 1 H), 2.13 (m, 1 H), 2.25 (m, 1 H), 2.45 (s, 3
H), 6.75 (m, 2 H), 7.32 (m, 2 H), 7.51 (m, 2 H) ppm. 1 C NMR
3
H), 2.47 (dd, J = 18.8, 2.5 Hz, 1 H), 2.72 (dd, J = 5.7, 2.8 Hz, 1
H), 2.76 (dt, J = 18.8, 3.0 Hz, 1 H), 3.73 (s, 3 H), 4.43 (m, 1 H),
2
(
6
100.6 MHz, CDCl
3
): δ = 16.22, 26.26, 41.84, 48.93, 50.75, 55.61,
2.11, 114.33 (2 C), 114.85 (2 C), 121.14, 128.02 (2 C), 131.89 (2
): ν˜ = 1725.8,
(386.28): calcd.
C 62.19, H 5.22, N 3.63; found C 62.36, H 5.39, N 3.72.
4
.55 (d, J = 2.4 Hz, 1 H), 6.63 (m, 2 H), 6.77 (m, 2 H), 7.21 (m, 4
1
3
H) ppm. C NMR (100.6 MHz, CDCl
3
): δ = 15.73, 22.26, 22.53,
C), 139.57, 142.27, 152.19, 213.32 ppm. IR (CHCl
3
–1
46.06, 49.42, 52.13, 55.61, 65.76, 114.64 (2 C), 114.72 (2 C), 126.22
1
513.5, 1246.8, 1040.5, 816.6 cm . C20H20BrNO
2
(
(
2 C), 127.05 (2 C), 137.40, 139.11, 142.31, 152.14, 211.81 ppm. IR
CHCl ): ν˜ = 1731.5, 1510.7, 1253.6, 1093.3, 894.3, 709.5, 646.6
3
–
1
rel-(1S,3R,4S)-3-(4-Fluorophenyl)-2-(4-methoxyphenyl)-2-azabicyclo- cm . C H NO S (353.48): C 71.35, H 6.56, N 3.96, S 9.07; found
2
1
23
2
[
3d]
[
2.2.2]octan-5-one
(endo 3f): Yield 30.6 mg (47%), pale brown
crystals; m.p. 154–156 °C. H NMR (400 MHz, CDCl ): δ = 1.75
m, 1 H), 2.03 (m, 1 H), 2.14 (m, 1 H), 2.26 (m, 1 H), 2.48 (dd, J
18.8, 2.3 Hz, 1 H), 2.71 (dd, J = 5.5, 2.7 Hz, 1 H), 2.75 (dt, J =
8.8, 3.1 Hz, 1 H), 3.73 (s, 3 H), 4.44 (m, 1 H), 4.57 (br. s, 1 H),
.62 (m, 2 H), 6.78 (m, 2 H), 7.00 (m, 2 H), 7.28 (m, 2 H) ppm.
3
C NMR (100.6 MHz, CDCl ): δ = 22.25, 22.45, 46.06, 49.53,
2.25, 55.60, 65.47, 114.71 (2 C), 114.73 (2 C) 115.76 (d, J =
C 71.45, H 6.68, N 4.02, S 9.13.
1
3
rel-(1S,3S,4S)-2-(4-Methoxyphenyl)-3-[(4-methylthio)phenyl]-2-aza-
(
=
bicyclo[2.2.2]octan-5-one (exo 4h): Yield 33.0 mg (47%), white crys-
1
tals; m.p. 96–98 °C. H NMR (400 MHz, CDCl
3
): δ = 1.62 (m, 1
1
6
H), 1.75 (m, 1 H), 1.89 (m, 1 H), 2.25 (m, 1 H), 2.38 (dd, J = 18.8,
.6 Hz, 1 H), 2.50 (s, 3 H), 2.63 (dd, J = 5.7, 2.8 Hz, 1 H), 2.76
dt, J = 18.8, 3.0 Hz, 1 H), 3.71 (s, 3 H), 4.43 (m, 1 H), 4.67 (d, J
2.2 Hz, 1 H), 6.56 (m, 2 H), 6.75 (m, 2 H), 7.27 (m, 2 H), 7.35
1
(
1
3
5
2
1
1
=
(
1.5 Hz, 2 C), 127.28 (d, J = 8.15 Hz, 2 C), 137.84, 142.18, 152.23,
62.02 (d, J = 245.7 Hz), 211.70 ppm. IR (CHCl ): ν˜ = 1730.9,
3
513.5, 1252.4, 1238.2, 1040.3, 818.1 cm .
1
3
m, 2 H) ppm. C NMR (100.6 MHz, CDCl
6.24, 41.82, 48.86, 50.91, 55.57, 62.20, 114.25 (2 C), 114.77 (2
C),126.72 (2 C), 126.82 (2 C), 137.24, 137.32, 142.47, 152.01, 213.65
ppm. IR (CHCl ): ν˜ = 1725.3, 1510.8, 1246.5, 1092.6, 909.2, 707.2,
S (353.48): calcd. C 71.35, H 6.56, N 3.96,
3
): δ = 15.70, 16.22,
2
–1
rel-(1S,3S,4S)-3-(4-Fluorophenyl)-2-(4-methoxyphenyl)-2-azabicyclo-
2.2.2]octan-5-one (exo 4f): Yield 24.0 mg (37%), pale yellow crys-
tals; m.p. 150–152 °C. H NMR (400 MHz, CDCl
3
–
1
6
50.6 cm . C21H23NO
2
[
1
S 9.07; found C 71.44, H 6.62, N 4.042, S 9.19.
3
): δ = 1.69 (m,
2
H), 1.90 (m, 1 H), 2.25 (m, 1 H), 2.39 (dd, J = 18.8, 1.7 Hz, 1
rel-(1S,3R,4S)-2,3-Bis(4-methoxyphenyl)-2-azabicyclo[2.2.2]octan-
H), 2.63 (dd, J = 5.7, 2.9 Hz, 1 H), 2.76 (dt, J = 18.8, 2.9 Hz, 1
H), 3.72 (s, 3 H), 4.44 (m, 1 H), 4.70 (br. s, 1 H), 6.55 (m, 2 H),
6
5
-one (endo 3i): Yield 22.3 mg (33 %), pale brown crystals; m.p.
1
3
145–147 °C. H NMR (400 MHz, CDCl ): δ = 1.73 (m, 1 H), 2.01
1
3
.76 (m, 2 H), 7.08 (m, 2 H), 7.40 (m, 2 H) ppm. C NMR
(
1
m, 1 H), 2.12 (m, 1 H), 2.26 (m, 1 H), 2.46 (dd, J = 18.8, 2.5 Hz,
H), 2.72 (dd, J = 5.7, 2.9 Hz, 1 H), 2.76 (dt, J = 18.8, 3.0 Hz, 1
H), 3.73 (s, 3 H), 3.77 (s, 3 H), 4.43 (m, 1 H), 4.55 (d, J = 2.5 Hz,
H), 6.64 (m, 2 H), 6.78 (m, 2 H), 6.85 (m, 2 H), 7.22 (m, 2 H)
(100.6 MHz, CDCl ): δ = 16.20, 26.28, 41.86, 48.96, 51.02, 55.62,
3
6
1
2
1
7
1.98, 114.33 (2 C), 114.84 (2 C), 115.66 (d, J = 21.5 Hz, 2 C),
27.76 (d, J = 8.0 Hz, 2 C), 135.96, 142.41, 152.14, 162.07 (d, J =
1
45.5 Hz), 213.58 ppm. IR (CHCl
3
): ν˜ = 1725.7, 1511.0, 1277.7,
246.3, 1225.5, 1040.7, 816.7 cm . C20 20FNO (325.32): calcd. C
3.83, H 6.20, N 4.30; found C 73.95, H 6.29, N 4.22.
13
ppm. C NMR (100.6 MHz, CDCl
9.28, 52.31, 55.13, 55.60, 65.62, 114.22 (2 C), 114.52 (2 C), 114.68
2 C), 126.69 (2 C), 134.16, 142.50, 151.96, 158.77, 212.35 ppm. IR
3
): δ = 22.23, 22.44, 46.03,
–1
H
2
4
(
(
–
1
CHCl
3
): ν˜ = 1729.8, 1510.2, 1248.6, 1037.9, 817.9 cm
(337.41): C 74.75, H 6.87, N 4.15; found C 74.65, H
.98, N 4.22.
.
rel-(1S,3R,4S)-2-(4-Methoxyphenyl)-3-(4-nitrophenyl)-2-azabicyclo-
2.2.2]octan-5-one (endo 3g): Yield 24.6 mg (35%), orange crystals;
21 3
C H23NO
6
[
1
m.p. 196–198 °C. H NMR (400 MHz, CDCl
3
): δ = 1.80 (m, 1 H),
2
2
3
.07 (m, 1 H), 2.19 (m, 1 H), 2.27 (m, 1 H), 2.52 (dd, J = 18.8,
.4 Hz, 1 H), 2.74 (dd, J = 5.6, 2.8 Hz, 1 H), 2.77 (dt, J = 18.8, one (exo 4i): Yield 31.0 mg (46%), pale brown crystals; m.p. 96–
.0 Hz, 1 H), 3.72 (s, 3 H), 4.46 (m, 1 H), 4.69 (d, J = 2.4 Hz, 1
rel-(1S,3S,4S)-2,3-Bis(4-methoxyphenyl)-2-azabicyclo[2.2.2]octan-5-
1
3
97 °C. H NMR (400 MHz, CDCl ): δ = 1.62 (m, 1 H), 1.77 (m, 1
H), 6.58 (m, 2 H), 6.78 (m, 2 H), 7.49 (m, 2 H), 8.18 (m, 2 H) ppm. H), 1.88 (m, 1 H), 2.26 (m, 1 H), 2.38 (dd, J = 18.7, 1.6 Hz, 1 H),
1
3
C NMR (100.6 MHz, CDCl
3
): δ = 22.27, 22.41, 46.09, 49.93, 2.63 (dd, J = 5.7, 2.8 Hz, 1 H), 2.75 (dt, J = 18.7, 2.9 Hz, 1 H),
51.87, 55.57, 65.47, 114.82 (2 C), 115.00 (2 C), 124.25 (2 C), 126.78 3.71 (s, 3 H), 3.82 (s, 3 H), 4.43 (m, 1 H), 4.67 (d, J = 2.4 Hz, 1
(
=
C
2 C), 141.52, 147.36, 149.68, 152.64, 210.86 ppm. IR (CHCl
1732.3, 1519.9, 1346.6, 1251.9, 1189.0, 1039.5, 818.5 cm
3
): ν˜
H), 6.57 (m, 2 H), 6.75 (m, 2 H), 6.92 (m, 2 H), 7.34 (m, 2 H) ppm.
C NMR (100.6 MHz, CDCl ): δ = 16.21, 26.26, 41.83, 48.83,
3
51.16, 55.21, 55.60, 62.06, 114.12 (2 C), 114.20 (2 C), 114.77 (2 C),
127.23 (2 C), 132.16, 142.68, 151.90, 158.83, 214.20 ppm. IR
–
1
13
.
20
H
20
N
2
O
4
(352.32): calcd. C 68.17, H 5.72, N 7.95; found C
6
8.26, H 5.79, N 7.99.
1218
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1214–1220

Direct Aza-Diels–Alder Reaction in Water
(
CHCl
3
): ν˜ = 1723.1, 1512.0, 1246.7, 1036.8, 816.4 cm–1
(337.41): calcd. C 74.75, H 6.87, N 4.15; found C
4.87, H 6.95, N 4.28.
.
ing projects COFIN and COFINLAB (CEMIN), are thanked for
financial support.
21 3
C H23NO
7
[
1] a) R. J. Sundberg, S. Q. Smith in The Alkaloids (Ed.: G. A. Car-
del), Academic Press, 2002, Vol. 59, p. 261; b) D. O’Hagan,
Nat. Prod. Rep. 2000, 17, 435; c) D. L. Boger, S. M. Weinreb,
Hetero Diels–Alder Methodology in Organic Synthesis, Aca-
demic Press, San Diego, CA, 1987.
rel-(1S,3R,4S)-2-(4-Methoxyphenyl)-3-(4-methylphenyl)-2-azabicyclo-
[3d]
[
2.2.2]octan-5-one (endo 3j):
Yield 24.7 mg (38%), yellow crys-
tals; m.p. 129–131 °C. H NMR (400 MHz, CDCl ): δ = 1.74 (m,
H), 2.02 (m, 1 H), 2.13 (m, 1 H), 2.26 (m, 1 H), 2.32 (s, 3 H),
1
3
1
2
2
.46 (dd, J = 18.8, 2.6 Hz, 1 H), 2.73 (m, J = 5.7, 2.9 Hz, 1 H),
.77 (dt, J = 18.8, 3.0 Hz, 1 H), 3.73 (s, 3 H), 4.44 (m, 1 H), 4.56
[
2] a) K. A. Jørgensen, Angew. Chem. Int. Ed. 2000, 39, 3558–
3588; b) S. Kobayashi, H. Ishitani, Chem. Rew. 1999, 99, 1069–
(
7
d, J = 2.5 Hz, 1 H), 6.64 (m, 2 H), 6.78 (m, 2 H), 7.12 (m, 2 H),
1094; c) N. S. Josephsohn, M. L. Snapper, A. H. Hoveyda, J.
Am. Chem. Soc. 2003, 125, 4018–4019; d) O. G. Mancheno, M.
Arrayas, J. C. Carretero, J. Am. Chem. Soc. 2004, 126, 456–457;
e) Y. Yamaschita, K. Mikzuki, S. Kobayashi, Tetrahedron Lett.
13
.20 (m, 2 H) ppm. C NMR (100.6 MHz, CDCl
3
): δ = 21.01,
22.28, 22.55, 46.05, 49.24, 52.30, 55.61, 66.00, 114.47 (2 C), 114.70
(2 C), 125.51 (2 C), 129.57 (2 C), 136.97, 139.18, 142.55, 151.96,
2
005, 46, 1803–1806; f) T. Akiyama, J. Itoh, K. Fuchibe, An-
2
12.13 ppm. IR (CHCl ): ν˜ = 1727.8, 1510.5, 1252.1, 1040.4, 816.1
3
–
1
gew. Chem. Int. Ed. 2006, 45, 4796–4798.
cm .
[
3] a) G. Babu, P. T. Perumal, Tetrahedron 1998, 54, 1627–1638; b)
G. Shanthi, P. T. Perumal, Synth. Commun. 2005, 35, 1319–
rel-(1S,3S,4S)-2-(4-Methoxyphenyl)-3-(4-methylphenyl)-2-azabicyclo-
1
327; c) H. Sundén, I. Ibrahem, L. Eriksson, A. Cordova, An-
[
2.2.2]octan-5-one (exo 4j): Yield 26.7 mg (42%), pale yellow crys-
1
gew. Chem. Int. Ed. 2005, 44, 4877–4880; d) H. Liu, L. F. Cun,
A. Q. Mi, Y. Z. Jiang, L. Z. Gong, Org. Lett. 2006, 8, 6023–
6
7
tals; m.p. 55–57 °C. H NMR (400 MHz, CDCl
3
): δ = 1.64 (m, 1
H), 1.76 (m, 1 H), 1.89 (m, 1 H),2.27 (m, 1 H), 2.37 (s, 3 H), 2.39
026; e) M. Rueping, C. Azap, Angew. Chem. Int. Ed. 2006, 45,
832–7835.
(
(
dd, J = 18.7, 1.8 Hz, 1 H), 2.65 (dd, J = 5.8, 2.9 Hz, 1 H), 2.76
dt, J = 18.7, 3.0 Hz, 1 H), 3.71 (s, 3 H), 4.44 (m, 1 H), 4.68 (br. s,
[
4] a) T. Akiyama, J. Itoh, K. Fuchibe, Adv. Synth. Catal. 2006,
48, 999–1010; b) T. Akiyama, Chem. Rev. 2007, 107, 5744–
5758.
1
H), 6.57 (m, 2 H), 6.75 (m, 2 H), 7.20 (m, 2 H), 7.32 (m, 2 H)
3
1
3
ppm. C NMR (100.6 MHz, CDCl
1.88, 48.81, 51.09, 55.63, 62.41, 114.20 (2 C), 114.80 (2 C), 126.12
2 C), 129.45 (2 C), 136.94, 137.32, 142.72, 151.91, 214.10 ppm. IR
3
): δ = 16.29, 21.05, 26.27,
4
[5] a) G. Alberti, M. Casciola, U. Costantino, R. Vivani, Adv. Ma-
ter. 1996, 8, 291–303; b) R. Vivani, F. Costantino, G. Alberti,
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(
(
–
1
CHCl
3
): ν˜ = 1723.6, 1511.8, 1245.7, 1040.6, 816.5 cm
(321.41): calcd. C 78.47, H 7.21, N 4.36; found C
8.35, H 7.38, N 4.24.
.
7
0; c) M. Curini, O. Rosati, U. Costantino, Curr. Org. Chem.
21 2
C H23NO
7
2004, 8, 591–606.
[
6] a) U. Costantino, F. Fringuelli, M. Nocchetti, O. Piermatti,
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rel-(1S,3R,4S)-4-[2-(4-Methoxyphenyl)-5-oxo-2-azabicyclo[2.2.2]-
[3d]
oct-3-yl]benzonitrile (endo 3k): Yield 29.2 mg (44%), pale yellow
1
crystals; m.p. 165–167 °C. H NMR (400 MHz, CDCl
3
): δ = 1.79
(m, 1 H), 2.06 (m, 1 H), 2.17 (m, 1 H), 2.27 (m, 1 H), 2.50 (dd, J
[
7] a) C. J. Li,; T. H. Chan, Organic reaction in Aqueous Media;
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2003, 7, 1661–1689; g) C. J. Li, Chem. Rev. 2005, 105, 3095–
=
18.8, 2.3 Hz, 1 H), 2.72 (dd, J = 5.6, 2.8 Hz, 1 H), 2.75 (dt, J =
18.8, 3.0 Hz, 1 H), 3.73 (s, 3 H), 4.45 (m, 1 H), 4.64 (d, J = 2.1 Hz,
1
H), 6.58 (m, 2 H), 6.78 (m, 2 H), 7.43 (m, 2 H), 7.61 (m, 2 H)
1
3
ppm. C NMR (100.6 MHz, CDCl
3
): δ = 22.26, 22.42, 46.07,
9.83, 51.84, 55.57, 65.63, 111.43, 114.80 (2 C), 114.93 (2 C),
18.61, 126.66 (2 C), 132.79 (2 C), 141.60,147.69, 152.57, 210.91
): ν˜ = 2231.8, 1733.6, 1511.0, 1252.0, 1040.1, 817.7
4
1
ppm. IR (CHCl
3
–1
cm .
3165; h) Organic Reactions in Water (Ed.: U. M. Lindstrom),
Blackwell Publishing 2007.
rel-(1S,3S,4S)-4-[2-(4-Methoxyphenyl)-5-oxo-2-azabicyclo[2.2.2]oct-
[
8] a) D. Amantini, F. Fringuelli, O. Piermatti, F. Pizzo, L. Vac-
caro, Green Chem. 2001, 3, 229–232; b) F. Fringuelli, M.
Matteucci, O. Piermatti, F. Pizzo, M. C. Burla, J. Org. Chem.
3
-yl]benzonitrile (exo 4k): Yield 24.0 (36%), pale yellow crystals;
1
m.p. 71–73 °C. H NMR (400 MHz, CDCl
3
): δ = 1.80 (m, 1 H),
2
2
3
.07 (m, 1 H), 2.19 (m, 1 H), 2.26 (m, 1 H), 2.52 (dd, J = 18.9,
.5 Hz, 1 H), 2.74 (dd, J = 5.6, 2.8 Hz, 1 H), 2.77 (dt, J = 18.9,
.0 Hz, 1 H), 3.72 (s, 3 H), 4.46 (m, 1 H), 4.69 (d, J = 2.4 Hz, 1
2
001, 66, 4661–4666; c) O. A. Attanasi, L. De Crescentini, P.
Filippone, F. Fringuelli, F. Mantellini, M. Matteucci, O. Pierm-
atti, F. Pizzo, Helv. Chim. Acta 2001, 84, 513–525; d) D. Aman-
tini, F. Fringuelli, F. Pizzo, J. Org. Chem. 2002, 67, 7238–7243;
e) D. Amantini, F. Fringuelli, O. Piermatti, F. Pizzo, L. Vac-
caro, J. Org. Chem. 2003, 68, 9263–9268; f) F. Fringuelli, O.
Piermatti, F. Pizzo, Synthesis 2003, 10, 2331–2334; g) F. Fring-
uelli, F. Pizzo, L. Vaccaro, J. Org. Chem. 2004, 69, 2315–2321;
h) F. Fringuelli, F. Pizzo, S. Tortoioli, L. Vaccaro, Org. Lett.
H), 6.58 (m, 2 H), 6.77 (m, 2 H), 7.49 (m, 2 H), 8.18 (m, 2 H) ppm.
13
3
C NMR (100.6 MHz, CDCl ): δ = 16.25, 26.26, 41.88, 49.08,
5
1
0.43, 55.57, 62.30, 111.35, 114.45 (2 C), 114.91 (2 C), 118.63,
27.13 (2 C), 132.66 (2 C), 141.87, 146.32, 152.44, 212.62 ppm. IR
(
CHCl
3
): ν˜ = 2231.3, 1712.3, 1510.7, 1246.8, 1224.1, 1040.7, 816.2
H N O
20 2 2
–
1
cm . C21 (332.40): calcd. C 75.88, H 6.06, N 8.43; found
2005, 7, 4411–4414; i) R. Girotti, A. Marrocchi, L. Minuti, O.
C 75.86, H 5.98, N 8.52.
Piermatti, F. Pizzo, L. Vaccaro, J. Org. Chem. 2006, 71, 70–74;
j) S. Bonollo, F. Fringuelli, F. Pizzo, L. Vaccaro, Green Chem.
2006, 8, 960–964; k) S. Bonollo, F. Fringuelli, F. Pizzo, L. Vac-
caro, Synlett 2007, 17, 2683–2686; l) F. Fringuelli, O. Piermatti,
F. Pizzo, L. Vaccaro in Organic Reaction in Water (Ed.: U. M.
Lindstrom), Blackwell Publishing, 2007, chapter 5, p. 146–184.
9] a) F. Fringuelli, A. Taticchi, Dienes in the Diels–Alder Reaction,
Wiley, New York, 1990; b) F. Fringuelli, A. Taticchi, The Diels–
Alder Reaction. Selected Practical Methods, Wiley, Chichester,
2002.
Supporting Information (see also the footnote on the first page of
1
13
this article): Copies of H and C NMR spectra.
Acknowledgments
[
The Ministero dell’Istruzione dell’Università e della Ricerca
(MIUR) and the Università degli studi di Perugia, within the fund-
Eur. J. Org. Chem. 2009, 1214–1220
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1219

O. Piermatti et al.
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Received: November 14, 2008
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Published Online: January 21, 2009
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www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1214–1220