Total regio- and stereoselective synthesis of perhydropyrrolo[3,4-c]pyrazole derivatives by [3+2] intramolecular dipolar cycloaddition reaction on chiral perhydro-1,3-benzoxazines

Article abstract of DOI:10.1055/s-2003-40193

Reaction of N-acyl-N′-methyl- or N-acyl-N′-phenylhydrazines with chiral 3-allyl-2-formylperhydro-1,3-benzoxazines form azomethine imines that cyclize to give perhydropyrrolo[3,4-c]pyrazole derivatives. The dipolar cycloaddition was totally regio- and stereoselective yielding a single diastereoisomer. The reaction conditions and the yields of the final compounds are dependent on the substitution pattern of the olefinic bond.

Full text of DOI:10.1055/s-2003-40193

SPECIAL TOPIC
1457
Total Regio- and Stereoselective Synthesis of Perhydropyrrolo[3,4-c]pyrazole
Derivatives by [3+2] Intramolecular Dipolar Cycloaddition Reaction on Chiral
Perhydro-1,3-benzoxazines
Regio- and Stereo
a
selective
S
f
ynthesis
a
of
P
erhydr
e
opyrrolo[3,
l
4-
c
]pyrazolesPedrosa,* Celia Andrés,* Alicia Maestro, Javier Nieto
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Dr. Mergelina s/n, 47011-Valladolid, Spain
Fax +34(983)423013; E-mail: pedrosa@qo.uva.es
Received 28 April 2003
nes in asymmetric 1,3-dipolar cycloaddition reactions is
Abstract: Reaction of N-acyl-N -methyl- or N-acyl-N -phenylhy-
very limited.15
drazines with chiral 3-allyl-2-formylperhydro-1,3-benzoxazines
form azomethine imines that cyclize to give perhydropyrrolo[3,4-
c]pyrazole derivatives. The dipolar cycloaddition was totally regio-
and stereoselective yielding a single diastereoisomer. The reaction
conditions and the yields of the final compounds are dependent on
the substitution pattern of the olefinic bond
We have recently reported the utility of chiral perhydro-
1,3-benzoxazines derived from (–)-8-aminomenthol in
the synthesis of enantiopure octahydropyrrolo[3,4-b]pyr-
roles by intramolecular 1,3-dipolar cycloaddition of
azomethine ylides.16 In this paper we present the synthesis
of enantiopure perhydropyrrolo[3,4-c]pyrazole deriva-
tives by stereoselective intramolecular 1,3-dipolar cy-
cloaddition of azomethine imines with unactivated
alkenes positioned on a chiral perhydro-1,3-benzoxazine
moiety.
Key words: asymmetric synthesis, azomethine imines, dipolar cy-
cloaddition, pyrazolidines, stereoselective synthesis
[3+2] Dipolar cycloaddition of 1,3-dipoles containing ni-
trogen atoms to unsaturated substrates constitutes one of
the simplest ways to the regio- and steroselective con-
struction of five-membered nitrogen heterocycles.1 In this
respect, nitrones,2 nitrile oxides3 and azomethine ylides4
have been widely used, whereas other nitrogen-containing
1,3-dipoles such as azomethine imines,5 although well
known since the 60’s,6 have been employed much less.
The 3-allyl-2-formylperhydro-1,3-benzoxazines 4a–f
were prepared in three steps and good yields from (–)-8-
aminomenthol (1) (Scheme 1). Condensation of 1 with the
dimer of glycolaldehyde in dichloromethane at room tem-
perature afforded quantitatively the perhydro-1,3-benzox-
azine 2 as a single compound which was alkylated with
the corresponding allyl bromides and potassium carbon-
ate in refluxing acetonitrile leading to 3a–f. The Swern
Due to the interest of azomethine imines as 1,3-dipoles,
there are several synthetic methods directed to the gener-
ation of this kind of intermediates. In this respect, azome-
thine imines have been prepared from protonated
hydrazones7 or hydrazones by tautomerization via a ther-
mal 1,2-hydrogen shift.8 -Silylnitrosamines were also
easily transformed into azomethine imines by thermally
promoted 1,4-silatropic shift of the silyl group to the oxy-
gen atom of the nitroso group.9 Some other reactions such
as catalytic dehydrogenation of trisubstituted hydra-
zines,10 thermal carbon–nitrogen bond cleavage of aziri-
dines bearing electron-withdrawing groups,11 or thermal
or photochemical decomposition of sydnones12 have been
also successfully used in the generation of azomethine
imines. Nevertheless, the most general and common way
to these intermediates is the condensation of N-acyl-N -
alkylhydrazines with aldehydes and ketones.13
H
N
NH2
H
OH
O
O
OH
O
+
OH
CH2Cl2, 99%
HO
2
1
Br
R2
R1
K2CO3
CH3CN, reflux
N
N
H
R2
R1
H
R2
O
R1
"Swern"
OH
O
O
The intramolecular version of this reaction results in the
formation of new fused or bridged diazabicyclic system
and takes place easily even with unactivated dipolaro-
philes such as terminal alkenes, and often turns out with
excellent diastereofacial discrimination exhibiting high
stereoselectivity.14 However, the use of azomethine imi-
4a: R1 = R2 = H
3a: R1 = R2 = H
4b: R1 = H, R2 = Me
4c: R1 = Me, R2 = H
4d: R1 = H, R2 = Ph
4e: R1 = Me, R2 = Ph
4f: R1 , R2 = -(CH2)4-
3b: R1 = H, R2 = Me
3c: R1 = Me, R2 = H
3d: R1 = H, R2 = Ph
3e: R1 = Me, R2 = Ph
3f: R1 , R2 = -(CH2)4-
Synthesis 2003, No. 9, Print: 03 07 2003.
Art Id.1437-210X,E;2003,0,09,1457,1461,ftx,en;C01603SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

1458
R. Pedrosa et al.
SPECIAL TOPIC
oxidation of alcohols 3a–f leads to aldehydes 4a–f in good good yields, but after 34–38 hours of reflux in the same
yields.
solvent (entries 7 and 9). Interestingly, trisubstituted dou-
ble bonds in compounds 4e–f also reacted slower than
mono- or disubstituted ones, and it was necessary to in-
crease the reaction time to obtain cyclization products in
lower yields (entries 5, 6). Finally, due to the lower reac-
tivity of the hydrazine derivative, and the structure of the
dipolarophile, the cyclizations of crotyl- 4b and meth-
acrylperhydro-1,3-benzoxazines 4d with N-acetyl-N -
phenylhydrazine have no synthetic interest because they
provided the final products in very low yields (entries 8
and 10). In this case, the long periods of heating allowed
the competition of carbonyl-ene cyclization,18 and these
kind of cycloadducts were detected as major products in
the final reaction mixtures.
The key step of the synthesis was the intramolecular trap-
ping of the azomethine imines formed in situ by the reac-
tion of 4a–f with N,N -disubstituted hydrazines, and the
results are summarized in Scheme 2 and Table 1.
O
N21
R3
3
N
O
10a R2
N
H
N
N
3a
H
R3
N
H
R1
R2
3b
O
O
R1
H
H
O
Toluene, reflux
5a-f: R3 = Me
6a-d: R3 = Ph
It is worthy to note that in all cases the cycloaddition oc-
curred with complete facial selectivity providing cis-syn
adducts as single diastereoisomers, and traces of other cy-
cloadducts were not detected in the 1H NMR spectra of the
reaction mixtures.
4a-f
Scheme 2
Table 1 Intramolecular 1,3-Dipolar Cycloaddition of Azomethine
Imines 4a–f
The relative configuration of adducts 5a–f and 6a–d was
established by 1H NMR, COSY and NOESY experiments.
The NOESY contacts point to a cis-fused bicycle with a
cis relationship between the substituents R1, R2 and H-3a
and trans for H-3b. On the other hand, the 1H NMR signal
for the hydrogen H-3b attached to the N,O-ketal carbon
atom appears as a singlet indicating that the dihedral angle
between H-3b and H-3a is near to 90° and therefore the
substituent attached to the nitrogen atom of the oxazine
moiety is in axial arrangement. As an example, Figure 1
shows the NOESY correlations for compound 5e.
Entry
R1
R2
R3
Time (h) Product Yield
(%)a
1
2
H
H
Me-
Me
Me
Me-
Me-
Me--
Ph
4
6
5a
5b
5c
5d
5e
5f
94
80
92
90
45
42
82
16
78
18
H
Me-
Ph
H
3
H
8
4
Me-
6
5
Me
Ph
20
20
34
28
36
30
6
-(CH-2)4-
7
H
H
6a
6b
6c
6d
O
8
H
Me
Ph
H
Ph
H
N
Me
N
H
9
H
Ph
Me
Ph
Me
N
Me
H
10
Me
Ph
H
a Yield of pure isolated compounds.
O
As expected, condensation took place at the more basic N-
alkyl- or N-phenyl substituted nitrogen, rather than at the
acyl susbtituted nitrogen, and the cyclization afforded,
with total regioselectivity, the 5,5-fused bicyclic system 5
and 6 and no bridged products.
N-Acetyl-N -methylhydrazine17 reacted much faster than
N-acetyl-N -phenylhydrazine. The former led to the cy-
clization products after 4–8 hours of reflux in toluene in
excellent yields when reacted with mono- or disubstituted
double bonds (entries 1–4), whereas the N-acetyl-N -phe-
nyl homolog also yielded the cyclization products in very
Me
Figure 1 1H NMR correlations for compound 5e
To account for the observed diastereoselectivity, we con-
sider that the [3+2] dipolar cycloaddition occurs in the
conformation depicted in Scheme 3. The dipole compo-
nent approach toward the dipolarophile, in axial arrange-
ment in the nitrogen atom, is in an endo mode as
previously observed for a similar 1,3-dipolar cycloaddi-
tion.16
Synthesis 2003, No. 9, 1457–1461 ISSN 1234-567-89 © Thieme Stuttgart · New York

SPECIAL TOPIC
Regio- and Stereoselective Synthesis of Perhydropyrrolo[3,4-c]pyrazole
1459
1H NMR (CDCl3): = 0.84–1.08 (m, 3 H), 0.92 (d, 3 H, J = 6.5 Hz),
1.10 (s, 3 H), 1.15 (s, 3 H), 1.25–1.40 (m, 1 H), 1.53–1.71 (m, 7 H),
1.82–1.92 (m, 3 H), 1.93–2.04 (m, 2 H), 2.23 (br s, 1 H), 2.89 (d, 1
H, J = 18.0 Hz), 3.20 (d, 1 H, J = 18.0 Hz), 3.46 (d, 2 H, J = 5.7 Hz),
3.47 (dt, 1 H, J1 = 4.1 Hz, J2 = 10.7 Hz), 4.61 (t, 1 H, J = 5.7 Hz),
5.77–5.78 (m, 1 H).
O
O
R3
+
R3
N
N
N
N
N
R2
R1
N
H
R2
H
O
R1
H
O
13C NMR (CDCl3): = 19.1, 22.1, 22.6, 22.7, 24.8, 24.9, 26.6, 26.8,
31.1, 34.8, 41.1, 47.2, 47.9, 56.3, 63.5, 75.6, 87.2, 120.9, 138.7.
5a-f, 6a-d
Anal. Calcd for C19H33NO2 (307.48): C, 74.22; H, 10.82; N, 4.56.
Found: C, 74.40; H, 10.98; N, 4.39.
Scheme 3
Swern Oxidation of Alcohols 4e and 4f; General Procedure
DMSO (1.8 mL, 25.3 mmol) was added dropwise to a stirred solu-
tion of oxalyl chloride (1.0 mL, 11.9 mmol) in CH2Cl2 (35 mL) at –
78 °C. The mixture was stirred at –78 °C for 15 min, and then a so-
lution of the corresponding alcohol 3e–f (10 mmol) in CH2Cl2 (25
mL) was added dropwise via a syringe. After 25 min of additional
stirring at –78 °C, Et3N (7.0 mL, 50 mmol) was added and the reac-
tion was allowed to warm to r.t. After 1 h, the mixture was poured
into sat. aq NaHCO3 solution (40 mL). The aqueous layer was ex-
tracted with CH2Cl2 (2 × 25 mL), the combined organic layers were
washed with H2O, dried and concentrated in vacuo. The residue was
chromatographed on silica gel using EtOAc–hexanes (1:30) as elu-
ent.
In summary, a novel totally diastereoselective synthesis of
perhydropyrrolo[3,4-c]pyrazole derivatives has been de-
veloped by intramolecular [3+2] dipolar cycloaddition.
The starting compounds can easily prepared from (–)-8-
aminomenthol in three steps, and a variety of different
substituents can be introduced into the heterocyclic nucle-
us depending on the substitution at the double bond and
the nature of the hydrazine derivative.
All reactions were carried out in anhydrous solvents under argon in
oven-dried glassware. Products were isolated by flash chromatogra-
1
phy using 240–400 mesh silica gel. H NMR (300MHz) and 13C
(2S,4aS,7R,8aR)-2-Formyl-4,4,7-trimethyl-N-(2-methyl-3-phe-
nylallyl)octahydro-1,3-benzoxazine (4e)
NMR were recorded in CDCl3 as solvent and TMS as internal stan-
dard. Chemical shifts are given in (ppm). Specific rotations were
determined on a digital polarimeter using a Na lamp, and concentra-
tion is given in g per 100 mL. Melting points are uncorrected.
Colorless oil; [ ]D25 –70.4 (c = 1.3, CH2Cl2).
IR (film): 3054, 3022, 2977, 2925, 2867, 1743, 743, 699 cm–1.
1H NMR (CDCl3): = 0.87–1.01 (m, 3 H), 0.94 (d, 3 H, J = 6.5 Hz),
1.18 (s, 3 H), 1.24 (s, 3 H), 1.45–1.56 (m, 2 H), 1.62–1.73 (m, 2 H),
1.77 (s, 3 H), 1.98–2.04 (m, 1 H), 3.26 (d, 1 H, J = 18.0 Hz), 3.33
(d, 1 H, J = 18.0 Hz), 3.53 (dt, 1 H, J1 = 4.1 Hz, J2 = 10.6 Hz), 4.89
(s, 1 H), 6.72 (s, 1 H), 7.15–7.33 (m, 5 H), 9.38 (s, 1 H).
Compounds 3a–d and 4a–d have been previously described.16
Alkylation of Perhydrobenzoxazine 2 with Allyl Bromides;
General Procedure
A mixture of perhydrobenzoxazine 2 (3.0 g, 14.1 mmol), K2CO3 (3
g, 21.2 mmol) and the corresponding allyl bromide (21.2 mmol) in
anhyd MeCN (8 mL) was heated in an oil-bath until the reaction was
complete (TLC, 30–80 h). The mixture was diluted with EtOAc, the
solid was separated by filtration and washed with hot EtOAc (3 × 25
mL). The solvents were evaporated under vacuum and the residue
was purified by flash chromatography on silica gel using hexanes–
EtOAc (15:1) as eluent.
13C NMR (CDCl3): = 16.4, 19.6, 22.1, 24.9, 26.1, 31.2, 34.7, 40.9,
46.6, 51.6, 56.7, 75.8, 89.7, 126.0, 126.6, 127.9 (2 C), 128.6 (2 C),
137.6, 138.0, 197.1.
Anal. Calcd for C22H31NO2 (341.50): C, 77.38; H, 9.15; N, 4.10.
Found: C, 77.56; H, 9.22; N, 4.28.
(2S,4aS,7R,8aR)-N-(Cyclohexen-1-enylmethyl)-2-formyl-4,4,7-
trimethyloctahydro-1,3-benzoxazine (4f)
Colorless oil; [ ]D25 –58.3 (c = 1.1, CH2Cl2).
(2S,4aS,7R,8aR)-2-Hydroxymethyl-4,4,7-trimethyl-N-(2-meth-
yl-3-phenylallyl)octahydro-1,3-benzoxazine (3e)
Colorless solid; mp 78–79 °C (EtOH); [ ]D25 –40.3 (c = 1.1,
CH2Cl2).
IR (film): 3020, 2926 1742, cm–1.
1H NMR (CDCl3): = 0.92–0.99 (m, 2 H), 0.93 (d, 3 H, J = 6.5 Hz),
1.02–1.20 (m, 1 H), 1.14 (s, 3 H), 1.17 (s, 3 H), 1.42–1.72 (m, 8 H),
1.87–1.96 (m, 2 H), 1.97–2.03 (m, 3 H), 2.98 (d, 1 H, J = 16.4 Hz),
3.17 (d, 1 H, J = 16.4 Hz), 3.49 (dt, 1 H, J1 = 4.0 Hz, J2 = 10.5 Hz),
4.75 (d, 1 H, J = 0.9 Hz), 5.71–5.72 (m, 1 H), 9.29 (d, 1 H, J = 0.9
Hz).
IR (Nujol): 3433 (br), 3046, 2925, 1458, 750, 698 cm–1.
1H NMR (CDCl3): = 0.83–1.09 (m, 3 H), 0.93 (d, 3 H, J = 6.5 Hz),
1.15 (s, 3 H), 1.22 (s, 3 H), 1.26–1.51 (m, 2 H), 1.53–1.72 (m, 2 H),
1.82 (s, 3 H), 1.90–2.19 (m, 1 H), 2.09–2.19 (m, 1 H), 3.12 (d, 1 H,
J = 18.5 Hz), 3.39 (d, 1 H, J = 18.5 Hz), 3.47–3,52 (m, 3 H), 4.70 (t,
1 H, J = 5.5 Hz), 6.75 (s, 1 H), 7.17–7,33 (m, 5 H).
13C NMR (CDCl3): = 16.5, 19.5, 22.2, 25.0, 26,4, 31.2, 34.9, 41.2,
47.3, 49.8, 56.7, 63.8, 75.8, 87.3, 124.2, 125.8, 127.9 (2 C), 128.7
(2 C), 138.3, 139.5.
13C NMR (CDCl3): = 19.0, 22.0, 22.4, 22.5, 24.8, 24.9, 26.3, 26.6,
31.1, 34.7, 40.8, 46.6, 49.8, 56.4, 75.6, 89.7, 124.6, 136.3, 196.9.
Anal. Calcd for C19H31NO2 (305.46): C, 74.71; H, 10.23; N, 4.59.
Found: C, 74.58; H, 10.09; N, 4.68.
Anal. Calcd for C22H33NO2 (343.51): C, 76.92; H, 9.68; N, 4.08.
Found: C, 76.78; H, 9.82; N, 4.19.
Azomethine Imine Generation and 1,3-Dipolar Cycloaddition;
General Procedure
A solution of the appropriate aldehyde 4a–f (2.0 mmol), and acyl-
hydrazine (2.6 mmol) in toluene (40 mL) was refluxed for the time
given in Table 1. The solution was concentrated under reduce pres-
sure, and the residue was chromatographed on silica gel using
EtOAc–hexanes (Table 1).
(2S,4aS,7R,8aR)-N-(Cyclohexen-1-enylmethyl)-2-hydroxyme-
thyl-4,4,7-trimethyloctahydro-1,3-benzoxazine (3f)
Colorless oil; [ ]D25 –43.4 (c = 1.3, CH2Cl2).
IR (film): 3457 (br), 2925, 2867, 1456 cm–1.
Synthesis 2003, No. 9, 1457–1461 ISSN 1234-567-89 © Thieme Stuttgart · New York

1460
R. Pedrosa et al.
SPECIAL TOPIC
(3aR,3bS,4aR,6R,8aS,10aS)-2-Acetyl-3,6,9,9-tetramethyl-
dodecahydro-4-oxa-2,3,9a-triazapentaleno[1,2-b]naphthalene
1 H), 2.99 (d, 1 H, J = 8.3 Hz), 3.12 (d, 1 H J = 11.7 Hz), 3.37 (dt,
1 H, J1 = 4.2 Hz, J2 = 11.7 Hz), 4.25 (d, 1 H, J = 11.7 Hz), 4.65 (s,
1 H).
13C NMR (CDCl3): = 19.8, 20.9, 22.1, 24.6, 25.0, 26.6, 31.1, 34.8,
41.1, 43.2, 45.4, 49.3, 52.3, 54.3, 57.9, 74.7, 82.3, 91.7, 171.9.
(5a)
Colorless solid; mp 96–97 °C (hexane); [ ]D25 –107.2 (c = 1.2,
CH2Cl2).
IR (Nujol): 2923, 1662 cm–1.
Anal. Calcd for C19H33N3O2 (335.49): C, 68.02; H, 9.91; N, 12.53.
Found: C, 67.91; H, 9.83; N, 12.64.
1H NMR (CDCl3): = 0.84–0.98 (m, 3 H), 0.91 (d, 3 H, J = 6.5 Hz),
1.04 (s, 3 H), 1.05 (s, 3 H), 1.26–1.31 (m, 1 H), 1.35–1.52 (m, 1 H),
1.54–1.57 (m, 1 H), 1.68–1.70 (m, 1 H), 1.83–1.87 (m, 1 H), 2.12
(s, 3 H), 2.53 (s, 3 H), 2.71 (dd, 1 H, J1 = 1.7 Hz, J2 = 8.5 Hz), 2.99–
3.07 (m, 1 H), 3.22–3.37 (m, 3 H), 3.39 (dt, 1 H, J1 = 4.2 Hz,
J2 = 10.6 Hz), 4.05 (dd, 1 H, J1 = 1.9 Hz, J2 = 11.8 Hz), 4.63 (s, 1
H).
(3aR,3bS,4aR,6R,8aS,10aS)-2-Acetyl-1-phenyl-3,6,9,9,10a-pen-
tamethyldodecahydro-4-oxa-2,3,9a-triazapentaleno[1,2-b]-
naphthalene (5e)
Coloress solid; mp 171–172 °C (hexane); [ ]D25 –124.2 (c = 0.9,
CH2Cl2).
13C NMR (CDCl3): = 19.7, 21.2, 22.0, 24.6, 26.6, 31.1, 34.8, 39.9,
41.2, 43.6, 45.3, 47.5, 50.5, 52.4, 74.4, 76.7, 90.6, 171.7.
IR (Nujol): 3031, 2925; 1665, 1603, 741, 707 cm–1.
1H NMR (CDCl3): = 0.85–1.08 (m, 3 H), 0.92 (d, 3 H, J = 6.5 Hz),
0.96 (s, 3 H), 1.11 (s, 6 H), 1.26–1.39 (m, 1 H), 1.42–1.51 (m, 1 H),
1.55–1.60 (m, 1 H), 1.67–1.72 (m, 1 H), 1.83–1.90 (m, 1 H), 2.21
(s, 3 H), 2.88 (s, 3 H), 3.05 (s, 1 H), 3.09 (d, 1 H, J = 8.5 Hz), 3.11
(d, 1 H, J = 8.5 Hz), 3.44 (dt, 1 H, J1 = 4.1 Hz, J2 = 10.5 Hz), 4.77
(s, 1 H), 5.31 (s, 1 H), 7.18–7.32 (m, 5 H).
13C NMR (CDCl3): = 20.9, 21.5, 22.2, 23.1, 24.9, 27.1, 31.2, 35.0,
41.4, 44.0, 47.6, 52.5, 54.2, 59.0, 72.2, 74.8, 84.2, 92.2, 126.3 (2 C),
126.6, 128.0 (2 C), 140.0, 172.1.
Anal. Calcd for C18H31N3O2 (321.47): C, 67.25; H, 9.72; N, 13.07.
Found: C, 67.41; H, 9.59; N, 13.18.
(1S,3aR,3bS,4aR,6R,8aS,10aS)-2-Acetyl-1,3,6,9,9-pentamethyl-
dodecahydro-4-oxa-2,3,9a-triazapentaleno[1,2-b]naphthalene
(5b)
Colorless oil; [ ]D25 –95.2 (c = 1.4, CH2Cl2).
IR (film): 2924, 1660 cm–1.
1H NMR (CDCl3): = 0.83–1.01 (m, 3 H), 0.91 (d, 3 H, J = 6.5 Hz),
1.04 (s, 3 H), 1.05 (s, 3 H), 1.10–1.33 (m, 1 H), 1.38 (d, 3 H, J = 6.9
Hz), 1.43–1.46 (m, 1 H), 1.52–1.58 (m, 1 H), 1.68–1.70 (m, 1 H),
1.83–1.87 (m, 1 H), 2.11 (s, 3 H), 2.72 (s, 3 H), 2.78–2.82 (m, 2 H),
3.22 (dd, 1 H J1 = 6.2 Hz, J2 = 8.8 Hz), 3.38 (dt, 1 H, J1 = 4.1 Hz,
J2 = 10.5 Hz), 3.41 (d, 1 H, J = 8.0 Hz), 4.24 (dq, 1 H, J1 = 3.0 Hz,
J2 = 6.9 Hz), 4.61 (s, 1 H).
Anal. Calcd for C25H37N3O2 (411.59): C, 72.95; H, 9.06; N, 10.21.
Found: C, 73.08; H, 9.18; N, 10.12.
(3aR,3bS,4aR,6R,8aS,10aS)-2-Acetyl-1,10a-tetramethylene-
3,6,9,9-tetramethyldodecahydro-4-oxa-2,3,9a-triazapentale-
no[1,2-b]naphthalene (5f)
Colorless solid; mp 128–129 °C (hexane); [ ]D25 –23.8 (c = 0.9,
CH2Cl2).
13C NMR (CDCl3): = 20.1, 21.2, 22.0, 23.1, 24.6, 26.6, 31.0, 34.7,
41.2, 43.7, 48.2 (2 C), 49.9, 52.3, 60.5, 74.6, 77.1, 90.6, 171.2.
IR (Nujol): 2925, 1660 cm–1.
Anal. Calcd for C19H33N3O2 (335.49): C, 68.02; H, 9.91; N, 12.53.
Found: C, 68.16; H, 10.02; N, 12.41.
1H NMR (CDCl3): = 0.89–0.98 (m, 3 H), 0.91 (d, 3 H, J = 6.5 Hz),
1.01 (s, 3 H), 1.08 (s, 3 H), 1.24–1.48 (m, 5 H), 1.52–1.62 (m, 3 H),
1.68–1.73 (m, 2 H), 1.82–1.86 (m, 1 H), 2.03–2.14 (m, 2 H), 2.13
(s, 3 H), 2.81 (d, 1 H, J = 8.7 Hz), 2.86 (s, 3 H), 2.90 (d, 1 H, J = 8.7
Hz), 3.05 (s, 1 H), 3.37 (dt, 1 H, J1 = 4.1 Hz, J2 = 10.5 Hz), 4.24 (dd,
1 H, J1 = 6.4 Hz, J2 = 11.6 Hz), 4.72 (s, 1 H).
13C NMR (CDCl3): = 20.9, 21.1, 21.5, 21.8, 22.2, 24.7, 26.6, 29.7,
31.2, 32.7, 35.0, 41.4, 42.8, 48.0, 52.4, 53.1, 59.4, 63.2, 74.6, 78.2,
91.7, 174.1.
(1R,3aR,3bS,4aR,6R,8aS,10aS)-2-acetyl-1-phenyl-3,6,9,9-tet-
ramethyldodecahydro-4-oxa-2,3,9a-triazapentaleno[1, 2-b]-
naphthalene (5c)
Colorless solid; mp 102–104 °C (hexane); [ ]D25 –75.9 (c = 1.3,
CH2Cl2).
IR (Nujol): 3025, 2922, 1664, 1602, 732, 698 cm–1.
1H NMR (CDCl3): = 0.91–1.07 (m, 3 H), 0.92 (d, 3 H, J = 6.5 Hz),
1.09 (s, 3 H), 1.10 (s, 3 H), 1.34–1.40 (m, 1 H), 1.42–1.55 (m, 1 H),
1.57–1.62 (m, 1 H), 1.65–1.71 (m, 1 H), 1.84–1.88 (m, 1 H), 2.25
(s, 3 H), 2.52 (s, 3 H), 3.05–3.08 (m, 1 H), 3.39–3.47 (m, 4 H), 4.74
(s, 1 H), 5.38 (s, 1 H), 7.20–7.35 (m, 5 H).
Anal. Calcd for C22H37N3O2 (375.56): C, 70.36; H, 9.93; N, 11.19.
Found: C, 70.52; H, 10.04; N, 11.17.
(3aR,3bS,4aR,6R,8aS,10aS)-2-Acetyl-3-phenyl-6,9,9-trimethyl-
dodecahydro-4-oxa-2,3,9a-triazapentaleno[1,2-b]naphthalene
(6a)
13C NMR (CDCl3): = 20.4, 21.5, 22.1, 24.7, 26.8, 31.1, 34.8, 41.2,
43.8, 47.6, 47.9, 50.8, 52.5, 67.1, 74.8, 77.7, 90.6, 125.6 (2 C),
126.6, 128.1 (2 C), 142.4, 172.6.
Colorless solid; mp 191–192 °C (hexane); [ ]D25 –12.49 (c = 1.7,
CH2Cl2).
IR (Nujol): 2920, 1682, 1595, 759, 696 cm–1.
Anal. Calcd for C24H35N3O2 (397.56): C, 72.51; H, 8.87; N, 10.57.
Found: C, 72.42; H, 8.73; N, 10.46.
1H NMR (CDCl3): = 0.88–1.05 (m, 3 H), 0.93 (d, 3 H, J = 6.5 Hz),
1.07 (s, 3 H), 1.11 (s, 3 H), 1.38–1.45 (m, 2 H), 1.55–1.58 (m, 1 H),
1.69–1.73 (m, 1 H), 1.91–1.97 (m, 1 H), 2.04 (s, 3 H), 2.78 (d, 1 H,
J = 8.2 Hz), 2.96–3.01 (m, 2 H), 3.29 (t, 1 H, J = 8.2 Hz), 3.46 (dt,
1 H, J1 = 4.0 Hz, J2 = 10.5 Hz), 4.10 (d, 1 H, J = 6.8 Hz), 4.36–4.41
(m, 1 H), 4.92 (s, 1 H), 6.92 (t, 1 H, J = 7.3 Hz), 6.95 (d, 2 H, J = 8.1
Hz), 7.26 (dd, 2 H, J1 = 7.3 Hz, J2 = 8.1 Hz).
(3aR,3bS,4aR,6R,8aS,10aS)-2-Acetyl-3,6,9,9,10a-pentamethyl-
dodecahydro-4-oxa-2,3,9a-triazapentaleno[1, 2-b]naphthalene
(5d)
Coloress solid; mp 78–79 °C (pentane); [ ]D25 –60.4 (c = 1.3,
CH2Cl2).
IR (Nujol): 2924, 2870, 1668 cm–1.
13C NMR (CDCl3): = 20.4, 21.1, 22.1, 24.6, 26.6, 31.1, 34.8, 41.1,
41.7, 42.8, 49.2, 50.4, 52.5, 74.8, 75.1, 90.7, 113.7 (2 C), 121.1,
129.1 (2 C), 149.8, 175.2.
1H NMR (CDCl3): = 0.88–0.95 (m, 2 H), 0.91 (d, 3 H, J = 6.5 Hz),
0.96–1.08 (m, 1 H), 1.01 (s, 3 H), 1.03 (s, 3 H), 1.23–1.48 (m, 2 H),
1.42 (s, 3 H), 1.51–1.56 (m, 1 H), 1.68–1.70 (m, 1 H), 1.82–1.87 (m,
1 H), 2.09 (s, 3 H), 2.63 (s, 3 H), 2.83 (d, 1 H, J = 8.3 Hz), 2.88 (s,
Anal. Calcd for C23H33N3O2 (383.54): C, 72.03; H, 8.67; N, 10.96.
Found: C, 72.19; H, 8.56; N, 11.08.
Synthesis 2003, No. 9, 1457–1461 ISSN 1234-567-89 © Thieme Stuttgart · New York

SPECIAL TOPIC
Regio- and Stereoselective Synthesis of Perhydropyrrolo[3,4-c]pyrazole
1461
(1S,3aR,3bS,4aR,6R,8aS,10aS)-2-Acetyl-3-phenyl-1,6,9,9-tet-
ramethyldodecahydro-4-oxa-2,3,9a-triazapentaleno[1,2-b]-
naphthalene (6b)
References
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Pergamon: Oxford, 1990, 269. (b) Padwa, A. In
Comprehensive Organic Synthesis, Vol. 4; Semmelhack,
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(7) Shimizu, T.; Hayashi, Y.; Miki, M.; Teramura, K. J. Org.
Chem. 1987, 52, 2277.
Colorless oil; [ ]D25 +7.8 (c = 0.8, CH2Cl2).
IR (film): 2920, 1650, 1597, 754, 703, 654 cm–1.
1H NMR (CDCl3): = 0.86–0.99 (m, 3 H), 0.93 (d, 3 H, J = 6.5 Hz),
1.02 (d, 3 H, J = 6.9 Hz), 1.06 (s, 3 H), 1.11 (s, 3 H), 1.13–1.33 (m,
1 H), 1.39–1.46 (m, 1 H), 1.54–1.58 (m, 1 H), 1.70–1.79 (m, 1 H),
1.91–1.98 (m, 1 H), 2.02 (s, 3 H), 2.14–2.82 (m, 2 H), 3.28 (t, 1 H,
J = 8.3 Hz), 3.46 (dt, 1 H, J1 = 4.1 Hz, J2 = 10.4 Hz), 4.19 (d, 1 H,
J = 5.3 Hz), 4.80 (q, 1 H, J = 6.9 Hz), 4.88 (s, 1 H), 6.88 (t, 1 H,
J = 7.3 Hz), 6.91–6.94 (m, 2 H), 7.22–7.28 (m, 2 H).
13C NMR (CDCl3): = 20.0, 20.9, 21.5, 22.2, 24.8, 26.8, 31.3, 35.0,
41.3, 42.8, 48.5, 50.1, 52.7, 59.1, 73.1, 75.0, 90.8, 112.9 (2 C),
120.3, 129.1 (2 C), 150.7, 176.4.
Anal. Calcd for C24H35N3O2 (397.56): C, 72.51; H, 8.87; N, 10.57.
Found: C, 72.39; H, 8.99; N, 10.43.
(8) (a) Grigg, R. Chem. Soc. Rev. 1987, 16, 89. (b) Noguchi,
M.; Yamada, K. Synthesis 1993, 145. (c) Sun, B.; Adachi,
K.; Noguchi, M. Tetrahedron 1996, 52, 901. (d) Sun, B.;
Adachi, K.; Noguchi, M. Synthesis 1997, 53. (e) Arrieta,
A.; Carrillo, J. R.; Cossío, F. P.; Díaz-Ortiz, A.; Gómez-
Escalonilla, M. J.; Hoz, A.; Langa, F.; Moreno, A.
Tetrahedron 1998, 54, 13167.
(9) (a) Washizuka, K. I.; Nagai, K.; Minakata, S.; Ryu, I.;
Konatsu, M. Tetrahedron Lett. 1999, 40, 8849.
(b) Washizuka, K. I.; Nagai, K.; Minakata, S.; Ryu, I.;
Konatsu, M. Tetrahedron Lett. 2000, 41, 691.
(10) Grigg, R.; Heaney, F.; Idle, J.; Somasunderam, A.
Tetrahedron Lett. 1990, 31, 2767.
(11) (a) Lehman, L. S.; Baclawski, L. M.; Harris, S. A.; Heine, H.
W.; Springer, J. P.; VandenHeuvel, W. J. A.; Arison, B. H.
J. Org. Chem. 1981, 46, 320. (b) Molchanov, A. P.; Sipkin,
D. I.; Koptelov, Y. B.; Kostikov, R. R. Synlett 2000, 1779.
(c) Molchanov, A. P.; Sipkin, D. I.; Koptelov, Y. B.;
Kostikov, R. R. Eur. J. Org. Chem. 2002, 453.
(1R,3aR,3bS,4aR,6R,8aS,10aS)-2-Acetyl-1,3-diphenyl-6,9,9-tri-
methyldodecahydro-4-oxa-2,3,9a-triazapentaleno[1, 2-b]naph-
thalene (6c)
Colorless oil; [ ]D25 +3.4 (c = 1.1, CH2Cl2).
IR (film): 2924, 2854, 1684, 1598, 746, 695 cm–1.
1H NMR (CDCl3): = 0.86–1.08 (m, 2 H), 0.95 (d, 3 H, J = 6.5 Hz),
1.12 (s, 3 H), 1.15 (s, 3 H), 1.18–1.23 (m, 1 H), 1.48–1.56 (m, 2 H),
1.57–1.63 (m, 1 H), 1.67–1.69 (m, 1 H), 1.94–1.98 (m, 1 H), 2.04
(s, 3 H), 2.96–2.99 (m 1 H), 3.42–3.49 (m, 2 H), 3.54 (dt, 1 H,
J1 = 4.0 Hz, J2 = 10.5 Hz), 4.41–4.44 (m, 1 H), 4.96 (s, 1 H), 5.75 (s
1 H), 6.62 (d, 2 H, J = 8.1 Hz), 6.74 (t, 1 H, J = 7.4 Hz), 7.05 (dd, 2
H, J1 = 7.4 Hz, J2 = 8.1 Hz), 7.10–7.26 (m, 5 H).
13C NMR (CDCl3): = 20.8, 21.5, 22.2, 24.8, 26.9, 31.3, 35.0, 41.3,
43.0, 46.6, 50.8, 52.9, 66.4, 74.3, 75.1, 91.1, 113.2 (2 C), 120.1,
127.3, 127.8 (2 C), 128.2 (2 C), 128.6 (2 C), 139.9, 149.5, 175.8.
Anal. Calcd for C29H37N3O2 (459.64): C, 75.78; H, 8.11; N, 9.14.
Found: C, 75.71; H, 8.23; N, 9.25.
(12) Meier, H.; Heimgartner, H. Helv. Chim. Acta 1986, 69, 927;
and references cited therein.
(3aR,3bS,4aR,6R,8aS,10aS)-2-Acetyl-3-phenyl-6,9,9,10a-tet-
ramethyldodecahydro-4-oxa-2,3,9a-triazapentaleno[1,2-b]-
naphthalene (6d)
(13) (a) Oppolzer, W. Tetrahedron Lett. 1970, 2199.
(b) Oppolzer, W. Tetrahedron Lett. 1970, 3091. (c) Jacobi,
P. A.; Martinelli, M. J.; Polanc, S. J. Am. Chem. Soc. 1984,
106, 5594. (d) Jungheim, L. N.; Sigmund, S. K. J. Org.
Chem. 1987, 52, 4007. (e) Kanemasa, S.; Tomoshige, N.;
Wada, E.; Tsuge, O. Bull. Chem. Soc. Jpn. 1989, 62, 3944.
(f) Fuchi, N.; Doi, T.; Cao, B.; Kahn, M.; Takahashi, T.
Synlett 2002, 285. (g) Fuchi, N.; Doi, T.; Harada, T.; Urba,
J.; Cao, B.; Kahn, M.; Takahashi, T. Tetrahedron Lett. 2001,
42, 1305.
(14) Wade, P. A. In Comprehensive Organic Synthesis, Vol. 4;
Semmelhack, M., Ed.; Pergamon: Oxford, 1991, 1111.
(15) Gothelf, K. V.; Jorgensen, K. A. Chem Rev. 1998, 98, 863.
(16) Pedrosa, R.; Andrés, C.; Heras, L.; Nieto, J. Org. Lett. 2002,
4, 2513.
Colorless oil; [ ]D25 +1.5 (c = 1.7, CH2Cl2).
IR (film): 2923, 1679, 1596, 1492, 754, 696 cm–1.
1H NMR (CDCl3 ): = 0.86–1.03 (m, 3 H), 0.94 (d, 3 H, J = 6.5 Hz),
1.05 (s, 3 H), 1.11 (s, 3 H), 1.24 (s, 3 H), 1.42–1.49 (m, 2 H), 1.50–
1.55 (m, 1 H), 1.70–1.88 (m, 1 H), 1.91–1.97 (m, 1 H), 2.03 (s, 3 H),
2.80 (d, 1 H, J = 11.3 Hz), 2.97 (d, 1 H, J = 8.4 Hz), 3.04 (d, 1 H,
J = 8.4 Hz), 3.45 (dt, 1 H, J1 = 4.1 Hz, J2 = 10.6 Hz), 3.67 (s, 1 H),
4.47 (d, 1 H, J = 11.3 Hz), 4.93 (s, 1 H), 6.91–6.97 (m, 3 H), 7.26
(dd, 2 H, J1 = 7.1 Hz, J2 = 8.8 Hz).
13C NMR (CDCl3): = 20.7, 21.0, 22.3, 23.9, 24.8, 26.8, 31.3, 35.0,
41.3, 42.8, 50.8, 52.7, 55.8, 57.7, 75.0, 81.1, 91.4, 113.8 (2 C),
121.2, 129.2 (2 C), 150.1, 175.3.
(17) Condon, F. E. J. Org. Chem. 1972, 37, 3608.
(18) Pedrosa, R.; Andrés, C.; Rosón, C. D.; Vicente, M. J. Org.
Chem. 2003, 68, 1852.
Anal. Calcd for C24H35N3O2 (397.56): C, 72.51; H, 8.87; N, 10.57.
Found: C, 72.63; H, 8.82; N, 10.46.
Acknowledgments
Authors thank the Ministerio de Ciencia y Tecnología (Project BQU
2002-1046) and Junta de Castilla y León (Project VA042/03) for fi-
nancial support.
Synthesis 2003, No. 9, 1457–1461 ISSN 1234-567-89 © Thieme Stuttgart · New York