Effective synthesis of enantiopure [1,2,3]triazolo[1,5-a]- and pyrazolo[1,5-a]-pyrrolo[2,1-c][1,4]benzodiazepines by diastereoselective intramolecular azide and nitrilimine cycloadditions

Article abstract of DOI:10.1055/s-2005-869991

The synthesis of new tetracyclic 1,4-benzodiazepinonic systems was performed in enantiopure form by totally diastereoselective intramolecular 1,3-dipolar cycloadditions. The absolute stereochemistry of the products was confirmed by X-ray crystallography a

Full text of DOI:10.1055/s-2005-869991

2246
PAPER
Effective Synthesis of Enantiopure [1,2,3]Triazolo[1,5-a]- and Pyrazolo[1,5-a]-
pyrrolo[2,1-c][1,4]benzodiazepines by Diastereoselective Intramolecular
Azide and Nitrilimine Cycloadditions
S
ynthesisof [1,2,3
i
]Triazo
a
lo[1,5-
a
]-
a
nd
P
yrazolo
l
[1,5-
a
]-
u
pyrrolo[2,1-
i
c
][1,4]
g
i
ines Broggini,*a Ivan De Marchi,a Michela Martinelli,a,b Giuseppe Paladino,b Tullio Pilati,c Alberto Terraneod
a
Dipartimento di Scienze Chimiche e Ambientali, Università dell’Insubria, via Valleggio 11, 22100 Como, Italy
Fax +39(031)2386449; E-mail: gianluigi.broggini@uninsubria.it
b
c
d
Istituto di Chimica Organica ‘A. Marchesini’, Facoltà di Farmacia, Università di Milano, via Venezian 21, 20133 Milano, Italy
Consiglio Nazionale delle Ricerche-Istituto di Scienze e Tecnologie Molecolari, via Golgi 19, 20133 Milano, Italy
Chorisis s.r.l., via Colombo 30/32, 22066 Mariano Comense (Como), Italy
Received 18 February 2005; revised 6 April 2005
the anthramycin antibiotics, a typical example of which is
abbeymycin 5.4 Recently, the tetracyclic compound 6
(Figure 2), referred to as bretazenil, has emerged in view
of its potential use towards neurodegenerative diseases.5
Abstract: The synthesis of new tetracyclic 1,4-benzodiazepinonic
systems was performed in enantiopure form by totally diastereose-
lective intramolecular 1,3-dipolar cycloadditions. The absolute ste-
reochemistry of the products was confirmed by X-ray
crystallography and the enantiomeric purity was determined by us-
ing chiral HPLC.
Key words: azides, diastereoselectivity, fused-ring systems, nitril-
imines, pyrrolo[2,1-c][1,4]benzodiazepines
The biological activity and the pharmaceutical impor-
tance of 1,4-benzodiazepines are well established since a
few decades.1 The array of the therapeutic applications of
this class of compounds has been impressively widened
upon annulation of the benzodiazepine skeleton to another
carbocyclic or heterocyclic ring. [1,2,4]Triazolo[4,3-a]-
and imidazo[3,4-a][1,4]benzodiazepines, exemplified by
triazolam 1 and midazolam 2 (Figure 1), respectively,
usually possess an improved efficacy as anti-anxiety
drugs,1 but the particular substrate 3 known as flumazenil
belongs better to anti-depressants and cognition enhanc-
ers.2 On the other hand, dibenzoannulated 1,4-benzodiaz-
epines such as the so-called tarpane 4 (Figure 2) exhibit
antihistaminic properties,3 while a number of pyrrolo[2,1-
c][1,4]benzodiazepin-5-ones constitute the new class of
Figure 2
On continuing a research line on the synthesis of 1,4-ben-
zodiazepine derivatives of pharmacological interest,6 we
turned our attention to new classes of tetracyclic com-
pounds,
namely
[1,2,3]triazolo[1,5-a]pyrrolo[2,1-
c][1,4]benzodiazepines 7 and pyrazolo[1,5-a]pyrrolo[2,1-
c][1,4]benzodiazepines 8. As strategy of approach, we
perceived the usefulness of intramolecular azide and ni-
trilimine cycloadditions in order to construct simulta-
neously the seven-membered heterocycle and the
triazole6e,f or pyrazole6c,d,g,7 one. Moreover, having in
mind the current requisites of synthetic methodologies in
the pharmaceutical field, we aimed at optically active tar-
gets and to this end we utilized the inexpensive L-proline
as source of chirality. While a preliminary communication
on this work has described the synthesis of only one sub-
strate,8 the present report substantiates the effectiveness
and the generality of our synthetic approach, also provid-
ing an unequivocal X-ray evidence about the stereochem-
ical outcome of the intramolecular cycloaddition process.
Figure 1
SYNTHESIS 2005, No. 13, pp 2246–2252
Advanced online publication: 13.07.2005
x
x.
x
x
.
2
0
0
5
DOI: 10.1055/s-2005-869991; Art ID: Z03905SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of [1,2,3]Triazolo[1,5-a]- and Pyrazolo[1,5-a]-pyrrolo[2,1-c][1,4]benzodiazepines
2247
Since we had devised the unsaturated anilines 12 as suit- of precursors of labile nitrilimine species. Actually, the re-
able precursors of both azide and nitrilimine 1,3-dipoles, action of 14 with Et3N in boiling toluene resulted in the
we first synthesized them upon reaction of the in situ gen- tetracyclic products 8, clearly due to an intramolecular cy-
erated (S)-2-vinylpyrrolidine (9) with 5-(un)substituted 2- cloaddition of the first formed nitrilimines 15. The stereo-
nitrobenzoyl chlorides 10 to afford the corresponding chemistry of the products was assigned on the basis of the
amides 11 and subsequent reduction of the nitro group NMR data in comparison with those of 7 as well as of pre-
(see Scheme 1). At this point, diazotization of 12 followed viously reported pyrrolo[2,1-c][1,4]benzodiazepines.9
by nucleophilic reaction with NaN3 provided the desired HPLC analysis with chiral column of 8a, performed in
azides 13, which were subjected to heat treatment in re- comparison to a sample of the corresponding racemic
fluxing CCl4 or toluene at 80 °C (see Scheme 2). After a mixture synthesized starting from the ( )-proline, proved
few hours, the tetracyclic products 7 were obtained in 68– an enantiomeric purity better than 99.5%.
75% yields; their structures being consistent with analyti-
While the unique regiochemistry of the cycloadditions
cal and spectral data. In particular, the vicinal coupling
just described was expected as a consequence of stringent
constant of the hydrogens with the stereogenic carbons
geometric constraints, the fully diastereoselective out-
suggested a trans configuration, which was confirmed on
come was not predictable and constitutes an important and
useful feature from the synthetic point of view. On exam-
ining molecular models, one can see that the bulk and
submitting compound 7b to X-ray diffractometric analy-
sis (see Figure 3).
rather rigid pyrrolidine moiety works against the intramo-
lecular approach of the dipole to the re face of the ethyl-
enic bond, so dictating the exclusive formation of the
trans diastereoisomers 8.
As a conclusion, the present paper reports a simple and ef-
ficient entry to the first representatives of the title tetracy-
clic systems. Moreover, they were accessible in
enantiopure form starting from the commercially avail-
able methyl ester of N-Boc-L-proline; no loss of optical
activity was observed along the synthetic step sequence.
Melting points were determined on a Büchi B-540 heating appara-
tus and are uncorrected. Optical rotation values were measured on a
Jasco P-1010 polarimeter at 23 °C. IR spectra were recorded on a
Jasco FT/IR 5300 spectrophotometer. 1H NMR and 13C NMR spec-
tra were obtained on an Avance Bruker 400 spectrometer. Chemical
shifts are given in ppm downfield from TMS. 13C NMR spectra are
1H-decoupled and the determination of the multiplicities was
achieved by the APT pulse sequence. The enantiopurity was deter-
mined using a Waters 510 HPLC [Daicel OD-H, 4.6 × 250 mm, mo-
Scheme 1
bile phase of hexane–EtOH (70:30), flow rate 1 mL/min] with a
Jasco UV-2075 detector at 231 nm. Mass spectra were determined
on a VG-7070 EQ-HF instrument. Elemental analyses were execut-
ed on Perkin-Elmer CHN Analyzer Series II 2400.
Nitroamides 11a–c; General Procedure
N-Boc-2-vinylpyrrolidine10 (552 mg, 2.8 mmol) was treated with
CF3COOH (0.7 mL) under N2 atmosphere for 1 h at r.t. After evap-
oration to dryness, the residue was taken with anhyd toluene (3 mL)
and added dropwise to a suspension of 10 (2.8 mmol) and K2CO3
(4.0 g, 29.0 mmol) in anhyd toluene (23 mL) at 40 °C. The mixture
was heated to reflux for 4 h, then poured in ice water (40 mL) and
extracted with Et2O (2 × 30 mL). The organic layer was dried over
Na2SO4 and the solvent was removed under reduced pressure to
give 11 in pure form as undistillable oil (compounds a and b) or
crystalline material (compound c).
Figure 3 ORTEP plot of 7b; only the most populated conformer is
reported. Thermal ellipsoids at 50% probability level; hydrogen
atoms not to scale.
(S)-(2-Nitrophenyl)-(2-vinylpyrrolidin-1-yl)methanone (11a)
Yield: 60%; colorless oil; [a]D –2.7 (c = 0.7, CHCl3).
IR (nujol): 1636 cm–1.
Major Conformer
Diazotization of the same intermediates 12 followed by
coupling with methyl 2-chloroacetoacetate furnished the
hydrazonyl chlorides 14, which belong to a typical class
1H NMR (CDCl3): d = 1.72–2.15 (m, 4 H), 3.93–3.97 (m, 1 H), 3.69
(ddd, J = 5.8, 6.2, 12.1 Hz, 1 H), 3.87 (ddd, J = 8.0, 8.2, 12.1 Hz, 1
H), 4.67 (d, J = 17.0 Hz, 1 H), 4.88 (d, J = 10.2 Hz, 1 H), 5.59 (ddd,
Synthesis 2005, No. 13, 2246–2252 © Thieme Stuttgart · New York

2248
G. Broggini et al.
PAPER
Scheme 2
J = 6.6, 10.2, 17.0 Hz, 1 H), 7.36 (dd, J = 1.3, 7.5 Hz, 1 H), 7.54
(ddd, J = 1.3, 7.6, 8.4 Hz, 1 H), 7.64 (dd, J = 7.5, 7.6 Hz, 1 H), 8.17
(d, J = 8.4 Hz, 1 H).
13C NMR (CDCl3): d = 24.15 (t), 32.91 (t), 48.89 (t), 62.26 (d),
115.91 (t), 126.64 (d), 127.76 (d), 130.21 (d), 135.88 (s), 137.94 (d),
141.61 (s), 143.61 (s), 165.66 (s).
13C NMR (CDCl3): d = 22.20 (t), 32.41 (t), 46.29 (t), 61.75 (d),
113.64 (s), 115.23 (t), 124.38 (d), 128.86 (d), 129.65 (d), 131.72 (s),
133.93 (d), 137.61 (d), 168.42 (s).
Anal. Calcd for C13H13ClN2O3: C, 55.62; H, 4.67; N, 9.98. Found:
C, 55.69; H, 4.46; N, 9.79.
(S)-(2-Nitro-5-fluorophenyl)-(2-vinylpyrrolidin-1-yl)metha-
none (11c)
Yield: 53%; pale yellow crystals from diisopropyl ether; mp 86–87
°C; [a]D –27.7 (c = 1.1, CHCl3).
Minor Conformer
1H NMR (CDCl3): d = 1.72–2.15 (m, 4 H), 3.18 (ddd, J = 6.9, 7.1,
10.7 Hz, 1 H), 3.23 (ddd, J = 4.6, 4.8, 10.7 Hz, 1 H), 4.81–4.89 (m,
1 H), 5.23 (d, J = 10.3 Hz, 1 H), 5.34 (d, J = 17.0 Hz, 1 H), 5.96
(ddd, J = 5.4, 10.3, 17.0 Hz, 1 H), 7.46 (dd, J = 1.2, 7.5 Hz, 1 H),
7.57 (ddd, J = 1.2, 7.4, 8.4 Hz, 1 H), 7.70 (dd, J = 7.4, 7.5 Hz, 1 H),
8.19 (d, J = 8.4 Hz, 1 H).
IR (nujol): 1647 cm–1.
Major Conformer
1H NMR (CDCl3): d = 1.74–2.17 (m, 4 H), 3.72 (ddd, J = 5.9, 6.3,
12.2 Hz, 1 H), 3.87 (ddd, J = 8.0, 8.1, 12.2 Hz, 1 H), 3.93–3.99 (m,
1 H), 4.71 (d, J = 17.0 Hz, 1 H), 4.94 (d, J = 10.2 Hz, 1 H), 5.62
(ddd, J = 6.8, 10.2, 17.0 Hz, 1 H), 7.07 (dd, J = 2.7, 7.8 Hz, 1 H),
7.20 (ddd, J = 2.7, 7.3, 9.1 Hz, 1 H), 8.22 (dd, J = 4.7, 9.1 Hz, 1 H).
13C NMR (CDCl3): d = 23.75 (t), 30.95 (t), 48.42 (t), 58.34 (d),
113.64 (s), 114.82 (t), 124.64 (d), 128.29 (d), 129.65 (d), 131.64 (s),
134.51 (d), 137.11 (d), 168.44 (s).
Anal. Calcd for C13H14N2O3: C, 63.40; H, 5.73; N, 11.38. Found: C,
63.27; H, 5.92; N, 11.49.
13C NMR (CDCl3): d = 23.95 (t), 32.68 (t), 48.69 (t), 62.02 (d),
115.58 (t), 116.23 (dd, JC–F = 24.8 Hz), 117.19 (dd, JC–F = 23.2 Hz),
127.82 (dd, JC–F = 9.8 Hz), 136.55 (d, JC–F = 8.3 Hz), 137.89 (d),
141.24 (s), 165.42 (s), 166.58 (d, JC–F = 257.6 Hz).
(S)-(2-Nitro-5-chlorophenyl)-(2-vinylpyrrolidin-1-yl)metha-
none (11b)
Yield: 56%; colorless oil; [a]D –15.1 (c = 1.1, CHCl3).
Minor Conformer
IR (nujol): 1643 cm–1.
1H NMR (CDCl3): d = 1.74–2.17 (m, 4 H), 3.16–3.22 (m, 1 H),
3.24–3.29 (m, 1 H), 4.83–4.89 (m, 1 H), 5.24 (d, J = 10.4 Hz, 1 H),
5.33 (d, J = 17.1 Hz, 1 H), 5.95 (ddd, J = 5.6, 10.4, 17.1 Hz, 1 H),
7.14 (dd, J = 2.7, 7.6 Hz, 1 H), 7.20 (ddd, J = 2.7, 7.3, 9.2 Hz, 1 H),
8.26 (dd, J = 4.7, 9.2 Hz, 1 H).
13C NMR (CDCl3): d = 22.39 (t), 31.15 (t), 46.60 (t), 59.22 (d),
114.95 (t), 115.94 (dd, JC–F = 24.7 Hz), 116.95 (dd, JC–F = 23.2 Hz),
128.11 (dd, JC–F = 9.7 Hz), 137.08 (d, JC–F = 8.1 Hz), 137.35 (d),
141.35 (s), 164.94 (s), 167.05 (d, JC–F = 258.3 Hz).
Major Conformer
1H NMR (CDCl3): d = 1.74–2.18 (m, 4 H), 3.89–3.94 (m, 1 H), 3.67
(ddd, J = 6.0, 6.1, 12.1 Hz, 1 H), 3.85 (ddd, J = 7.9, 8.1, 12.1 Hz, 1
H), 4.67 (d, J = 17.0 Hz, 1 H), 4.92 (d, J = 10.2 Hz, 1 H), 5.61 (ddd,
J = 6.8, 10.2, 17.0 Hz, 1 H), 7.34 (d, J = 1.9 Hz, 1 H), 7.49 (dd, J =
1.9, 8.9 Hz, 1 H), 8.12 (d, J = 8.9 Hz, 1 H).
13C NMR (CDCl3): d = 22.60 (t), 31.33 (t), 46.84 (t), 59.44 (d),
115.46 (t), 126.33 (d), 128.74 (d), 130.15 (d), 135.25 (s), 137.24 (d),
141.00 (s), 143.51 (s), 165.13 (s).
Anal. Calcd for C13H13FN2O3: C, 59.09; H, 4.96; N, 10.60. Found:
C, 58.90; H, 5.08; N, 10.75.
Minor Conformer
1H NMR (CDCl3): d = 1.74–2.18 (m, 4 H), 3.19 (ddd, J = 7.0, 7.1,
10.1 Hz, 1 H), 3.25 (ddd, J = 4.9, 4.7, 10.1 Hz, 1 H), 4.86–4.92 (m,
1 H), 5.22 (d, J = 10.4 Hz, 1 H), 5.32 (d, J = 17.1 Hz, 1 H), 5.94
(ddd, J = 5.5, 10.4, 17.1 Hz, 1 H), 7.41 (d, J = 2.2 Hz, 1 H), 7.52 (dd,
J = 2.2, 8.9 Hz, 1 H), 8.15 (d, J = 8.9 Hz, 1 H).
Aminoamides 12a–c; General Procedure
A solution of 11 (1.6 mmol) in EtOH (8 mL) and 20% aq AcOH (1.5
mL) was treated with iron dust (715 mg, 12.8 mmol), then heated to
reflux for 5 h under vigorous stirring. The mixture was taken up
with EtOAc (20 mL) and filtered over Celite. The organic layer was
Synthesis 2005, No. 13, 2246–2252 © Thieme Stuttgart · New York

PAPER
Synthesis of [1,2,3]Triazolo[1,5-a]- and Pyrazolo[1,5-a]-pyrrolo[2,1-c][1,4]benzodiazepines
2249
washed first with 5% aq NaHCO3 (20 mL), then with water (2 × 15
mL) and dried over Na2SO4. The solvent was removed under re-
duced pressure to give 12 as undistillable oils.
Major Conformer
1H NMR (CDCl3): d = 1.72–2.14 (m, 4 H), 3.65 (ddd, J = 6.0, 6.3,
12.3 Hz, 1 H), 3.77 (ddd, J = 8.1, 8.2, 12.3 Hz, 1 H), 4.11 (ddd, J =
1.1 6.0, 6.1 Hz, 1 H), 4.68 (d, J = 17.0 Hz, 1 H), 4.88 (d, J = 10.3
Hz, 1 H), 5.54 (ddd, J = 6.1, 10.3, 17.0 Hz, 1 H), 7.09 (dd, J = 7.5,
7.9 Hz, 1 H), 7.16 (d, J = 7.9 Hz, 1 H), 7.21 (dd, J = 1.5, 7.5 Hz, 1
H), 7.37 (ddd, J = 1.5, 7.9, 7.9 Hz, 1 H).
(S)-(2-Aminophenyl)-(2-vinylpyrrolidin-1-yl)methanone (12a)
Yield: 82%; colorless oil; [a]D –68.5 (c = 0.5, CHCl3).
IR (nujol): 3457, 3341, 1613 cm–1.
13C NMR (CDCl3): d = 22.44 (t), 31.23 (t), 46.22 (t), 58.81 (d),
115.28 (t), 118.91 (d), 125.01 (d), 128.29 (d), 130.00 (s), 130.60 (d),
136.45 (s), 137.98 (d), 167.79 (s).
1H NMR (CDCl3): d = 1.73–1.98 (m, 3 H), 2.06 (br s, 1 H), 3.57 (br
s, 2 H, missing after deuteriation), 4.51–4.62 (m, 3 H), 5.01–5.17
(m, 2 H), 5.70–5.82 (m, 1 H), 6.67 (dd, J = 7.8, 8.4 Hz, 1 H), 6.68
(d, J = 8.4 Hz, 1 H), 7.13 (dd, J = 7.7, 7.8 Hz, 1 H), 7.22 (d, J = 7.7
Hz, 1 H).
13C NMR (CDCl3): d = 22.91 (t), 26.69 (t), 47.71 (t), 57.07 (d),
111.94 (t), 116.98 (d), 117.38 (d), 128.37 (d), 131.03 (d), 135.67 (s),
138.41 (d), 171.30 (s), 173.75 (s).
Minor Conformer
1H NMR (CDCl3): d = 1.72–2.14 (m, 4 H), 3.19 (ddd, J = 7.3, 7.4,
10.5 Hz, 1 H), 3.30 (ddd, J = 4.6, 4.9, 10.5 Hz, 1 H), 4.83 (ddd, J =
1.1, 4.7, 4.8, Hz, 1 H), 5.18 (d, J = 10.4 Hz, 1 H), 5.32 (d, J = 17.1
Hz, 1 H), 5.88 (ddd, J = 4.8, 10.4, 17.1 Hz, 1 H), 7.14 (dd, J = 7.5,
7.9 Hz, 1 H), 7.20 (d, J = 7.9 Hz, 1 H), 7.30 (dd, J = 1.5, 7.5 Hz, 1
H), 7.41 (ddd, J = 1.5, 7.9, 7.9 Hz, 1 H).
Anal. Calcd for C13H16N2O: C, 72.19; H, 7.46; N, 12.95. Found: C,
72.01; H, 7.61; N, 13.14.
13C NMR (CDCl3): d = 23.64 (t), 32.72 (t), 48.59 (t), 61.51 (d),
114.84 (t), 118.82 (d), 125.55 (d), 128.63 (d), 130.50 (s), 130.69 (d),
136.51 (s), 137.35 (d), 166.19 (s).
(S)-(2-Amino-5-chlorophenyl)-(2-vinylpyrrolidin-1-yl)metha-
none (12b)
Yield: 78%; colorless oil; [a]D –101.4 (c = 0.73, CHCl3).
IR (nujol): 3455, 3348, 1646 cm–1.
Anal. Calcd for C13H14N4O: C, 64.45; H, 5.82; N, 23.12. Found: C,
64.67; H, 5.64; N, 23.27.
1H NMR (CDCl3): d = 1.70–1.95 (m, 3 H), 2.10 (br s, 1 H), 3.55 (br
s, 2 H, missing after deuteriation), 4.55–4.61 (m, 3 H), 5.04–5.13
(m, 2 H), 5.80 (br s, 1 H), 6.65 (d, J = 8.6 Hz, 1 H), 7.11 (dd, J = 2.4,
8.6 Hz, 1 H), 7.21 (d, J = 2.4 Hz, 1 H).
13C NMR (CDCl3): d = 29.74 (t), 30.08 (t), 45.98 (t), 58.44 (d),
115.20 (t), 118.19 (d), 121.89 (s), 127.82 (d), 130.84 (d), 138.13 (d),
144.70 (s), 158.10 (s), 168.97 (s).
(S)-(2-Azido-5-chlorophenyl)-(2-vinylpyrrolidin-1-yl)metha-
none (13b)
Yield: 91%; colorless oil; [a]D –56.5 (c = 0.23, CHCl3).
IR (nujol): 2125, 1636 cm–1.
Major Conformer
1H NMR (CDCl3): d = 1.75–2.11 (m, 4 H), 3.63 (ddd, J = 6.1, 6.2,
12.3 Hz, 1 H), 3.71 (ddd, J = 7.7, 8.0, 12.3 Hz, 1 H), 4.08 (ddd, J =
1.2, 6.2, 6.3 Hz, 1 H), 4.68 (d, J = 17.0 Hz, 1 H), 4.90 (d, J = 10.3
Hz, 1 H), 5.54 (ddd, J = 6.3, 10.3, 17.0 Hz, 1 H), 7.05 (d, J = 8.6 Hz,
1 H), 7.17 (d, J = 2.2 Hz, 1 H), 7.31 (dd, J = 2.2, 8.6 Hz, 1 H).
Anal. Calcd for C13H15ClN2O: C, 62.28; H, 6.03; N, 11.17. Found:
C, 62.16; H, 5.90; N, 11.37.
(S)-(2-Amino-5-fluorophenyl)-(2-vinylpyrrolidin-1-yl)metha-
none (12c)
Yield: 92%; colorless oil; [a]D –91.9 (c = 0.68, CHCl3).
IR (nujol): 3453, 3353, 1687 cm–1.
1H NMR (CDCl3): d = 1.74–1.94 (m, 3 H), 2.08 (br s, 1 H), 3.46 (br
s, 2 H, missing after deuteriation), 4.32–4.39 (m, 2 H), 4.74 (br s, 1
H), 5.10 (br s, 2 H), 5.78 (br s, 1 H), 6.61 (dd, J = 4.5, 8.6 Hz, 1 H),
6.86 (ddd, J = 2.9, 8.6, 8.7 Hz, 1 H), 6.94 (dd, J = 2.9, 8.8 Hz, 1 H).
13C NMR (CDCl3): d = 30.15 (t), 31.07 (t), 46.61 (t), 59.36 (d),
114.11 (dd, JC–F = 25.1 Hz), 114.96 (t), 117.43 (dd, JC–F = 8.9 Hz),
117.67 (dd, JC–F = 24.7 Hz), 121.96 (s), 138.14 (d), 142.33 (d,
JC–F = 8.6 Hz), 154.84 (d, JC–F = 234.4 Hz), 168.87 (s).
13C NMR (CDCl3): d = 22.40 (t), 31.18 (t), 46.39 (t), 58.98 (d),
115.00 (t), 120.25 (d), 128.30 (d), 130.28 (s), 130.53 (d), 131.17 (s),
135.15 (s), 137.06 (d), 166.18 (s).
Minor Conformer
1H NMR (CDCl3): d = 1.72–2.12 (m, 4 H), 3.19 (ddd, J = 7.3, 7.4,
10.4 Hz, 1 H), 3.30 (ddd, J = 4.3, 4.6, 10.4 Hz, 1 H), 4.78 (ddd, J =
1.1, 4.7, 4.9 Hz, 1 H), 5.16 (d, J = 10.4 Hz, 1 H), 5.29 (d, J = 15.4
Hz, 1 H), 5.84 (ddd, J = 4.9, 10.4, 15.4 Hz, 1 H), 7.11 (d, J = 8.6 Hz,
1 H), 7.26 (d, J = 2.2 Hz, 1 H), 7.35 (dd, J = 2.2, 8.6 Hz, 1 H).
13C NMR (CDCl3): d = 23.95 (t), 32.81 (t), 48.55 (t), 61.61 (d),
115.55 (t), 120.36 (d), 128.66 (d), 130.66 (d), 130.84 (s), 131.60 (s),
135.30 (s), 137.88 (d), 165.61 (s).
Anal. Calcd for C13H15FN2O: C, 66.65; H, 6.45; N, 11.96. Found:
C, 66.82; H, 6.34; N, 12.11.
Anal. Calcd for C13H13ClN4O: C, 56.43; H, 4.74; N, 20.25. Found:
C, 56.35; H, 4.92; N, 20.01.
Azidoamides 13a–c; General Procedure
NaNO2 (153 mg, 2.2 mmol) was added portionwise to a solution of
12 (1.1 mmol) in Et2O (17 mL) and 10 N aq HCl (11 mL) under stir-
ring and cooling at 0 °C. The mixture was stirred for 30 min, then
NaN3 (360 mg, 5.5 mmol) was added portionwise under vigorous
stirring and ice-cooling. After 40 min, the organic layer was sepa-
rated, washed with aq NaHCO3 (20 mL) and dried over Na2SO4.
The solvent was removed under reduced pressure to give 13 in
crude state.
(S)-(2-Azido-5-fluorophenyl)-(2-vinylpyrrolidin-1-yl)metha-
none (13c)
Yield: 75%; colorless oil; [a]D –46.9 (c = 1.12, CHCl3).
IR (nujol): 2128, 1631 cm–1.
Major Conformer
1H NMR (CDCl3): d = 1.72–2.06 (m, 4 H), 3.59 (ddd, J = 6.1, 6.2,
10.3 Hz, 1 H), 3.70 (ddd, J = 8.1, 8.2, 10.3 Hz, 1 H), 4.06 (ddd, J =
1.3, 6.1, 6.2 Hz, 1 H), 4.65 (d, J = 17.0 Hz, 1 H), 4.86 (d, J = 10.3
Hz, 1 H), 5.51 (ddd, J = 6.2, 10.3, 17.0 Hz, 1 H), 6.88 (dd, J = 2.2,
8.0 Hz, 1 H), 7.02–7.12 (m, 2 H).
(S)-(2-Azidophenyl)-(2-vinylpyrrolidin-1-yl)methanone (13a)
Yield: 75%; colorless oil; [a]D –54.2 (c = 1.15, CHCl3).
IR (nujol): 2128, 1632 cm–1.
13C NMR (CDCl3): d = 22.36 (t), 31.17 (t), 46.34 (t), 58.95 (d),
114.94 (t), 117.51 (dd, JC–F = 23.1 Hz), 120.55 (dd, JC–F = 14.5 Hz),
Synthesis 2005, No. 13, 2246–2252 © Thieme Stuttgart · New York

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G. Broggini et al.
PAPER
(3aS,3bS)-10-Fluoro-3,3a,3b,4,5,6-hexahydropyrrolo[2,1-
c][1,2,3]triazolo[1,5-a][1,4]benzodiazepin-8-one (7c)
Yield: 71%; pale yellow crystals from diisopropyl ether; mp 166–
167 °C; [a]D +522.4 (c = 0.22, CHCl3).
120.59 (dd, JC–F = 8.2 Hz), 131.33 (d, JC–F = 6.9 Hz), 132.32 (s),
137.11 (d), 159.56 (d, JC–F = 244.7 Hz), 166.20 (s).
Minor Conformer
1H NMR (CDCl3): d = 1.72–2.06 (m, 4 H), 3.15 (ddd, J = 7.3, 7.6,
10.5 Hz, 1 H), 3.28 (ddd, J = 4.4, 4.7, 10.5 Hz, 1 H), 4.75 (ddd, J =
1.2, 4.8, 4.9 Hz, 1 H), 5.13 (d, J = 10.4 Hz, 1 H), 5.26 (d, J = 16.1
Hz, 1 H), 5.81 (ddd, J = 4.9, 10.4, 16.1 Hz, 1 H), 6.97 (dd, J = 2.6,
7.9 Hz, 1 H), 7.02–7.12 (m, 2 H).
IR (nujol): 1626 cm–1.
1H NMR (CDCl3): d = 1.72–1.79 (m, 2 H), 1.95–1.99 (m, 1 H),
2.30–2.33 (m, 1 H), 3.52 (m, 1 H), 3.70 (ddd, J = 2.3, 8.3, 11.9 Hz,
1 H), 3.71–3.75 (m, 1 H), 3.80–3.88 (m, 1 H), 4.33 (dd, J = 11.9,
17.4 Hz, 1 H), 4.63 (dd, J = 8.3, 17.4 Hz, 1 H), 7.16 (dd, J = 2.9, 9.2
Hz, 1 H), 7.92 (dd, J = 5.0, 9.2 Hz, 1 H), 7.96 (dd, J = 2.9, 10.6 Hz,
1 H).
13C NMR (CDCl3): d = 23.93 (t), 32.77 (t), 48.50 (t), 61.53 (d),
115.43 (t), 117.64 (dd, JC–F = 23.1 Hz), 120.44 (dd, JC–F = 8.2 Hz),
120.47 (dd, JC–F = 14.4 Hz), 131.72 (d, JC–F = 6.5 Hz), 132.47 (s),
137.92 (d), 159.97 (d, JC–F = 245.4 Hz), 165.64 (s).
13C NMR (CDCl3): d = 22.73 (t), 30.97 (t), 50.34 (t), 59.44 (d),
60.28 (d), 70.99 (t), 119.38 (dd, JC–F = 24.4 Hz), 119.78 (dd, JC–F
=
Anal. Calcd for C13H13FN4O: C, 59.99; H, 5.03; N, 21.53. Found:
C, 60.21; H, 4.85; N, 21.39.
6.8 Hz), 120.59 (dd, JC–F = 23.1 Hz), 105.27 (d JC–F = 5.6 Hz),
134.60 (s), 158.64 (d, JC–F = 241.6 Hz), 163.82 (s).
MS (EI, 70 eV): m/z (%) = 260 (3) [M+], 232 (47), 204 (13), 163
(29), 150 (18), 135 (100), 95 (18), 94 (22), 70 (32).
1,3-Dipolar Cycloadditions of the Azides 13a–c; General Proce-
dure
A solution of 13 (1.3 mmol) in CCl4 (38 mL) was heated to reflux
for 5 h. The solvent was removed under reduced pressure to give 7
in crude state.
Anal. Calcd for C13H13FN4O: C, 59.99; H, 5.03; N, 21.53. Found:
C, 59.98; H, 4.81; N, 21.71.
Hydrazonyl Chlorides 14a–c; General Procedure
(3aS,3bS)-3,3a,3b,4,5,6-Hexahydropyrrolo[2,1-c][1,2,3]triazo-
lo[1,5-a][1,4]benzodiazepin-8-one (7a)
Yield: 68%; mp 123–124 °C; white crystals from diisopropyl ether;
[a]D +445.3 (c = 0.2, CHCl3).
A solution of 12 (1.6 mmol) in 6 M aq HCl (0.92 mL) and MeOH
(2.5 mL) was cooled to 0 °C. NaNO2 (221 mg, 3.2 mmol) was added
portionwise keeping the temperature under 5 °C. After 30 min, the
pH was adjusted to 5 by adding NaOAc, then a solution of
MeCOCHClCO2Me (241 mg, 1.6 mmol) in MeOH (1 mL) was add-
ed under vigorous stirring and ice-cooling. The mixture was al-
lowed to stand overnight under stirring at r.t. After concentration
under reduced pressure the resulting mixture was extracted with
Et2O (2 × 15 mL). The organic layer was washed first with 5% aq
NaHCO3 (15 mL), then with water (30 mL) and dried over Na2SO4.
The residue was chromatographed on a silica gel column with
EtOAc–light petroleum (2:1) as eluent to give 14 as undistillable
oils.
IR (nujol): 1635 cm–1.
1H NMR (CDCl3): d = 1.73–1.92 (m, 2 H), 2.00–2.08 (m, 1 H),
2.31–2.40 (m, 1 H), 3.57 (ddd, J = 7.9, 8.2, 8.4 Hz, 1 H), 3.68 (ddd,
J = 6.5, 10.3, 11.8 Hz, 1 H), 3.76 (ddd, J = 8.1, 8.4, 12.0 Hz, 1 H),
3.84–3.93 (m, 1 H), 4.36 (dd, J = 8.1, 17.4 Hz, 1 H), 4.69 (dd, J =
12.0, 17.4 Hz, 1 H), 7.15 (ddd, J = 1.1, 8.1, 8.4 Hz, 1 H), 7.48 (ddd,
J = 1.6, 8.1, 8.2, 1 H), 8.04 (dd, J = 1.1, 8.4 Hz, 1 H), 8.32 (dd, J =
1.6, 8.2 Hz, 1 H).
13C NMR (CDCl3): d = 22.79 (t), 31.03 (t), 50.14 (t), 59.60 (d),
60.11 (d), 70.76 (t), 117.69 (d), 118.17 (s), 122.94 (d), 132.80 (d),
134.01 (d), 138.02 (s), 165.25 (s).
Methyl (S)-2-Chloro-2-{2-[(2-vinylpyrrolidin-1-yl)carbon-
yl]phenylhydrazono}acetate (14a)
Yield: 61%; red oil; [a]D –107.8 (c = 0.86, CHCl3).
IR (nujol): 3223, 1729, 1618 cm–1.
MS (EI, 70 eV): m/z (%) = 242 (5) [M+], 214 (56), 186 (19), 145
(32), 132 (24), 117 (100), 77 (15), 76 (21), 70 (34).
Anal. Calcd for C13H14N4O: C, 64.45; H, 5.82; N, 23.12. Found: C,
64.34; H, 6.01; N, 23.29.
1H NMR (DMSO, 100 °C): d = 1.71–1.77 (m, 1 H), 1.81–1.90 (m,
2 H), 2.07–2.13 (m, 1 H), 3.53–3.57 (overlapping, 2 H), 3.86 (s, 3
H), 4.58–4.63 (m, 1 H), 5.01 (d, J = 10.4 Hz, 2 H), 5.79–5.85 (m, 1
H), 7.07 (ddd, J = 1.2, 7.7, 8.6 Hz, 1 H), 7.45 (ddd, J = 1.2, 8.2, 8.6
Hz, 1 H), 7.49 (d, J = 7.7 Hz, 1 H), 7.52 (d, J = 8.2, 1 H), 10.33 (s,
1 H, missing after deuteriation).
13C NMR (CDCl3): d = 23.55 (t), 31.97 (t), 52.21 (t), 53.59 (q),
59.91 (d), 115.24 (t), 116.19 (d), 117.68 (s), 121.26 (s), 121.62 (d),
128.34 (d), 131.80 (d), 138.11 (d), 141.61 (s), 160.60 (s), 169.23 (s).
(3aS,3bS)-10-Chloro-3,3a,3b,4,5,6-hexahydropyrrolo[2,1-
c][1,2,3]triazolo[1,5-a][1,4]benzodiazepin-8-one (7b)
Yield: 75%; pale yellow crystals from diisopropyl ether; mp 134–
136 °C; [a]D +424.4 (c = 0.87, CHCl3).
IR (nujol): 1620 cm–1.
1H NMR (CDCl3): d = 1.77–1.83 (m, 1 H), 1.85–1.90 (m, 1 H),
2.01–2.09 (m, 1 H), 2.33–2.38 (m, 1 H), 3.58 (ddd, J = 7.4, 8.0, 8.3
Hz, 1 H), 3.70 (ddd, J = 2.2, 7.0, 12.1 Hz, 1 H), 3.75 (ddd, J = 8.0,
8.5, 12.0 Hz, 1 H), 3.91 (ddd, J = 6.5, 6.8, 12.1 Hz, 1 H), 4.38 (dd,
J = 12.0, 17.5 Hz, 1 H), 4.71 (dd, J = 8.5, 17.5 Hz, 1 H), 7.42 (dd,
J = 2.6, 9.0 Hz, 1 H), 7.99 (d, J = 9.0 Hz, 1 H), 8.31 (d, J = 2.6 Hz,
1 H).
13C NMR (CDCl3): d = 22.65 (t), 30.76 (t), 50.21 (t), 58.93 (d),
59.96 (d), 71.17 (t), 118.19 (s), 119.11 (d), 127.58 (s), 132.44 (d),
132.91 (d), 136.62 (s), 163.45 (s).
Anal. Calcd for C16H18ClN3O3: C, 57.23; H, 5.40; N, 12.51. Found:
C, 57.15; H, 5.59; N, 12.33.
Methyl (S)-2-Chloro-2-{2-[5-chloro-(2-vinylpyrrolidin-1-
yl)carbonyl]phenylhydrazono}acetate (14b)
Yield: 60%; orange crystals from diisopropyl ether; mp 125–127
°C; [a]D –94.9 (c = 0.90, CHCl3).
IR (nujol): 3224, 1732, 1620 cm–1.
1H NMR (CDCl3): d = 1.80–2.21 (m, 4 H), 3.65 (br s, 2 H), 3.95 (s,
3 H), 4.78–4.84 (m, 1 H), 5.17 (d, J = 10.0 Hz, 2 H), 5.82–5.89 (m,
1 H), 7.37 (d, J = 8.7 Hz, 1 H), 7.44 (br s, 1 H), 7.65 (d, J = 8.7 Hz,
1 H), 10.33 (s, 1 H, missing after deuteriation).
MS (EI, 70 eV): m/z (%) = 276 (4) [M+], 250 (26), 248 (67), 222 (8),
220 (25), 181 (18), 179 (44), 168 (9), 166 (23), 153 (42), 151 (100),
113 (6), 112 (9), 111 (16), 110 (25), 70 (34).
Anal. Calcd for C13H13ClN4O: C, 56.43; H, 4.74; N, 20.25. Found:
C, 56.51; H, 4.63; N, 20.11.
13C NMR (CDCl3): d = 23.81 (t), 39.98 (t), 47.75 (t), 53.84 (q),
56.98 (d), 115.85 (s), 117.57 (d), 118.26 (s), 121.90 (s), 126.69 (t),
128.12 (d), 131.77 (d), 137.93 (d), 140.06 (s), 160.42 (s), 167.81 (s).
Synthesis 2005, No. 13, 2246–2252 © Thieme Stuttgart · New York

PAPER
Synthesis of [1,2,3]Triazolo[1,5-a]- and Pyrazolo[1,5-a]-pyrrolo[2,1-c][1,4]benzodiazepines
2251
Anal. Calcd for C16H17Cl2N3O3: C, 51.91; H, 4.63; N, 11.35. Found:
C, 52.04; H, 4.42; N, 11.38.
MS (EI, 70 eV): m/z (%) = 335 (22) [M+ + 2], 333 (65) [M+], 304
(3), 302 (9), 266 (15), 265 (20), 264 (48), 263 (38), 208 (6), 207
(29), 206 (23), 205 (87), 181 (18), 179 (54), 70 (100).
Methyl (S)-2-Chloro-2-{2-[5-fluoro-(2-vinylpyrrolidin-1-yl)car-
bonyl]phenylhydrazono}acetate (14c)
Yield: 84%; red oil; [a]D –95.8 (c = 0.57, CHCl3).
Anal. Calcd for C16H16ClN3O3: C, 57.58; H, 4.83; N, 12.59. Found:
C, 57.67; H, 4.88; N, 12.77.
IR (nujol): 3237, 1730, 1626 cm–1.
(3aS,3bS)-2-Carbomethoxy-10-fluoro-3,3a,3b,4,5,6-hexahydro-
pyrrolo[2,1-c][1,2,3]pyrazolo[1,5-a][1,4]benzodiazepin-8-one
(8c)
Yield: 63%; pale yellow crystals from diisopropyl ether; mp 154–
156 °C; [a]D +512.0 (c = 0.78, CHCl3).
1H NMR (CDCl3): d = 1.78–2.03 (m, 4 H), 3.62 (br s, 2 H), 3.92 (s,
3 H), 4.76–4.83 (m, 1 H), 5.14 (d, J = 10.3 Hz, 2 H), 5.78–5.85 (m,
1 H), 7.12 (dd, J = 2.6, 7.8 Hz, 1 H), 7.15 (dd, J = 2.6, 9.0 Hz, 1 H),
7.64 (dd, J = 4.6, 9.0 Hz, 1 H), 10.39 (s, 1 H, missing after deuteri-
ation).
IR (nujol): 1707, 1624 cm–1.
13C NMR (CDCl3): d = 21.42 (t), 30.04 (t), 46.68 (t), 53.81 (q),
56.13 (d), 114.82 (dd, JC–F = 6.1 Hz), 117.64 (s), 117.95 (d), 118.86
(dd, JC–F = 28.5 Hz), 137.76 (dd, JC–F = 28.1 Hz), 144.81 (t), 157.28
(d, JC–F = 242.60 Hz), 160.59 (s), 167.87 (s), 168.25 (s), 169.77 (s).
1H NMR (CDCl3): d = 1.79–1.90 (m, 2 H), 2.01–2.05 (m, 1 H),
2.37–2.44 (m, 1 H), 3.11 (dd, J = 10.7, 18.0 Hz, 1 H), 3.43 (dd, J =
12.4, 18.0 Hz, 1 H), 3.71–3.76 (m, 1 H), 3.85–3.90 (m, 2 H), 3.91
(s, 3 H), 4.25 (ddd, J = 8.0, 10.7, 12.4 Hz, 1 H), 7.15 (ddd, J = 3.1,
6.9, 9.4 Hz, 1 H), 7.78 (dd, J = 5.1, 9.4 Hz, 1 H), 7.98 (dd, J = 3.1,
10.4 Hz, 1 H).
13C NMR (CDCl3): d = 22.77 (t), 31.32 (t), 36.96 (t), 50.26 (t), 52.82
(q), 60.42 (d), 68.40 (d), 118.87 (s), 119.50 (dd JC–F = 6.4 Hz),
120.36 (dd, JC–F = 23.0 Hz), 126.28 (dd, JC–F = 24.3 Hz), 136.69 (s),
139.48 (s), 157.95 (d, JC–F = 240.0 Hz), 162.83 (s), 164.10 (s).
Anal. Calcd for C16H17ClFN3O3: C, 54.32; H, 4.84; N, 11.88.
Found: C, 54.21; H, 4.98; N, 11.69.
1,3-Dipolar Cycloadditions of the Nitrilimines 15a–c; General
Procedure
A solution of 14 (0.4 mmol) in anhyd toluene (18 mL) was treated
with TEA (0.22 mL, 1.6 mmol) and heated to reflux for 24 h. The
mixture was washed first with 5% aq NaHCO3 (15 mL), then with
water (30 mL) and dried over Na2SO4. The solvent was removed un-
der reduced pressure to give 8 as crystalline materials.
MS (EI, 70 eV): m/z (%) = 317 (71) [M+], 286 (12), 248 (47), 247
(51), 216 (16), 189 (100), 163 (58), 70 (96).
Anal. Calcd for C16H16FN3O3: C, 60.56; H, 5.08; N, 13.24. Found:
C, 60.39; H, 5.21; N, 13.32.
(3aS,3bS)-2-Carbomethoxy-3,3a,3b,4,5,6-hexahydropyrro-
lo[2,1-c][1,2,3]pyrazolo[1,5-a][1,4]benzodiazepin-8-one (8a)
Yield: 76%; pale yellow crystals from diisopropyl ether; mp 185–
187 °C; [a]D +748.9 (c = 0.49, CHCl3). Chiral HPLC: Racemate:
tR = 13.7, 21.2 min; 8a: tR = 21.2 min.
X-ray Crystal Analysis of 7b
Single-crystal X-ray diffraction measurements were performed on a
Bruker SMART-APEX diffractometer, graphite monochromator,
Mo-Ka radiation (l = 0.71073 Å). C13H13ClN4O, Mr = 276.72,
orthorhombic, space group P212121, a = 7.300 (3), b = 9.009 (4),
c = 18.979 (9) Å, V = 1248.2 (10) Å3, Z = 4, Dc = 1.473 g cm–3,
m(Mo – Ka) = 0.303 mm–1. 20427 collected data up to 2q = 55.08°;
2882 unique [2261 with Io > 2s(Io)], Rave = 0.0382. Structure solved
by SIR-9211 and refined by SHELX-97;12 final disagreement factors
for all (observed) reflections: Rw(F2) = 0.1098(0.0955) and R =
0.0593(0.0397), goodness-of-fit = 1.057, 212 parameters, 9 re-
straints. The molecule is partially disordered: the pyrrolidine ring
(C6, C7, C8, C9, N10) is present in two conformations. The atoms
C7 and C8 and related H atoms were split and refined with some
geometric restraints; the population factors ratio for the two con-
formers was 0.726/0.274; Figure 3 shows a projection of the most
populated conformation. All crystallographic data (excluding struc-
ture factors) were deposited at the Cambridge Crystallographic
Data Centre as supplementary publication No. CCDC 262662. Cop-
ies of the data can be obtained free of charge on application to
CCDC, 2 Union Road, Cambridge CB2 1EZ, UK; e-mail: depos-
it@ccdc.cam.ac.uk.
IR (nujol): 1707, 1615 cm–1.
1H NMR (CDCl3): d = 1.81–1.89 (m, 2 H), 2.01–2.05 (m, 1 H),
2.39–2.41 (m, 1 H), 3.10 (dd, J = 11.0, 18.0 Hz, 1 H), 3.42 (dd, J =
12.4, 18.0 Hz, 1 H), 3.72–3.74 (m, 1 H), 3.89–3.91 (m, 2 H), 3.93
(s, 3 H), 4.27 (ddd, J = 7.8, 11.0, 12.4 Hz, 1 H), 7.05 (dd, J = 7.9,
8.1 Hz, 1 H), 7.45 (ddd, J = 1.3, 7.9, 8.5 Hz, 1 H), 7.81 (d, J = 8.5
Hz, 1 H), 8.25 (dd, J = 1.3, 8.1 Hz, 1 H).
13C NMR (CDCl3): d = 2.83 (t), 31.32 (t), 36.86 (t), 50.01 (t), 52.79
(q), 60.16 (d), 68.59 (d), 117.48 (d), 118.42 (s), 121.74 (d), 132.66
(d), 133.92 (d), 139.53 (s), 140.07 (s), 162.92 (s), 165.47 (s).
MS (EI, 70 eV): m/z (%) = 299 (54) [M+], 268 (8), 230 (62), 229
(35), 198 (17), 171 (100), 145 (67), 70 (62).
Anal. Calcd for C16H17N3O3: C, 64.20; H, 5.72; N, 14.04. Found: C,
64.19; H, 5.66; N, 13.89.
(3aS,3bS)-2-Carbomethoxy-10-chloro-3,3a,3b,4,5,6-hexahy-
dropyrrolo[2,1-c][1,2,3]pyrazolo[1,5-a][1,4]benzodiazepin-8-
one (8b)
Yield: 74%; white crystals from diisopropyl ether; mp 186–188 °C;
[a]D +664.9 (c = 0.77, CHCl3).
Acknowledgment
MIUR (Cofin 2004) is acknowledged for financial support. We are
also grateful to the Centro Interuniversitario sulle Reazioni Perici-
cliche.
IR (nujol): 1709, 1618 cm–1.
1H NMR (CDCl3): d = 1.79–1.86 (m, 2 H), 2.02–2.06 (m, 1 H),
2.39–2.41 (m, 1 H), 3.11 (dd, J = 11.2, 18.1 Hz, 1 H), 3.43 (dd, J =
12.0, 18.1 Hz, 1 H), 3.70–3.73 (m, 1 H), 3.86–3.91 (m, 2 H), 3.91
(s, 3 H), 4.25 (ddd, J = 7.8, 11.2, 12.0 Hz, 1 H), 7.45 (dd, J = 2.6,
9.1 Hz, 1 H), 7.75 (d, J = 9.1 Hz, 1 H), 8.23 (d, J = 2.6 Hz, 1 H).
13C NMR (CDCl3): d = 22.77 (t), 31.28 (t), 37.01 (t), 50.18 (t), 52.83
(q), 60.17 (d), 68.31 (d), 119.17 (d), 119.28 (s), 126.76 (s), 132.49
(d), 133.06 (d), 138.73 (s), 140.22 (s), 162.65 (s), 164.05 (s).
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Synthesis 2005, No. 13, 2246–2252 © Thieme Stuttgart · New York

2252
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PAPER
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Synthesis 2005, No. 13, 2246–2252 © Thieme Stuttgart · New York