Concise diastereospecific pyrrolo[1,2-a][1,4]benzodiazepinone synthesis

Article abstract of DOI:10.1016/j.tet.2007.09.062

A concise synthesis of the novel pyrrolo[1,2-a]benzodiazepine system, by using the metallo carbenoid/spiro-[6,5]-ammonium ylide/Stevens[1,2]-shift with ring-expansion approach, was reported. The overall cascade process resulted stereospecific.

Full text of DOI:10.1016/j.tet.2007.09.062

Tetrahedron 63 (2007) 12232–12238
Concise diastereospecific pyrrolo[1,2-a][1,4]benzodiazepinone
synthesis
b
Mauro Mucedda,a Daniele Muroni,a Antonio Sabaa, and Carlo Manassero
*
aDipartimento di Chimica, Facoltaꢀ di Scienze, Universitaꢀ di Sassari, Via Vienna 2, 07100 Sassari, Italy
bDipartimento di Chimica Strutturale e Stereochimica Inorganica, Facoltaꢀ di Scienze, Universitaꢀ di Milano,
Via Venezian 21, 20133 Milano, Italy
Received 25 May 2007; revised 29 August 2007; accepted 13 September 2007
Available online 29 September 2007
Abstract—A concise synthesis of the novel pyrrolo[1,2-a]benzodiazepine system, by using the metallo carbenoid/spiro-[6,5]-ammonium
ylide/Stevens[1,2]-shift with ring-expansion approach, was reported. The overall cascade process resulted stereospecific.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
O
H
N
N
Amongst the privileged class within medicinal chemistry
1,4-benzodiazepines, most attention has been paid to related
tricyclic systems such as pyrrolo[2,1-c][1,4]benzodiazepi-
nones 1 (PBDs), due to a broad and ever evolving field of
biological activities.1 PBDs continue to attract great interest.
In fact such compounds are potentially therapeutic agents in
the treatment of some cancer and as interactive antitumor
antibiotics, due to their ability to recognize and bind with
specific sequences of the minor groove of DNA.2
N
N
H
O
O
1
2
Figure 1.
importance in organic synthesis. Moreover, such intermedi-
ate metallo carbenoids often show high levels of stereoselec-
tivity despite their high reactivity.7
Instead, in this area, it is surprising that, to date, there are no
publications on the synthesis of the other possible isomer
bearing the cyclic amine nitrogen engaged in the pyrrolidine
ring, namely the pyrrolo[1,2-a]benzodiazepinone system 2
(Fig. 1).
2. Results and discussion
The tetrahydroquinazolinones 4a–e, bearing a diazo func-
tion at the proper position on the keto ester chain tethered
to the amine nitrogen atom, have been selected as the appro-
priate carbenoid cyclization precursors for accessing target
structures (Scheme 1).
As apart of the ongoing program on the tandem carbenoid/
ammonium ylide cascade protocol,3 which is a very concise
and powerful approach to construct enantiopure bicyclic and
tricyclic alkaloids from easy available starting materials,4
herein we describe the synthesis of pyrrolo[1,2-a]benzodiaze-
pinones 2 by using the metallo carbenoid/spiro-[6,5]-ammoni-
um ylide5/Stevens[1,2]-shift with ring-expansion sequence.6
(ꢀ)-3-Benzyl-4-oxo-1,2,3,4-tetrahydro-quinazoline-2-carb-
oxylic acid ethyl ester starting material for diazoesters 4a
and 4b, and (ꢀ)-3-benzyl-5,7-dichloro-4-oxo-1,2,3,4-tetra-
hydro-quinazoline-2-carboxylic acid ethyl ester, for 4d,
have been, respectively, prepared in one step from the corre-
sponding 2-aminobenzamides.8 The remaining (ꢀ)-3-ben-
zyl-2-phenyl-2,3-dihydro-1H-quinazolin-4-one, precursor of
4c and 4e, has been synthesized from isatoic anhydride,
according to a three-component protocol reported recently.9
Tandem or cascade processes of metallo carbenoids gener-
ated by transition metal catalyzed reactions of diazo com-
pounds and leading to ammonium ylides, which undergo
sigmatropic rearrangements, has gained significant
The diazo compounds 4a–e were prepared efficiently in two
steps by conjugate addition of 3 to ethyl-3-ketopent-4-
enoate10 or (ꢁ)-menthyl-3-ketopent-4-enoate,4d followed
by diazo group transfer reaction with tosyl azide.
Keywords: Benzodiazepines; Diazo compounds; Cascade process; Ste-
vens[1,2]-shift.
* Corresponding author. Tel.: +39 79 229538; fax: +39 79 229559; e-mail:
saba@uniss.it
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.062

M. Mucedda et al. / Tetrahedron 63 (2007) 12232–12238
12233
O
O
R2
R2
O
N
OR4
O
1)
2)
cat.
NR
NR
R1
TsN3, Et3N
R1
O
R3
N
H
R3
O
OR4
N2
3
4a-e
R2
R2
O
O
O
R3
NR
CO2R4
R1
NR
N
+
N
R1
R1
[1,2]shift
R3
R4O2C
N
R3
_
N
MLn
R2
R
O
R4O2C
5a-e
O
2a-e
O
6a-e
R
R1
CO2Et
CO2Et
Ph
CO2Et
Ph
R2
H
H
H
Cl
H
R3
H
H
H
Cl
H
R4
Et
(-)Ment
(-)Ment
Et
a
b
c
d
e
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
Et
Scheme 1.
The aim of obtaining chiral diastereomers, permitting to
attempt their separation, has suggested the preparation of
(ꢁ)-menthyldiazoesters 4b and 4c, both bearing the chiral
auxiliary.
Interestingly, compounds 2a, 2d, and 2e have been obtained
as single diastereoisomers bearing the substituents at C-3a
and C-4 trans disposed. As expected, the chiral compounds
2b and 2c have been achieved as a 1:1 mixture of trans
diastereomers. Unfortunately, all attempts in resolving that
mixture by column chromatography failed.
All the diazoketocarboxylates 4a–e are stable compounds
and reliable to be handled and safe is their preparation by
diazo transfer reaction with tosyl azide.11
Such high stereoselectivity suggests that a previous forma-
tion of ylide 6 could happen, and this is consistent with
a probable approach of the electrophilic carbenoid by the nu-
cleophilic amine from the opposite face of the quinazolinone
ring such as the ethyl ester or phenyl substituent. In Scheme
2 this attack is depicted by both the enantiomeric forms of
the precursor racemic metallo carbenoid.
As depicted in Scheme 1, the intermediates spiro-[6,5]-am-
monium ylides 6 might be expected to form, via the nitrogen
trapping of the metallo carbenoid group correctly situated on
the pendant of 5, whenever the amine is part of a pre-existing
ring system. The ylides’ sigmatropic rearrangement would
furnish the tricyclic targets 2. The presence of a conjugative
stabilizing phenyl or ester group on the putative migrating
carbon was foreseen for the [1,2]-shift to be successful.
Such presence was reported to favor an efficient carbon
migration in Stevens rearrangement.12,3d
Isolation of compound 2e crystals enabled the single crystal
X-ray analysis to be performed. As shown in Figure 2, the
trans configuration of the substituents at C-3a and C-4 is
consequently assigned.
Two transition metal catalysts have been studied (Table 1).
The Cu(acac)2 or Rh2(OAc)4 catalyzed diazo-decomposition
of 4a–d has been performed in refluxing toluene, giving the
desired benzodiazepinones (2a–d) as the sole product. Best
yields were achieved when the diazo-decompositions were
performed in the presence of Rh2(OAc)4 as catalyst, in
contrast to data previously reported.13 Only in the case of
4e, the copper-based catalysis has demonstrated to be
more effective.
Table 1. Diazo-decomposition of 4a–e in refluxing toluene
Substrate
Catalyst
Yielda (%)
Product
4a
4a
4b
4b
4c
4c
4d
4d
4e
4e
Rh2(OAc)4
Cu(acac)2
Rh2(OAc)4
Cu(acac)2
Rh2(OAc)4
Cu(acac)2
Rh2(OAc)4
Cu(acac)2
Rh2(OAc)4
Cu(acac)2
65
54
71
62
83
53
70
58
68
80
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
Notwithstanding the double stabilizing effect applied on the
ylide carbon atom by the presence of both carbonyl and ester
groups, isolation of the spirocyclic ammonium ylide inter-
mediates 6, previously observed by us in similar cases,4c
was unsuccessful.
a
Isolated yield after column chromatography.

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M. Mucedda et al. / Tetrahedron 63 (2007) 12232–12238
4a-e
cat
O
O
R4
R4
MLn
R1
H
MLn
R3
R3
:
R1
H
N
O
:
N
N
N
R
R
O
R2
R2
5a-e
O
O
R4
R1
R4
R1
H
R
R3
R3
N
O
N
O
H
N
N
R
R2
R2
6a-e
Figure 2. ORTEP view of compound 2e. Hydrogen atoms omitted for clar-
ity: only the hydrogen atom at C-4 is shown.
O
O
Cl
N
N
Cl
CH2OH
CH2OH
O
O
R3
R3
R4
R4
N
N
O
R1
N
N
R1
H
R
O
Bn
H
Bn
Cl
Cl
O
O
N
N
R2
R2
R
7
O
O
Figure 3.
2a-e
Scheme 2.
Due to a combination of two or more distinct reactions into
a single transformation, cascade or tandem processes are
a powerful method for constructing polycyclic structures
from relatively simple starting materials with proper regio-
and stereo-chemical control.16
Moreover, by reducing with NaBH4, compound 2d afforded
the racemic tetracyclic lactone 7 resulting in accord with the
trans configuration of the ester substituents (Fig. 3).
Given the predicted stereoselectivity in the nitrogen quater-
nization step,14 the high diastereoselectivity of the overall
process needs elevated stereoselectivity in the subsequent
Stevens [1,2]-shift. Within this context, the migration path-
way most accepted15 involves homolytic cleavage of the
carbon–nitrogen bond to the most stable potential carbon
centered radical, generating a radical pair that is held tightly
together by a solvent cage. This is followed by solvent cage/
rapid recombination of the radical center with the neighbor
ylide carbon to generate the rearranged product, thus ac-
counting for the high degree of stereoselectivity observed.
It is interesting to note that conformationally constrained
amino esters can be recognized in the 1,4-diazepinone
frames of 2a–e; conformationally constrained analogs of
natural amino acids is a matter of great interest.17
Moreover, all the pyrrolo[1,2-a][1,4]benzodiazepinones
prepared are besides characterized by the presence of a
quaternary carbon stereocenter whose construction is still
a challenging and dynamic area in organic synthesis.18
Biological evaluations and structure–activity relationship
(SAR) will be reported in due course.
3. Conclusion
4. Experimental
4.1. General
This work reports a very concise and convenient stereospe-
cific synthesis of novel pyrrolo-benzodiazepinone alkaloids
in three steps and 45–60% total yield from the readily
available tetrahydroquinazolinones, by utilizing the cascade
spiro-to-fused strategy.
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were
recorded on a Varian VXR-300 spectrometer with TMS as

M. Mucedda et al. / Tetrahedron 63 (2007) 12232–12238
12235
internal standard. Infrared (IR) spectra were performed on
a FT/IR-480plus JASCO spectrophotometer. All reagents
and solvents employed were reagent grade materials; puri-
fied by standard methods and redistilled before use.
and stirred at room temperature for 2 days. The solvent was
evaporated and to the residue a solution of tosyl azide
(0.25 g, 1.26 mmol) and Et3N (0.2 mL, 1.42 mmol) in
CH2Cl2 (2 mL) was added dropwise at 0 ꢂC. After the addi-
tion was complete, the solution was stirred at room temper-
ature overnight. The solvent was evaporated and the residue
gave, after flash chromatography (hexanes/ethyl ether 8:2),
the diazo compound 4b (0.355 g, 71.7%), yellow crystals,
4.1.1. ( )-3-Benzyl-1-(4-diazo-4-ethoxycarbonyl-3-oxo-
butyl)-4-oxo-1,2,3,4-tetrahydro-quinazoline-2-carboxy-
lic acid ethyl ester 4a. To a stirred solution of (ꢀ)-3-ben-
zyl-4-oxo-1,2,3,4-tetrahydro-quinazoline-2-carboxylic acid
ethyl ester (0.856 g, 2.16 mmol), and 3-oxo-pent-4-enoic
acid ethyl ester (0.45 g, 3.17 mmol), in CH2Cl2 (10 mL),
few drops of aqueous 50% HCl were added and stirred at
room temperature for 1 day. The solvent was evaporated
and to the residue a solution of tosyl azide (0.638 g,
3.2 mmol) and Et3N (0.44 mL, 3.1 mmol) in CH2Cl2
(10 mL) was added dropwise at 0 ꢂC. After the addition
was complete, the solution was stirred at room temperature
overnight. The solvent was evaporated and the residue
gave, after flash chromatography (light petroleum ether/eth-
yl acetate 7:3), the diazo compound 4a (0.742 g, 72%) as
1
mp 41–43 ꢂC (mixture of diastereomers). H NMR (CDCl3):
d 0.77 (d, 3H, J¼7.8 Hz), 0.87–0.93 (m, 6H), 0.97–1.01 (m,
1H), 1.14 (t, 3H, J¼7.8 Hz), 1.09–1.25 (m, 1H), 1.32–1.56
(m, 3H), 1.68–1.83 (m, 3H), 2.0–2.04 (m, 1H), 2.92–3.04 (m,
1H), 3.15–3.28 (m, 1H), 3.57–3.73 (m, 2H), 4.00–4.10 (m,
2H), 4.24 (AB system, 1H), 4.77 (4.78) (dt, 1H, J¼10.2,
5.0 Hz), 5.14 (5.16) (s, 1H), 5.47 (5.52) (AB system, 1H),
6.73 (dd, 1H, J¼8.6, 2.0 Hz), 6.87 (t, 1H, J¼8.3 Hz), 7.26–
7.41 (m, 6H), 7.99 (d, 1H, J¼8.3 Hz). 13C NMR (CDCl3):
d 13.9, 16.4, 20.6, 21.8 (21.9), 23.4, 26.4, 31.3, 33.9, 38.8
(38.8), 40.9, 43.8 (43.9), 48.6 (48.7), 61.7, 73.0 (73.1), 75.8,
111.7, 117.0, 118.8, 127.5, 127.4, 128.3, 128.4, 128.7, 129.3,
133.7, 136.3, 145.3, 160.5, 162.7, 190.4 (190.5). IR (Nujol):
2957, 2870, 2136, 1742, 1710, 1658, 1606, 1493, 1476,
1
a yellow oil. H NMR (CDCl3): d 1.14 (t, 3H, J¼8.0 Hz),
1.30 (t, 3H, J¼8.0 Hz), 2.95–3.04 (m, 1H), 3.14–3.25 (m,
1H), 3.57–3.73 (m, 2H), 4.07 (dq, 2H, J¼6.6, 1.3 Hz), 4.20
(AB system, 1H), 4.24 (q, 2H, J¼6.6 Hz), 5.14 (s, 1H), 5.51
(AB system, 1H), 6.75 (d, 1H, J¼8.7 Hz), 6.87 (t, 1H,
J¼8.7 Hz), 7.27–7.41 (m, 6H), 8.00 (dd, 1H, J¼8.7,
2.0 Hz). 13C NMR (CDCl3): d 13.9, 14.2, 38.7, 43.9, 48.6,
61.4, 61.7, 62.1, 73.0, 76.0, 111.8, 117.1, 118.9, 127.5,
128.4, 128.5, 129.3, 133.7, 136.3, 137.3, 145.3, 160.9,
162.7, 169.3, 190.4. IR (neat): 2981, 2136, 1716, 1655,
1455, 1423, 1370, 1303, 1214, 1133, 999, 736, 701 cmꢁ1
.
Anal. Calcd for C33H40N4O6: C, 67.33; H, 6.85%; N, 9.52.
Found: C, 67.24; H, 6.64; N, 9.27%.
4.1.4. (L)-Menthyl ( )-5-benzyl-3,6-dioxo-2,3,5,6-tetra-
hydro-1H-4H-pyrrolo[1,2-a][1,4]benzo diazepine-4-
carboxyethyl-3a-carboxylate 2b.
A solution of the
diazoketoester 4b (0.840 g, 1.42 mmol) in toluene (15 mL)
was refluxed for 40 min in the presence of Rh2(OAc)4
(0.016 g, 0.036 mmol). The solvent was evaporated and
the residue gave, after flash chromatography (hexanes/
Et2O 1:1), the dicarboxylate 2b (0.568 g, 71%), white crys-
1606, 1493, 1374, 1307, 1173, 1051, 754, 726, 702 cmꢁ1
.
Anal. Calcd for C25H26N4O6: C, 66.65; H, 5.82; N, 6.22%.
Found: C, 66.23; H, 5.65; N, 6.07%.
1
4.1.2. ( )-Diethyl 5-benzyl-3,6-dioxo-2,3,5,6-tetrahydro-
1H-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepine-3a,4-dicar-
boxylate 2a. A solution of the diazoketoester 4a (0.440 g,
0.92 mmol) in toluene (10 mL) was refluxed for 40 min in
the presence of Rh2(OAc)4 (0.013 g, 0.029 mmol). The sol-
vent was evaporated and the residue gave, after flash chro-
matography (light petroleum ether/ethyl acetate 7:3), the
dicarboxylate 2a (0.269 g, 65%) as a colorless oil. 1H
NMR (CDCl3): d 0.61 (t, 3H, J¼8.0 Hz), 1.21 (t, 3H,
J¼8.0 Hz), 2.74–2.98 (m, 2H), 3.46 (dq, 1H, J¼8.0,
4.0 Hz), 3.61 (dq, 1H, J¼8.0, 4.0 Hz), 3.76 (dt 1H, J¼10.0,
4.0 Hz), 3.90 (dt, 1H, J¼10.0, 5.7 Hz), 4.04 (AB system,
1H), 4.10–4.28 (m, 2H), 5.15 (s, 1H), 5.82 (AB system,
1H), 6.84 (d, 1H, J¼8.4 Hz), 6.90 (t, 1H, J¼8.1 Hz), 7.27–
7.35 (6H, m), 8.29 (1H, dd, J¼8.1, 1.8 Hz). 13C NMR
(CDCl3): d 13.1, 14.0, 33.0, 44.4, 55.41, 61.8, 63.2, 64.4,
77.9, 113.7, 118.3, 119.6, 127.5, 128.2, 129.6, 132.6, 135.2,
136.4, 142.1, 165.6, 167.5, 168.3, 201.8. IR (Nujol): 2929,
1773, 1731, 1626, 1492, 1478, 1453, 1372, 1241, 1153,
1020, 750, 704 cmꢁ1. Anal. Calcd for C25H26N2O6: C,
66.65; H, 5.82; N, 6.22%. Found: C, 66.42; H, 5.59; N, 5.97%.
tals, mp 44–46 ꢂC (mixture of diastereomers). H NMR
(CDCl3): d 0.51 (d, 3H, J¼7.8 Hz), 0.59 (dt, 3H, J¼7.8,
3.0 Hz), 0.69 (dd, 2H, J¼7.8, 2.8 Hz), 0.75–1.02 (m, 6H),
1.23–1.40 (m, 3H), 1.58–1.76 (m, 3H), 1.95–2.04 (m, 1H),
2.68–2.98 (m, 2H), 3.43–3.67 (m, 2H), 3.74–3.85 (m, 2H),
4.02 (4.04) (AB system, 1H), 4.53–4.70 (m, 1H), 5.13
(5.14) (s, 1H), 5.90 (5.92) (AB system, 1H), 6.81 (d, 1H,
J¼9.6 Hz), 6.90 (t, 1H, J¼8.3 Hz), 7.13–7.46 (m, 6H),
8.31 (8.42) (dd, 1H, J¼9.6, 1.6 Hz). 13C NMR (CDCl3):
d 13.1 (13.2), 15.4, 16.0, 20.6 (20.7), 21.7 (21.8), 22.7
(23.2), 25.3, 26.4, 29.6, 31.2 (31.3), 33.0, 33.7 (33.9), 39.8
(40.3), 44.3 (44.5), 46.7 (46.9), 55.3 (55.9), 61.6 (61.7),
64.2 (64.6), 77.6 (77.7), 77.8 (77.9), 113.0 (113.1), 118.2
(118.3), 119.3 (119.6), 127.5, 128.1 (128.4), 129.6 (129.7),
132.5 (132.6), 135.3 (135.6), 136.5 (136.6), 141.9 (142.1),
165.7 (165.9), 167.4 (167.6), 201.9 (202.4). IR (CHBr3):
3406, 1725, 1623, 1452, 1374, 1371, 1244, 1142,
748 cmꢁ1. Anal. Calcd for C33H40N2O6: C, 70.69; H, 7.19;
N, 5.00%. Found: C, 70.44; H, 7.05; N, 4.77%.
4.1.5. ( )-5-(3-Benzyl-4-oxo-2-phenyl-3,4-dihydro-2H-qui-
nazolin-1-yl)-2-diazo-3-oxo-pentanoic acid (L)-menthyl
ester 4c. To a stirred solution of (ꢀ)-3-benzyl-2-phenyl-
2,3-dihydro-1H-quinazolin-4-one (1.30 g, 4.14 mmol),
and 3-oxo-pent-4-enoic acid (ꢁ)-menthyl ester (1.15 g,
4.56 mmol), in CH2Cl2 (15 mL), few drops of aqueous
50% HCl were added and stirred at room temperature for
3 days. The solvent was evaporated and to the residue a solu-
tion of tosyl azide (1.22 g, 6.2 mmol) and Et3N (1.03 mL,
4.1.3. ( )-3-Benzyl-1-(4-diazo-4-ethoxycarbonyl-3-oxo-
butyl)-4-oxo-1,2,3,4-tetrahydro-quinazoline-2-carb-
oxylic acid (L)-menthyl ester 4b. To a stirred solution of
(ꢀ)-3-benzyl-4-oxo-1,2,3,4-tetrahydro-quinazoline-2-carboxy-
lic acid ethyl ester (0.275 g, 0.85 mmol), and 3-oxo-pent-
4-enoic acid (ꢁ)-menthyl ester (0.236 g, 0.93 mmol), in
CH2Cl2 (5 mL), two drops of aqueous 50% HCl were added

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M. Mucedda et al. / Tetrahedron 63 (2007) 12232–12238
7.6 mmol) in CH2Cl2 (10 mL) was added dropwise at 0 ꢂC.
After the addition was complete, the solution was stirred at
room temperature overnight. The solvent was evaporated
and the residue gave, after flash chromatography (hexanes/
ethyl acetate 8:2), the diazo compound 4c (1.65 g, 70.5%),
yellow crystals, mp 51–53 ꢂC (mixture of diastereomers).
1H NMR (CDCl3): d 0.76 (d, 3H, J¼7.8 Hz), 0.87–0.93 (m,
7H), 0.9–1.13 (m, 2H), 1.21–1.83 (m, 5H), 1.98–2.05 (m, 1H),
2.74–2.86 (m, 1H), 3.11–3.22 (m, 1H), 3.34–3.58 (m, 2H),
3.65 (AB system, 1H), 4.76 (ddt, 1H, J¼10.2, 2.6, 2.3 Hz),
5.58 (5.59) (s, 1H), 5.62 (5.63) (AB system, 1H), 6.61 (6.62)
(d, 1H, J¼9.0 Hz), 6.86 (t, 1H, J¼8.3 Hz), 7.25–7.38 (m,
11H), 8.06 (8.07) (d, 1H, J¼8.3 Hz). 13C NMR (CDCl3):
d 16.4, 20.6, 21.9, 23.4, 26.4, 31.3, 33.9, 38.1, 40.9, 43.1
(43.2), 46.8 (46.9), 75.7 (75.8), 112.1, 116.6, 118.1, 126.5,
127.4, 128.1, 128.5, 128.7, 128.9, 129.1, 133.8, 136.5, 138.4
(138.5), 145.2, 160.5, 162.2, 190.31. IR (Nujol): 2925, 2134,
1713, 1654, 1605, 1457, 1376, 1303, 1132, 1042, 996,
700 cmꢁ1. Anal. Calcd for C36H40N4O4: C, 72.95; H, 6.80;
N, 9.45%. Found: C, 73.24; H, 6.65; N, 9.65%.
3.59 (t, 2H, J¼6.3 Hz), 4.09 (q, 2H, J¼8.0 Hz), 4.24 (AB
system, 1H), 4.27 (q, 2H, J¼8.0 Hz), 5.14 (s, 1H), 5.48
(AB system, 1H), 6.70 (d, 1H, J¼0.2 Hz), 6.90 (d, 1H,
J¼0.2 Hz), 7.27–7.35 (5H, m). 13C NMR (CDCl3): d 13.9,
36.5, 44.4, 48.4, 61.5, 62.1, 72.2, 111.0, 113.2, 122.3,
127.7, 128.4, 128.5, 136.0, 137.3, 138.7, 159.6, 160.8,
168.7, 190.0. IR (neat): 2923, 2854, 2152, 1736, 1698,
1671, 1643, 1586, 1452, 1382, 1316, 1249, 1217, 1142,
1087, 1056, 1021, 835, 746, 726, 696 cmꢁ1. Anal. Calcd
for C25H24Cl2N4O6: C, 54.85; H, 4.42; Cl, 12.95; N,
10.24%. Found: C, 55.03; H, 4.25; Cl, 12.78; N, 9.97%.
4.1.8. ( )-Diethyl 5-benzyl-3,6-dioxo-7,9-dichloro-
2,3,5,6-tetrahydro-1H-4H-benzo[f]pyrrolo[1,2-a][1,4]di-
azepine-3a,4-dicarboxylate 2d. A solution of the diazoke-
toester 4d (0.290 g, 0.52 mmol) in toluene (8 mL) was
refluxed for 40 min in the presence of Rh2(OAc)4 (6.8 mg,
0.015 mmol). The solvent was evaporated and the residue
gave, after flash chromatography (hexanes/Et2O 1:1), the di-
carboxylate 2d (0.198 g, 70%), white crystals, mp 128–
1
130 ꢂC. H NMR: d 0.81 (t, 3H, J¼8.0 Hz), 1.29 (t, 3H,
4.1.6. (L)-Menthyl-( )-5-benzyl-3,6-dioxo-4-phenyl-
2,3,5,6-tetrahydro-1H-4H-benzo[f]pyrrolo[1,2-a][1,4]di-
azepine-3a-carboxylate 2c. A solution of the diazoke-
toester 4c (0.620 g, 1.02 mmol) in toluene (15 mL) was
refluxed for 40 min in the presence of Rh2(OAc)4 (8.8 mg,
0.020 mmol). The solvent was evaporated and the residue
gave, after flash chromatography (hexanes/Et2O 1:1), the
carboxylate 2c (0.49 g, 83%), white crystals, mp 61–63 ꢂC
J¼8.0 Hz), 2.83–2.94 (m, 1H), 3.60 (q, 1H, J¼8.0 Hz),
3.70 (q, 1H, J¼10.0 Hz), 3.84–3.92 (m, 1H), 3.96 (AB sys-
tem, 1H), 4.20–4.33 (m, 2H), 5.04 (s, 1H), 5.69 (AB system,
1H), 6.74 (d, 1H, J¼3.0 Hz), 6.94 (d, 1H, J¼3.0 Hz), 7.26–
7.36 (5H, m), 7.47 (d, 2H, J¼7.0 Hz). 13C NMR (CDCl3):
d 13.2, 14.0, 32.5, 45.2, 53.8, 62.26, 62.3, 63.8, 79.3,
111.5, 120.5, 128.2, 128.3, 129.5, 135.4, 136.4, 136.9,
143.6, 165.4, 165.8, 167.3, 199.9. IR (neat): 2923, 2853,
1771, 1737, 1666, 1582, 1438, 1408, 1240, 1140, 1053,
1
(mixture of diastereomers). H NMR (CDCl3): d 0.40 (d,
1H, J¼7.1 Hz), 0.59 (t, 2H, J¼7.1 Hz), 0.66–1.03 (m, 9H),
1.25–1.79 (m, 6H), 2.37–2.53 (m, 1H), 3.50–3.56 (m, 1H),
3.57 (AB system, 1H), 4.43–4.53 (m, 1H), 4.70 (AB system,
2H), 4.79 (s, 1H), 5.35 (5.39) (s, 1H), 6.90–7.06 (m, 4H),
7.10–7.29 (m, 8H), 7.43–7.49 (m, 1H), 8.72 (t, 1H,
J¼7.3 Hz). 13C NMR (CDCl3): d 15.1 (15.9), 20.6 (20.8),
21.7 (21.8), 23.4, 26.2, 29.6, 30.9 (31.2), 33.8 (33.9), 34.6
(34.9), 39.5 (39.9), 44.4 (44.6), 46.4 (46.7), 54.3 (55.0),
66.9 (67.0), 78.5 (78.7), 113.5 (113.8), 119.2, 119.5, 126.9
(127.0), 127.9 (128.0), 128.1 (128.2), 128.8, 129.2, 129.5,
132.6 (132.8), 136.1 (136.2), 136.8, 136.9 (137.0), 165.8
(165.9), 166.0 (166.1), 205.5. IR (neat): 2956, 2869, 1770,
1732, 1617, 1492, 1478, 1451, 1379, 1307, 1153, 949,
749, 700 cmꢁ1. Anal. Calcd for C36H40N2O4: C, 76.57; H,
7.14; N, 4.96%. Found: C, 76.34; H, 6.95; N, 5.17%.
1021, 827, 753, 712, 656 cmꢁ1
. Anal. Calcd for
C25H24Cl2N2O6: C, 57.81; H, 4.66; Cl, 13.65; N, 5.39%.
Found: C, 57.62; H, 4.59; Cl, 13.48; N, 5.12%.
4.1.9. ( )-5-(3-Benzyl-4-oxo-2-phenyl-3,4-dihydro-2H-
quinazolin-1-yl)-2-diazo-3-oxo-pentanoic acid ethyl ester
4e. To a stirred solution of (ꢀ)-3-benzyl-2-phenyl-2,3-dihy-
dro-1H-quinazolin-4-one (0.860 g, 2.73 mmol), and 3-oxo-
pent-4-enoic acid ethyl ester (0.77 g, 5.46 mmol), in
CH2Cl2 (15 mL), few drops of aqueous 50% HCl were added
and stirred for 3 days at room temperature. The solvent was
evaporated and to the residue a solution of tosyl azide
(0.806 g, 4.09 mmol) and Et3N (0.76 mL, 5.46 mmol) in
CH2Cl2 (10 mL) was added dropwise at 0 ꢂC. After the ad-
dition was complete, the solution was stirred at room tem-
perature overnight. The solvent was evaporated and the
residue gave, after flash chromatography (hexanes/ethyl ace-
tate 8:2), the diazo compound 4e (0.874 g, 66.4%), as a yel-
low oil. 1H NMR (CDCl3): d 1.27 (t, 3H, J¼8.0 Hz), 2.78–
2.87 (m, 1H), 3.09–3.20 (m, 1H), 3.36–3.56 (m, 2H), 3.63
(AB, 1H), 4.21 (q, 2H, J¼8.0 Hz), 5.59 (s, 1H), 5.63 (AB,
1H), 6.62 (d, 1H, J¼9.0 Hz), 6.84 (t, 1H, J¼8.3 Hz), 7.25–
7.33 (m, 11H), 8.06 (dd, 1H, J¼8.3, 1.3 Hz). 13C NMR
(CDCl3): d 14.1, 37.9, 42.9, 46.8, 61.3, 75.6, 76.0, 112.0,
116.5, 118.0, 126.4, 127.3, 128.0, 128.4, 128.6, 128.8,
128.9, 133.7, 136.4, 138.4, 145.1, 160.7, 162.1, 190.1. IR
(neat): 2924, 2854, 2125, 1716, 1650, 1601, 1464, 1455,
1397, 1301, 1227, 1177, 998, 752, 700 cmꢁ1. Anal. Calcd
for C28H26N4O4: C, 69.70; H, 5.43; N, 11.61%. Found: C,
69.92; H.55; N, 11.78%.
4.1.7. ( )-3-Benzyl-5,7-dichloro-1-(4-diazo-4-ethoxycar-
bonyl-3-oxo-butyl)-4-oxo-1,2,3,4-tetrahydro-quinazo-
line-2-carboxylic acid ethyl ester 4d. To a stirred solution
of (ꢀ)-3-benzyl-5,7-dichloro-4-oxo-1,2,3,4-tetrahydro-qui-
nazoline-2-carboxylic acid ethyl ester (1.32 g, 3.36 mmol),
and 3-oxo-pent-4-enoic acid ethyl ester (0.936 g,
6.6 mmol), in CH2Cl2 (20 mL), few drops of aqueous 50%
HCl were added and stirred at room temperature for 9
days. The solvent was evaporated and to the residue a solu-
tion of tosyl azide (0.99 g, 5.0 mmol) and Et3N (0.90. mL,
6.6 mmol) in CH2Cl2 (15 mL) was added dropwise at
0 ꢂC. After the addition was complete, the solution was
stirred at room temperature overnight. The solvent was evap-
orated and the residue gave, after flash chromatography (pe-
troleum ether/ethyl acetate 7:3), the diazo compound 4d
1
(1.43 g, 77.9%) as a yellow oil. H NMR: d 1.18 (t, 3H,
J¼8.0 Hz), 1.28 (t, 3H, J¼8.0 Hz), 2.95–3.16 (m, 2H),
4.1.10. ( )-Ethyl 5-benzyl-3,6-dioxo-4-phenyl-2,3,5,6-tet-
rahydro-1H-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepine-

M. Mucedda et al. / Tetrahedron 63 (2007) 12232–12238
12237
3a-carboxylate 2e. A solution of the diazoketoester 4e
Acknowledgements
(0.210 g, 0.43 mmol) in toluene (7 mL) was refluxed for
5 min in the presence of Cu(acac)2 (3.5 mg, 0.013 mmol).
The solvent was evaporated under reduced pressure and
the residue gave, after flash chromatography (hexanes/ethyl
acetate 8:2), the carboxylate 2e (0.158 g, 80.2%), white
crystals, mp 160–161 ꢂC. 1H NMR: d 0.92 (t, 3H,
J¼8.0 Hz), 1.59–1.73 (m, 1H), 2.43–2.53 (m, 1H), 3.51–
3.63 (m, 1H), 3.81 (dq, 1H, J¼8.0, 2.7 Hz), 4.04 (dq, 1H,
J¼8.0, 2.7 Hz), 4.64 (AB system, 1H), 4.87 (AB system,
1H), 5.41 (s, 1H), 6.86 (d, 1H, J¼8.0 Hz), 6.93 (d, 2H,
J¼8.0 Hz), 7.01 (t, 1H, J¼8.3 Hz), 7.13–7.30 (m, 9H),
7.45 (dt, 1H, J¼9.0, 1.7 Hz), 8.70 (dd, 1H, J¼9.0, 1.7 Hz).
13C NMR (CDCl3): d 13.7, 34.7, 44.2, 54.6, 62.5, 66.9,
78.7, 113.6, 119.2, 119.3, 127.1, 128.0, 128.2, 128.8,
129.4, 132.9, 135.9, 136.4, 136.6, 144.4, 165.4, 165.8,
166.3, 205.3. IR (Nujol): 2924, 2853, 1766, 1729, 1617,
1491, 1452, 1374, 1241, 1153, 1019, 752, 701 cmꢁ1. Anal.
Calcd for C28H26N2O4: C, 73.99; H, 5.77; N, 6.16%. Found:
C, 73.74; H, 5.49; N, 6.32%.
The authors are thankful to Fondazione Banco di Sardegna
for financial support.
References and notes
1. Some recent examples of PBDs’ syntheses: (a) Kamal, A.;
Devaiah, V.; Reddy, K. L.; Shankaraiah, N. Adv. Synth. Catal.
2006, 348, 249; (b) Cooper, N.; Hagan, D. R.; Tiberghien, A.;
Ademefun, T.; Matthews, C. S.; Howard, P. V.; Thurnston,
D. E. Chem. Commun. 2002, 1784; (c) Kamal, A.; Reddy,
G. S. K.; Reddy, K. L. Tetrahedron Lett. 2001, 42, 6969; (d)
O’Neall, I. A.; Thompson, S.; Murray, C. L.; Tarraga, A.;
Kalindjian, S. B. Tetrahedron Lett. 1998, 39, 3609; (e)
O’Neall, I. A.; Murray, C. L.; Kalindjian, S. B. Synlett 1997,
75; (f) O’Neall, I. A.; Murray, C. L.; Potter, A. J.; Kalindjian,
S. B. Tetrahedron Lett. 1997, 38, 3609; (g) Molina, P.; Diaz,
D. Tetrahedron 1995, 51, 5617; (h) Eguchi, S.; Yamashita, K.;
Matsushita, Y.; Kakehi, A. J. Org. Chem. 1995, 60, 4006.
2. Thurston, D. E.; Bose, D. S. Chem. Rev. 1994, 94, 433.
3. Recent examples of spiro-to-fused ammonium ylides strategy:
(a) Curtis, E. A.; Padwa, A.; Worsencroft, K. J. Tetrahedron
Lett. 1997, 38, 3319; (b) Padwa, A.; Brodney, M. A.; Marino,
J. P., Jr.; Sheean, S. M. J. Org. Chem. 1997, 62, 78; (c)
Padwa, A.; Price, A. T. J. Org. Chem. 1998, 63, 5556; (d)
Padwa, A.; Snyder, J. P.; Curtis, E. A.; Sheean, S. M.;
Worsencroft, K. J.; Kappe, C. O. J. Am. Chem. Soc. 2000,
122, 8155; (e) Vanecko, J. A.; West, F. G. Org. Lett. 2002, 4,
2813; (f) Vanecko, J. A.; West, F. G. Org. Lett. 2005, 7, 2949.
4. (a) Saba, A. Tetrahedron Lett. 2003, 44, 2895; (b) Muroni, D.;
Saba, A.; Culeddu, N. Tetrahedron: Asymmetry 2004, 15, 2609;
(c) Muroni, D.; Saba, A.; Culeddu, N. Tetrahedron 2006, 62,
1459; (d) Muroni, D.; Saba, A.; Culeddu, N. Heterocycles
2006, 68, 47.
4.1.11. Crystal data and structure refinement for com-
pound 2e. Suitable crystals for X-ray structure determina-
tion of compound 2e were obtained by recrystallization
from ethyl acetate/light petroleum ether 10:1. The substance
(C28H26N2O4, Mr¼454) crystallized in the monoclinic space
˚
group P21/c, a¼15.107(1), b¼10.3999(9), c¼14.662(1)A;
3
ꢂ
ꢂ
ꢂ
˚
a¼90 , b¼99.105(1) , g¼90 ; V¼2274.6(4) A , Z¼4,
Dcalcd¼1.327 g/cm3, F (000)¼960, T¼150 K; crystal size
0.25ꢃ0.35ꢃ0.40 mm, q¼3–27ꢂ, reciprocal space explored:
full sphere, reflections collected¼18,950, independent re-
flections¼5352 [Rint¼0.0311], completeness to q¼27ꢂ:
100%, max. and min. transmissions: 1.000 and 0.689,
refinement method: full-matrix least-squares on F2, data¼
5352, restrains¼0, parameters¼411, goodness-of-fit on
F2¼0.972, final R indices [I>2s(I)]: R1¼0.037, wR2¼
0.035, R indices (all data, F2): R2¼0.054, wR2¼0.074, laꢁrg3-
5. For reviews of ammonium ylides generated by diazo com-
pounds, see: (a) Doyle, M. P.; McKervey, M. A.; Ye, T.
Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds; John Wiley and Sons: New York, NY, 1997; (b)
West, F. G.; Naidu, B. N. J. Am. Chem. Soc. 1993, 116, 1177;
(c) Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263;
(d) Padwa, A.; Beall, L. S. Advances in Nitrogen
Heterocycles; JAI: Stamford, CT, 1998; Vol. 3, pp 117–158.
6. For general reviews of the Stevens rearrangement, see: (a)
˚
est diff. peak and hole¼0.310(109) and ꢁ0.320(109) eA
.
Crystallographic data have been deposited with the Cam-
bridge Crystallographic Data Center (deposition number:
CCDC 648,015).
4.1.12. ( )-5-Benzyl-7,9-dichloro-10c-hydroxymethyl-
1,2,2a,4a,5,10c-hexahydro-3-oxa-5,10b-diaza-benzo[f]-
cyclopenta[cd]azulene-4,6-dione 7. To a solution of 2d
(0.100 g, 0.19 mmol), in anhydrous MeOH (5 mL), NaBH4
(0.77 g, 0.57 mmol) was added and the resulting mixture
stirred at room temperature under nitrogen for 20 h. The sol-
vent was evaporated under reduced pressure and the residue
was purified by chromatography on silica gel (hexanes/ethyl
acetate 1:1), to afford the tetracyclic lactone 7 (0.063 g,
ꢀ
Marko, I. E. Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 913–
973; (b) West, F. G.; Clark, J. S. Nitrogen, Oxygen and Sulfur
Ylide Chemistry; Clark, J. S., Ed.; Oxford University Press:
Oxford, 2002; (c) See also: Stevens, T. S.; Creighton, E. M.;
Gordon, A. B.; Macincol, M. T. J. Chem. Soc. 1928, 3193.
7. For a recent review of the Stevens rearrangement of ammonium
ylides, see: Vanecko, J. A.; Wan, H.; West, F. G. Tetrahedron
2005, 61, 1043.
8. Bonanomi, N.; Palazzo, G. Il Farmaco 1977, 32, 490.
9. Dabiri, M.; Salhei, P.; Otokesh, S.; Baghbanzadeh, M.;
Kozehgary, G.; Mohammadi, A. A. Tetrahedron Lett. 2005,
46, 6123.
10. Zibuck, R.; Streiber, J. M. J. Org. Chem. 1989, 54, 4717.
11. (a) Regitz, M.; Maas, G. Diazo Compounds; Academic: Orlando,
FL, 1986; (b) Bollinger, F. W.; Tuma, L. D. Synlett 1996, 407.
12. Padwa, A.; Beall, L. S.; Eidell, C. K.; Worsencroft, K. J. J. Org.
Chem. 2001, 66, 2414.
1
73.7%), white crystals, mp 230–231 ꢂC. H NMR: d 2.0–
2.09 (m, 1H), 2.23–2.29 (m, 1H), 2.74 (dt, 1H, J¼9.0,
2.7 Hz), 3.12 (q, 1H, J¼9.0 Hz), 3.62–3.69 (m, 1H), 3.79
(AB system, 1H), 4.06 (AB system, 1H), 4.08–4.15 (m, 1H),
4.30 (s, 1H), 4.31 (AB system, 1H), 5.69 (AB system, 1H),
6.77 (s, 1H,), 7.21–7.45 (m, 6H). 13C NMR (CDCl3): d 29.7,
31.7, 43.1, 49.4, 50.4, 69.3, 75.6, 77.1, 80.6, 117.9, 126.4,
126.6, 127.8, 128.6, 128.8, 135.6, 136.4, 137.5, 144.4,
165.8, 171.2. IR (Nujol): 3406, 2923, 2853, 1780, 1645,
1577, 1463, 1376, 1253, 1107, 983, 827, 734 cmꢁ1. Anal.
Calcd for C21H18Cl2N2O4: C, 58.21; H, 4.19; Cl, 16.36;
N, 6.47%. Found: C, 57.92; H, 4.01; Cl, 16.07; N, 6.71%.

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M. Mucedda et al. / Tetrahedron 63 (2007) 12232–12238
13. (a) West, F. G.; Naidu, B. N.; Tester, R. W. J. Org. Chem. 1994,
59, 6892; (b) West, F. G.; Glaeske, K. W.; Naidu, B. N.
Synthesis 1993, 977.
14. Glaeske, K. W.; West, F. G. Org. Lett. 1999, 1, 31.
15. Ollis, W. D.; Rey, M.; Sutherland, I. O. J. Chem. Soc., Perkin
Trans. 1 1983, 1009.
16. Overman, L. E.; Pennington, L. D. J. Org. Chem. 2003, 68,
7143.
17. (a) West, F. G.; Naidu, B. N. J. Org. Chem. 1994, 59, 6051; (b)
Cativela, C.; Diaz de Villegas, M. D. Tetrahedron: Asymmetry
1998, 9, 3517; (c) Hanessian, S.; McNaughton-Smith, G.;
Lombard, H. G.; Lubell, W. D. Tetrahedron 1997, 53, 12789;
(d) Clark, J. S.; Middleton, M. D. Org. Lett. 2002, 4, 765.
18. (a) Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42,
1688; (b) Dehli, J. R.; Gotor, V. J. Org. Chem. 2002, 67,
1716; (c) For reviews, see: Christoffers, J.; Mann, A. Angew.
Chem., Int. Ed. 2001, 40, 4591; (d) Fuji, K. Chem. Rev. 1993,
93, 2037; (e) Corey, E. J.; Guzman-Perez, A. Angew. Chem.,
Int. Ed. 1998, 37, 388; (f) Martin, S. F. Tetrahedron 1980,
36, 419.