Synthesis of 5-arylpyrrolo[2,1-c][1,4]benzodiazepines under mild cyclodehydration conditions

Article abstract of DOI:10.1016/j.tet.2010.01.109

The efficiency of a cyclodehydration reaction leading to benzodiazepinones is markedly improved by N-methylation of the amide link connecting the nucleophile and the electrophile, which is attributed to its favouring both the more reactive E-rotamer and the exit of the leaving group.

Full text of DOI:10.1016/j.tet.2010.01.109

Tetrahedron 66 (2010) 2718–2722
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 5-arylpyrrolo[2,1-c][1,4]benzodiazepines under mild
cyclodehydration conditions
*
´
´
Loreto Legeren, Domingo Domınguez
´
´
Departamento de Qu´ımica Organica, Facultad de Quımica, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The efficiency of a cyclodehydration reaction leading to benzodiazepinones is markedly improved by
N-methylation of the amide link connecting the nucleophile and the electrophile, which is attributed to
its favouring both the more reactive E-rotamer and the exit of the leaving group.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 6 November 2009
Received in revised form 12 January 2010
Accepted 28 January 2010
Available online 10 February 2010
Keywords:
Pyrrolobenzodiazepine
Proline
Benzodiazepinone
Amidoalcohol
Cyclodehydration
1. Introduction
The 5-aryl-1,4-benzodiazepin-2-ones constitute an important
class of ‘privileged structures’ that are able to bind to diverse
receptors, including the cholecystokinin (CCK) receptor and
several central nervous system (CNS) receptors.1 Pyrrolo[2,1-
c][1,4]benzodiazepin-11-ones are likewise biologically versatile:2
they have anxiolytic3 and anti-ischaemic4 properties, and their
N10–C11 imino derivatives are gene-specific antitumour agents.5
In view of the biological relevance of these molecular families,
we recently developed a synthetic approach to a structure
combining the two, exemplified by the preparation of 5-phe-
Figure 1. Synthesis of 5-phenylpyrrolo[2,1-c][1,4]benzodiazepin-11-ones by
cyclodehydration.
nylpyrrolo[2,1-c][1,4]benzodiazepin-11-one
(1a)
and
its
The difficulty of preparing 1a was attributed fundamentally to the
preferential adoption of the Z conformation exhibited by the pre-
cursor amide of Figure 1,7 which keeps the reaction partners far apart
and thereby favours the occurrence of alternative reactions upon
activation of the hydroxyl; similar conformation-dependence has
been reported for several other cyclizations in which part of the ring
being formed is an amide link.8 In the case of the chromeno de-
rivative 2, the lifetime of the remarkably stable intermediate xan-
thylium cation seems to be long enough for the reaction to proceed
via the minority E-rotamer, but this evidently does not occur for 1a.
Furthermore, a preliminary study of the effects of substituents on the
phenyl rings showed that while destabilization of the diphe-
nylcarbocation intermediate with halogens worsened matters as
expected, its stabilization by a methoxy group failed to overcome the
presumed adverse influence of conformation: attempted cyclization
chromeno-fused derivative 2 (Fig. 1).6 Unfortunately, the effi-
ciency of the key step, the cyclodehydration of the corresponding
amidoalcohol, depended heavily on the substrate: whereas the
chromeno derivative 2 was obtained stereo- and enantiose-
lectively in good yield under very mild conditions (AcOH, rt), the
unsubstituted 1a could only be obtained non-stereoselectively,
and even that required thermal cyclodehydration under very
harsh conditions (dichlorobenzene at 180 ꢀC), although the yield
was high (86%).
* Corresponding author. Fax: þ34 981595012.
´
E-mail address: domingo.dominguez@usc.es (D. Domınguez).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.109

L. Leger´en, D. Dom´ınguez / Tetrahedron 66 (2010) 2718–2722
2719
Scheme 1. Syntheses of 5-arylpyrrolo[2,1-c][1,4]benzodiazepin-11-ones 1 and 3.
of 7d (Scheme 1) afforded only complex reaction mixtures regardless
of whether the reaction was performed under the same conditions
as for 1a (DCB, 180 ꢀC) or with Lewis acid catalysis (BF3$OEt2, di-
chloroethane, 0 ꢀC to reflux); while attempted cyclization of 7e
resulted in its decomposition under harsh conditions (DCB, 180 ꢀC),
and led mainly to the recovery of starting material under milder
conditions (AcOH, rt, 72 h).6
In the work described here we re-examined the effect of stabi-
lizing the carbocation, and we also found that N-methylation of the
amide link promotes cyclization even in the presence of
carbocation-destabilizing substituents, presumably by favouring
the propitious E-rotamer.
presence of isobutyl chloroformate, deprotection with TFA, and
final reduction with NaBH4 (Scheme 1). Attempts to cyclize the
aza analogues 7b and 7c under thermal conditions (DCB, 180 ꢀC)
led mainly to complex mixtures resulting from decomposition of
the starting amidoalcohols, which was attributed to de-
stabilization of the intermediate carbocation by the
p-deficient
pyridine ring. Attempts to promote the cyclization of 7b by acid
or basic catalysis (0.1 equiv of p-TsOH or DMAP) likewise led to
decomposition after 3.5 h of heating in DCB at 150 ꢀC; and ami-
doalcohol 7d behaved as described in Section 1 above.6 Thus
carbocation-destabilizing modifications of 7a all had the expected
effect on the cyclization reaction. Since 7e, with its carbocation-
stabilizing methoxy group, also behaved as described in Section
1,6 we decided to seek a means of propitiating the favourable
conformation of the cyclodehydration precursors, and to in-
vestigate whether this conformation would allow cyclo-
dehydration regardless of the presence of substituents on the
phenyl rings.
2. Results and discussion
2.1. Cyclodehydration of secondary amides 7a–e
As reported previously,6 cyclization of amidobenzhydrol 7a
requires heating in dichlorobenzene at 180 ꢀC in a sealed tube for
3.5 h (entry 1, Table 1), which affords an 86% yield of 1a as a 1:1
mixture of the enantiomerically pure cis and trans stereoiso-
mers.9 To explore the effects of electronic modifications we
prepared 7b and 7c, in which one of the phenyls is replaced by
2.2. Cyclodehydration of tertiary amides 10a–e
Reasoning that the reactive E conformation would be favoured if
the hydrogen of the amide were replaced with a larger group,10 we
decided to prepare 10a–e, the N-methylated analogues of 7a–e. The
required tertiary amides 9a–e were prepared straightforwardly and
in excellent yields from amides 5a–e by reaction with methyl iodide
a
p-deficient pyridyl. Like 7a, compounds 7b and c were obtained
in good overall yields by condensation of the corresponding
amino-substituted diarylmethanone
4
with L-Boc-Pro in the
Table 1
Cyclodehydration of amides 7 and 9
Entry
Starting amide
X
Y
Z
Conditions
Product (% yield)
Trans/cis ratioc
eed (%)
1
2
3
4
5
6
7a
9a
9b
9c
9d
9e
CH
CH
CH
CH
CCl
CH
CH
CH
N
CH
CF
CH
CH
CH
CH
N
CH
COMe
DCB, 180 ꢀC, 3.5 h
1a (86%)a
3a (63%)b
3b (93%)b
3c (62%)a
3d (53%)a
3e (68%)a
50/50
75/25
90/10
95/05
30/70
80/20
>99
0
11
2
4
1
NaBH4, EtOH, rt, 10 min
NaBH4, EtOH, rt, 40 min
NaBH4, EtOH, rt, 20 min
NaBH4, EtOH, rt, 10 min
NaBH4, EtOH, rt, 10 min
a
Isolated yield of the unseparated mixture of trans and cis isomers.
Combined yield after separation of trans and cis isomers.
b
c
By integration of the 1H NMR signals of the crude reaction mixture, following their identification by X-ray and NOE experiments.
Enantiomeric excess determined by chiral HPLC.
d

2720
L. Leger´en, D. Dom´ınguez / Tetrahedron 66 (2010) 2718–2722
in DMF in the presence of NaH, followed by deprotection with TFA;
and HPLC of 8a and 9a on chiral columns confirmed the preserva-
tion of the stereochemical integrity of the proline stereocentre.
Treatment of 9a with NaBH4 and EtOH at rt for 10 min did not
produce amidobenzhydrol 10a, but instead a 75:25 mixture of
trans- and cis-3a that after chromatographic separation amounted
to a 63% combined yield (entry 2, Table 1). Thus alkylation of the
amide nitrogen seems not only to have favoured the propitious E
conformation, but also to have promoted the elimination of the
hydroxyl leaving group and the closure of the diazepine ring.11
Attribution of cis relative configuration to the less polar 3a isomer
was supported by the 1% NOE of the singlet at 5.02 ppm (H5) when
the triplet at 3.14 ppm (H11a) was saturated, and was confirmed by
X-ray crystallography (Fig. 2a).
HCl$EtOH). It therefore seems likely that it is the unisolated in-
termediate 10a that undergoes racemization under the conditions
employed for its formation, regardless of whether these conditions
are acidic or basic.12
To determine whether the beneficial effect of N-methylation was
sufficient to overcome the presence of carbocation-destabilizing
substituents, we proceeded to investigate the reactions of 9b–d. As
hoped, reduction of 9b with NaBH4 in EtOH at rt for 40 min directly
afforded benzodiazepinone 3b, the 90:10 mixture of trans and cis
isomers amounting to a 93% combined yield after chromatographic
separation (entry 3). NOE-based attribution of the trans relative
configuration to the major isomer [the doublet at 3.76 ppm (H11a
)
showed no change upon saturation of the singlet at 4.74 ppm (H5)]
was further confirmed by X-ray crystallography (Fig. 3).
The crystallographic data also showed a unit cell with a symme-
try centre (Fig. 2b), indicating that racemization had taken place at
Similarly, reduction of the 4-pyridyl analogue 9c directly afforded
Figure 3. ORTEP plot of the molecular structure of trans-3b.
pyrrolobenzodiazepinone 3c, in this case with only 5% of the cis
isomer (entry 4); and reduction of the halogenated methanone 9d
directly gave 3d, although in this case the stereoselectivity was re-
versed (entry 5). Finally, reduction of methanone 9e, with its
carbocation-stabilizing para methoxy, directly afforded 3e (entry 6).
In conclusion, we have shown that in the preparation of 5-aryl-
pyrrolo[2,1-c][1,4]benzodiazepin-11-ones by cyclodehydration,
alkylating the amide nitrogen of the future diazepine ring in the
cyclodehydration precursor has a decisive influence on the course of
the reaction. Secondary amides, which exist mainly as Z-rotamers,
cyclize only under very harsh conditions; by contrast, tertiary am-
ides, in which the E-rotamer predominates, cyclize spontaneously
and in good yield (albeit with racemization) upon reduction of the
methanone precursor at rt in EtOH.
Figure 2. ORTEP plots of the structure of cis-3a as determined by X-ray crystallogra-
phy: (a) Molecular structure. (b) The unit cell.
some point between 9a and crystallization of 3a. In fact, chiral HPLC
of cis- and trans-3a showed complete racemization in both cases.
This process appears to have occurred prior to the formation of 3a,
because (a) 3a obtained by methylation of enantiopure 1a was only
partially racemized (er 68:32) even though it was obtained under
strongly basic conditions (NaH, MeI, DMF); and (b) this enantiomeric
ratio was not changed when the 3a so obtained was subjected to the
conditions employed for cyclodehydration (NaBH4, EtOH, 10 min).
Furthermore, chiral-HPLC-proven racemization also took place when
acidic conditions were employed for reduction of 9a (NaCNBH3,
3. Experimental
3.1. General procedures
1H and 13C NMR spectra were recorded in CDCl3 at 500.13,
300.05 and 125.75, 75.46 MHz, respectively, using TMS as internal

L. Leger´en, D. Dom´ınguez / Tetrahedron 66 (2010) 2718–2722
2721
reference. All air-sensitive reactions were run under dried de-
oxygenated argon, in oven dried glassware, with magnetic stirring;
reagents were added by syringe through septa. All solvents for air
or moisture-sensitive reactions were dried by standard procedures.
All new compounds were chromatographically pure and both
identity and homogeneity were provided by HRMS and by 1H and
13C NMR spectroscopy. The enantiomeric excess was determined by
HPLC using a Chiralcel OD-H column eluted with n-hexane:2-
propanol (gradient from 80:20 to 50:50) at 0.5 mL/min and by UV
detection at 254 nm.
26.04 (CH2). MS (EI) (m/z): 294 (Mþ, 1), 224 (1), 196 (21), 70 (100).
HRMS (EI) calcd for C18H18N2O2 294.1368, found: 294.1371.
3.3.2. N-{2-[Hydroxy(phenyl)methyl]phenyl}-
L-prolinamide (7a). A
solution of N-(2-benzoylphenyl)- -prolinamide (6a) (130 mg,
L
0.4 mmol) and NaBH4 (50 mg, 1.2 mmol) in EtOH (8 mL) was stirred
at rt for 30 min. The resulting mixture was cooled in an ice bath and
neutralized with a 10% aqueous HCl solution, and the solvent was
removed under reduced pressure. The residue was dissolved in
CH2Cl2, washed with brine (3ꢁ10 mL), dried with anhydrous Na2SO4,
filtered and the solvent evaporated. Purification by flash chroma-
tography (SiO2, 95:5 CH2Cl2/MeOH) afforded 7a (128 mg, 99%) as
a 60:40 mixture of diastereomers. IR (KBr) 3357 (NHR2), 2961, 2927,
3.2. Typical procedure for acylation of aminobenzo
phenones 4 with L-Boc-Pro
1656 (HNC]O), 1585, 1521, 1452 cmꢂ1. 1H NMR
d: 10.16 (br s, 0.4H,
3.2.1. (S)-tert-Butyl 2-{[(2-benzoylphenyl)amino]carbonyl}pyrroli-
dine-1-carboxilate (5a). A solution of -Boc-Proline (1.29 g,
HNCO), 10.04 (br s, 0.6H, NH), 8.09 (d, J¼8.1 Hz, 0.4H), 8.04 (dd, J¼8.1
and 0.8 Hz, 0.6H), 7.35–7.26 (m, 6H), 7.23 (dd, J¼7.7 and 1.1 Hz, 1H),
7.11 (td, J¼7.6 and 1.1 Hz, 1H), 5.90 (s, 1H), 3.72 (dd, J¼8.2 and 5.6 Hz,
0.4H), 3.65 (dd, J¼9.2 and 5.2 Hz, 0.6H), 3.0–2.93 (m, 1H), 2.90–2.83
(m,1H), 2.46 (br s, 2H), 2.03–2.01 (m,1H),1.92–1.82 (m,1H),1.70–1.61
L
6.00 mmol) and Et3N (0.85 mL, 6.00 mmol) in dry THF (20 mL)
under Ar at 0 ꢀC was treated with isobutyl chloroformate
(0.778 mL, 6.00 mmol). After stirring for 1 h a solution of ami-
nobenzophenone 4a (1 g, 5.10 mmol) in dry THF (20 mL) was
added. The mixture was further stirred at rt for 72 h and con-
centrated in vacuum. The residue was dissolved in CH2Cl2 (15 mL)
and the solution was washed with HCl 10% (3ꢁ10 mL), Na2CO3
(3ꢁ10 mL) and H2O (3ꢁ10 mL). The organic layer was dried with
anhydrous Na2SO4, concentrated in vacuum and purified by flash
(m, 2H). 13C NMR/DEPT
d: 174.06 (HNC]O), 141.67 (C), 135.82 (C),
133.32(C),128.70 (CH),128.52 (CH),128.28 (2ꢁCH),127.52 and 127.47
(CH),126.56 and 126.44 (2ꢁCH),124.39 (CH),122.85 and 122.78 (CH),
74.49 and 73.94 (CH), 61.00 (CH), 47.19 and 47.14 (CH2), 30.83 and
30.75 (CH2), 26.10 and 25.95 (CH2). MS (IE) (m/z): 296 (Mþ, 3), 226 (5),
198 (8), 180 (100). HRMS (IE) calcd for C18H20N2O2 296.1525, found:
296.1525.
chromatography (SiO2, 3:7 EtOAc/hexane) to give yellow solid 5a
20
(2.01 g, quant.): mp 128–130 ꢀC; [
a
]
ꢂ145.2 (c 1 , CH2Cl2). IR
D
(KBr): 3297 (N–H st), 1697 (C]O), 1638 (C]O), 1599, 1528, 1382,
1264, 1160 cmꢂ1 1H NMR (splitting of some signals is observed
due to the presence of two rotamers of the carbamate in 60:40
ratio) : 11.32 (br s, 0.4H, NH) and 11.25 (br s, 0.6H, NH), 8.65
3.4. Cyclodehydration of benzhydrol 7a
.
3.4.1. (5R, 11aS)- and (5S, 11aS)-5-Phenyl-1,2,3,5,10,11a-hexahydro-
11H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one (1a). A solution of
amidoalcohol 7a (370 mg,1.3 mmol) in dichlorobenzene (12 mL) was
deoxygenated with a stream of argon and stirred at 180 ꢀC for 3.5 h in
a sealed tube. The solvent was evaporated under reduced pressure
and the residue (50:50 mixture of stereoisomers) was purified by
flash chromatography on silica gel (95:5 CH2Cl2/MeOH), affording
a mixture of the cis and trans diastereomers 1a (40:60 ratio, 311 mg,
86%) as a yellow solid: >99% ee each. IR (CHCl3) 3216, 3204 (N–H st),
d
(broad, 1H), 7.67 (broad, 2H), 7.56 (broad, 3H), 7.45 (broad, 2H),
7.08 (broad, 1H), 4.41 (broad, 0.4H, CH) and 4.26 (broad, 0.6H,
CH), 3.73 (broad, 1H), 3.56–3.44 (m, 1H), 2.28–2.21 (m, 1H),
2.19–2.13 (m, 1H), 1.91–1.87 (m, 2H), 1.40 (br s, 3.6H, CH3) and
1.27 (br s, 5.4H, CH3). 13C NMR/DEPT
d: 199.05 (CO), 172.36 and
171.86 (HNCO), 154.90 and 154.02 (NCOO), 139.92 (C), 138.53 and
138.41 (C), 134.01 and 133.93 (CH), 133.42 and 133.22 (CH),
132.22 and 132.07 (CH), 129.68 (2ꢁCH), 128.06 (2ꢁCH), 123.39
(C), 122.14 and 122.0 (CH), 121.0 (CH), 80.10 (C), 62.41 and 61.86
(HCN), 47.01 and 46.72 (CH2), 31.36 and 30.19 (CH2), 28.10
(3ꢁCH3), 24.27 and 23.72 (CH2). MS (CI) (m/z): 395 ([MþH]þ, 22),
296 (100), 295 (95). HRMS (CI) calcd for C23H27N2O4 [(MþH)þ]
395.1971, found: 395.1974.
1674 (CO), 1487 cmꢂ1. 1H NMR
d: 7.95 (br s, 0.6H, NH) and 7.60 (br s,
0.4H, NH), 7.50–7.00 (m, 8H), 6.84 (d, J¼7.5 Hz, 0.4H) and 6.58
(d, J¼7.5 Hz, 0.6H), 5.02 (s, 0.4H, H5) and 4.69 (s, 0.6H, H5), 3.77
(d, J¼7.0 Hz, 0.6H, H11a) and 3.64 (dd, J¼8.7 and 2.8 Hz, 0.4H, H11a),
2.93 (td, J¼8.4 and 2.3 Hz, 0.6H) and 2.82 (t, J¼6.8 Hz, 0.4H),
2.66–2.58 (m, 0.4H) and 2.44–2.34 (m, 1.8H), 2.02–1.77 (m, 3H). 13C
NMR/DEPT d: 174.49 and 171.94 (CO), 145.28 and 140.21(C), 137.53
3.3. Typical procedure for the synthesis of secondary
amidoalcohols 7
and 135.29 (C), 134.96 and 133.63 (C), 131.28 and 129.27 (CH), 128.71
and 128.50 (2ꢁCH), 128.42 and 128.17 (2ꢁCH), 127.76 and 127.68
(CH), 127.50 and 127.17 (CH), 125.38 and 124.45 (CH), 122.30 and
121.04 (CH), 75.57 and 66.57 (CH), 60.86 and 60.84 (CH), 55.71 and
52.17 (CH2), 25.51 and 24.73 (CH2), 24.04 and 23.19 (CH2). MS (CI), m/z
(%): 279 ([MþH]þ,100), 278 (Mþ, 36), 251 (20), 182 (35). MS (EI), m/z
(%): 278 (Mþ,11),179 (100). HRMS (EI) calcd for C18H18N2O: 278.1419,
found: 278.1411.
3.3.1. N-(2-Benzoylphenyl)-L-prolinamide (6a). To a solution of
carbamate 5a (687 mg, 2.33 mmol) in dichloromethane (15 mL)
was added trifluoroacetic acid (5 mL) and the mixture was stirred at
rt for 30 min. The solution was concentrated in vacuum, and the
residue was dissolved in dichloromethane and treated with 5 N
NaOH aqueous solution until pH 9–11. The mixture was extracted
with CH2Cl2 (3ꢁ10 mL), washed with brine (3ꢁ10 mL), dried with
3.5. Typical procedure for the synthesis of tertiary
amidoketones 9
anhydrous Na2SO4, filtered and the solvent evaporated to afford
20
yellow solid 6a (512 mg, quant.): mp 95–97 ꢀC; [
a
]
D
þ105.6 (c 1,
CH2Cl2). IR (neat): 3353, 3226 (NHR2), 1683 (C]O), 1645 (HNC]O),
3.5.1. (S)-tert-Butyl 2-{[(2-benzoylphenyl)(methyl) amino] carbonyl}-
pyrrolidine-1-carboxylate (8a). Sodium hydride (50%, 233 mg,
4.85 mmol) was added to a stirred solution of amide 5a (1.06 g,
2.69 mmol) in DMF (15 mL) at 0 ꢀC. After 10 min, methyl iodide
(0.251 mL, 4.03 mmol) was added and the solution was further
stirred at room temperature for 5.5 h. The mixture was treated with
H2O (10 mL) and extracted with CH2Cl2 (3ꢁ5 mL). The combined
organic layers were washed with water and brine, dried with an-
hydrous Na2SO4, filtered and concentrated. Purification by flash
1577, 1509, 1447, 1264 cmꢂ1. 1H NMR
d
: 11.60 (br s, 1H, HNCO), 8.60
(dd, J¼8.4 and 0.7 Hz, 1H), 7.72 (dd, J¼8.3 and 1.2 Hz, 2H), 7.55–7.49
(m, 2H), 7.47–7.41 (m, 3H), 7.05 (td, J¼7.6 and 1.1 Hz, 1H), 3.80 (dd,
J¼9.1 and 5.2 Hz, 1H, HCN), 3.10–3.0 (m, 2H), 2.20–2.13 (m, 1H), 2.11
(br s,1H, NH),1.98–1.97 (m,1H),1.76–1.66 (m, 2H). 13C NMR/DEPT
d:
198.13 (CO), 174.83 (HNCO), 139.33 (C), 138.77 (C), 133.32 (CH),
132.50 (CH), 132.27 (CH), 129.88 (2ꢁCH), 128.17 (2ꢁCH), 125.35 (C),
122.10 (CH), 121.57 (CH), 61.67 (HCN), 47.26 (CH2), 30.96 (CH2),

2722
L. Leger´en, D. Dom´ınguez / Tetrahedron 66 (2010) 2718–2722
chromatography (SiO2, 95:5 CH2Cl2/MeOH) afforded yellow oil 8a
(CH), 68.13 (C5), 59.99 (C11a), 54.00 (C3), 34.31 (NMe), 25.26 (C2),
22.54 (C1).
20
(1.07 g, 98%): [
(C]O), 1669 (C]O), 1597, 1397, 1164 cmꢂ1. 1H NMR (the splitting of
signals corresponding to the NMe and the -hydrogen of the pro-
a
]
þ8.8 (c 1, CH2Cl2), >99% ee. IR (KBr) 2975, 1694
D
(Trans-3a): 0% ee 1H NMR
d: 7.39–7.35 (m, 3H), 7.33–7.28
a
(m, 2H), 7.25 (td, J¼7.8 and 1.5 Hz, 1H), 7.16 (dd, J¼7.8 and 1.2 Hz,
1H), 6.98 (td, J¼7.7 and 1.2 Hz, 1H), 6.59 (dd, J¼7.7 and 1.5 Hz, 1H,),
4.53 (s, 1H, H5), 3.69 (d, J¼7.1 Hz, 1H, H11a), 3.48 (s, 3H, NMe),
2.95–2.91 (m, 1H, H3b), 2.43–2.39 (m, 1H, H1), 2.33 (q, J¼8.7 Hz, 1H,
line unit indicates the presence of the two rotamers of the tertiary
amide in a 60:40 ratio, with further splitting due to the coexistence
of rotamers of the carbamate)
d: 7.88 (d, J¼7.9 Hz, 0.4H), 7.84–7.81
(m, 1H), 7.80 (dd, J¼8.2 and 1.1 Hz, 1.2H), 7.60 (d, J¼7.6 Hz, 1H),
7.56–7.51 (m, 1.2H), 7.46 (d, J¼7.7 Hz, 1.4H), 7.40–7.39 (m, 1.6H),
7.37–7.31 (m, 1H), 7.25 (d, J¼7.9 Hz, 0.2H), 4.64 (dd, J¼8.6 and
2.7 Hz, 0.2H) and 4.57 (dd, J¼8.6 and 2.9 Hz, 0.2H), 4.40 (dd, J¼8.2
and 4.5 Hz, 0.1H) and 4.37 (dd, J¼8.2 and 3.8 Hz, 0.5H), 3.60–3.52
(m, 0.6H), 3.46–3.41 (m, 0.2H), 3.40 (s, 0.6H, NMe) and 3.39 (s, 0.6H,
NMe), 3.31–3.27 (m, 0.8H), 3.23–3.16 (m, 0.2H), 3.10 (s, 0.3H, NMe)
and 3.09 (s, 1.5H, NMe), 2.04–1.93 (m. 1.8H), 1.75–1.68 (m, 0.8H),
1.67–1.60 (m,1.6H),1.54 (s,1.6H, CH3), 1.46 (s, 4.6H, CH3) and 1.40 (s,
H3a), 2.07–2.00 (m,1H, H1),1.84–1.73 (m, 2H, H2). 13C NMR
d: 170.03
(CO), 143.01 (C), 139.87 (C), 136.06 (C), 128.52 (2ꢁCH), 128.36 (CH),
128.26 (2ꢁCH), 128.02 (CH), 127.45 (CH), 125.44 (CH), 121.15 (CH),
66.00 (C5H), 61.11 (C11aH), 51.92 (C3H2), 34.70 (NMe), 24.10 (C1H2),
23.28 (C2H2). MS (CI), m/z (%): 293 ([MþH]þ, 100). HRMS (CI) calcd
for C19H21N2O [(MþH)þ]: 293.1654, found: 293.1646.
Acknowledgements
2.8H, CH3). 13C NMR/DEPT
d: 195.83, 194.88 and 194.43 (CO), 172.79,
Support of this work by the Spanish Ministry of Science and
Innovation (through Project CTQ2008-03253) and by the Xunta de
Galicia (through Project 2007/XA084, and Pre-doctoral grant to L.L.)
is gratefully acknowledged.
172.06, 171.97, and 171.76, (NCO), 154.16, 153.78 and 153.50 (NCOO),
142.31 and 142.13 (C), 137.24 and 136.84 (C), 136.65, 136.16 and
135.95 (C),133.45, 132.98 and 132.83 (CH), 131.88,131.73 and 131.38
(CH), 131.03 and 130.69 (CH), 130.02, 129.65, 129.27, and 129.04
(2ꢁCH), 128.44, 128.20 and 128.08 (2ꢁCH), 127.47, 127.24 and
127.01 (CH), 126.52 and 126.32 (CH), 79.73, 79.20, 79.12 and 78.89
(C), 56.84, 56.55 and 56.41 (CH), 47.05, 46.40 and 46.18 (CH2), 38.86
and 37.92 (NMe), 30.50 and 29.73 (CH2), 28.63, 28.41, 28.30 and
28.23 (3ꢁCH3), 24.07, 23.62, 23.10 and 22.83 (CH2). MS (CI) (m/z):
409 ([MþH]þ, 16), 309 (100). HRMS (CI) calcd for C24H29N2O4
[(MþH)þ] 409.2127, found: 409.2130.
Supplementary data
Experimental procedures and characterization data for all
reported compounds, including X-ray diffraction analysis data of
compounds 3a (CCDC 748705) and 3b (CCDC 748704), and copies of
the 1H NMR and 13C NMR/DEPT spectra for all new compounds
associated with this article can be found in the online version, at
doi:10.1016/j.tet.2010.01.109.
3.5.2. N-(2-Benzoylphenyl)-N-methyl-L-prolinamide (9a). To a solu-
tion of 8a (1.07 g, 2.63 mmol) in dichloromethane (15 mL) was
added trifluoroacetic acid (5 mL) and the mixture was stirred at rt
for 30 min. The solution was concentrated in vacuum, and the
residue was dissolved in dichloromethane and treated with 5 N
NaOH aqueous solution until pH 9–11. The mixture was extracted
with CH2Cl2 (3ꢁ10 mL), washed with brine (3ꢁ10 mL), dried with
References and notes
1. (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.;
Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti, V.
J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J.
J. Med. Chem. 1988, 31, 2235–2246; (b) Horton, D. A.; Bourne, G. T.; Smythe, M. L.
Chem. Rev. 2003, 103, 893–930; (c) Ferrini, S.; Ponticelli, F.; Taddei, M. J. Org.
Chem. 2006, 71, 9217–9220.
2. Kamal, A.; Ramana, A. V.; Reddy, K. S.; Ramana, K. V.; Hari Babu, A.; Prasad, B. R.
Tetrahedron Lett. 2004, 45, 8187–8190.
3. Wright, W.B. Jr. U.S. Patent 3,947,408, 1976; Chem. Abstr. 1976, 85, 46771.
4. Mishra, J. K.; Garg, P.; Dohare, P.; Kumar, A.; Siddiqi, M. I.; Ray, M.; Panda, G.
Bioorg. Med. Chem. Lett. 2007, 17, 1326–1331.
anhydrous Na2SO4, filtered and the solvent evaporated to afford
20
oil 9a (726 mg, 90%): [
a
]
ꢂ6.2 (c 1, CH2Cl2), >99% ee. Due to its
D
high instability was used in the next step without further
purification.
5. Puvvada, M. S.; Forrow, S. A.; Hartley, J. A.; Stephenson, P.; Gibson, I.; Jenkins,
T. C.; Thurston, D. E. Biochemistry 1997, 36, 2478–2484.
´
´
´
6. Legeren, L.; Gomez, E.; Domınguez, D. Tetrahedron Lett. 2008, 49, 7174–7177.
7. The strong preference of secondary amides for Z conformation around the
amide bond is attributed to its placing the largest groups anti to each other. See:
Eliel, E. L.; Wilen, S. H.; Doyle, M. P. Basic Organic Stereochemistry; John Wiley &
Sons: New York, NY, 2001; p 392.
3.6. Typical procedure for cyclodehydration of tertiary
amides 9
3.6.1. (5R*, 11aS*)- and (5S*, 11aS*)-10-Methyl-5-phenyl-1,2,3,5,10,11a-
hexahydro-11H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one (3a). NaBH4
(267 mg, 7.06 mmol) was added portion-wise to a stirred solution
of 9a (726 mg, 2.35 mmol) in EtOH (15 mL). After 10 min at rt, the
resulting clear solution was cooled to 0 ꢀC in an ice bath, 10%
aqueous HCl was added until pH¼6, and the solvent was removed
under reduced pressure. The residue was portioned between
CH2Cl2 and brine and the organic layer was washed with water,
dried with anhydrous Na2SO4, filtered and concentrated to afford
a crude 25:75 mixture of both diastereomers of 3a. Flash chroma-
tography on silica gel (SiO2, 95:5 CH2Cl2/MeOH) provided less polar
cis-3a (56 mg, 8%) and trans-3a: (378 mg, 55%) as two yellow solids.
8. For some representative examples, see the following and references therein: (a)
For radical cyclizations: Tamura, O.; Matsukida, H.; Toyao, A.; Takeda, Y.;
Ishibashi, H. J. Org. Chem. 2002, 67, 5537–5545; (b) For intramolecular Diels–
Alder cycloadditions: Padwa, A.; Brodney, M. A.; Lynch, S. M.; Rashatasakhon,
P.; Wang, Q.; Zhang, H. J. Org. Chem. 2004, 69, 3735–3745; (c) For intramolecular
SNAr: Abrous, L.; Jokiel, P. A.; Friedrich, S. R.; Hynes, J., Jr.; Smith, A. B., III;
Hirschmann, R. J. Org. Chem. 2004, 69, 280–302.
9. All the trans/cis diastereomeric ratios mentioned in this paper were de-
termined by integration of well-resolved 1H NMR signals of the crude reaction
mixtures. Relative stereochemistry was in all cases assigned on the basis of
NOE and/or X-ray crystallography (3a and 3b). For the whole series 3a–e, the
H5 singlet of the trans isomer lies at higher field (4.86–4.48 ppm) than that of
the cis isomer (5.27–4.93 ppm).
10. InthecaseofN-methylanilides, astrongpreferencefortheEconformationhasbeen
shown by both X-ray crystallography (Itai, A.; Toriumi, Y.; Saito, S.; Kagechika, H.;
Shudo, K. J. Am. Chem. Soc.1992,114,10649–10650) and theorethical studies (Saito,
S.; Toriumi, Y.; Tomioka, N.; Itai, A. J. Org. Chem. 1995, 60, 4715–4720).
11. The elimination of the hydroxyl may be due to the greater donating ability of
the tertiary amide nitrogen and would generate a reactive aza- ortho-xylylene,
(Cis-3a): mp: 180–182 ꢀC; 0% ee. IR (neat) 1673,1572,1492 cmꢂ1
.
1H NMR
d
: 7.36 (td, J¼7.2 and 1.5 Hz, 1H), 7.35 (td, J¼7.7 and 1.8 Hz,
1H), 7.28–7.21 (m, 5H), 7.15–7.12 (m, 2H), 5.02 (s, 1H, H5), 3.21 (td,
J¼8.0 and 2.1 Hz, 1H, H3a), 3.14 (t, J¼7.2 Hz, 1H, H11a), 2.81 (s, 3H,
NMe), 2.73 (q, J¼8.2 Hz, 1H, H3b), 2.52–2.46 (m, 1H, H2b), 2.06–1.98
for
a review on which see: Wojciechowski, K. Eur. J. Org. Chem. 2001,
3587–3605.
12. Like the spontaneous cyclization, the racemization, which appears to take place
in the unisolated amidobenzhydrol intermediate 10a, may be due to the for-
mation of an aza-o-xylylene, which would increase the racemization-
(m, 1H, H1a), 1.82–1.75 (m, 2H, H2a, H1b).13C NMR/DEPT
d: 169.69
(CO), 144.10 (C), 141.98 (C), 135.09 (C), 130.64 (CH), 128.40 (CH),
127.94 (2ꢁCH), 126.41 (CH), 126.18 (2ꢁCH), 125.92 (CH), 123.82
proneness of what was formerly the proline a-hydrogen.