An efficient asymmetric synthesis of 2-substituted 1,4-benzodiazepin-3-one as a potential molecular scaffold

Article abstract of DOI:10.1002/ejoc.200400682

2-Substituted 1,4-benzodiazepine-2-one compounds (9-12) were obtained by a highly diastereoselective alkylation of a seven-membered ring benzolactam (8) in the presence of (R)-pbenylglydnol as a chiral inductor. The corresponding add derivative (16) affor

Full text of DOI:10.1002/ejoc.200400682

FULL PAPER
An Efficient Asymmetric Synthesis of 2-Substituted 1,4-Benzodiazepin-3-one as
a Potential Molecular Scaffold
Nuria Cabedo,[a] Xavier Pannecoucke,*[a] and Jean-Charles Quirion*[a]
Keywords: Alkylation / Chiral auxiliaries / Lactams / Peptidomimetics
2-Substituted 1,4-benzodiazepine-2-one compounds (9–12)
were obtained by a highly diastereoselective alkylation of a
seven-membered ring benzolactam (8) in the presence of (R)-
phenylglycinol as a chiral inductor. The corresponding acid
derivative (16) afforded a conformationally constrained struc-
ture suitable for preparing peptidomimetic analogues useful
as a novel molecular scaffold. After cleavage of the chiral
appendage this approach might also lead efficiently to enan-
tiomerically pure 2-substituted benzodiazepines (15).
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
1,4-Benzodiazepine (1,4-BDZ) compounds have been ex-
tensively investigated owing to their important biological
properties, and in recent times their structure has been
widely used as a “molecular scaffold”. Indeed, several of
these nitrogen-containing heterocycles have been identified
as antitumour antibiotics (DC-81),[1] anti-HIV[2] and
antithrombotic[3] (Lotrafiban, SB-214857) agents, in ad-
dition to their well-known anxiolytic,[4] sedative[5] and anti-
convulsant[6] activities. Moreover, because of both their
structural motifs and physicochemical properties, this struc-
ture has been considered among novel non-peptide peptido-
mimetics. Indeed, 1,4-BDZ can act as a mimic of peptide
secondary structures such as γ- and β-turns.[3,7]
As a consequence, numerous stereocontrolled synthetic
approaches to 1,4-benzodiazepine compounds have been
developed. Reductive cyclisation of amino aldehydes,[8]
amino thioacetals,[9] cyclisation via isatoic anhydride by
condensation with an amino acid derivative,[10] coupling of
NCAs (N-carboxy α-amino acid anhydrides) with anthra-
nilic acid derivatives,[11] condensation between 2-amino-
benzophenone and α-substituted glycine derivatives[7a,12] or
use of a chiral auxiliary attached to the 1,4-benzodiazepine
structure,[10b,13,14] figure among the most important strate-
gies. In some cases, an enzymatic resolution of the dia-
stereomeric racemates of the final benzodiazepine has been
successfully employed by using an immobilized form of
Candida antarctica B lipase.[15] However, relatively little
work has been done on the asymmetric synthesis of 2-sub-
stituted-1,4-benzodiazepines (Scheme 1).[16]
Scheme 1. Access to 2-substituted 1,4-benzodiazepine.
By targeting the synthesis of nitrogen-containing com-
pounds of biological interest we are developing new syn-
thetic methods based upon the diastereoselective alkylation
of lactams using a chiral auxiliary from the chiral pool:
phenylglycinol[17–19] or 2,3,4,6-di-O-isopropylidene-2-keto-
l-gulonic acid (DIGA).[20] In connection with our work on
diastereoselective alkylations, we wish to report here a novel
route towards the asymmetric synthesis of 1,4-benzodiazep-
ine core derivatives. A chiral benzolactam derived from
commercially available (R)-phenylglycinol was easily alkyl-
ated at the C-2 position by 1,4-stereoinduction of the enol-
ate derivative of lactam (R)-9. This strategy led us to pre-
pare several 2-substituted 1,4-BDZ in good to high dia-
stereoselectivities and chemical yields. Further transforma-
[a] INSA et Université de Rouen, IRCOF, UMR CNRS 6014,
1 rue Tesnière, 76131 Mont Saint-Aignan, France
Fax: +33-235-52-2959
E-mail: quirion@ircof.insa-rouen.fr
1590
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400682
Eur. J. Org. Chem. 2005, 1590–1596

An Efficient Asymmetric Synthesis of 2-Substituted 1,4-Benzodiazepin-3-one
FULL PAPER
tions could lead to chiral diamine or dipeptide analogues This could be detected when a combination of the following
(Scheme 1).
reaction conditions was present: a temperature higher
than –78 °C and the presence of additives.
Finally, the best results were obtained using nBuLi as
base, performing the deprotonation at –40 °C, adding an
excess of electrophile at –78 °C, then allowing the alkylation
to proceed at –40 °C for 6 h. Under these conditions, meth-
ylated lactam 9 was obtained in 83% yield as a 98:2 ratio
of two isomers. After chromatography, the major isomer
was isolated as a pure compound. The absolute configura-
tion of the newly created stereogenic centre of the major
isomer [(2R,12R)-9] was unambiguously determined by sin-
gle-crystal X-ray diffraction analysis (Figure 1). The stereo-
chemistry of the newly created centre can be explained by
the approach of the electrophile to the opposite side of the
N–Li bond[17] (Figure 2).
Results and Discussion
Prior to the diastereoselective alkylation step, we had to
prepare the enantiopure 1,4-benzodiazepine-3-one 8 from
(R)-phenylglycinol (Scheme 2).
This approach began with a reductive amination of alde-
hyde 1, using standard methods, to introduce the chiral in-
ductor. The nitro group was then readily reduced under hy-
drogenation conditions without cleavage of the chiral auxil-
iary. This absence of reactivity of such secondary benzyl
derivatives of amino alcohols has already been observed
previously.[18] Selective protection of both the primary
alcohol with tBuPh2SiCl and the aromatic amine with
Boc2O in the presence of NaH furnished the secondary ben-
zylamine 6. The resulting amine was then treated with bro-
moacetyl bromide[21] to give the N-acylated derivative 7. In-
tramolecular cyclisation followed by silyl group deprotec-
tion was performed in a one-pot procedure, using NaH
(3 equiv.) in DMF, to afford the seven-membered ring lac-
tam 8 in 57% yield and 16% overall yield from 1.
Our first experiments were conducted with two equiva-
lents of lithiated base (nBuLi, sBuLi, tBuLi). The formation
of the corresponding enolate was observed at –78 °C with
tBuLi, but a higher temperature (–40 °C) was necessary to
obtain complete deprotonation when nBuLi or sBuLi was
used. Contrary to what has been observed in some other
series,[17–20] the addition of lithium salts (LiBr, LiCl) did
not improve the chemical yields. Furthermore, addition of
HMPA led to a complex mixture of compounds. One of
these side products was the dialkylated product arising from
Figure 1. X-ray crystallographic structure and conformation of 2-
methylation at both the 2-position and the alcohol function. methyl-3-oxo-2,3,4,5-benzodiazepine derivative 9.
Scheme 2. Reagents and conditions: (a) (R)-phenylglycinol (2), MeOH, reflux, 3 h; (b) NaBH4, room temp., overnight (quant.); (c) H2
(1 atm)/10% Pd-C, EtOH, room temp. 18 h (83%); (d) tBuPh2SiCl, imidazole, and DMF, room temp., 18 h (72%); (e) i. 95% NaH, anh.
THF, 0 °C, 15 min; ii. Boc2O, 0 °C to room temp., overnight (66%); (f) ClCOCH2Br, NEt3, CH2Cl2, –20 °C to room temp., overnight
(71%); (g) 95% NaH 3 equiv., dry DMF, 0 °C to room temp. 3h30 min (57%).
Eur. J. Org. Chem. 2005, 1590–1596
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N. Cabedo, X. Pannecoucke, J.-C. Quirion
FULL PAPER
Figure 2. Rigid chelated enolate intermediate.
Under the above-mentioned conditions, different electro-
philes (alkyl or allyl) were introduced into the C-2 position
of the chiral benzodiazepine lactam 8. The results for the
preparation of compounds 10–12 are summarised in
Table 1. Diastereomeric excesses (de) were determined by
Scheme 3. Synthesis of chiral diamine 15. Reagents and conditions:
HPLC using an ODS column eluting with a CH3CN/H2O (a) TFA/CH2Cl2 (1:1), 0 °C to room temp., 2 h (90%); (b) LiAlH4,
room temp. to reflux, overnight (91%); (c) H2 (1 atm)/10% Pd-C,
(40:60) system containing 0.1% TFA.
5% HCl/EtOH, room temp., 8 h (65%).
Table 1. Diastereoselective alkylations.
A dipeptide mimic could also be obtained by simple oxi-
dation of the primary alcohol of compound 9 using Jones’
reagent to afford the corresponding acid 16 in 68.5% yield
(Scheme 4).[17] In the course of the synthesis of compound
16, no epimerisation was detected by 1H NMR spec-
troscopy or HPLC analysis. The 2-substituted 1,4-benzodi-
azepine-3-one acids are constrained dipeptide analogues
that could promote particular secondary structures of pep-
tides, such as β- or γ-turns. It should be noted that other
amino acid derived β-amino alcohols can act as chiral aux-
iliaries leading to a large variety of dipeptide analogues.
En-
try
RX
Product
Yield [%]
de [%][a]
1
2
3
4
MeI
BnBr
CH2=CHCH2I
BrCH2CO2tBu
9
85
63
63
40
95
93
86
96
10
11
12
Scheme 4. Synthesis of dipeptide analogue 16. Reagents and condi-
tions: (a) Jones’ reagent, acetone, 0 °C, 30 min (68.5%).
[a] Determined by HPLC analysis.
The expected alkylation reactions α to the amide took
place in good to excellent yield. Nevertheless, a lower yield
In summary, chiral benzolactam 8 has been prepared in
was obtained with tert-butylbromoacetate as an electrophile good yield by standard reactions from 2-nitrobenzaldehyde
(entry 4). The absolute configuration of the 2-alkyl or 2- and with (R)-phenylglycinol as the source of chirality. We
allyl compounds was assigned by analogy to the (2R,12R)- have proposed an easy methodology to provide 2-substi-
9 derivative.
tuted 1,4-benzodiazepines with good stereoselectivities and
The preparation of the chiral diamine from the chiral chemical yields by alkylation with various electrophiles.
benzodiazepine lactam could be achieved by a three-step Cleavage of the chiral appendage provides a conformation-
procedure: N-Boc-deprotection in acidic medium (TFA/ ally restricted enantiopure diamine [(+)-15] whose use as a
CH2Cl2), followed by reduction of the carbonyl group with possible chiral ligand in future reactions might be possible.
LiAlH4 and finally cleavage of the chiral appendage by The corresponding acid derivative of 1,4-benzodiazepin-3-
catalytic hydrogenation in the presence of 5% HCl etha- one [(+)-16] could be used as a molecular scaffold and its
nolic solution. Following that procedure, the (2R,12R)-9 incorporation into a peptide sequence would give us more
benzolactam was transformed into the seven-membered information about the effect of this peptidomimetic on the
ring diamine 15 without detectable racemisation (chiral GC peptide conformation. These studies are currently in pro-
analysis; Scheme 3).
gress.
1592
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 1590–1596

An Efficient Asymmetric Synthesis of 2-Substituted 1,4-Benzodiazepin-3-one
FULL PAPER
8.26 mmol) was added dropwise to
a solution of 4 (2.0 g,
Experimental Section
8.26 mmol) and imidazole (0.55 g, 8.26 mmol) in dry DMF
(25 mL). The mixture was then stirred at room temperature for 18 h
under argon atmosphere, and H2O (15 mL) was added. The reac-
tion mixture was extracted with CH2Cl2 (3×20 mL) and the or-
ganic layer was washed with 10% aq. NaHCO3 (2×15 mL) solu-
tion, brine (2×15 mL) and H2O (2×15 mL), dried with MgSO4
and the solvent was evaporated to give a residue. The residue was
purified by flash column chromatography (cyclohexane/AcOEt,
92:8) to provide 2.86 g of compound 5 as a yellow oil (5.95 mmol,
General: Solvents were purified by conventional methods prior to
use. TLC was performed on Merck 60F-250 silica gel plates and
column chromatography with silica gel SI 60 (230–240 mesh). Melt-
ing points were measured on a Kofler apparatus and are uncor-
rected. Elemental analyses were carried out on a Carlo–Erba EA
1100 analyser. NMR spectra were recorded on a Bruker DPX 300
spectrometer operating at 300 MHz for H and 75.4 MHz for 13C
1
NMR. This probe is equipped with pulsed-field (z) gradients.
Chemical shifts (δ) are expressed in ppm relative to TMS for 1H
and 13C nuclei; coupling constants (J) are given in Hertz (Hz). Op-
tical rotations were measured using a sodium lamp at ambient tem-
perature and are reported as follows: [α]λ = αobs/c (c in g/100 mL,
l-dm cell). IR spectra were recorded using KBr pellets or NaCl
plates, and only partial data are reported. Mass spectra were ob-
tained on an HP5890 spectrometer (electronic impact 70 eV).
72%). α]2D0 = –48 (c = 1, EtOH). IR (neat): νmax = 3435 cm–1, 3320
˜
(NH), 3069, 2930, 2857, 1618, 1495, 1460, 1427, 1112, 823, 743,
701. 1H NMR (CDCl3, 300 MHz): δ = 7.63–7.53 (m, 4 H, Ar),
7.45–7.23 (m, 11 H, Ar), 7.08 (t, J = 7.5 Hz, 1 H, H-5), 6.98 (d, J
= 7.17 Hz, 1 H, H-3), 6.71–6.63 (m, 2 H, H-4 and H-6), 4.50 (br.,
3 H, NH, NH2), 3.80–3.70 (m, 4 H, CH2OH, CH2aNH and CH-
Ph), 3.56 (d, J = 12.51 Hz, 1 H, CH2bNH), 1.02 (s, 9 H, 3×CH3)
ppm. 13C NMR (CDCl3, 75 MHz): δ = 146.7 and 140.9 (C), 135.74
and 135.69 (CH, Ar), 133.56 and 133.41 (C), 129.96, 129.87,
129.79, 128.53, 128.39, 127.83, 127.79, 127.76 and 127.59 (CH, Ar),
124.50 (C), 117.96 and 115.80 (CH, Ar), 68.60 (CH2O), 64.87 (CH-
Ph), 50.83 (CH2NH), 26.99 (3×CH3), 19.34 (C) ppm.
Diastereomeric excesses (de) were determined by HPLC using an
ODS (4.6×250 mm; 5 μm) column eluting with a CH3CN/H2O
(40:60) system containing 0.1% TFA.
(R)-2-(2-Nitrobenzylamino)-2-phenylethanol (3): A solution of 2-ni-
trobenzaldehyde (1; 4.85 g, 32.12 mmol, 1.1 equiv.) and (R)-phenyl-
glycinol (2, 4.0 g, 29.20 mmol) in methanol (70 mL) was heated at
reflux for 3 h. The mixture was cooled to 0 °C and NaBH4 (2.2 g,
58.4 mmol) was added portionwise over 30 min. The reaction mix-
ture was allowed to warm to room temperature and stirred over-
night. Then, 10% aq. NaHCO3 solution (20 mL) was slowly added
at 0 °C. The reaction mixture was extracted with CH2Cl2
(3×75 mL), and the organic layers were combined, washed with
brine (3×50 mL) and H2O (3×50 mL), dried with MgSO4 and
then concentrated under reduced pressure to give 2-(2-nitroben-
zylamino)-2-phenylethanol (3, 8.2 g, quant.) as a pale-yellow pow-
der which was used without further purification. [α]2D0 = –47 (c =
tert-Butyl
2-{[(R)-2-(tert-Butyldiphenylsilyloxy)-1-phenylethyl-
amino]methyl}phenylcarbamate (6): A solution of 5 (5, 3.3 g,
6.87 mmol) in THF (10 mL) was cooled to 0 °C under argon and
then a suspension of 95% NaH (0.177 g, 7 mmol) in THF (5 mL)
was added dropwise. After stirring at the same temperature for
15 min, a solution of Boc2O (1.5 g, 6.87 mmol) in THF (5 mL) was
added to the reaction mixture. The resulting suspension was stirred
at room temperature for 18 h, cooled to 0 °C and quenched by
careful addition of H2O (5 mL). The mixture was warmed to room
temperature and poured into CH2Cl2. The organic layer was sepa-
rated, washed successively with aq. NaHCO3 saturated solution
(3×20 mL), H2O (2×20 mL) and brine (2×20 mL), dried with
MgSO4 and filtered. The solvent was removed under reduced pres-
sure and the residue was purified by flash column chromatography
(cyclohexane/ AcOEt, 97:3) to obtain 2.63 g of compound 6 as a
0.85, EtOH). IR (neat): ν
= 3319 cm–1, 3062, 2918, 2854, 1608,
˜
max
1578, 1524, 1494, 1453, 1429, 1342, 1108, 1060, 922, 860, 790, 765,
1
748, 702. H NMR (CDCl3, 300 MHz): δ = 7.90 (d, J = 7.92 Hz,
1 H, H-6), 7.60–7.20 (m, 8 H, Ar), 4.02 (d, J = 14.2 Hz, 1 H,
CH2aNH), 3.85 (d, J = 14.2 Hz, 1 H, CH2bNH), 3.80 (m, 1 H,
CH2aOH), 3.68 (dd, J = 10.87, 4.08 Hz, 1 H, CH2bOH), 3.55 (m,
1 H, CH–Ph), 2.55 (br., 2 H, NH, OH) ppm. 13C NMR (CDCl3,
75 MHz) 149.28, 140.10 and 135.32 (C), 133.17, 131.71, 128.80,
128.22, 127.85, 127.38 and 124.82 (CH, Ar), 69.66 (CH2OH), 67.05
(CH–Ph), 48.69 (CH2NH) ppm.
yellow oil (66%). [α]2D0 = –25 (c = 1, EtOH). IR (neat): ν
=
˜
max
3293 cm–1 (NH), 2976, 2934, 2852, 1724 (N–CO), 1589, 1516, 1452,
1
1366, 1233, 1156, 1127, 1111, 1045, 1023, 830, 773, 704. H NMR
(CDCl3, 300 MHz): δ = 9.62 (br., 1 H, NHBoc), 8.02 (d, J =
8.19 Hz, 1 H, H-6), 7.65–7.55 (m, 4 H, Ar), 7.49–7.23 (m, 12 H,
Ar), 7.05 (d, J = 7.42 Hz, 1 H, H-3), 6.92 (t, J = 7.42 Hz, 1 H, H-
4), 3.77–3.68 (m, 4 H, CH2OH, CH2aNH and CH–Ph), 3.50 (d, J
= 12.8 Hz, 1 H, CH2bNH), 2.40 (br., 1 H, NH), 1.56 (s, 9 H, Boc),
1.02 (s, 9 H, 3×CH3) ppm. 13C NMR (CDCl3, 75 MHz): δ =
153.34 (CO, Boc), 139.90 and 139.22 (C), 135.70 and 135.65 (CH,
Ar), 133.46 and 133.25 (C), 129.96, 129.90, 129.47, 128.67, 128.40,
127.90, 127.89 and 127.82 (CH, Ar), 127.03 (C), 122.22 and 119.62
(CH, Ar), 79.66 (C), 68.61 (CH2O), 65.71 (CH–Ph), 51.68
(CH2NH), 28.65 (3×CH3, Boc), 27.02 (3×CH3), 19.33 (C).
(R)-2-(2-Aminobenzylamino)-2-phenylethanol (4): A suspension of
2-(2-nitrobenzylamino)-2-phenylethanol (3; 8.2 g, 30.15 mmol) and
10% Pd/C (150 mg) in absolute ethanol (150 mL) was hydrogenated
for 18 h at room temperature and 1 atm pressure until TLC indi-
cated that reduction was complete. Then, the reaction mixture was
filtered through Celite to remove the catalyst and the filtrate was
concentrated under reduced pressure. The residue was purified by
flash column chromatography (cyclohexane/AcOEt, 50:50) to af-
ford 6.0 g of compound 4 as a yellow oil (25.0 mmol, 83%). [α]2D0
tert-Butyl
2-[{2-Bromo-N-[(R)-2-(tert-butyldiphenylsilyloxy)-1-
= –126 (c = 1, EtOH). IR (neat): ν
= 3334 cm–1, 3027, 2841,
˜
max
phenylethyl]acetamido}methyl]phenylcarbamate (7): A solution of
amine 6 (1 g, 1.72 mmol) and triethylamine (0.6 mL, 4.3 mmol) in
anhydrous CH2Cl2 (8 mL) was cooled to –20 °C under argon. Bro-
moacetyl bromide (0.225 mL, 2.59 mmol) was dissolved in CH2Cl2
(5 mL) and was added dropwise over 15 min with stirring. The re-
action mixture was warmed to room temperature and stirred over-
night. Then, the mixture was washed with 5% aq. NaHCO3 solu-
tion (3×20 mL), and brine (3×20 mL), dried with MgSO4, filtered
and the solvents evaporated in vacuo. The crude product was puri-
1621, 1583, 1495, 1455, 1314, 1282, 1200, 1101, 1048, 752, 703. 1H
NMR (CDCl3, 300 MHz): δ = 7.40–7.25 (m, 5 H, Ar), 7.10 (t, J =
7.42 Hz, 1 H, H-5), 6.95 (d, J = 7.17 Hz, 1 H, H-3), 6.68 (m, 2 H,
H-4 and H-6), 3.90–3.50 (m, 5 H, CH2NH, CH-Ph and CH2OH),
3.45 (br., 4 H, NH, NH2, OH) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 146.0 and 140.3 (C), 129.95, 128.56, 128.33, 127.56 and 127.28
(CH, Ar), 123.88 (C), 117.99 and 115.81 (CH, Ar), 66.63 (CH2OH),
64.08 (CH-Ph), 49.83 (CH2NH) ppm.
2-{[(R)-2-(tert-Butyldiphenylsilyloxy)-1-phenylethylamino]methyl}- fied by flash column chromatography (cyclohexane/AcOEt, 96:4)
phenylamine (5): tert-Butylchlorodiphenylsilane (2.16 mL, to afford 856 mg of compound 7 as a yellow oil (1.22 mmol, 71%).
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N. Cabedo, X. Pannecoucke, J.-C. Quirion
FULL PAPER
[α]2D0 = –64 (c = 1, EtOH). IR (neat): νmax = 3298 cm–1, 3071, 2932,
4.25 (m, 1 H, CH2OH), 4.2–4.1 (m, 1 H, CH2OHЈ), 3.75 (d, J =
13.9 Hz, 1 H, H-5Ј), 3.10 (br., 1 H, OH), 1.40 (m, 9 H, Boc), 1.30
(d, J = 7.17 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3, 75 MHz): δ
= 173.2 (3-CO), 153.9 (CO, Boc), 139.4, 135.3 and 134.8 (C), 129.3,
˜
2858, 1726, 1639, 1591, 1523, 1450, 1366, 1300, 1240, 1159, 1113,
1
1051, 823, 741, 702. H NMR (CDCl3, 300 MHz): δ = 10.10 (br.,
1 H, NHBoc), 7.90 (d, J = 8.19 Hz, 1 H, H-6), 7.65–7.55 (m, 4 H,
Ar), 7.49–7.23 (m, 12 H, Ar), 7.05 (d, J = 7.42 Hz, 1 H, H-3), 6.92 128.8, 128.5, 128.2, 128.1 and 127.4 (CH-Ar), 62.07 (CH2OH), 59.0
(t, J = 7.42 Hz, 1 H, H-4), 4.30–3.70 (m, 7 H, CH2OH, CH2NH, (CH-Ph), 44.6 (5-CH2), 28.4 (3×CH3), 20.1 (CH3) ppm. LSIMS:
CH2Br and CH-Ph), 3.50 (d, J = 12.8 Hz, 1 H, CH2bNH), 1.56 (s,
m/z 419 [M + 23]+, 397 [MH]+, 341, 221. C23H28N2O4 (396.48):
calcd. C 69.67, H 7.12, N 7.07; found C 69.44, H 7.36, N 7.14.
9 H, Boc), 1.02 (s, 9 H, 3×CH3) ppm. LSIMS: m/z = 701 [M]+
tert-Butyl
2,3,4,5-Tetrahydro-4-[(R)-2-hydroxy-1-phenylethyl]-3- (R)-tert-Butyl 2-Benzyl-2,3,4,5-tetrahydro-4-[(R)-2-hydroxy-1-phen-
oxobenzo[e][1,4]diazepine-1-carboxylate (8): Compound 7 (0.5 g,
0.713 mmol) was dissolved in dry DMF (12 mL) and cooled to 0 °C
with an ice bath. Then, a suspension of 95% NaH (0.56 g,
2,2 mmol) dissolved in dry DMF (5 mL) was added dropwise over
10 min. The reaction mixture was allowed to warm to room tem-
perature and stirred for 3.5 h under argon. The mixture was cooled
again to 0 °C and quenched by careful addition of H2O (2 mL).
The resulting solution was then diluted with AcOEt (200 mL) and
washed successively with 10% aq. NaHCO3 solution (3×100 mL),
H2O (3×100 mL) and brine (3×100 mL). The organic layer was
dried with MgSO4, filtered and concentrated under vacuum to give
a crude which was purified by flash column chromatography (cy-
clohexane/AcOEt, 88:12) to afford deprotected benzodiazepine 8
ylethyl)-3-oxobenzo[e][1,4]diazepine-1-carboxylate (10): The synthe-
sis was performed following the general procedure. After work up
and purification, we obtained 62 mg of 2-benzylbenzodiazepine 10
(0.132 mmol, 63%) as a pale-yellow oil. [α]2D0 = –64 (c = 1, EtOH).
IR (neat): νmax = 3420 cm–1, 3008, 2979, 2931, 1702 (N–CO), 1614,
˜
1497, 1455, 1431, 1387, 1368, 1326, 1255, 1216, 1158, 1117, 1048,
1025, 943, 852, 756, 700. 1H NMR (CDCl3, 300 MHz): δ = 7.4–7.1
(m, 12 H, Ar), 7.02 (t, J = 7.2 Hz, 1 H, H-8), 6.21–6.12 (m, 2 H,
H-9 and CH-Ph), 5.89 (br., 1 H, H-2), 4.49 (d, J = 14.1 Hz, 1 H,
H-5), 4.40–4.30 (m, 1 H, CH2OH), 4.29–4.15 (m, 1 H, CH2OHЈ),
3.78 (d, J = 14.1 Hz, 1 H, H-5Ј), 3.58 (d, J = 15.4 Hz, 1 H, CH2Ph),
3.10 (br., 1 H, OH), 2.52 (q, 1 H, H-2), 2.40 (m, 1 H, CH2PhЈ)
1.40–1.10 (m, 9 H, Boc) ppm. 13C NMR (CDCl3, 75 MHz): δ =
172.3 (3-CO), 154.1 (CO, Boc), 139.0, 129.6 and 128.9 (C), 128.6,
(155 mg, 0.406 mmol, 57%) as a white solid. M.p. 159 °C. [α]2D0
=
–127 (c = 1, EtOH). IR (neat): νmax = 3393 cm–1, 2924, 2853, 1702, 126.6, 126.3 and 128.2 (CH-Ar), 62.2 (CH2OH), 59.3 (CH-Ph),
˜
1618, 1497, 1459, 1368, 1248, 1158, 1047, 1027, 963, 865, 758, 701. 44.7 (5-CH2), 39.07 (CH2Ph), 28.1 (3×CH3, Boc) ppm. LSIMS:
1H NMR (CDCl3, 300 MHz): δ = 7.4–7.2 (m, 7 H), 7.09 (t, J =
m/z = 416 [MH – tBu]+. C29H32N2O4 (472.57): calcd. C 73.70,
7.4 Hz, 1 H, H-8), 6.56 (d, J = 7.4 Hz, 1 H, H-9), 6.05 (dd, J = H 6.83, N 5.93; found C 68.98, H 7.09, N 6.28.
5.4, 7.9 Hz, 1 H, CH–Ph), 4.80 (d, J = 18.2 Hz, 1 H, H-2), 4.43 (d,
(R)-tert-Butyl 2-Allyl-2,3,4,5-tetrahydro-4-[(R)-2-hydroxy-1-phenyl-
J = 18.2 Hz, 1 H, H-2Ј), 4.26 (d, J = 14.3 Hz, 1 H, H-5), 4.3–4.1
(m, 2 H, CH2OH), 4.01 (d, J = 14.3 Hz, 1 H, H-5Ј), 1.41 (s, 9 H,
Boc) ppm. 13C NMR (CDCl3, 75 MHz): δ = 169.6 (3-CO), 154.0
(CO, Boc), 141.7, 136.6 and 134.8 (C), 129.0, 128.8, 127.4 and
127.3 (CH-Ar), 81.6 (C), 61.7 (CH2OH), 59.0 (CH-Ph), 52.5 (2-
CH2), 44.7 (5-CH2), 28.3 (3×CH3, Boc) ppm. MS (FAB): m/z =
383 [MH]+. C22H26N2O4 (382.45): calcd. C 69.09, H 6.85, N 7.32;
found C 69.13, H 6.93, N 7.34.
ethyl]-3-oxobenzo[e][1,4]diazepine-1-carboxylate (11): The title com-
pound was obtained according to the general procedure. After
work up, the crude was purified by column chromatography on
silica gel (cyclohexane/AcOEt, 70:30) to give 56 mg of 2-allylbenzo-
diazepine (11, 0.133 mmol, 63.5%) as a pale-yellow oil. [α]2D0
=
–166 (c = 1, EtOH). IR (neat): νmax = 3422 cm–1, 2978, 2931, 1702
˜
(CO), 1615, 1497, 1458, 1386, 1368, 1325, 1254, 1162, 1047, 1024,
1
921, 854, 757, 700. H NMR (CDCl3, 300 MHz): δ = 7.4–7.2 (m,
General Procedure for Diastereoselective Alkylation at the 2-Position
to Provide a 2-Substituted 1,4-Benzodiazepine (9–12): Benzodiazep-
ine 8 (1 equiv.) was dissolved in anhydrous THF (2 mL) under ar-
gon, cooled in a dry ice/acetone bath to –78 °C, and treated slowly
with nBuLi in THF solution (2 equiv.). Then, the resulting orange
solution was warmed to –40 °C for 15 min and cooled again to –
78 °C to introduce the appropriate alkyl or allyl halide (1.5 equiv.).
The reaction mixture was stirred for between 6 h and overnight at –
40 °C depending on the electrophile. The reaction was quenched
by addition of aq. NH4Cl saturated solution (2 mL), H2O was
added (3 mL) and extracted with CH2Cl2 (3×5 mL). The organic
layer was washed with brine (2×5 mL) and H2O (2×5 mL), fil-
tered, dried with MgSO4 and the solvents evaporated in vacuo. The
crude products were purified by column chromatography on silica
gel (cyclohexane/AcOEt, 70:30). The absolute configuration of 9
was established by single-crystal X-ray analysis.
7 H, Ar), 7.02–6.96 (m, 1 H, H-8), 6.15 (d, J = 7.41 Hz, 1 H, H-
9), 6.10 (dd, J = 8.0, 5.5 Hz, 1 H, CH-Ph), 5.91–5.78 (m, 1 H, CH2-
CH=CH2), 5.57 (q, 1 H, H-2), 5.17–5.06 (m, 2 H, CH2–CH=CH2),
4.50 (d, J = 13.9 Hz, 1 H, H-5), 4.33–4.10 (m, 2 H, CH2OH), 3.76
(d, J = 13.9 Hz, 1 H, H-5Ј), 2.89 (d, J = 14.1 Hz, 1 H, CH2–
CH=CH2), 2.55 (br., 1 H, OH), 2.10–1.96 (m, 1 H, CH2–
CH=CH2Ј) 1.37 (m, 9 H, Boc) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 171.98 (3-CO), 154.39 (CO, Boc), 139.18, 136.58 and 135.29
(C), 134.99 (CH2-CH=CH2), 129.63, 128.86, 128.56, 128.27 and
128.07 (CH-Ar), 118.0 (CH2-CH=CH2), 62.11 (CH2OH), 59.12
(CH-Ph), 44.57 (CH2-5), 37.62 (CH2-CH=CH2), 28.32 (3×CH3,
Boc) ppm. LSIMS: m/z = 445 [M + 23]+, 366 [MH – tBu]+, 246.
C25H30N2O4 (422.52): calcd. C 71.07, H 7.16, N 6.63; found C
70.91, H 7.39, N 6.61.
(R)-tert-Butyl 2-[(tert-Butoxycarbonyl)methyl]-2,3,4,5-tetrahydro-4-
[(R)-2-hydroxy-1-phenylethyl)-3-oxobenzo[e][1,4]diazepine-1-carbox-
(R)-tert-Butyl 2,3,4,5-Tetrahydro-4-[(R)-2-hydroxy-1-phenylethyl]-2- ylate (12): The synthesis was performed following the general pro-
methyl-3-oxobenzo[e][1,4]diazepine-1-carboxylate (9): The synthesis
was performed following the general procedure. After work up and
purification, we obtained 68.7 mg of 2-methylbenzodiazepine 9
cedure. After work up and purification, we obtained 40 mg of
benzodiazepine 12 (0.084 mmol, 40%) as a pale-yellow oil. [α]2D0
= –96 (c = 1, EtOH). IR (neat): νmax = 3428 cm–1, 2978, 2931, 1707
˜
(0.173 mmol, 83%). [α]2D0 = –186.3 (c = 1, EtOH). IR (neat): ν
(CO), 1629, 1497, 1458, 1389, 1368, 1323, 1257, 1154, 1049, 1027,
946, 847, 758, 700. 1H NMR (CDCl3, 300 MHz): δ = 7.35–7.20 (m,
7 H, Ar), 7.03 (t, J = 7.0 Hz, 1 H, H-8), 6.30–6.15 (m, 1 H, H-9),
˜
max
= 3383 cm–1, 2978, 2935, 1697 (CO), 1601, 1499, 1475, 1458, 1432,
1
1391, 1368, 1326, 1258, 1164, 1126, 1095, 1057, 847, 761, 701. H
NMR (CDCl3, 300 MHz): δ = 7.4–7.1 (m, 7 H), 7.01 (m, 1 H, H- 6.05–6.00 (m, 1 H, CH–Ph), 5.90–5.65 (m, 1 H, H-2), 4.47 (d, J =
8), 6.18 (d, J = 7.2 Hz, 1 H, H-9), 6.08 (dd, J = 5.4, 8.2 Hz, 1 H,
CH–Ph), 5.47 (br., 1 H, H-2), 4.49 (d, J = 13.9 Hz, 1 H, H-5), 4.29–
14.07 Hz, 1 H, H-5), 4.40–4.10 (m, 2 H, CH2OH), 3.78 (d, J =
14.07 Hz, 1 H, H-5Ј), 3.15–2.85 (m, 1 H, CH2COOtBu), 2.32 (br.,
1594
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 1590–1596

An Efficient Asymmetric Synthesis of 2-Substituted 1,4-Benzodiazepin-3-one
FULL PAPER
1 H, OH), 2.30–2.15 (m, 1 H, CH2COOtBu), 1.48 (s, 9 H, 3×CH3), (R)-2,3,4,5-Tetrahydro-2-methyl-1H-benzo[e][1,4]diazepine (15): The
1.34 (q, 9 H, Boc) ppm. 13C NMR (CDCl3, 75 MHz): δ = 171.15
(3-CO), 169.44 (CO2tBu), 153.75 (CO, Boc), 138.93, 136.44 and
amine 14 (150 mg, 0.532 mmol) was dissolved in 5% ethanolic HCl
solution (25 mL) in the presence of 10% Pd/C (64 mg) and the
135.17 (C), 129.44–127.80 (9×CH-Ar), 80.90 (C), 61.84 (CH2OH), mixture was hydrogenated at atmospheric pressure for 48 h. The
59.45 (CH-Ph), 58.10 (2-CH), 44.84 (CH2-5), 39.51 (CH2CO), catalyst was then filtered off, and the filtrate was partially evapo-
28.17 (3×CH3), 28.02 (3×CH3, Boc) ppm. LSIMS: m/z = 518 [M –
rated, diluted with AcOEt and made basic with aqueous 10 %
1 + 23] +, 440 [MH – tBu]+, 383 [MH – 2tBu]+, 366 [M – tBu – NH4OH solution. The mixture was extracted with AcOEt
OtBu]+. C28H36N2O6 (496.59): calcd. C 67.72, H 7.31, N 5.64;
found C 68.02, H 7.86, N 5.79.
(3×20 mL), the combined organic layers were dried with MgSO4,
filtered and the solvent was removed in vacuo. The crude product
was purified by silica gel column chromatography (CH2Cl2/MeOH,
90:10) to obtain 56 mg of diamine 15 as a pale-brown oil
(R)-1,2,4,5-Tetrahydro-4-[(R)-2-hydroxy-1-phenylethyl]-2-methyl-
benzo[e][1,4]diazepin-3-one (13): 2-Methylated benzodiazepine 9
(380 mg, 0.96 mmol) was dissolved in TFA/CH2Cl2 solution
(20 mL, 1:1) at 0 °C under argon. The reaction mixture was stirred
for 2 h at room temperature and then quenched with aqueous 10 n
NaOH solution (10 mL). The mixture was extracted with AcOEt
(3×20 mL), the organic layers were combined and washed success-
ively with brine (3×25 mL), H2O (3×25 mL), filtered, and concen-
trated under reduced pressure. The crude was purified by column
chromatography (CH2Cl2/AcOEt, 40:60) to afford 254 mg of N-
deprotected benzodiazepine 13 (0.86 mmol, 90%) as a yellow oil.
(0.345 mmol, 65%). [α]2D0 = +52 (c = 1, EtOH). IR (neat): ν
=
˜
max
3400 cm–1, 2977, 2900, 1646, 1453, 1410, 1087, 1047, 880, 668. H
NMR (CDCl3, 300 MHz): δ = 7.12–7.09 (m, 2 H, H-6 and H-8),
6.86–6.75 (m, 2 H, H-9 and H-7), 4.58 (br., 2 H, NH), 4.02 (d, J
= 14.46 Hz, 1 H, H-5), 3.80 (d, J = 14.46 Hz, 1 H, H-5Ј), 3.15–
3.01 (m, 2 H, H-3 and H-2), 2.65 (dd, J = 13.18, 9.61 Hz, 1 H, H-
3Ј), 1.18 (d, J = 6.39 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3,
75 MHz): δ = 148.6 (C), 130.2, 130.0 and 128.4 (CH-Ar), 121.2
(C), 119.6 (CH-Ar), 57.1 (3-CH2), 54.1 (2-CH), 52.9 (5-CH2), 20.6
(CH3). MS: m/z = 162 [M]+, 142, 118 (100). C10H14N2 (162.23):
calcd. C 74.03, H 8.70, N 17.27; found C 73.72, H 8.96, N 16.89.
1
[α]2D0 = –27.5 (c = 1, EtOH). IR (neat): ν
= 3566 cm–1, 3480,
˜
max
3352, 2982, 2936, 1654 (3-CO), 1645, 1609, 1583, 1494, 1456, 1328,
1262, 1219, 1157, 1122, 1065, 1047, 850, 743, 696. 1H NMR
(CDCl3, 300 MHz): δ = 7.14 (s, 5 H), 6.94–6.90 (m, 1 H, H-8), 6.43
(d, J = 7.9 Hz, 1 H, H-6), 6.34–6.26 (m, 1 H, H-7), 6.11 (d, J =
7.17 Hz, 1 H, H-9), 5.84 (dd, J = 8.13, 5.12 Hz, 1 H, CH–Ph), 5.20
(d, J = 16.5 Hz, 1 H, H-5), 4.82 (q, J = 6.39 Hz, 1 H, H-2), 4.20–
4.10 (m, 4 H, CH2OH, OH, NH), 3.77 (d, J = 16.5 Hz, 1 H, H-
5Ј), 1.44 (d, J = 6.39 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3,
75 MHz): δ = 173.4 (3-CO), 145.1 and 136.8 (C), 129.2, 128.4,
128.2, 128.0 and 127.7 (CH-Ar), 119.6 (C), 117.7 and 116.2 (CH-
Ar), 61.7 (CH2OH), 58.9 (CH-Ph), 50.3 (2-CH), 47.5 (5-CH2), 17.2
(CH3) ppm. LSIMS: m/z = 278 [M – H2O] +, 131. C18H20N2O2
(296.36): calcd. C 72.95, H 6.80, N 9.45; found C 73.18, H 6.91, N
9.48.
(R)-2-[(R)-1-(tert-Butoxycarbonyl)-2,3-dihydro-2-methyl-3-oxo-1H-
benzo[e][1,4]diazepin-4(5H)-yl]-2-phenylacetic Acid (16): The 2-
methylbenzodiazepine 9 (45 mg, 0.114 mmol) was dissolved in ace-
tone (1 mL) and cooled to 0 °C with an ice-water bath. The solu-
tion was treated with freshly prepared Jones’ reagent (2.7 g of CrO3
+ 7 mL of water + 2.3 mL of concd. H2SO4; 44 μL, 1.1 equiv.), and
stirred for 30 min at 0 °C. 2-Propanol (1 mL) was then added and
the mixture was stirred for 30 min more. H2O was added (10 mL)
and the aqueous phase was extracted with AcOEt (2×10 mL). The
organic layers were combined, washed with water, (2×10 mL),
brine (2×10 mL), dried with Na2SO4 and concentrated under re-
duced pressure. The crude was purified by silica gel column
chromatography (cyclohexane/AcOEt/acetic acid, 70:30:0.5) to ob-
tain 32 mg of the acid 16 as a colourless oil (0.078 mmol, 68.5%).
[α]2D0 = –155 (c = 1, EtOH). IR (neat): ν
= 3453 cm–1, 2979,
˜
max
(R)-2-[(R)-2,3-Dihydro-2-methyl-1H-benzo[e][1,4]diazepin-4(5H)-
yl]-2-phenylethanol (14): Lactam 13 (153 mg, 0. 517 mmol) was dis-
solved in anhydrous THF (15 mL), stirred at room temperature
under argon and carefully treated with LiAlH4 (88 mg, 2.32 mmol).
The reaction mixture was heated to reflux overnight and then co-
oled to 0 °C, whereupon a solution of concentrated NH4OH (1 mL)
in THF (6 mL) was added dropwise. The suspension was stirred at
room temperature for 1 h, diluted with H2O (10 mL) and extracted
with AcOEt (3×15 mL). The combined organic layers were washed
with brine (2×15 mL), filtered, dried with MgSO4 and the solvent
evaporated off. The crude was purified by column chromatography
(CH2Cl2/MeOH, 98:2) to afford 133 mg of the benzodiazepine 14
(0.47 mmol, 91%) as a colourless oil. [α]2D0 = +56 (c = 0.84, EtOH).
2930, 1744 (CO2 H), 1706 (1-NCO), 1638 (3-CON), 1498, 1459,
1389, 1324, 1255, 1208, 1165, 1124, 1092, 1048, 924, 856, 759, 738,
702. 1H NMR (CDCl3, 300 MHz): δ = 7.50–6.95 (m, 9 H, Ar), 6.68
(s, 1 H, CH–Ph), 6.14 (br., 1 H, CH-9), 5.55 (br., 1 H, H-2), 4.74
(d, J = 14.58 Hz, 1 H, H-5), 3.85 (d, J = 14.58 Hz, 1 H, H-5Ј), 1.38
(s, 9 H, Boc), 1.31 (d, J = 7.41 Hz, 3 H, CH3) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 173.80 (CO2 H), 172.50 (3-CO), 153.87 (CO,
Boc), 138.90, 135.30 and 133.98 (C), 129.34, 129.13, 128.81, 128.67,
128.0, 127.58 and 127.20 (CH–Ar), 81.12 (C), 61.46 (CH–Ph),
56.14 (2-CH), 45.49 (5-CH2), 28.12 (3×CH3), 19.52 (CH3) ppm.
MS-CI: m/z = 411 [MH]+, 355 [MH – tBu]+. C23H26N2O5 (410.46):
calcd. C 67.30, H 6.38, N 6.82; found C 67.82, H 6.89, N 6.66.
IR (neat): ν
= 3323 cm–1, 2925, 2859, 1604, 1483, 1453, 1360,
˜
max
1327, 1294, 1262, 1166, 1069, 1026, 966, 893, 866, 767, 707. 1H
NMR (CDCl3, 300 MHz): δ = 7.40–7.30 (m, 6 H, Ar), 7.15–7.09
(m, 1 H, H-8), 6.90–6.85 (m, 1 H, H-7), 6.76–6.73 (m, 1 H, H-9),
4.05–3.80 (m, 4 H, CH-Ph, CH2OH and H-5), 3.50 (d, J =
14.07 Hz, 1 H, H-5), 3.24–3.18 (m, 1 H, H-2), 2.87 (d, J = 12.58 Hz,
1 H, H-3), 2.63 (dd, J = 12.58, 9.36 Hz, 1 H, H-3Ј), 1.12 (d, J =
6.66 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3, 75 MHz): δ = 148.62
and 137.43 (C), 130.50 (CH-Ar), 128.94 (C), 128.54, 128.44, 128.04,
and 127.85 (CH-Ar), 120.88 (CH-7), 118.99 (CH-9), 67.89 (CH-
Ph), 62.63 (CH2-3), 61.61 (CH2OH), 55.28 (CH2-5), 51.42 (CH-2),
20.86 (CH3) ppm. LSIMS: m/z = 282 [M]+, 120 [MH – CHPh –
CH2OH]+, 145. C18H22N2O (282.38): calcd. C 76.56, H 7.85, N
9.92; found C 76.84, H 8.26, N 10.23.
Acknowledgment
The authors want to thank the Fundacion Ana y Jose Royo and
the region Haute-Normandie for financial support (postdoctoral
fellowship to N. C.).
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Eur. J. Org. Chem. 2005, 1590–1596
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1595

N. Cabedo, X. Pannecoucke, J.-C. Quirion
FULL PAPER
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