Developments in Meyers' lactamization methodology: En route to Bi(hetero)aryl structures with defined axial chirality

Article abstract of DOI:10.1021/jo401259w

Highly atroposelective Meyers' lactamization promoted by pivalic acid under microwave irradiation is reported which allows the construction of nonracemic substituted-dibenzo(di)azepine derivatives through a center to axial chirality transfer principle, controlling the otherwise configurationally labile biaryl axis. This approach provides a straightforward entry to enantioenriched analogues of biorelevant architectures.

Full text of DOI:10.1021/jo401259w

Note
pubs.acs.org/joc
Developments in Meyers’ Lactamization Methodology: En Route to
Bi(hetero)aryl Structures with Defined Axial Chirality
Svetlana Postikova,† Mohamad Sabbah,† Daniel Wightman,† Ich Tuan Nguyen,† Morgane Sanselme,‡
Thierry Besson,† Jean-Francois Briere,*,† Sylvain Oudeyer,† and Vincent Levacher*,†
̧
̀
†Normandie Univ, COBRA, UMR 6014 et FR 3038; Univ Rouen; INSA Rouen; CNRS, IRCOF, 1 rue Tesnier
̀
e, 76821 Mont Saint
Aignan Cedex, France
‡Laboratoire SMS − Unite
de cristallogenese IRCOF, 1 rue Tesniere, 76821 Mont Saint Aignan Cedex, France
́ ̀ ̀
S
* Supporting Information
ABSTRACT: Highly atroposelective Meyers’ lactamization promoted
by pivalic acid under microwave irradiation is reported which allows the
construction of nonracemic substituted-dibenzo(di)azepine derivatives
through a center to axial chirality transfer principle, controlling the
otherwise configurationally labile biaryl axis. This approach provides a
straightforward entry to enantioenriched analogues of biorelevant
architectures.
mong the privileged biaryl architectures in pharmaceutical
ingredients,1 the dibenzazepine and dibenzodiazepine
derivatives of type 1 occupy a significant place (Figure 1).
datin F (1c) and homologues belong to naturally occurring
quinazolinone alkaloids with a large array of biological
activities.8 Their stereoselective construction is mainly based
on amino acid precursors following a chiral pool strategy. On
the other hand, Baudoin and co-workers described an original
and enantioselective synthesis of a 5-methyl-6,7-dihydro-5H-
dibenzo[c,e]azepine 1d, analogue of allocolchicine, manifesting
an aR chiral axis as a direct consequence of the C-5
pseudoequatorial position adopted by the methyl group
connected to a R stereogenic center.9,10 Actually, the synthesis
of enantiopure dibenzo(dia)zepines of type 1 via diastereose-
lective or enantioselective methodologies is not common
despite the benefit of such skeletons for the elaboration of
axially chiral ligands or biorelevant compounds.4 In that
context, the pioneered development of nonracemic 5,7-
dimethyl-6,7-dihydro-5H-dibenzo[c,e]azepine as a chiral lithium
A
Figure 1. Dibenzo(di)azepine derivatives.
The −(CH2NR2CHR1−) bridge not only affords opportunities
for structure/activity modulation but belongs to a seven-
membered ring whose conformation dictates both the dihedral
angle and the absolute configuration of the biaryl axis.
Consequently, a substituent, either pseudoequatorial or
pseudoaxial, at the α-position of the nitrogen atom may lead
to a central/axial chirality communication establishing a well-
defined 3D-topology (Figure 1),2,3 a crucial feature for the
design of either catalysts or atropoisomeric bioligands.4 For
instance, along with the large family of benzodiazepines as
therapeutics targeting central nervous system disorders, the
racemic phenyl-substituted pyrrolobenzodiazepine 1a and
benzyl-substituted homologue 1b displayed promising anti-
fungal and antinociceptive activities, respectively.5−7 Circum-
amide base precursor by Kundig is noteworthy.11 Recently, a
̈
larger array of 5-substituted dibenzazepines was described by
Page and co-workers through a chiral auxiliary-based approach.
Thus, a diastereoselective addition reaction of Grignard
reagents to an azepinium precursor was achieved.12
A few years ago, the team of Wallace13 and our group14
developed independently a Meyers’ lactamization process
leading to axially chiral 7,5-fused lactams 3 with high
diastereomeric excesses from biaryl precursors 2 (Scheme
1).15 This alternative strategy allowed us to master in a one-step
Received: June 13, 2013
© XXXX American Chemical Society
A
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Note
of conversion, respectively, together with more than 96:4
diastereomeric ratio (entries 3 and 4). Interestingly, the
reaction efficacy increased as the pKa of the acid additive
increased to reach that of MeCO2H (entries 3 and 4), likely
preventing a complete protonation of the phenylglycinol chiral
auxiliary. Eventually, the best results were obtained with pivalic
acid giving 76% of conversion (entry 5). Then, attempts to use
pivalic acid catalytically resulted in a dramatic drop in the
reaction conversion (entries 6 and 7), while no significant
solvent effect was detected by using α,α,α-trifluorotoluene,
nevertheless renowned for being more efficient under micro-
wave activation (entry 6). However, 1.2 equiv of t-BuCO2H was
enough to furnish product 3b in 79% yield at higher
temperature (150 °C) with a high diastereomeric ratio, as
less than 4% of the minor isomer was detected in the 1H NMR
spectrum of the crude product (entry 8). This lack of dr
erosion in the presence of acid additives is welcome for keto-
ester 2c considering that keto-acid 2b affording 3b in one day
with significant lower diastereomeric excesses (see Scheme 1,
2b versus 2c). To our delight, more than 90% yield for 3b was
provided (entry 9) if the reaction was pursued during 2.5 h,
which constitutes a great advance with respect to the previously
required 5 days for the Dean−Stark reaction in refluxing
toluene for keto-ester 2c. This acid-promoted transformation
could also be carried out without solvent (entry 10), but these
reaction conditions were somewhat irreproducible with other
substrates. Moreover, although comparable reaction conver-
sions could be reached under a conventional preheated oil bath
at 150 °C (into sealed-vessel microwave reactors), crude
products could not be obtained as clean as with MW heating
and made the purification somewhat tricky (entry 11).17
Next, we sought to apply these efficient atroposelective
Meyers’ lactamization conditions to the elaboration of various
R1 substituted analogues of 3b and/or dibenzodiazepines
possessing a heterocyclic backbone. A cross-coupling approach,
between ketone- and ester-substituted (hetero)aromatics,
appeared to be an appealing synthetic pathway in terms of
convergence and structural diversity issues to access the
required bi(hetero)aryl structures. Nevertheless, in our hands,
known metal-catalyzed strategies were not easily extrapolated
to yield the corresponding products 2 (Scheme 2)14a,18 or 8
(Table 2)19 from different electron-poor coupling partners 4, 5,
and 7. As far as the biaryl architectures 2 are concerned
(Scheme 2), it was found that Fu’s Suzuki-type coupling
reaction employed efficient conditions for building methyl-,
ethyl-, and phenyl-substituted compounds 2c−e20 from readily
Scheme 1. Scope and Limitations in Atropoisomeric Meyers’
Lactamization
operation both the absolute configuration of the stereogenic
center bearing the pseudoaxial R1 substituent and the aR biaryl
axis configuration derived thereof, central to axial chirality
transfer in action indeed. Despite the promises of this approach
to control an otherwise configurationally unstable biaryl axis,
important bottlenecks remain: (1) limitation to R1 = Me and
few heterocyclic benzodiazepine derivatives probed besides
biaryl compounds, and (2) better diastereoselectivities (>95%
de) were usually obtained by means of keto-ester 2c instead of
aldehyde ester 2a or keto-carboxylic acid 2b (82−86% de)
starting materials, but several days of reaction were required to
reach completion.13,14 Herewith, we are pleased to report a
novel development of this original methodology allowing the
construction of dibenzo(di)azepine architectures flanked by
various R1 substituents requiring only few hours of reaction
upon the use of a suited coacid and microwave irradiation.
At the onset, we desired to take advantage of recent
investigations demonstrating a significant acceleration of
Meyers’ lactamization reactions upon microwave irradiation
(Table 1).16 Unfortunately, no transformation of the model
Table 1. Optimization of Meyers’ Lactamization under MW
a
(2c to 3b)
b,
c
d
entry
acid (equiv)
temp (°C) time (h) conv (%) yield (%)
1
110
110
110
110
110
110
110
150
150
150
150
1
0
2
PTSA (2)
1
0
3
PhCO2H (2)
1
17
4
MeCO2H (2)
t-BuCO2H (2)
t-BuCO2H (1.2)
t-BuCO2H (0.3)
t-BuCO2H (1.2)
t-BuCO2H (1.2)
t-BuCO2H (1.2)
t-BuCO2H (1.2)
1
53
5
1
76
e
6
1
56 (58)
24
7
1
8
1
91
79
92
93
88
9
2.5
2.5
2.5
99
f
10
11
93
g
91
a
Scheme 2. Suzuki Coupling Reaction toward Dibenzazepine
Precursors
Ketoester 2c (1 equiv, 0.5 M), phenylglycinol (1.2 equiv), acid (x
a
equiv), and toluene in a sealed tube under microwave irradiation.
b
1
>96:4 ratio of diastereomers for 3b measured by H NMR of the
c
crude product in all cases. 2c/3b ratio determined on the 1H NMR of
the crude product. Isolated yield after silica gel column chromatog-
raphy. In C6H5CF3 as solvent. Without solvent. In a sealed tube
d
e
f
g
with a conventional oil bath heating.
keto-ester 2c in the presence of phenylglycinol was observed at
110 °C as representative temperature in either toluene or
α,α,α-trifluorotoluene solutions (entry 1). Taking into account
that keto-acid 2b gave a faster reaction rate (Scheme 1, 2b
versus 2c), we investigated the use of acid additives. Although 2
equivalents of p-toluenesulfonic acid turned out to be
ineffective (entry 2), the lactamization process took place
within 1 h by means of benzoic or acetic acids with 17 and 53%
a
Key: (a) Pd2(dba)3 (1 mol %), HP(t-Bu)3·BF4(2.4 mol %), KF·2H2O
dioxane, 110 °C, 18−24 h; (b) NaOH, 88% yield from 2e.
B
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precursors (vide infra), the carboxylic acid 6 was also
synthesized by a smooth saponification transformation.
Table 2. Buchwald’s Cross-Coupling Reaction toward
Dibenzodiazepine Precursors
Subsequently, an Ullman cross-coupling methodology was
applied to construct heteroaryl−aryl architectures 8 through a
C−N bond formation (Table 2). After slight modifications, the
diamine-copper catalyzed Buchwald’s conditions furnished the
corresponding ester-functionalized 8a, acetyl-functionalized
pyrrole 8d (entries 1 and 4), and indole 8b (entry 2)
derivatives.19 Better results could be obtained in some cases
with ortho-iodinated compounds instead of bromo analogues
(entries 3 and 4). Once again, benzyl-functionalized ketone
derivative 7d did not furnish the corresponding product 8e
(entry 5), likely due to the sensitivity of the enolizable position.
Eventually, pyrrole 8e was synthesized from a commercially
available N-phenylpyrrole precursor by means of a Friedel−
Crafts reaction involving 2-phenylacetyl chloride, following a
literature procedure (see the Experimental Section).22
With these precursors in hands, we tackled the scope of
pivalic acid promoted Meyers’ lactamization reaction at 1 M
concentration (Scheme 3). These reaction conditions allowed
the straightforward formation of methyl (3b), ethyl (3c), and
benzyl lactam (3d) derivatives with excellent diastereomeric
ratios (>96:4). A complete conversion could be reached in
more difficult cases by increasing the reaction time from 2.5 to
5 h (see product 3c and 3d). The limitation was met with the
less reactive benzophenone 2e. Pleasingly, a smooth trans-
formation was achieved by means of the more reactive
carboxylic acid 6 (see Scheme 1 for discussion), but once
again, the presence of pivalic acid was also required. This
outcome points out the usefulness of these new pivalic acid-
promoted reaction conditions. In the heterocyclic series,
b
entry
R1
X
R2
yield (%)
1
2
3
4
5
Me
Br (5a)
Br (5a)
Br (5b)
I (5c)
OMe (pyrrole) (7a)
OMe (indole) (7b)
Me (pyrrole) (7c)
Me (pyrrole) (7c)
Bn (pyrrole) (7d)
78 (8a)
80 (8b)
0 (8c)
Me
OEt
OMe
OMe
71 (8d)
0 (8e)
I (5c)
a
Heterocycles (1 equiv), halogenated compound (2 equiv), CuI (5
mol %), trans-N,N′-Dimethylcyclohexane-1,2-diamine (20 mol %),
K2CO3 (2.1 equiv), toluene, 110 °C. Isolated yield after silica gel
b
column chromatography.
or commercially available ortho-halogenated ketone partners
5,21 even from chlorinated benzophenone 5e. Unfortunately,
ketone 5f flanked by a benzyl moiety underwent the cross-
coupling reaction with a modest 36% conversion into product
2f, whose isolation by column chromatography turned out to
be unsuccessful in our hands due to a complex crude mixture.
Alternatively, compound 2f was eventually synthesized upon
the direct Claisen condensation−reaction of phenyl acetic acid
to diphenic anhydride following an adapted Huang’s procedure
and the subsequent esterification reaction.21b In order to
investigate further the reactivity of these new Meyers’ lactam
Scheme 3. Meyers’ Lactamization toward Dibenzo(di)azepine Synthesis
C
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Ethyl 2′-Acetyl-1,1′-biphenyl-2-carboxylate (2c). 1-(2-
Bromophenyl)ethanone (135 μL, 1 mmol), 2-(ethoxycarbonyl)-
phenylboronic acid (213 mg, 1.1 mmol), Pd2(dba)3/[HP(t-Bu)3]BF4
(16.2 mg, 0.01 mmol of Pd2(dba)3), and KF·2H2O (311 mg, 3.3
mmol) gave 2c (petroleum ether/diethyl ether 4/1) as a colorless oil
(240 mg, 90%). The analytical data match the previously reported
NMR analysis.14a
methyl-substituted pyrrole 9a, trisubstituted indole 9b, and
pyridine 9c14a were easily synthesized with excellent yields and
diastereomeric ratios. On the other hand, the methyl- and
benzylpyrrole homologues 9d−e were obtained by starting
from the corresponding keto-esters 8d,e possessing ketone and
ester substituents at reverse positions with regard to pyrrole 9a.
Interestingly, the initial 86% conversion of 8d into 9d observed
after 5 h could be pushed up to completion by using 2
equivalents of pivalic acid. However, under the same
conditions, pyrrole 9e flanked by a benzyl moiety led to slow
reaction rates with 78% of conversion even after 10 h at 150 °C.
Eventually, the structures of compounds 9a, 9b, and 9d were
unequivocally proven by X-ray diffraction analyses.
Ethyl 2′-(1-Oxopropyl)[1,1′-biphenyl]-2-carboxylate (2d). 1-
(2-Bromophenyl)propan-1-one (533 mg, 2.5 mmol), 2-
(ethoxycarbonyl)phenylboronic acid (533 mg, 2.75 mmol),
Pd2(dba)3/[HP(t-Bu)3]BF4 (20 mg, 0.025 mmol of Pd2(dba)3), and
KF·2H2O (776 mg, 8.25 mmol) gave 2d (petroleum ether/diethyl
ether 4/1; Rf = 0.22) as a colorless oil (675 mg, 96%): IR (νmax/ cm−1)
1
2980, 1715, 1688, 1595, 1439, 1365, 1247, 1128, 1086, 946, 752; H
NMR (300 MHz; CDCl3) δ 7.98 (1H, dd, J = 7.7 Hz, 1.4 Hz), 7.66−
7.63 (1H, m), 7.54−7.39 (4H, m), 7.21−7.16 (2H, m), 4.07 (2H, q, J
= 7.2 Hz), 2.55−2.45 (2H, m), 1.02 (3H, t, J = 7.1 Hz), 0.93 (3H, t, J
= 7.3 Hz); 13C NMR (75.4 MHz; CDCl3) δ 205.5 (C), 167.4 (C),
142.4 (C), 140.7 (C), 139.2 (C), 131.5 (CH), 130.9 (CH), 130.38
(CH), 130.36 (CH), 130.28 (C), 130.23 (CH), 127.8 (CH), 127.7
(CH), 127.4 (CH), 60.9 (CH2), 34.9 (CH2), 13.8 (CH3), 8.4 (CH3);
HRMS (ESI+): calcd for C18H19O3 [M + H+] 283.1334, found
283.1331.
In order to probe the usefulness of these new compounds
(see Figure 1), we attempted the reductive cleavage of the
chiral auxiliary moiety of pyrrole derivatives 9a or 9d.
Interestingly, these precursors were obtained as a single
diastereomer after a simple recrystallization (Scheme 4). In
Scheme 4. Alane Reduction
Ethyl 2′-Benzoyl[1,1′-biphenyl]-2-carboxylate (2e). (2-
Chlorophenyl)(phenyl)methanone (217 mg, 1.0 mmol), 2-
(ethoxycarbonyl)phenylboronic acid (213 mg, 1.1 mmol),
Pd2(dba)3/[HP(t-Bu)3]BF4 (16 mg, 0.01 mmol of Pd2(dba)3), and
KF·2H2O (311 mg, 3.3 mmol) gave 2e (petroleum ether/diethyl ether
3/2; Rf = 0.39) as a yellowish oil (170 mg, 52%). The analytical data
match the previously reported NMR analysis.23
Methyl 2′-(Phenylacetyl)[1,1′-biphenyl]-2-carboxylate (2f).
To a suspension of diphenic anhydride (1.12 g, 5.0 mmol) and 2-
phenylacetic acid (681 mg, 5.0 mmol) in dry THF was added 2 M
solution of NaHMDS in THF (10 mL, 20 mmol) at −78 °C under Ar
atmosphere. The mixture was slowly warmed to 0 °C and stirred for 5
h. Then 10% HCl was added, and reaction mixture was stirred at room
temperature for 1 h. The aqueous phase was extracted with ethyl
acetate (3 × 50 mL), and the combined organic extracts were washed
with saturated aqueous NaCl, dried over MgSO4, and concentrated
under vacuum. The crude product was dissolved in MeOH (10 mL)
and toluene (36 mL), and a 2 M solution of trimethylsilyldiazo-
methane in hexane (5 mL, 10 mmol) was added at room temperature.
The resulting mixture was stirred for 2 h and concentrated under
vacuum. The residue was purified by chromatography on silica gel
(eluent: DCM; Rf = 0.68) to afford as colorless solid 2f (130 mg, 13%
over two steps): mp = 102−103 °C; IR (νmax/ cm−1) 1721, 1688,
1432, 1252, 1195, 1126,1086, 988, 750; 1H NMR (300 MHz; CDCl3)
δ 8.03−8.00 (1H, m), 7.68−7.65 (1H, m), 7.54−7.40 (4H, m), 7.27−
7.14 (5H, m), 7.01−6.98 (2H, m), 3.91 (1H, d, J = 15.6 Hz), 3.73
(1H, d, J = 15.7 Hz), 3.68 (3H, s); 13C NMR (75.4 MHz; CDCl3) δ
202.2 (C), 167.7 (C), 142.3 (C), 140.6 (C), 139.0 (C), 134.4 (C),
131.8 (CH), 131.2 (CH), 130.6 (CH), 130.5 (CH), 130.2 (CH),
129.9 (C), 129.6 (CH), 128.5 (CH), 128.1 (CH), 127.8 (CH), 127.5
(CH), 126.8 (CH), 52.1 (CH3), 48.4 (CH2); HRMS (ESI+) calcd for
C22H19O3 [M + H+] 331.1334, found 331.1346.
the past, Meyers demonstrated that alane reagents allowed
highly stereoselective reduction of the oxazolidine ring, as
nicely exemplified by Wallace on 5-methyl-6,7-dihydro-5H-
dibenzo[c,e]azepine compound.3b In our hands, the alane
reduction took place with high diastereoselectivity to give
products 10a and 10b (the minor isomer was hardly seen by 1H
NMR), differing from each other by the position of the methyl
substituents. Then, a simple palladium-catalyzed debenzylation
furnished the corresponding pyrroles 11a and 11b with high
yields over two steps. The pyrrole structures 11a,b appeared as
a single diastereomeric atropoisomer (with >99:1 ratio on the
1H NMR spectra in CDCl3) with likely pseudoequatorial
methyl substitutent.3b This constitutes an unprecented access
to enantioenriched dibenzodiazepines analogues incorporating
a pyrrole subunit.
In conclusion, we have demonstrated the ability of metal-
catalyzed cross-coupling processes followed by an original acid
promoted highly atroposelective Meyers’ lactamization to
provide a straightforward and unprecedented entry to non-
racemic substituted dibenzo(di)azepine derivatives, analogues
of biorelevant architectures.
2′-Benzoyl[1,1′-biphenyl]-2-carboxylic Acid (6).24 NaOH (10
M aqueous solution, 2.3 mL) was added dropwise to a solution of
ethyl 2′-benzoyl[1,1′-biphenyl]-2-carboxylate (2e) (770 mg, 2.33
mmol) in 12 mL of EtOH at 0 °C. The resulting mixture was stirred
for an additional 18 h at rt. The solvent was evaporated under reduced
pressure, and the residue was dissolved in 20 mL mixture of CH2Cl2/1
M HCl: 1/1. The water phase was extracted with CH2Cl2 (3 × 20
mL). Combined organic extracts were washed with brine, dried over
Na2SO4, and concentrated. The residue was purified by column
chromatography on silica gel (petroleum ether/diethyl ether 1/1; Rf =
0.18) to afford the colorless solid 6 (618 mg, 88%): mp = 50−52 °C;
EXPERIMENTAL SECTION
■
Representative Procedure for Suzuki Coupling Reaction.
Premixed catalyst Pd2(dba)3/[HP(t-Bu)3]BF4 (Pd/P(t-Bu)3 = 1:1.2; 1
mol % of Pd2(dba)3), 2-(ethoxycarbonyl)phenylboronic acid (1.1
equiv), and KF·2H2O (3.3 equiv) were added into a vial with a septum
cap and flushed with argon for 3 min. Dry dioxane and the aryl halide
(1.0 equiv, 0.5 M) were added, and the mixture was stirred at 110 °C
(oil bath temperature) for 18 h. The reaction was cooled to room
temperature, diluted with Et2O, and filtered through a plug of Celite.
The filtrate was concentrated under vacuum, and the residue was
purified by flash chromatography on silica gel.
1
IR (νmax/ cm−1) 1686, 1657, 1594, 1448, 1269, 1154, 929; H NMR
(300 MHz; CDCl3) δ 10.51 (br, 1H), 7.85−7.83 (1 H, m), 7.78−7.75
(2H, m), 7.57−7.45 (4H, m), 7.43−7.32 (5H, m), 7.17−7.15 (1H, m);
13C NMR (75.4 MHz; CDCl3) δ 199.1 (C), 171.2 (C), 141.0 (C),
D
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Note
140.8 (C), 137.8 (C), 137.0 (C), 133.6 (CH), 131.6 (CH), 130.9
(CH), 130.8 (CH), 130.7 (CH), 130.2 (CH), 129.1 (CH), 128.4
(CH), 127.9 (CH), 127.2 (CH) two carbon signals are overlapped with
other ones; HRMS (ESI−) calcd for C20H13O3 [M − H+] 301.0865,
found 301.0860.
1493, 1406, 1260, 1082; 1H NMR (300 MHz; CDCl3) δ 7.98 (1H, dd,
J = 7.6, 1.5 Hz), 7.55 (1H, td, J = 7.6, 1.7 Hz), 7.45 (1H, td, J = 7.6, 1.4
Hz), 7.30−7.20 (7H, m), 6.89 (1H, dd, J = 2.6, 1.7 Hz), 6.36 (1H, dd,
J = 4.0, 2.6 Hz), 4.07 (1H, d, J = 14.6 Hz), 4.00 (1H, d, J = 14.6 Hz),
3.51 (3H, s); 13C NMR (75 MHz; CDCl3) δ 187.0 (C), 165.4 (C),
141.0 (C), 135.4 (C), 132.5 (CH), 131.9 (C), 131.1 (CH), 130.8
(CH), 129.4 (2CH), 128.7 (CH), 128.5 (2CH), 128.1 (CH), 128 (C),
126.6 (CH), 119.7 (CH), 109.4 (CH), 52 (CH3), 45.69 (CH2);
HRMS (ESI+) calcd for C20H18NO3 [M + H+] 320.1287, found
320.1288.
Representative Procedure for Meyers’ Lactamization. A
solution of keto-ester 5 (1.0 equiv, 1 M), (R)-2-amino-2-phenyl-
ethanol (1.2 equiv), and pivalic acid (1.2 equiv) in toluene was placed
in a sealed microwave tube under argon and heated in a microwave at
150 °C for 2.5 to 5 h (80 W). The reaction mixture was cooled to
room temperature and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel. In all
cases, >96:4 diastereomeric ratios were measured on 1H NMR spectra
of the crude products.
(4bS,7R)-4b-Methyl-7-phenyl-6,7-dihydrodibenzo[c,e][1,3]-
oxazolo[3,2-a]azepin-9(4bH)-one 3b. Ethyl 2′-acetyl-1,1′-biphen-
yl-2-carboxylate (2c) (114 mg, 0.42 mmol), (R)-2-amino-2-phenyl-
ethanol (70 mg, 0.51 mmol), and pivalic acid (52 mg, 0.51 mmol) gave
3b (petroleum ether/diethyl ether 3/2; Rf = 0.43) after 2.5 h as a white
solid (138 mg, 95%, diastereomeric mixture of lactams 3c). The pure
major diastereomer could be isolated by column chromatography (134
mg, 92%). The analytical data match the previously reported NMR
analysis.14a
(4bS,7R)-4b-Ethyl-7-phenyl-6,7-dihydrodibenzo[c,e][1,3]-
oxazolo[3,2-a]azepin-9(4bH)-one (3c). Ethyl 2′-(1-oxopropyl)-
[1,1′-biphenyl]-2-carboxylate (2d) (482 mg, 1.7 mmol), (R)-2-
amino-2-phenylethanol (281 mg, 2.05 mmol), and pivalic acid (209
mg, 2.05 mmol) gave 3c (petroleum ether/diethyl ether: 3/2; Rf =
0.18) after 5 h as a white solid (548 mg, 90%, diastereomeric mixture
of lactams 3c). The pure major diastereomer could be isolated by
column chromatography (492 mg, 81%): white solid; mp = 102−104
°C; IR (νmax/ cm−1) 2877, 1632, 1446, 1396, 1290, 1174, 1082, 1041;
1H NMR (300 MHz; CDCl3) δ 7.86 (1H, dd, J = 7.7 Hz, 1.0 Hz,),
7.65−7.27 (12H, m), 5.47 (1H, d, J = 6.3 Hz), 4.40 (1H, dd, J = 8.7
Hz, 6.3 Hz), 4.30 (1H, dd, J = 8.7 Hz, 1.3 Hz), 1.84−1.71 (m, 2H),
0.64 (3H, t, J = 7.4 Hz); 13C NMR (75 MHz, CDCl3) δ 165.0 (C),
140.8 (C), 140.1 (C), 137.2 (C), 136.0 (C), 133.6 (C), 131.3 (CH),
130.9 (CH), 130.3 (CH), 128.83 (CH), 128.82 (CH), 128.6 (CH),
128.08 (CH), 128.06 (CH), 127.6 (CH), 127.3 (CH), 124.1 (CH),
96.6 (C), 70.8 (CH2), 61.6 (CH), 30.6 (CH2), 9.1 (CH3); HRMS
(ESI+) calcd for C24H21NO2 [M + H+] 356.1651, found 356.1649.
Characteristic peaks of the minor diastereomer: 1H NMR spectrum of
a 1/4 minor/major mixture of lactams 6b (300 MHz; CDCl3) δ 5.68
(1H, m), 4.89 (1H, dd, J = 8.8 Hz, 7.1 Hz), 4.37 (1H, dd, J = 8.8 Hz,
6.2 Hz), 1.07 (3H, t, J = 7.3 Hz).
(4bS,7R)-4b-Benzyl-7-phenyl-6,7-dihydrodibenzo[c,e][1,3]-
oxazolo[3,2-a]azepin-9(4bH)-one (3d). Methyl 2′-(phenylacetyl)-
[1,1′-biphenyl]-2-carboxylate (2f) (165 mg, 0.5 mmol), (R)-2-amino-
2-phenylethanol (82 mg, 0.6 mmol), and pivalic acid (102 mg, 1
mmol) gave 3d (petroleum ether/diethyl ether 3/2; Rf = 0.38) after 5
h as a white solid (173 mg, 83%, major diastereomer): mp =72−74
°C; IR (νmax/ cm−1) 2246, 1629, 1495, 1447, 1396, 1162, 1036, 905;
1H NMR (300 MHz; CDCl3) δ 8.00 (1H, m), 7.67−7.64 (3H, m),
7.62−7.51 (1H, m), 7.47−7.37 (2H, m), 7.34−7.29 (6H, m), 7.16−
7.06 (3H, m), 6.83−6.80 (2H, m), 5.45 (1H, dd, J = 6.4, 1.1 Hz), 4.42
(1H, dd, J = 8.7, 6.6 Hz), 4.30 (1H, dd, J = 8.7, 1.3 Hz), 3.07 (2H, s);
13C NMR (75 MHz, CDCl3) δ 165.1 (C), 140.6 (C), 140.3 (C), 137.3
(C), 135.8 (C), 135.2 (C),133.9 (C), 131.6 (CH), 130.7 (CH), 130.6
(CH), 130.4 (CH), 128.9 (CH), 128.8 (CH), 128.5 (CH), 128.3
(CH), 128.1 (CH), 127.8 (CH), 127.3 (CH), 127.0 (CH), 126.7
(CH), 123.9 (CH), 96.1 (C), 70.8 (CH2), 61.7 (CH), 43.0 (CH2);
HRMS (ESI+) calcd for C29H24NO2 [M + H+] 418.1807, found
418.1802.
Representative Procedure for the Synthesis of Compounds
8 by N-Arylation of Heterocycles. CuI (5 mol %), the heterocycle
(1.0 equiv), and base (2.1 equiv) were added into a reaction vessel
fitted with a rubber septum. The vessel was evacuated and backfilled
with argon. The aryl halide (2.0 equiv), trans-N,N′-dimethyl-1,2-
cyclohexanediamine ligand (20 mol %), and toluene were then
successively added under a stream of argon. The reaction tube was
quickly sealed, and the contents were stirred while heating in an oil
bath at 110 °C for 24−72 h. At ambient temperature, the mixture was
diluted with ethyl acetate, filtered through a plug of silica gel,
concentrated, and purified by column chromatography on silica gel.
Methyl 1-(2-Acetylphenyl)-1H-pyrrole-2-carboxylate (8a).
Methyl 2-pyrrolecarboxylate (1.0 g, 7.90 mmol), 1-(2-bromophenyl)-
1-ethanone (2.2 mL, 15.8 mmol), K2CO3 (2.2 g, 15.9 mmol), CuI (75
mg, 0.4 mmol), and ligand (255 μL, 1.58 mmol) in dry toluene (8 mL)
gave 8a (pentane/ethyl acetate: 3/1; Rf = 0.34) as a colorless viscous
oil (1.5 g, 78%): IR (νmax/ cm−1) 2950, 1706, 1685, 1489, 1436, 1264,
1112, 1091; 1H NMR (300 MHz; CDCl3) δ 7.73 (1 H, dd, J = 1.8, 7.4
Hz), 7.55−7.43 (2 H, m), 7.27 (1 H, dd, J = 1.7, 7.7 Hz), 7.11 (1 H,
dd, J = 1.8, 3.9 Hz), 6.86 (1 H, dd, J = 1.8, 2.6 Hz), 6.34 (1 H, dd, J =
2.6, 3.9 Hz), 3.69 (3 H, s), 1.99 (3 H, s); 13C NMR (75 MHz; CDCl3)
δ 200.0 (C), 160.9 (C), 138.6 (C), 137.3 (C), 131.8 (CH), 130.2
(CH), 128.9 (CH), 128.7 (CH), 128.6 (CH), 124.1 (C), 118.9 (CH),
110.2 (CH), 51.4 (CH3), 28.4 (CH3); HRMS (ESI+) calcd for
C14H14NO3 [M + H+] 244.0974, found 244. 0969.
Methyl 1-(2-Acetylphenyl)-1H-indole-2-carboxylate (8b).
Methyl 2-indolecarboxylate (25 mg, 0.14 mmol), 1-(2-iodophenyl)-
1-ethanone (40 μL, 0.28 mmol), K2CO3 (43 mg, 0.29 mmol), CuI (3
mg, 0.014 mmol), and ligand (10 μL, 0.028 mmol) in dry toluene
(0.56 mL) gave 8b (pentane/ether: 7/3; Rf = 0.19) as a colorless
viscous oil (33 mg, 80%): IR (νmax/ cm−1) 3059, 3002, 2952, 1712,
1
1684, 1453, 1260, 1216, 1181 cm−1; H NMR (300 MHz; CDCl3) δ
7.91 (1 H, dd, J = 1.8, 7.3 Hz), 7.79−7.73 (1 H, m), 7.71−7.55 (2 H,
m), 7.52 (1 H, d, J = 0.9 Hz), 7.35−7.15 (3 H, m), 6.95 (1 H, dd, J =
0.9, 8.3 Hz), 3.80 (3 H, s), 1.91 (3 H, s); 13C NMR (75 MHz; CDCl3)
δ 199.6 (C), 161.7 (C), 140.7 (C), 138.1 (C), 136.8 (C), 132.5 (CH),
129.8 (CH), 129.6 (CH), 128.9 (CH), 126.3 (2C), 126.2 (CH), 122.7
(CH), 121.7 (CH), 112.1 (CH), 111.2 (CH), 51.9 (CH3), 28.6
(CH3); HRMS (ESI+) calcd for C18H16NO3 [M + H+] 294.1126,
found 294. 1130.
Methyl 2-(2-Acetyl-1H-pyrrol-1-yl)benzoate (8d). 2-Acetylpyr-
role (25 mg, 0.23 mmol), 1-(2-iodophenyl)-1-ethanone (70 μL, 0.46
mmol), K2CO3 (136 mg, 0.48 mmol), CuI (3 mg, 0.013 mmol), and
ligand (8 μL, 0.093 mmol) in dry toluene (2 mL) gave 8d (pentane/
EtOAc 8/2; Rf = 0.28) as a colorless solid (40 mg, 71%): mp = 65−67
°C; IR (νmax/ cm−1) 3098, 2952, 1727, 1645, 1494, 1408, 1258, 1083;
1H NMR (300 MHz; CDCl3) δ 8.02 (1H, dd, J = 7.7, 1.6 Hz), 7.57
(1H, td, J = 7.6, 1.7 Hz), 7.48 (1H, td, J = 7.6, 1.4 Hz), 7.27 (1H, dd, J
= 7.7, 1.3 Hz), 7.09 (1H, dd, J = 4.0, 1.7 Hz), 6.87 (1H, dd, J = 2.6, 1.7
Hz), 6.34 (1H, dd, J = 4.0, 2.6 Hz), 3.66 (3 H, s), 2.38 (3 H, s); 13C
NMR (75 MHz; CDCl3) δ 187.2 (C), 165.3 (C), 141.1 (C), 132.4
(CH), 132.3 (C), 130.6 (CH), 130.5 (CH), 128.5 (CH), 128.1 (CH),
128.0 (C), 119.4 (CH), 109.2 (CH), 52.1 (CH3), 26.6 (CH3); HRMS
(ESI+) calcd for C14H14NO3 [M + H+] 244.0974, found 244.0964.
Methyl 2-(2-(2-Phenylacetyl)-1H-pyrrol-1-yl)benzoate (8e).
To a solution of phenylacetyl chloride (8.7 mL, 66.0 mmol) and BF3·
OEt2 (9 mL, 72.9 mmol) in 300 mL of dichloromethane under a
nitrogen atmosphere was added methyl 2-(1H-pyrrol-1-yl)benzoate
(3g, 14.9 mmol) at room temperature. The mixture was stirred for 20
h, quenched with ice/water solution, extracted with dichloromethane,
and evaporated. The two 3- and 5-regioisomers (3 g, 63%, ratio 1:1 by
NMR of the crude product) was separated by column chromatography
on silica gel (pentane/EtOAc 8/2; Rf = 0.24), and the title compound
was obtained after washing with ethanol as a pure white solid (1.5 g,
32%): mp = 78−80 °C ; IR (νmax/ cm−1) 3137, 2946, 1728, 1663,
(4bS,7R)-4b,7-Diphenyl-6,7-dihydrodibenzo[c,e][1,3]-
oxazolo[3,2-a]azepin-9(4bH)-one (3e). 2′-Benzoyl[1,1′-biphenyl]-
E
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Note
2-carboxylic acid (6) (101 mg, 0.33 mmol), (R)-2-amino-2-phenyl-
ethanol (55 mg, 0.4 mmol), and pivalic acid (41 mg, 0.4 mmol) gave
3e (petroleum ether/ethyl acetate 4/1; Rf = 0.26) after 5 h as a white
solid (101 mg, 75%, diastereomeric mixture of lactams 3e). The main
diastereomer was isolated by column chromatography. Major
diastereomer (96 mg, 71%): white solid; mp =255−257 °C; IR
(νmax/ cm−1) 2117, 1634, 1493, 1444, 1385, 1280, 1210, 1136, 1082,
1066; 1H NMR (300 MHz; CDCl3) δ 7.99−7.96 (1H, m), 7.75−7.73
(2H, m), 7.63−7.51 (4H, m), 7.44−7.33 (3H, m), 7.22−7.12 (2H, m),
7.10−6.89 (6H, m), 5.61 (1H, d, J = 5.6 Hz), 4.66 (1H, dd, J = 8.6 Hz,
6.5 Hz), 4.50 (1H, d, J = 8.8 Hz); 13C NMR (75.4 MHz; CDCl3) δ
165.7 (C), 141.1 (C), 140.2 (C), 138.8 (C), 137.2 (C), 136.6 (C),
134.5 (C), 131.0 (CH), 130,7 (CH), 129.3 (CH), 129.2 (CH), 129.0
(CH), 128.6 (CH), 128.4 (CH), 128.3 (CH), 128.1 (CH), 127.8
(CH), 127.6 (CH), 127.5 (CH), 127.4 (CH), 123.7 (CH), 97.0 (C),
72.1 (CH2), 61.7 (CH); HRMS (ESI+) calcd for C28H22NO2 [M +
H+] 404.1651, found 404.1642.
Methyl 2-(2-acetyl-1H-pyrrol-1-yl)benzoate (8d) (25 mg, 0.1
mmol), (R)-2-phenylglycinol (17 mg, 0.12 mmol) and pivalic acid
(21 mg, 0.2 mmol) gave 9d (pentane/EtOAc 7/3; Rf = 0.29) after 5 h
as a colorless oil (34 mg, 92%, diastereomeric mixture of lactams 9d).
The pure major diastereomer could be isolated by recrystallization
from absolute ethanol (24 mg, 72%): white solid; mp = 189−191 °C;
1
IR (νmax/ cm−1) 3109, 3036, 2895, 1630, 1490, 1373, 1213, 1036; H
NMR (300 MHz; CDCl3) δ 7.80 (1 H, dd, J = 7.8, 1.5 Hz,), 7.54 (2 H,
m), 7.50 − 7.26 (8 H, m), 6.95 (1 H, dd, J = 2.9, 1.9 Hz), 6.26 - 6.15
(2 H, m), 5.38 (1 H, pd, J = 6 Hz), 4.50 (1 H, dd, J = 8.7, 6.2 Hz), 4.25
(1 H, dd, J = 8.7, 1.0 Hz), 1.52 (3 H, s); 13C NMR (75 MHz, CDCl3)
δ 163.2 (C), 140.5 (C), 136.6 (C), 135.8 (C), 132.6 (CH), 132.0
(CH), 128.7 (2CH), 127.7 (2CH), 127.0 (2CH), 126.1 (CH), 122
(CH), 121.2 (CH), 110.1 (CH), 104.9 (CH), 91.1 (C), 71.8 (CH2),
61.7 (CH), 26.6 (CH3); HRMS (ESI+) calcd for C21H19N2O2 [M +
H+] 331.1447, found 331.1439.
(aR,3bR,6R)-3b-Benzyl-6-phenyl-6,6a-dihydro-3bH-benzo-
[f]furo[2,3-c]pyrrolo[1,2-a]azepin-7(5H)-one (9e). Methyl 2-(2-
(2-phenylacetyl)-1H-pyrrol-1-yl)benzoate (8e) (65 mg, 0.19 mmol),
(R)-2-phenylglycinol (33 mg, 0.24 mmol), and pivalic acid (39 mg,
0.38 mmol) gave 9e (pentane/EtOAc: 8/2; Rf = 0.15) after 10 h as a
colorless oil (58 mg, 72%, diastereomeric mixture of lactams 9d,
conversion of 78%). The pure major diastereomer could be isolated by
recrystallization from absolute ethanol (45 mg, 54%): white solid; mp
=69−71 °C; IR (νmax/ cm−1) 3029, 2884, 1726, 1634, 1494, 1391,
1256, 1153; 1H NMR (300 MHz; CDCl3) δ 7.90 (1H, dd, J = 7.8, 1.5
Hz), 7.56 (1H, ddd, J = 8.1, 7.3, 1.5 Hz), 7.42 (1H, dd, J = 8.1, 0.9
Hz), 7.37−7.30 (1H, m), 7.28−7.19 (5H, m), 7.15−7.0 (3H, m), 6.99
(1H, dd, J = 2.9, 1.8 Hz), 6.72 (2H, dd, J = 7.6, 1.8 Hz), 6.17 (1H, dd,
J = 3.5, 2.9 Hz), 5.98 (1H, dd, J = 3.5, 1.8 Hz), 5.41 (1H, dd, J = 6.5,
1.4 Hz), 4.51 (1H, dd, J = 8.7, 6.5 Hz), 4.28 (1H, dd, J = 8.7, 1.4 Hz),
3.05 (1H, d, J = 14.0 Hz), 2.99 (1H, d, J = 14.0 Hz). 13C NMR (75
MHz, CDCl3) δ 163.8 (C), 140.2 (C), 136.8 (C), 134.9 (C), 133.7
(C), 132.9 (CH), 132.1 (CH), 130.5 (2CH), 128.6 (2CH), 128.1 (C),
127.9 (2CH), 127.5 (CH), 127.1 (2CH), 127.0 (CH), 126.3 (CH),
121.9 (CH), 120.9 (CH), 110.3 (CH), 107.4 (CH), 93.6 (C), 71.7
(CH2), 61.64 (CH), 44.4 (CH2); HRMS (ESI+) calcd for C27H23N2O2
[M + H+] 407.1760, found 407.1764.
(aR,4bS,7R)-4b-Methyl-7-phenyl-6,7-dihydrobenzo[f ]-
oxazolo[3,2-d]pyrrolo[1,2-a][1,4]diazepin-9(4bH)-one (9a).
Methyl-1-(2-acetylphenyl)-1H-pyrrole-2-carboxylate (8a) (300 mg,
1.22 mmol), (R)-2-phenylglycinol (190 g, 1.46 mmol), and pivalic
acid (150 mg, 1.47 mmol) gave 9a (pentane/EtOAc 7/3; Rf = 0.24)
after 2.5 h as a colorless oil (370 mg, 93%, diastereomeric mixture of
lactams 9a). The pure major diastereomer could be isolated by
recrystallization from absolute ethanol (240 mg, 59%): white solid; mp
= 137−139 °C; IR (νmax/ cm−1) 3029, 2935, 2891, 1625, 1487, 1388,
1
1029; H NMR (300 MHz; CDCl3) δ 7.69 (1 H, m), 7.54 (2 H, m),
7.48 − 7.26 (6 H, m), 7.15 (1 H, dd, J = 2.8, 1.8 Hz), 7.03 (1 H, dd, J
= 3.8, 1.8 Hz), 6.41 (1 H, dd, J = 3.8, 2.8 Hz), 5.32 (1 H, pd, J = 5.4
Hz), 4.39 (1 H, dd, J = 8.7, 5.7 Hz), 4.33 (1 H, dd, J = 8.7, 1.2 Hz),
1.56 (3 H, s); 13C NMR (75 MHz, CDCl3) δ 157.5 (C), 140.7 (C),
136.6 (C), 135.4 (C), 129.7 (CH), 128.6 (2CH), 127.8 (C), 127.6
(CH), 127.1 (2CH), 127.0 (CH), 124.2 (CH), 123.7 (2CH), 117.6
(CH), 111.0 (CH), 92.8 (C), 71.6 (CH2), 61.5 (CH), 25.7 (CH3);
HRMS (ESI+) calcd for C21H19N2O2 [M + H+] 331.1447, found
1
331.1457. Characteristic peaks of the minor diastereomer: H NMR
spectrum of a 15/85 minor/major mixture of lactams (300 MHz;
CDCl3) δ 5.46 (1 H, dd, J = 6.7, 4.3 Hz), 4.58 (1 H, dd, J = 8.9, 6.7
Hz), 4.15 (1 H, dd, J = 8.9, 4.3 Hz), 1.48 (3H, s).
Representative Procedure A for Lactam Reduction. A portion
of aluminum chloride (1.2 equiv) was slowly diluted in THF (0.1 M)
under nitrogen at 0 °C. After the mixture was stirred for 5 min, a
solution of LiAlH4 (1 M in THF, 3.5 equiv) was slowly added at 0 °C
and the mixture was then stirred for 20 min at room temperature. The
solution was then cooled to 0 °C and treated with a precooled (0 °C)
solution of the lactam 9 (1 equiv) in dry THF (0.1 M) and stirred at 0
°C for 1 h and at room temperature for 3 h. The reaction was
quenched by the cautious addition of 1 M aq HCl. Water was then
added, and the aqueous layer was extracted with EtOAc. The
combined organic extract was washed with 2 M aq NaOH, dried over
MgSO4, and evaporated under reduced pressure, giving the
(aR,4bS,7R)-4b-Methyl-7-phenyl-6,7-dihydrobenzo[6,7]-
oxazolo[3′,2′:4,5][1,4]diazepino[1,2-a]indol-9(4bH)-one (9b).
Methyl 1-(2-acetylphenyl)-1H-indole-2-carboxylate (8b) (250 mg,
0.85 mmol), (R)-2-phenylglycinol (230 mg, 1.63 mmol), and pivalic
acid (166 mg, 1.63 mmol) gave 9b (pentane/EtOAc: 9/1; Rf = 0.27)
after 2.5 h as a colorless oil (300 mg, 93%, diastereomeric mixture of
lactams 9b). The pure major diastereomer could be isolated by
recrystallization from absolute ethanol (266 mg, 82%): colorless solid;
mp = 178−180 °C; IR (νmax/ cm−1) 2982, 2950, 2901, 1624, 1450,
1
1325, 1242, 1036; H NMR (300 MHz; CDCl3) δ 7.90−7.70 (4 H,
m), 7.65−720 (10 H, m), 5.45 (1 H, pd, J = 5.4 Hz), 4.47 (1 H, dd, J =
8.7, 5.9 Hz), 4.40 (1 H, dd, J = 8.7, 1.2 Hz), 1.57 (3 H, s); 13C NMR
(75 MHz, CDCl3) δ 157.9 (C), 140.4 (C), 136.8 (C), 136.7 (C),
135.0 (C), 133 (C), 129.2 (CH), 128.7 (2CH), 127.7 (CH), 127.6
(C), 127.1 (2CH), 126.7 (CH), 125.5 (CH), 124.9 (CH), 124.0
(CH), 122.6 (CH), 122.1 (CH), 112.2 (CH), 110.4 (CH), 93.2 (C),
71.5 (CH2), 61.4 (CH), 25.4 (CH3); HRMS (ESI+) calcd for
C25H21N2O2 [M + H+] 381.1603, found 381.1596. Characteristic
peaks of the minor diastereomer: 1H NMR spectrum of a 40/60
minor/major mixture of lactams (300 MHz; CDCl3) δ 5.48 (1 H, dd, J
= 6.6, 3.5 Hz), 4.6 (1 H, dd, J = 8.9, 6.7 Hz), 4.21 (1 H, m), 1.5 (3H,
s).
1
intermediate compound 10 (dr >99:1 by H NMR spectroscopy) as
a waxy solid which was used without further purification.
(R)-2-((R)-6-Methyl-4H-benzo[f ]pyrrolo[1,2-a][1,4]diazepin-
1
5(6H)-yl)-2-phenylethanol (10a): H NMR (300 MHz; CDCl3) δ
7.27−7.10 (7H, m), 7.01 (1H, br s), 6.85 (1H, br s), 6.19 (1H, br s),
6.04 (1H, br s), 4.09 (1H, q, J = 7.1 Hz), 4.03−3.91 (2H, m), 3.72
(1H, m), 3.62 (1H, d, J = 12.7 Hz), 3.19 (1H, s), 3.09 (1H, d, J = 12.7
Hz), 0.83 (3H, d, J = 7.1 Hz).
(R)-2-((R)-4-Methyl-4H-benzo[f ]pyrrolo[1,2-a][1,4]diazepin-
1
5(6H)-yl)-2-phenylethanol (10b): H NMR (300 MHz, CDCl3) δ
7.30−7.20 (7H, m), 7.1−6.9 (1H, d, J = 4.0 Hz), 6.85 (1H, d, J = 7.4
Hz), 6.81 (1H, dd, J = 2.9, 1.7 Hz), 6.17−6.13 (1H, m), 6.01 (1H, dd,
J = 3.4, 1.7 Hz), 4.22 (1H, q, J = 6.9 Hz), 4.11- 3.95 (2H, m), 3.79-
3.72 (1H, m), 3.47 (1H, d, J = 12.5 Hz), 3.34 (1H, d, J = 12.5 Hz),
3.06 (1H, s), 1.18 (3H, d, J = 6.9 Hz).
Representative Procedure B for Debenzylation. To a solution
of 10 (1 equiv) in absolute ethanol (0.1 M) was added 10% Pd/C (10
mol %). The flask was fitted with a balloon containing hydrogen and
stirred at room temperature for 16 h. The reaction mixture was filtered
through Celite and the pad was rinsed with EtOAc. The solvents were
(aR,4bS,7R)-4b-Methyl-7-phenyl-6,7-dihydrobenzo[c]-
oxazolo[3,2-a]pyrido[2,3-e]azepin-9(4bH)-one (9c). The methyl
keto-ester pyridine14a (25 mg, 0.09 mmol), (R)-2-amino-2-phenyl-
ethanol (16 mg, 0.12 mmol), and pivalic acid (12 mg, 0.12 mmol) gave
9c (petroleum ether/AcOEt 6/4; Rf = 0.5) after 2.5 h as a white solid
(29 mg, 88%, pure major diastereomer 9c). The analytical data match
the previously reported NMR analysis.14a
(aR,3bR,6R)-3b-Methyl-6-phenyl-5,6-dihydrobenzo[e]-
oxazolo[3,2-a]pyrrolo[2,1-c][1,4]diazepin-8(3bH)-one (9d).
F
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The Journal of Organic Chemistry
Note
evaporated under reduced pressure, and the residue was purified by
chromatography over silica gel (packed with hexane plus a few drops
of Et3N, eluted with EtOAc, then EtOAc/MeOH/Et3N 18:2:1, Rf =
0.32).
(R)-6-Methyl-5,6-dihydro-4H-benzo[f ]pyrrolo[1,2-a][1,4]-
diazepine (11a). Compound 9a (73 mg, 0.22 mmol) gave a waxy
2011, 54, 7005. (f) Aikawa, K.; Mikami, K. Chem. Commun. 2012, 48,
11050.
(5) Meerpoel, L.; Gestel, J. V.; Gerven, F. V.; Woestenborghs, F.;
Marichal, P.; Sipido, V.; Terence, G.; Nash, R.; Corens, D.; Richards,
R. D. Bioorg. Med. Chem. Lett. 2005, 15, 3453.
(6) Mai, A.; Di Santo, R.; Massa, S.; Artico, M.; Pantaleoni, G. C.;
Giorgi, R.; Coppolino, M. F.; Barracchini, A. Eur. J. Med. Chem. 1995,
30, 593.
(7) For other examples in indole and imidazole series, see: (a) Ilyn,
A. P.; Trifilenkov, A. S.; Kuzovkova, J. A.; Kutepov, S. A.; Nikitin, A.
V.; Ivachtchenko, A. V. J. Org. Chem. 2005, 70, 1478. (b) Ohta, Y.;
Chiba, H.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008, 10, 3535.
(c) Glass, L. S.; Bapat, A.; Kelley, M. R.; Georgiadis, M. M.; Long, E.
C. Bioorg. Med. Chem. Lett. 2010, 20, 1685. (d) Wang, H.-J.; Wang, Y.;
Camara, F.; Paquette, W. D.; Csakai, A. J.; Mangette, J. E. Tetrahedron
Lett. 2011, 52, 541.
(8) For recent selected examples, see: (a) Tseng, M.-C.; Yang, H.-Y.;
Chu, Y.-H. Org. Biomol. Chem. 2010, 8, 419. (b) Sorra, K.; Mukkanti,
K.; Pusuluri, S. Tetrahedron 2012, 68, 2001 and references cited
therein.
solid (40 mg, 92% 11a): [α]25 −54.8 1 (c 1.9, CHCl3); IR (νmax
/
D
cm−1) 2963, 1604, 1492, 1325, 1174, 888; 1H NMR (300 MHz;
CDCl3) δ 7.60 (4H, m), 6.97 (1H, dd, J = 2.8, 1.7 Hz), 6.29 (1H, m),
6.26−6.17 (m, 1H), 4.02−3.87 (2H, m), 3.62 (1H, d, J = 14.1 Hz),
3.25 (1H, s), 1.47 (3H, d, J = 6.7 Hz); 13C NMR (75 MHz, CDCl3) δ
140.2 (C), 134.1 (C), 131.4 (C), 128.7 (CH), 127.0 (CH), 126.8
(CH), 122.3 (CH), 120.1 (CH), 109.2 (CH), 107.4 (CH), 50.5 (CH),
41.6 (CH2), 19.1 (CH3); HRMS (ESI+) calcd for C13H15N2 [M + H+]
199.1235, found 199.1241.
(R)-4-Methyl-5,6-dihydro-4H-benzo[f ]pyrrolo[1,2-a][1,4]-
diazepine (11b). Compound 9d (58 mg, 0.17 mmol) gave a waxy
solid (27 mg, 80% 11b): [α]25 −35.5 1 (c 1.9, CHCl3); IR (νmax
/
D
cm−1) 2966, 1603, 1493, 1327, 1167, 1117; H NMR (300 MHz;
CDCl3) δ 7.48- 7.21 (4H, m), 6.99 (1H, dd, J = 2.8, 1.7 Hz), 6.37−
6.28 (1H, m), 6.20 (1H, m), 3.78 (3H, m), 2.46 (1H, s), 1.48 (1H, d, J
= 6.6 Hz); 13C NMR (75 MHz, CDCl3) δ 140.5 (C), 135.5 (C), 132.0
(C), 130.0 (CH), 129.0 (CH), 126.7 (CH), 121.9 (CH), 120.1 (CH),
108.9 (CH), 105.7 (CH), 48.7 (CH2), 46.5 (CH), 19.1 (CH3); HRMS
(ESI+) calcd for C13H15N2 [M + H+] 199.1235, found 199.1245.
1
́
(9) Joncour, A.; Decor, A.; Liu, J.-M.; Tran Huu Dau, M.-E.;
Baudoin, O. Chem.Eur. J. 2007, 13, 5450.
(10) For other dibenzo[c,e]azepinones of this type, see: Mehta, V. P.;
Modha, S. G.; Ruijter, E.; Van Hecke, K.; Van Meervelt, L.;
Pannecouque, C.; Balzarini, J.; Orru, R. V. A.; Van der Eycken, E. J.
Org. Chem. 2011, 76, 2828.
ASSOCIATED CONTENT
(11) Saudan, L. A.; Bernardinelli, G.; Kundig, E. P. Synlett 2000,
̈
■
2000, 483.
S
* Supporting Information
(12) Bulman Page, P. C.; Bartlett, C. J.; Chan, Y.; Day, D.; Parker, P.;
Buckley, B. R.; Rassias, G. A.; Slawin, A. M. Z.; Allin, S. M.; Lacour, J.;
Pinto, A. J. Org. Chem. 2012, 77, 6128.
(13) (a) Edwards, D. J.; Pritchard, R. G.; Wallace, T. W. Tetrahedron
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(14) (a) Penhoat, M.; Levacher, V.; Dupas, G. J. Org. Chem. 2003, 68,
General experimental information, copies of NMR spectra for
all newly formed products, and X-ray crystal data for
compounds 9a, 9b, and 9d. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
9517. (b) Penhoat, M.; Bohn, P.; Dupas, G.; Papamicael, C.; Marsais,
̈
Corresponding Author
F.; Levacher, V. Tetrahedron: Asymmetry 2006, 17, 281. (c) Bouet, A.;
Heller, B.; Papamicael, C.; Dupas, G.; Oudeyer, S.; Marsais, F.;
Levacher, V. Org. Biomol. Chem. 2007, 5, 1397.
*E-mail: (J.-F.B.) jean-francois.briere@insa-rouen.fr; (V.L.)
vincent.levacher@insa-rouen.fr.
(15) For reviews on Meyers’ lactamization, see: (a) Groaning, M. D.;
Notes
Meyers, A. I. Tetrahedron 2000, 56, 9843. (b) Amat, M.; Per
́
ez, M.;
The authors declare no competing financial interest.
Bosch, J. Synlett 2011, 143.
(16) (a) Jida, M.; Deprez-Poulain, R.; Malaquin, S.; Roussel, P.;
Agbossou-Niedercorn, F.; Deprez, B.; Laconde, G. Green Chem. 2010,
ACKNOWLEDGMENTS
■
12, 961. (b) Sarkar, S.; Husain, S. M.; Schepmann, D.; Frohlich, R.;
̈
This work has been partially supported by INSA Rouen, Rouen
University, CNRS, EFRD, and Labex SynOrg (ANR-11-LABX-
Wunsch, B. Tetrahedron 2012, 68, 2687.
̈
(17) For discussion on microwave effect vs standard heating method,
see: Kappe, C. O.; Pieber, B.; Dallinger, D. Angew. Chem., Int. Ed.
2013, 52, 1088.
́
0029), together with the “Region Haute-Normandie”. This
work is part of the Immunochim project (no. 34209) funded by
the European Union through a FEDER support engaged in
region Haute-Normandie.
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dx.doi.org/10.1021/jo401259w | J. Org. Chem. XXXX, XXX, XXX−XXX