A one-pot azido reductive tandem mono-N-alkylation employing dialkylboron triflates: Online ESI-MS mechanistic investigation

Article abstract of DOI:10.1021/jo200931m

An efficient one-pot reductive tandem mono-N-alkylation of both aromatic and aliphatic azides using dialkylboron triflates as alkylating agents has been examined under standardized reaction conditions. This methodology after optimization has been employed toward the syntheses of various secondary alkyl as well as aryl amines, including the synthesis of N10-butylated pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones via in situ azido reductive-cyclization process. This protocol is particularly attractive to provide an environmentally benign and practical method for mono-N-alkylation from organic azides without the use of toxic catalysts or corrosive alkylating agents. In addition, the mechanistic aspects have been investigated and the intermediates associated with this selective transformation have been intercepted and characterized by online monitoring of the reaction by ESI-MS/MS.

Full text of DOI:10.1021/jo200931m

ARTICLE
pubs.acs.org/joc
A One-Pot Azido Reductive Tandem Mono-N-Alkylation Employing
Dialkylboron Triflates: Online ESI-MS Mechanistic Investigation
Nagula Shankaraiah,‡ Nagula Markandeya,§ Vunnam Srinivasulu,† Kokkonda Sreekanth,†
Ch. Sanjeeva Reddy,*,§ Leonardo S. Santos,# and Ahmed Kamal*,†,^
†Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 607, India
‡National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad-500 037, India
§Department of Chemistry, Kakatiya University, Warangal 506 009, A.P, India
#Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, University of Talca, Talca, P.O. Box 747, Chile
^Catalytic Chemistry Chair, Chemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia
S Supporting Information
b
ABSTRACT: An efficient one-pot reductive tandem mono-N-
alkylation of both aromatic and aliphatic azides using dialkyl-
boron triflates as alkylating agents has been examined under
standardized reaction conditions. This methodology after opti-
mization has been employed toward the syntheses of various
secondary alkyl as well as aryl amines, including the synthesis of
N10-butylated pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones
via in situ azido reductive-cyclization process. This protocol is
particularly attractive to provide an environmentally benign and
practical method for mono-N-alkylation from organic azides without the use of toxic catalysts or corrosive alkylating agents. In
addition, the mechanistic aspects have been investigated and the intermediates associated with this selective transformation have
been intercepted and characterized by online monitoring of the reaction by ESI-MS/MS.
’ INTRODUCTION
they have been extensively used in ‘click’ chemistry16 for the syn-
thesis of 1,2,3-triazoles, tetrazoles, anilines, and N-alkylated
anilines.17 Brown and co-workers18aÀf efficiently reported the use
There is considerable interest in the conversion of primary
amines into N-alkylated amines for the construction of a vast range
of natural products, bioactive molecules, and industrial materials.1
Secondary amine building blocks are also interesting organic
compounds because of their physiological activity and their
potential as organic intermediates in the field of bioorganic
chemistry.2 With this increasing repertoire of applications,
developing efficient methods for the synthesis of N-alkylated
amines has drawn much attention in recent years. However, many
different ways to alkylate amines have been reported,3 which are
mostly reductive methods for imines,4 amides,5 direct alkylation
by halide,6 displacement of sulfonate7 or tosylate,8 epoxide ring-
opening,9 and reductive amination of carbonyls.10 These methods
are applicable to many synthetic conditions, but the majority of them
have several drawbacks such as the use of toxic and corrosive
alkylating reagents11 and the frequent generation of wasteful salts
as byproduct that are undesirable in view of the environmental
concerns.12 Moreover, the reaction conditions are often drastic
(high temperature, basic conditions, etc.), including tedious
workup, long reaction times, and poor selectivity. To overcome
these difficulties, development of a convenient protocol for
mono-N-alkylation is an important synthetic goal for chemists.
However, despite their explosive properties, organic azides are
valuable intermediates in organic synthesis.13À15 In recent years,
of R3B and their halogenated organoborohydrates (BHCl2 SMe2,
3
BHBr2 SMe2, etc.) for the reductive N-alkylation of organic
3
azides into their corresponding secondary amines. Most of
these azido reductive mono-N-alkylation reaction procedures are
reported and performed under reflux conditions apart from the use
of xylene as the solvent in a number of the cases. It is also known that
a number of amines or imines decompose at higher temperatures
and prolonged reaction times. Carboni and co-workers18g stu-
died reductive N-alkylation reactions with alkyldichloroboranes
by using functionalized azides as substrates. Herein, we report an
entirely new, direct one-pot azido reduction with concomitant
mono-N-alkylation of both aromatic and aliphatic azides using
dialkylboron triflates. Such tandem reactions offer an effective
and convenient one-pot process for the synthesis of various
N-alkylated amine motifs. In this connection, we have
explored different types of dialkylboron triflates such as Bu2-
BOTf, Et2BOTf, and Cy2BOTf which are used for the azido-
reductive mono-N-alkylation process under mild reaction condi-
tions. Among the above triflates, one of the triflates, namely
Received: May 9, 2011
Published: July 21, 2011
r
2011 American Chemical Society
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diethylboron triflate, was freshly prepared in situ by mixing of
Et3B and trifluoromethanesulfonic acid.
present reactions proceed well even with sterically hindered
organic azides, employing Cy2BOTf and Bu2BOTf.
It is well-known that the use of metal triflates in many organic
transformations has grown significantly in the last two decades.
Recently, we developed a facile chemoselective azido-reductive
cyclization approach by using various metal triflates in combina-
tion with NaI and studied their mechanistic aspects.19 The
dialkylboron triflates are particularly useful reagents for the
enolization of carbonyl compounds, including ketones, thioe-
sters, and acyloxazolidinones.20 The most prominent metal
Lewis acid catalyst is Bu2BOTf, since it is stable and especially
used in Evan’s aldol reaction.21 Moreover, Bu2BOTf is found to
be an efficient catalyst in regioselective reductive ring-opening of
benzylidene acetals in carbohydrates.22 Benjamin and co-workers
reported anti-aldol additions of Oppolzer’s sultam that is effi-
ciently promoted by Et2BOTf.23 The Cy2BOTf is also found to
be an effective metal catalyst for the enolization of carboxylic
esters.24 However, very few applications have been reported by
employing dialkylboron triflates.
This development suggests that diethyl or di-n-butylboron
triflates might be provide a spontaneous reaction with organic
azides. As these results were encouraging, a series of organic
azides were investigated and these results are summarized in
Table 1. It was observed that with less hindered organoboranes
or azides (such as diethyl or di-n-butyl), the reaction is rapid,
evolving gas, at room temperature whereas in more hindered
cases, such as as dicyclohexyl, the reaction is slightly slower and
requires about 20 min for the completion of the reaction.
On the basis of the interesting findings of this investigation, a
variety of organoboranes were reacted with different organic
azides, thus providing a general synthetic procedure for the
secondary amines. The required azido starting materials
(1aÀn) were obtained according to our previously reported
methods.25 The reactions were conducted by adding the corre-
sponding dialkylboron triflate (1.0 mmol) to a stirred solution of
azides (1.0 mmol) in CH2Cl2 as a solvent at 0 ꢀC to ambient
temperature for 5À20 min, and all the reactions were monitored
by observing the disappearance of the starting material, as
indicated by TLC. We further validated the reaction conditions
by considering the reaction of various substituted azido deriva-
tives with different dialkylboron triflates. In this protocol, one of
the noncommercial boronates Et2BOTf23 was freshly prepared
for the mono-N-alkylation of substrates (entries 1a and 1b) as
shown in Table 1. The mono-N-alkylated secondary amines
2aÀn were obtained from 1aÀn in good to excellent yields
(80À95%), and the results are summarized in Table 1. Sub-
stituted azido derivatives (entries 1a, 1b, 1h, and 1i) bearing both
electron-donating as well as electron-withdrawing groups in the
aromatic ring proceeded smoothly and selectively to the corre-
sponding mono-N-alkylated anilines (entries 2a, 2b, 2h, and 2i)
in good yields (80À88%, Table 1). It is noteworthy that
reducible functional groups such as nitro (entry 1f) and ester
(entries 1a, 1b, 1h, and 1i) survived with this protocol. The
observations were similar in cases of more electron-donating
groups in the aromatic ring such as trimethoxy substitution
(entry 1g, Table 1), which gave 88% yield. The reaction of
nitro-substituted azido benzene (entry 1f, Table 1) proceeded
smoothly and gave cleaner mono-N-alkylated aniline (90% yield,
entry 2f). In the case of the p-chloro-azido benzene (1d) the
reaction proceeded very well with excellent yield (entry 2d,
95%). Mono-N-cyclohexyl aniline derivatives (80À85% yields,
entries 2kÀm, Table 1) were also obtained significantly by
employing similar reaction conditions. However, the reaction
time is prolonged up to 20 min, which is due to the bulky group of
Cy2BOTf. The aliphatic azido compounds (entry 1c and 1n,
Table 1) were also converted to their corresponding secondary
amines (entry 2c and 2n). Interestingly, a Boc-protected mono-
N-butylated proline secondary amine building block (entry 2n,
Table 1) was obtained efficiently without changing its stereo-
chemistry, confirmed by optical rotation of the pure product 2n.
Indeed, it is plausible to achieve mono-N-alkyl anilines via a one-
pot process without the separation of the aniline intermediate.
In our ongoing research program, we have been involved in
the development of new azido reductive methodologies in
solution as well as of solid-phase systems for the preparation of
bioactive natural products, such as pyrrolobenzodiazepines26 and
their derivatives. In this context, we explored this reaction
protocol toward the synthesis of not only the secondary amines
but also mono-N-alkylation followed by a tandem ring-closing
’ RESULTS AND DISCUSSION
This investigation began from our curiosity based on Brown’s
azido reductive mono-N-alkylation approach by using different
types of R3B or R2BCl. Herein, it was considered of interest to
utilize various Lewis acid-assisted dialkylboron triflates
(Bu2BOTf, Et2BOTf, and Cy2BOTf) for the reductive mono-
N-alkylation of aromatic azides. Moreover, this aromatic azido
reduction reaction was carried out in a one-pot manner with
tandem mono-N-alkylation within a short period of time at room
temperature and interestingly without the use of catalyst. On this
success, the applicability of this procedure toward the mono-N-
alkylation of aliphatic primary azides was also explored. Thus, to
investigate the generality of this application, we initially opti-
mized the reaction conditions by using a variety of solvents, for
example CH3CN, THF, CH2Cl2, Et2O, and toluene, with the aim
to increase yields, shorten reaction times, and to obtain clean
products. In nonpolar solvent such as toluene, the reactions were
slower and yields were unsatisfactory. Similar results were
obtained in Et2O due to poor solubility of the substrates. Among
the solvents examined, CH2Cl2 gave the most favorable results
with good conversions as well as yields. Then employing
CH2Cl2, we investigated the requirement of the optimum
amount of dialkylboron triflates (Bu2BOTf, Et2BOTf, and
Cy2BOTf). These studies suggested that 1 equiv of triflate is
sufficient for the reductive mono-N-alkylation of both aliphatic as
well as aromatic azides. However, the di-N-alkylated (tert-amine)
product was also observed considerably when the reaction was
performed with excess dialkylboron triflate, such as diethyl or di-
n-butylboron triflate. Similarly, when this reaction was per-
formed with an excess of Cy2BOTf, it did not produce the
tertiary amine as a side product probably because of the steric
aspect of this triflate.
These reactions are considerably spontaneous compared to
the related reactions with the corresponding trialkylboranes. In
contrast to trialkylboranes, dialkylchloroboranes, even dialkyl-
boron triflates containing a secondary alkyl group, readily react
with organic azides to give good to excellent yields of secondary
amines after hydrolysis mainly due to the increase in Lewis acidic
nature of the dialkylboron triflates. Earlier, it was pointed out by
Brown that the reaction of hindered azides with hindered tri-
alkylboranes completely fails.18e However in another case, the
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Table 1. One-Pot Synthesis of Mono-N-alkylated Derivatives
(2aÀn) from Organic Azides (1aÀn) Employing Dialkyl-
boron Triflates
pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones (PBDs) in a
one-pot manner. These are well-known naturally occurring
antitumor antibiotics that are produced by various Streptomyces
species and exert their biological activity by interacting with
DNA in a sequence-selective manner.27 PBD-5,11-diones have
been employed as intermediates in the synthesis of naturally
occurring and synthetically modified PBD imines, such as tomay-
mycin and chicamycin. This tricyclic PBD ring system has
been used for a number of pharmaceutical applications, such as
a template for the design and assembly of antituberculosis
agents,28 peptidomimetics,29 anxiolytic drugs,30 anticonvulsants,31
and herbicides.32
The key intermediates 3aÀh were synthesized by employing
our earlier reported methods.19,33 The mono-N10-butylated
PBD-5,11-diones (4aÀh) were obtained in an efficient manner
by employing Bu2BOTf as the alkylating agent and yields ranged
from 72% to 92% as depicted in Table 2. However, during this
reaction process, a considerable number of the mono-N10-
butylated benzoylproline esters (5aÀh) were observed in almost
70% yield within a period of 5 min; the other final compounds
(4aÀh) were obtained in 30% yield as shown in Scheme 1, and
no trace of tert-amines was observed. Next, this reaction mixture
was treated with NaH as base dissolved in THF solvent at room
temperature for 30 min to provide the final cyclized compounds
4aÀh. This protocol was successfully applied for the synthesis of
the A-aromatic ring/C-C2-substituted N10-butylated PBD-5,11-
diones in good yields (entries 4dÀh, Table 2) ranging from 72%
to 88%. It is interesting to note that the substrates such as
C2-mesylated (entries 3e and 3f, Table 2), C2-tosylated (entry
3g), and C2-OPMB protected (entry 3g) intermediates were
efficiently converted to their mono-N10-butylated ring-closing
dilactams (entries 4eÀh, Table 2) by employing this protocol
without any deprotection. However, it was observed that when
this reaction was carried out with C2-OTBDMS protected
precursor, the OTBDMS group was completely deprotected
under similar reaction conditions. Then, this direct one-pot
azido-reductive mono-N-alkylation approach was also applied
chemoselectively for the synthesis of (S)-1-(2-(butylamino)-
benzoyl)-N-methoxy-N-methylpyrrolidine-2-carboxamide(7) from
precursor 633a with n-Bu2BOTf as shown in Scheme 2. As a
result, the Weinreb amide protection is not effected by using this
di-n-butylboron triflate. This key intermediate is also one of the
very important precursors for the synthesis of PBD-carbinols as
an essential pharmacophoric scaffold.
Mechanistic Studies. In the reaction proposed by Brown and
co-workers, organic azides lead to secondary amines upon
reaction with dialkylboranes, which could involve reversible
coordination of the azide with trialkylborane followed by loss
of N2 with subsequent (or concurrent) migration of the alkyl
group from boron to nitrogen18e,f and thereby affording the final
product after hydrolysis.
Complete mechanistic investigations generally require kinetic
data obtained by monitoring over long time scales, frequently by
UV, IR, or NMR spectroscopy. However, these techniques are
often not appropriate for the short time scales required for
investigating transient species, as unequivocal assignments of UV
and IR bands or NMR peaks and couplings, principally for more
complex or transient structures, may be challenging and some-
times impossible. Electrochemical techniques have also been
used to monitor short-lived species, but they provide limited
structural information on the detected intermediates. On the
other hand, during the last two decades there has been
a All reactions were conducted at 0 ꢀC to rt with 1.0 mmol of 1aÀn,
1.0 mmol of dialkylboron triflates (Bu2BOTf, Et2BOTf, and Cy2BOTf)
in 2 mL of CH2Cl2 for 2À20 min. b All compounds were characterized
1
by H/13C NMR and HRMS. c Isolated yields (purified by column
chromatography).
reaction process. The main objective was to utilize this mono-
N-alkylation approach for the introduction of an additional
pharmacophoric scaffold in the bioactive molecules, such as
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Table 2. One-Pot Synthesis of N10-Butylated Pyrrolo[2,1-c][1,4]benzodiazepin-5,11-diones (4aÀh) Using Bu2BOTf as
Alkylating Agent
a All reactions were conducted at 0 ꢀC to rt with 1.0 mmol of 3aÀh and 1.0 mmol of Bu2BOTf in 2 mL of CH2C12 for 5 min. Later this reaction mixture
was stirred with NaH (2 equiv) in THF (3 mL) for 30 min. b All compounds were characterized by 1H/13C NMR and HRMS. Isolated yields represent
purification by column chromatography.
considerable growth in the development of electrospray ioniza-
tion (ESI) for molecular analysis by mass spectrometry (MS) as a
practical method in the study of reaction mechanisms.34,35 ESI is
an interesting ‘ion-fishing’ technique because it gently transfers
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Scheme 1. Synthesis of N10-Butylated Pyrrolo[2,1-c][1,4]benzodiazepin-5,11-diones
Scheme 2. One-Pot Azido-Reductive Tandem Mono-N-al-
kylation for the Synthesis of (S)-1-(2-(Butylamino)benzoyl)-
N-methoxy-N-methylpyrrolidine-2-carboxamide by Employ-
ing Bu2BOTf
mechanisms of several reactions.39 Thus, to study the mechanism
of alkylation reaction, we employed a microreactor coupled to
ESI-MS by attempting to “fish” the previously proposed inter-
mediates (Figure 1 and Scheme 3). Figure 1a shows the ESI-MS
spectrum of 1i in neat CH2Cl2 wherein the major ion detected in
the mass spectrum corresponds to [1i À N2 + H]+ of m/z
286.1070 (calculated 286.1079) and [1i + H]+ of m/z 314.1135
(calculated 314.1146). At this stage, it was not possible to obtain
the net protonated azide 1i (Figure 1a) because of the great
lability of the N3 group. Those ions were then mass-selected and
structurally characterized via CID with argon in ESI-MS/MS
measurements affording neutral losses of N2 followed by
CH3OH as the main fragmentation pathway (spectra not
shown). Then, we investigated the formation of the intermediate
species in a reaction solution that was prepared by online mixing
of 1i with Bu2BOTf via the microreactor (insert in Figure 1)
following Brown’s procedure. The reaction of 1i solution with
Bu2BOTf/CH2Cl2 using the microreactor resulted in a very
clean spectrum (Figure 1b) displaying two cationic species
that were easily identified by their absolute masses at reaction
times of 0.33 s: [8 + H]+ (m/z 588.2165, calculated 588.2163)
and [9 + H]+ (m/z 560.2105, calculated 560.2096). After
addition of water to the reaction mixture, the final product of
the reaction was obtained as [2i + H]+ of m/z 344.1870
(calculated 344.1862). According to ESI-MS data, strong
evidence for the currently accepted mechanism has been
collected, thus confirming the proposals initially made by
Brown and co-workers.
preformed ions directly from solution to the gas phase,36 and it is
rapidly becoming the technique of choice for fast screening of
intermediates directly from solution37 and in high throughput
screening of homogeneous catalysis reactions, providing hitherto
unavailable chemical information to mechanistic studies.35 In this
context, we became interested in employing the online ESI-MS
technique to identify and characterize the species that are
involved in the synthetic route for the one-pot azido reduction
through dialkylboron triflates.
We monitored the reaction via ESI-MS(/MS) experiments by
attempting to intercept ionic intermediates and collect the
mechanistic information that could guide the optimization of
reaction conditions. We monitored the reaction of 1i and
Bu2BOTf solution by direct infusion with reaction times around
15 s via ESI-MS operating in the positive ion mode. However, no
intermediates were detected, mainly due to the short lifetime of
these intermediates. Thus, direct ESI-MS was discarded as the
technique for this mechanistic study.38 Microreactors coupled to
an ESI-MS ion source have been used by us to organic reaction
mechanistic studies, thus allowing the interception of transient
and short lifetime compounds.35,37a,37c Since ESI-MS can trans-
fer the ions directly from solution to gas phase with efficiency and
gentleness (no or little dissociation), reaction times around 0.33 s
can be screened through coupling the microreactor depicted in
the insert of Figure 1, thus providing proper snapshots of the ion
composition of the reaction solutions in shorter reaction times.
We have been using this technique extensively to investigate the
’ CONCLUSION
In summary, we have investigated and presented a valuable
alternative methodology for selective azido-reductive direct
mono-N-alkylation of both aromatic and aliphatic azides using
dialkylboron triflates as alkylating agents. This methodology is
particularly attractive, as it provides secondary amine building
blocks as pharmacophoric scaffolds for drug discovery. More-
over, the one-pot azido-reductive mono-N-alkylation fol-
lowed by a tandem cyclization sequence is an innovative
development for the synthesis N10-butylated PBD-5,11-
diones. Furthermore, the presented protocol is facile and
environmentally benign.
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Figure 1. ESI(+)-MS spectra for the reaction of 1i with Bu2BOTf: (a) 1i in CH2Cl2 (control experiment); (b) online monitoring of the mixture of 1i and
Bu2BOTf at 0.33 s of reaction time and interception of intermediates 8and9; (c) production of 2i after addition of H2O. Other unidentified ions/compounds
are mainly hydrated triflates, and these are mostly water and solvent clusters of the triflate of m/z 150.9 (favorably ionized under positive-ion ESI).
Scheme 3. Proof of the Mechanism for the Conversion of Aryl Azide into N-Alkylated Aniline by Using Bu2BOTf as an Alkylating
Agent Based on ESI(+)-MS(/MS) Online Monitoring
’ EXPERIMENTAL SECTION
silane. Spin multiplicities are described as s (singlet), br s (broad singlet),
d (doublet), dd (double doublet), t (triplet), q (quartet), or m
(multiplet). Coupling constants are reported in hertz (Hz). Mass spectra
were recorded by electrospray ionization mass spectrometry (ESI-MS),
and the online mechanistic studies were carried out by using
ESI(+)-MS(/MS) in a Q-Tof Micro equipment. Column chromatog-
raphy was performed by using 60À120 mesh silica gel. TLC analyses
were performed with silica gel plates using iodine, KMnO4, and a UV
lamp for visualization.
General Reaction Procedure for the Preparation of Com-
pounds 2aÀn. A dry 25 mL round-bottom flask equipped with a
septum inlet and magnetic stirring bar was flushed with nitrogen. A 2 mL
amount of dry CH2Cl2 and 1.0 mmol of dialkylboron triflate were added
to a round-bottom flask at 0 ꢀC, and 1.0 mmol of organic azide (1aÀn)
dissolved in 2 mL of dry CH2Cl2 was added by using a syringe. Later, the
reaction mixture was monitored by observing the disappearance of the
General Methods. Purchased chemical reagents were used without
further purification. Anhydrous CH2Cl2, THF, CH3CN, toluene, and
ether used in reactions were prepared by distillation under nitrogen over
sodium/benzophenone, CaH2, sodium/P2O5, and CaH2/molecular
sieves, respectively. Solvents for extraction and column chromatography
were distilled prior to use. Sodium azide was handled with care for the
preparation of various substituted 2-azidobenzoic acids by wearing safety
glasses, facemask, and gloves, and the reactions were performed in a
fume hood. FT-IR spectra for all the compounds were recorded by using
thin film as well as KBr disk. 1H and 13C NMR spectra were recorded on
200, 300, and 400 MHz spectrometers using tetramethylsilane as the
internal standard (Note: Most of the compounds of ‘NH’ protons did
not appear in 1H NMR spectra because of D2O exchange). Chemical shifts
are reported in parts per million (ppm) downfield from tetramethyl
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starting material, as indicated by TLC. After the nitrogen gas evolution had
ceased, the solution was cooled to 0 ꢀC and very carefully hydrolyzed by
slowly adding 3À5mLofH2O and additionally an excess of H2O was added
and the precipitate removed by filtration. The combined aqueous layers and
precipitate were washed with saturated NaHCO3 solution and followed by
brine wash. The mono-N-alkylated amines were extracted with EtOAc. The
crude products were purified by column chromatography (60À120 mesh
silica gel) using EtOAc:hexane as eluent.
6.49 (d, 2H, J = 8.81 Hz), 3.71 (s, 3H), 3.07 (t, 2H, J = 6.61 Hz), 1.33À
1.66 (m, 4H), 0.96 (t, 3H, J = 7.34 Hz); 13C NMR (75 MHz, CDCl3):
δ = 151.9, 142.7, 114.8, 113.9, 55.7, 44.7, 31.7, 20.3, 13.9; HRMS (ESI):
m/z Calcd for C11H17NONa 202.1193, found 202.1199 [M + Na]+.
N-Butyl-4-nitroaniline (2f). Brown solid. Mp: 54À56 ꢀC; FT-IR:
(cmÀ1) 3345, 2957, 2869, 1605, 1473, 1298, 1189, 1109, 834, 752, 659;
1H NMR (200 MHz, CDCl3): δ = 8.06 (d, 2H, J = 9.55 Hz), 6.49 (d, 2H,
J = 8.81 Hz), 4.83 (s, 1H), 3.23 (q, 2H), 1.39À1.72 (m, 4H), 0.98 (t, 3H,
J = 7.34 Hz); 13C NMR (75 MHz, CDCl3): δ = 153.5, 137.6, 126.4,
110.8, 43.1, 31.1, 20.1, 13.7; HRMS (ESI): m/z Calcd for C10H14N2O2-
Na 217.0952, found 217.0962 [M + Na]+.
N-Butyl-3,4,5-trimethoxyaniline (2g). Dark brown liquid. FT-IR:
(cmÀ1) 3401, 2925, 1603, 1320, 1112; 1H NMR (200 MHz, CDCl3):
δ = 6.52 (s, 1H), 5.93 (s, 1H), 5.78 (s, 1H), 3.58À4.12 (m, 9H),
3.03À3.23 (m, 2H), 1.28À1.82 (m, 4H), 0.78À1.03 (m, 3H); 13C NMR
(75 MHz, CDCl3): δ = 153.8, 145.3, 129.7, 90.1, 61.0, 55.8, 44.0, 31.6,
20.2, 13.8. HRMS (ESI): m/z Calcd for C13H22NO3 240.1599, found
240.1610 [M + H]+.
Methyl 2-(Butylamino)-4-hydroxy-5-methoxybenzoate (2h). Red-
dish brown solid. Mp: 72À74 ꢀC; FT-IR: (cmÀ1) 3360, 2926, 2854,
1742, 1677, 1589, 1521, 1462, 1435, 1377, 1309, 1237, 1195, 1092, 1031,
867, 765; 1H NMR (300 MHz, CDCl3): δ = 7.35 (s, 2H), 6.55 (s, 1H),
3.86 (s, 6H), 3.17 (t, 2H, J = 6.98 Hz), 1.65À1.75 (m, 2H), 1.39À1.51
(m, 2H), 0.98 (t, 3H, J = 7.17 Hz); 13C NMR (75 MHz, CDCl3): δ =
168.6, 152.4, 149.1, 136.8, 127.7, 113.1, 97.2, 56.6, 51.2, 42.9, 31.3, 20.3,
13.9. HRMS (ESI): m/z Calcd for C13H20NO4 254.1392, found
254.1388 [M + H]+.
Methyl 4-(Benzyloxy)-2-(butylamino)-5-methoxybenzoate (2i).
White solid. Mp: 81À83 ꢀC; FT-IR: (cmÀ1) 3351, 2955, 2927, 2864,
1674, 1619, 1586, 1523, 1460, 1442, 1384, 1363, 1336, 1270, 1245, 1221,
1200, 1173, 1097, 1034, 1004, 967, 872, 772, 738, 697; 1H NMR (300
MHz, CDCl3): δ = 7.25À7.42 (m, 6H), 6.11 (s, 1H), 5.16 (s, 2H), 3.80
(s, 6H), 3.04 (t, 2H, J = 6.79 Hz), 1.58 (qt, 2H), 1.36À1.48 (m, 2H),
0.95 (t, 3H, J = 6.79 Hz); 13C NMR (75 MHz, CDCl3): δ = 168.5, 154.5,
148.4, 139.3, 136.5, 128.6, 127.9, 127.1, 114.5, 101.0, 96.6, 70.5, 56.9,
51.2, 42.9, 31.2, 20.3, 13.8; HRMS (ESI): m/z Calcd for C20H26NO4
344.1862, found 344.1870 [M + H]+.
Methyl 2-(Ethylamino)-4-hydroxy-5-methoxybenzoate (2a). Triethyl-
borane (1 mL, 1 M in hexane, 1.0 mmol) solution was added to freshly
distilled triflouromethanesulfonic acid (88 μL, 1.0 mmol). The reaction
mixture was stirred at room temperature for 1 h in which the solution
appeared as homogeneous pale yellow/orange. Then, it was cooled to
0 ꢀC, and methyl 2-azido-4-hydroxy-5-methoxybenzoate (1a, 223 mg,
1.0 mmol) in dry CH2Cl2 (5 mL) was added. Later, the reaction mixture
was monitored by observing the disappearance of the starting material,
as indicated by TLC. After 5 min, this reaction mixture was quenched
with saturated NaHCO3 solution, another 10 mL of CH2Cl2 was added,
and the precipitate was removed by filtration. The organic phase was
separated and dried over anhydrous Na2SO4. The crude product thus
obtained was purified by column chromatography using a silica gel
(60À120 mesh) pad employing ethyl acetate/hexane (30:70) as eluent
to afford the brownish crystalline solid 2a (191 mg, 85%). Mp:
70À72 ꢀC; FT-IR: (cmÀ1) 3525, 3471, 3384, 2924, 2853, 1655, 1590,
1538, 1429, 1393, 1335, 1278, 1242, 1176, 1085, 1025, 957, 866, 827,
772; 1H NMR (300 MHz, CDCl3): δ = 7.32 (s, 1H), 7.25 (s, 1H), 6.33
(br, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.20 (q, 2H), 1.35 (t, 3H, J = 7.17 Hz);
13C NMR (100 MHz, CDCl3): δ = 168.5, 152.2, 148.7, 136.8, 112.9,
100.8, 97.2, 56.5, 51.2, 37.8, 14.5; HRMS (ESI): m/z Calcd for
C11H16NO4 226.1106, found 226.1116 [M + H]+.
Methyl 4-(Benzyloxy)-2-(ethylamino)-5-methoxybenzoate (2b).
Reddish brown solid. Mp: 90À92 ꢀC; FT-IR: (cmÀ1) 3352, 2924, 2855,
1668, 1582, 1516, 1456, 1366, 1238, 1165, 1104, 994, 909, 862, 810, 774,
743, 701; 1H NMR (400 MHz, CDCl3): δ= 7.26À7.46 (m, 6H), 6.09
(s, 1H), 5.16 (s, 2H), 3.80 (s, 6H), 3.07À3.12 (m, 2H), 1.25 (t, 2H, J = 7.05
Hz); 13C NMR (75 MHz, CDCl3): δ = 168.5, 154.5, 148.3, 139.3, 136.5,
128.6, 127.9, 127.1, 114.6, 100.9, 96.5, 70.5, 56.8, 51.1, 37.6, 14.4; HRMS
(ESI): m/z Calcd for C18H22NO4 316.1548, found 316.1554 [M + H]+.
N-Benzylbutan-1-amine (2c). To a stirred solution of Bu2BOTf
(1.46 mL, 1.502 mmol) in dry CH2Cl2 (2 mL), 1-(azidomethyl)benzene
(1c, 200 mg, 1.502 mmol) dissolved in dry CH2Cl2 (2 mL) was added at
0 ꢀC and stirred at room temperature for 2 min. The reaction mixture
was neutralized with saturated aqueous NaHCO3 solution, extracted the
organic layer, dried over Na2SO4 and evaporated under reduced
pressure. The crude product thus obtained was purified by column
chromatography through silica gel (60À120 mesh) pad employing ethyl
acetate/hexane (80:20) as eluent to afford the compound 2c (220 mg,
90%). White solid. Mp: 54À56 ꢀC; FT-IR: (cmÀ1) 3419, 3074, 2924,
N-Butylnaphthalen-1-amine (2j). Dark brown solid. Mp: 72À74 ꢀC;
FT-IR: (cmÀ1): 3432, 3057, 2956, 2927, 2863, 1623, 1582, 1526, 1476,
1408, 1375, 1343, 1283, 1218, 1183, 1028, 766; 1H NMR (200 MHz,
CDCl3): δ = 7.70À7.75 (m, 2H), 7.13À7.43 (m, 4H), 6.49À6.58 (m,
1H), 4.22 (br, 1H), 3.22 (t, 2H, J = 6.61 Hz), 1.69À1.83 (m, 2H),
1.43À1.63 (m, 2H), 0.98À1.06 (t, 3H, J = 7.34 Hz); 13C NMR (75
MHz, CDCl3): δ = 143.5, 134.2, 128.6, 126.6, 125.6, 124.5, 123.3, 119.7,
117.0, 104.2, 43.9, 31.5, 20.5, 13.9; HRMS (ESI): m/z Calcd for
C14H18N 200.1439, found 200.1431 [M + H]+.
4-Chloro-N-cyclohexylaniline (2k). To a stirred solution of Cy2BOTf
(424 mg, 1.302 mmol) in dry CH2Cl2 (2 mL) was added p-chloro-azido
benzene (1k, 200 mg, 1.302 mmol) dissolved in dry CH2Cl2 (2 mL) at
0 ꢀC, and the mixture was stirred at room temparature for 20 min. The
reaction mixture was neutralized with saturated aqueous NaHCO3
solution, extracted the organic layer, dried over Na2SO4, and evaporated
under reduced pressure. The crude product thus obtained was purified
by column chromatography through silica gel (60À120 mesh) pad
employing ethyl acetate/hexane (80:20) as eluent to afford the com-
pound 2k as brown liquid. FT-IR: (cmÀ1) 3401, 2928, 2853, 1601, 1504,
1
2852, 1604, 1438, 1383, 1240, 1170, 1032, 750, 639; H NMR (300
MHz, CDCl3): δ = 7.26À7.36 (m, 5H), 4.38 (br, 1H), 3.89 (s, 2H),
2.67À2.72 (t, 2H, J = 7.54 Hz), 1.52À1.61 (m, 2H), 1.22À1.40 (m, 2H),
0.88À0.93 (t, 3H, J = 7.17 Hz); 13C NMR (75 MHz, CDCl3): δ 133.5,
129.4, 128.9, 128.7, 52.1, 47.4, 29.2, 19.9, 13.5; HRMS (ESI): m/z Calcd
for C11H18N 164.1439, found 164.1432 [M + H]+.
N-Butyl-4-chloroaniline (2d). Reddish brown liquid. FT-IR: (cmÀ1
)
3417, 2958, 2928, 2866, 1600, 1501, 1399, 1318, 1256, 1176, 1141, 1092,
813, 763; 1H NMR (200 MHz, CDCl3): δ = 7.06 (d, 2H, J = 8.81 Hz),
6.46 (d, 2H, J = 8.81 Hz), 3.50 (br, 1H), 3.05 (t, 2H, J = 6.61 Hz),
1.33À1.66 (m, 4H), 0.96 (t, 3H, J = 7.34 Hz); 13C NMR (100 MHz,
CDCl3): δ = 146.9, 128.9, 121.5, 113.7, 43.7, 31.4, 20.2,13.8; HRMS
(ESI): m/z Calcd for C10H15NCl 184.0893, found 184.0890 [M + H]+.
1
1320, 1117, 772, 747, 691; H NMR (200 MHz, CDCl3): δ = 6.98
(d, 2H, J = 8.79 Hz), 6.37 (d, 2H, J = 8.06 Hz), 3.43 (s, 1H), 3.08À3.16
(m, 1H), 2.24 (t, 1H, J = 7.34 Hz), 1.92À1.99 (m, 4H), 1.73 (tt, 3H, J =
3.66, 4.39 Hz), 1.53À1.62 (m, 2H); 13C NMR (75 MHz, CDCl3): δ =
147.4, 129.2, 116.8, 113.1, 51.7, 33.5, 25.9, 25.0. HRMS (ESI): m/z
Calcd for C12H17NCl 210.1049, found 210.1054 [M + H]+.
N-Butyl-4-methoxyaniline (2e). Reddish brown liquid, FT-IR: (cmÀ1
)
3372, 2957, 2868, 1671, 1603, 1511, 1462, 1295, 1244, 1177, 1146, 1033,
N-Cyclohexyl-4-methoxyaniline (2l). Reddish brown liquid. FT-IR:
827, 756; 1H NMR (200 MHz, CDCl3): δ = 6.73 (d, 2H, J = 8.81 Hz),
(cmÀ1) 3446, 2924, 1509, 772; 1H NMR (200 MHz, CDCl3): δ = 6.72
7023
dx.doi.org/10.1021/jo200931m |J. Org. Chem. 2011, 76, 7017–7026

The Journal of Organic Chemistry
ARTICLE
(d, 2H, J = 8.81 Hz), 6.49 (d, 2H, J = 9.55 Hz), 3.73 (s, 3H), 3.06À3.21
(m, 1H), 2.38 (br, 1H), 2.04 (dd, 2H, J = 2.93, 12.49 Hz), 1.58À1.80 (m,
3H), 1.00À1.46 (m, 5H); 13C NMR (100 MHz, CDCl3): δ = 152.0,
140.9, 115.1, 114.8, 55.7, 53.0, 33.3, 25.8, 24.9. HRMS (ESI): m/z Calcd
for C13H20NO 206.1544, found 206.1538 [M + H]+.
1.97À2.13 (m, 1H), 1.22À 1.38 (m, 2H), 1.03À1.15 (m, 2H), 0.78
(t, 3H, J = 7.36 Hz); 13C NMR (75 MHz, CDCl3): δ = 168.4, 165.5,
150.3, 147.3, 135.9, 131.9, 128.7, 128.2, 126.8, 114.2, 111.6, 108.3, 71.1,
69.2, 56.3, 53.7, 49.4, 48.2, 34.8, 30.6, 19.7, 13.6. HRMS (ESI): m/z calcd
for C24H29N2O5 425.2010, found 425.2037 [M + H]+.
N-Cyclohexylnaphthalen-1-amine (2m). Dark brown solid. Mp:
(2R,11aS)-10-Butyl-2-hydroxy-7,8-dimethoxy-2,3-dihydro-1H-benzo-
[e]pyrrolo[1,2-a][1,4]diazepine-5,11(10H,11aH)-dione (4e). Pale yellow
1
76À78 ꢀC; H NMR (200 MHz, CDCl3): δ = 7.67À7.75 (m, 2H),
7.09À7.38 (m, 4H), 6.57 (d, 1H, J = 7.01 Hz), 4.18 (br, 1H), 3.40À3.49
(m, 1H), 2.14À2.21 (m, 2H), 1.64À1.90 (m, 3H), 1.1À1.56 (m, 6H);
13C NMR (100 MHz, CDCl3): δ = 134.4, 128.6, 126.5, 125.5, 124.4,
123.3, 119.7, 116.6, 104.7, 51.7, 33.2, 29.6, 26.0, 25.0. HRMS (ESI): m/z
Calcd for C16H20N 226.1595, found 226.1593 [M + H]+.
viscous liquid. [R]25D = +201.230 (c = 0.012, CHCl3); FT-IR: (cmÀ1
)
2957, 1663, 1637, 1603, 1518, 1442, 1361, 1268, 1176, 1025, 964.4, 901,
752, 530. 1H NMR (300 MHz, CDCl3): δ = 7.32 (s, 1H), 6.68 (s, 1H),
5.29À5.39 (m, 1H), 4.12À4.32 (m, 1H), 3.95 (s, 3H), 3.90 (s, 3H),
3.39À3.71 (m, 2H), 3.13À3.24 (m, 2H), 3.02 (s, 3H), 2.38À2.49 (m, 1H),
1.19À1.55 (m, 5H), 0.90 (t, 3H, J = 7.55 Hz); 13C NMR (75 MHz,
CDCl3): δ = 167.6, 165.3, 152.1, 147.1, 133.1, 122.4, 114.3, 111.4, 78.2,
56.3, 55.7, 51.6, 48.6, 38.6, 33.5, 29.8, 29.7, 19.8, 13.7. HRMS (ESI): m/z
calcd for C19H27N2O7S 427.1538, found 427.1548 [M + H]+.
(2R,11aS)-8-(Benzyloxy)-10-butyl-7-methoxy-5,11-dioxo-2,3,5,10,11,
11a-hexahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-2-yl Methane-
sulfonate (4f). Pale yellow liquid. [R]25D = +158.521 (c = 0.015, CHCl3);
FT-IR: (cmÀ1) 2929, 1641, 1635, 1603, 1435, 1355, 1173, 1035, 771; 1H
NMR (500 MHz, CDCl3): δ = 7.33À7.38 (m, 5H), 7.28À7.31 (m, 1H),
6.63 (s, 1H), 5.12À5.25 (m, 2H), 4.32À4.34 (m, 1H), 4.17À4.20 (m,
1H), 3.97 (s, 3H), 3.74À3.75 (m, 2H), 3.40À3.44 (m, 2H), 3.00 (s, 3H),
2.37À2.41 (m, 1H), 1.51À1.57 (m, 1H), 1.33À1.39 (m, 2H), 1.08À
1.12 (m, 2H), 0.82 (t, 3H, J = 7.00 Hz). 13C NMR (75 MHz, CDCl3):
δ = 167.3, 165.0, 150.6, 147.5, 135.8, 132.6, 128.7, 128.2, 126.8, 122.3,
111.6, 108.3, 78.0, 71.0, 56.1, 55.5, 51.5, 48.3, 38.4, 33.3, 29.6, 19.6, 13.5;
HRMS (ESI): m/z calcd for C25H30N2O7SNa 525.1671, found
525.1661 [M + Na]+.
(2R,11aS)-10-Butyl-7,8-dimethoxy-5,11-dioxo-2,3,5,10,11,11a-hexa-
hydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-2-yl 4-Methylbenzene-
sulfonate (4g). Colorless viscous liquid. [R]25D = +124.423 (c = 0.010,
CHCl3); FT-IR: (cmÀ1). 2930, 1642, 1605, 1517, 1455, 1364, 1258,
1219, 1122, 1017, 772; 1H NMR (CDCl3, 500 MHz): δ = 7.77À7.79
(m, 1H), 7.36 (s, 2H), 6.94 (s, 1H), 6.73 (s, 2H), 5.36À5.42 (m, 1H),
4.17À4.35 (m, 1H), 3.93 (s, 6H), 3.70À3.72 (m, 2H), 3.45 (t, 2H, J =
7.00 Hz), 2.45 (s, 3H), 1.86À2.15 (m, 2H), 1.29À1.38 (m, 2H),
1.18À1.24 (m, 2H), 0.81 (3H, J = 7.00 Hz); 13C NMR (75 MHz,
CDCl3): δ = 167.1, 161.5, 151.7, 147.0, 133.0, 130.7, 130.0, 127.8, 127.0,
112.5, 111.5, 105.8, 78.3, 56.8, 56.0, 55.6, 48.5, 29.8, 23.7, 19.8, 13.7;
HRMS (ESI): m/z calcd for C25H30N2O7SNa 525.1671, found
525.1690 [M + Na]+.
(S)-tert-Butyl 2-((Butylamino)methyl)pyrrolidine-1-carboxylate (2n).
White solid. Mp: 54À56 ꢀC; [R]25D = À26.62 (c = 0.0015, CHCl3); FT-IR:
1
(cmÀ1) 3435, 2925, 2854, 2103, 1683, 1417; H NMR (300 MHz,
CDCl3): δ = 5.02À4.90 (dd, 1H, J = 7.79, 10.95 Hz), 3.39 (t, 2H, J = 6.98,
7.17 Hz), 2.40 (t, 2H, J = 8.12 Hz), 2.06À1.97 (m, 4H), 1.46À1.25
(m, 14H), 0.95 (t, 2H, J = 7.17, 7.36 Hz), 0.87 (t, 2H, J = 6.42, 6.79 Hz);
13C NMR (75 MHz, CDCl3): δ = 139.2, 81.9, 55.2, 53.4, 49.4, 47.8, 33.7,
31.8, 29.6, 23.6, 22.6, 19.5, 17.5, 14.0; HRMS (ESI): m/z Calcd for
C14H29N2O2 257.2229, found 257.2220 [M + H]+.
(S)-10-Butyl-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-
5,11(10H,11aH)-dione (4a). Brown solid. Mp: 93À94 ꢀC; [R]25
=
D
+121.36 (c = 0.0012, CHCl3); FT-IR: (cmÀ1): 2926, 2872, 1670, 1641,
1600, 1455, 1405, 1288, 1242, 1154, 1082, 958, 843, 768, 709; 1H NMR
(500 MHz, CDCl3): δ = 7.92 (d, 1H, J = 7.28 Hz), 7.52 (t, 1H, J = 7.28
Hz), 7.29 (qt, 2H), 4.19À4.25 (m, 1H), 4.01 (d, 1H, J = 6.24 Hz), 3.78À
3.82 (m, 1H), 3.53À3.65 (m, 2H), 2.73 (d, 1H, J = 11.45 Hz), 2.09À2.18
(m, 1H), 1.94À2.03 (m, 2H), 1.41À1.59 (m, 2H), 1.20À1.27 (m, 2H),
0.85 (t, 3H, J = 7.28 Hz); 13C NMR (75 MHz, CDCl3): δ = 169.1, 164.9,
139.3, 131.8, 130.9, 130.1, 125.7, 122.4, 57.2, 47.9, 46.4, 29.9, 26.5, 23.7,
19.8, 13.5; HRMS (ESI): m/z Calcd for C16H21N2O2 273.1603, found
273.1599 [M + H]+.
(S)-10-Butyl-8-chloro-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]-
diazepine-5,11(10H,11aH)-dione (4b). Yellowish solid. Mp: 70À72 ꢀC;
[R]25 = +162.037 (c = 0.0011, CHCl3); FT-IR: (cmÀ1) 2926, 2858,
D
1681, 1639, 1590, 1440, 1372, 1280, 1235, 1204, 1157, 1094, 1027, 924,
841, 801, 770, 710; 1H NMR (500 MHz, CDCl3): δ = 7.86 (d, 1H, J =
7.28 Hz), 7.26 (t, 2H, J = 7.28 Hz), 4.23 (qt, 1H), 3.98 (d, 1H, J = 6.24
Hz), 3.76À3.80 (m, 1H), 3.51À3.62 (m, 2H), 2.71À2.76 (m, 1H),
2.09À2.20 (m, 1H), 1.95À2.04 (m, 2H), 1.53À1.62 (m, 2H),
1.41À1.51 (m, 2H), 0.89 (t, 3H, J = 7.28 Hz). 13C NMR (75 MHz,
CDCl3): δ 168.9, 164.2, 140.5, 137.7, 131.6, 129.5, 126.0, 122.6, 57.3,
48.2, 46.6, 29.9, 26.6, 23.8, 19.8, 13.5; HRMS (ESI): m/z Calcd for
C16H20N2O2Cl 307.1213, found 307.1202 [M + H]+.
(2R,11aS)-8-(Benzyloxy)-10-butyl-7-methoxy-2-(4-methoxybenzyl-
oxy)-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5,11(10H,
11aH)-dione (4h). Colorless viscous liquid. [R]25D = +94.723 (c = 0.02,
CHCl3); FT-IR: (cmÀ1) 2928, 2870, 1634, 1602, 1510, 1115, 720 ; 1H
NMR (CDCl3, 500 MHz): δ = 7.31À7.40 (m, 5H), 7.22À7.26 (m, 2H),
6.86 (d, 3H, J = 9.00 Hz), 6.64 (s, 1H), 5.15À5.28 (m, 2H), 4.42À4.49
(m, 3H), 4.11À4.26 (m, 1H), 3.95 (s, 3H), 3.79 (s, 3H), 3.70À3.75 (m,
2H), 3.46 (t, 2H, J = 7.00 Hz), 2.01À 2.16 (m, 2H), 1.52À1.59 (m, 2H),
1.30À1.43 (m, 2H), 0.91 (t, 3H, J = 7.00 Hz); 13C NMR (75 MHz,
CDCl3): δ = 168.5, 165.3, 152.8, 150.3, 147.3, 135.9, 130.8, 129.7, 129.3,
128.7, 128.2, 127.9, 126.8, 113.8, 111.6, 108.3, 75.7, 72.5, 71.2, 56.2, 56.1,
55.2, 50.6, 48.1, 38.6, 31.5, 19.1, 13.8; HRMS (ESI): m/z calcd for
C32H36N2O6Na 567.2471, found 567.2461 [M + Na]+.
(S)-10-Butyl-7,8-dimethoxy-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a]-
[1,4]diazepine-5,11(10H,11aH)-dione (4c). White crystalline solid. Mp:
118À120 ꢀC; [R]25D = +22.123 (c = 0.0011, CHCl3); FT-IR: (cmÀ1
)
3445, 2945, 2872, 1678, 1629, 1518, 1435, 1370, 1252, 1211, 1115, 1013,
1
874, 783, 726; H NMR (300 MHz, CDCl3): δ = 7.31 (s, 1H), 6.66
(s, 1H), 4.22À4.32 (m, 1H), 4.01 (d, 1H, J = 6.04 Hz), 3.94 (s, 3H), 3.89
(s, 3H), 3.71À3.77 (m, 1H), 3.45À3.57 (m, 2H), 2.73 (d, 1H, J = 10.95
Hz), 2.09À2.33 (m, 1H), 1.88À2.05 (m, 2H), 1.38À1.49 (m, 2H),
1.18À1.30 (m, 2H), 0.87 (t, 3H, J = 7.18 Hz); 13C NMR (75 MHz,
CDCl3): δ = 169.1, 164.9, 151.55, 146.7, 132.2, 123.7, 111.2, 105.5, 57.4,
56.1, 56.0, 48.0, 46.4, 29.9, 26.5, 23.8, 19.8, 13.6; HRMS (ESI): m/z
Calcd for C18H25N2O4 333.1814, found 333.1819 [M + H]+.
(S)-Methyl 1-(2-(Butylamino)benzoyl)pyrrolidine-2-carboxylate (5a).
)
Brown liquid. [R]25D = +345.00 (c = 0.0011, CHCl3); FT-IR: (cmÀ1
(2R,11aS)-8-(Benzyloxy)-10-butyl-2-hydroxy-7-methoxy-2,3-dihydro-
1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5,11(10H,11aH)-dione (4d).
Colorless viscous liquid. [R]25D = +147.327 (c = 0.011, CHCl3); FT-IR:
(cmÀ1) 3414, 2929, 1660, 1617, 1422, 1261, 1220, 1182, 722. 1H NMR
(300 MHz, CDCl3): δ = 7.34À7.39 (m, 6H), 6.65 (s, 1H), 5.13À5.34
(m, 2H), 4.59À4.69 (m, 1H), 4.15À4.24 (m, 1H), 3.94 (s, 3H), 3.60À
3.65 (m, 2H), 3.25À3.40 (m, 2H), 2.90À3.01 (m, 1H), 2.33À2.43 (m, 1H),
3378, 2957, 2871, 1742, 1676, 1629, 1584, 1517, 1456, 1404, 1320,
1288, 1200, 1091, 1036, 921, 799, 751; 1H NMR (300 MHz, CDCl3):
δ = 7.14À7.19 (m, 2H), 6.53À6.59 (m, 2H), 5.49 (br, 1H), 4.62 (br,
1H), 3.75 (s, 3H), 3.64À3.69 (m, 1H) 3.45À3.56 (m, 1H), 3.09 (t, 2H,
J = 6.79 Hz), 2.24À2.36 (m, 1H), 1.84À2.06 (m, 3H), 1.64 (qt, 2H),
1.38À1.51 (m, 2H), 0.96 (t, 3H, J = 6.79 Hz); 13C NMR (100 MHz,
CDCl3): δ = 172.9, 170.1, 146.7, 131.2, 127.6, 119.4, 114.9, 110.9, 58.7,
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1
1167, 1095, 999, 754; H NMR (500 MHz, CDCl3): δ = 7.18À7.22
(m, 2H), 6.58À6.62 (m, 2H), 5.58 (s, 1H), 5.08 (s, 1H), 3.87 (s, 3H),
3.63À3.73 (m, 1H) 3.36À3.48 (m, 1H), 3.24 (s, 3H), 3.06À3.16 (m,
2H), 2.26À2.39 (m, 1H), 1.90À2.04 (m, 2H), 1.81À1.88 (m, 1H),
1.62À1.70 (m, 2H), 1.38À1.46 (m, 2H), 0.93 (t, 3H, J = 7.8 Hz); 13C
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114.9, 110.3, 60.9, 56.1, 48.5, 42.8, 30.8, 29.2, 28.8, 24.6, 19.9, 13.4;
HRMS (ESI): m/z Calcd for C18H27N3O3Na 356.1950, found 356.1934
[M + Na]+.
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dure and compound characterization with H/13C NMR and
1
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Rodrigues, J. A. R.; Abramovitch, R. A.; de Souse, J. D. F.; Leiva, G. C.
J. Org. Chem. 2004, 69, 2920–2928.
HRMS. This material is available free of charge via the Internet at
http://pubs.acs.org.
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’ AUTHOR INFORMATION
Corresponding Author
*Tel: +91-40-27193157; fax: +91-40-27193189; e-mail:
ahmedkamal@iict.res.in (A.K.); tel: 9849077509; e-mail: chsrkuc@
yahoo.co.in (C.S.R.).
’ ACKNOWLEDGMENT
N.M.K., V.S., and K.S., are thankful to CSIR, New Delhi, for
awarding of research fellowships. L.S.S. thanks FONDECYT
(1110022), IFS (F/4195-1) and the Organization for the Pro-
hibition of Chemical Weapons for the support of this research.
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Hirota, K. Org. Lett. 2004, 6, 4977–4980.
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