Chemoselective aromatic azido reduction with concomitant aliphatic azide employing Al/Gd Triflates/Nal and ESI-MS mechanistic studies

Article abstract of DOI:10.1002/chem.200900853

Aluminium and gadolinium inflates catalyze the chemoselective reduction of aromatic azides to the corresponding amines in combination with sodium iodide. This mild chemoselective method has been applied to the synthesis of various aryl amines, C2azido-substituted pyrrolo[2,1-c]-[1,4]benzodiazepines, and fused[2,1b]quinazolinones by an intramolecular azido reduction tandem cyclization reaction. Interestingly, this methodology selectively reduces aryl azides with enhanced yields and proceeds in shorter reaction times than previous strategies. 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.

Full text of DOI:10.1002/chem.200900853

FULL PAPER
DOI: 10.1002/chem.200900853
Chemoselective Aromatic Azido Reduction with Concomitant Aliphatic
Azide Employing Al/Gd Triflates/NaI and ESI-MS Mechanistic Studies
Ahmed Kamal,*[a] Nagula Markandeya,[b] Nagula Shankaraiah,[c] C. Ratna Reddy,[a]
S. Prabhakar,[a] C. Sanjeeva Reddy,*[b] Marcos N. Eberlin,[c] and Leonardo Silva Santos[d]
Abstract: Aluminium and gadolinium
triflates catalyze the chemoselective re-
duction of aromatic azides to the corre-
sponding amines in combination with
sodium iodide. This mild chemoselec-
tive method has been applied to the
synthesis of various aryl amines, C2-
b]quinazolinones by an intramolecular
azido reduction tandem cyclization re-
action. Interestingly, this methodology
selectively reduces aryl azides with en-
hanced yields and proceeds in shorter
reaction times than previous strategies.
The mechanistic aspects have been in-
vestigated and the intermediates asso-
ciated with this selective transforma-
tion have been intercepted and charac-
terized by online monitoring of the re-
action by ESI-MS.
Keywords: amines
cyclization
mass spectrometry · reduction
·
azides
·
·
·
heterocycles
azido-substituted
pyrroloACHUTNGTRENNUNG
G
Introduction
found use in peptide synthesis as excellent protecting
groups.[6] In the literature, various procedures are available
for the synthesis of amines, however, the reduction of azides
is the most attractive method because of their easy accessi-
bility.[7] A variety of reducing reagents have been reported
in the literature[2] for the transformation of azides into
amines. The most prominent ones are LiAlH4,[8] borohy-
drides,[9] triphenylphosphine,[10] metal-catalyzed hydrogena-
tions,[11] and radical initiators.[12] These methods are applica-
ble to many synthetic conditions, but the majority of them
have several drawbacks, including tedious work-up, long re-
action times, harsh reaction conditions, and poor selectivity.
Accordingly, these drawbacks have stimulated the search for
better catalysts that could be superior to the existing ones
with regard to selectivity, handling, toxicity, and environ-
mental compatibility.
The interconversion of aryl azides into anilines has received
modest interest in synthetic chemistry, and the azides are
mostly obtained from anilines through their diazonium
salts.[1,2] However, inspite of their explosive properties, or-
ganic azides are valuable intermediates in organic synthe-
sis.[1,3] Recently, they have been extensively used in ꢀclickꢁ
chemistry[4] for the synthesis of 1,2,3-triazoles, tetrazoles,
anilines, N-alkylated anilines,[5] and nitrenes. They have also
[a] Dr. A. Kamal, C. R. Reddy, S. Prabhakar
Chemical Biology Laboratory
Indian Institute of Chemical Technology
Hyderabad 500 007 (India)
Fax : (+91)40-27193189
E-mail: ahmedkamal@iict.res.in
[13]
[b] N. Markandeya, Prof. C. S. Reddy
Department of Chemistry
Kakatiya University
Previous studies have shown that Lewis acids like TiCl4
in combination with NaI offer a useful alternative to existing
methods for the reduction of amines, N-oxides, and nitrones.
Based on this analogy, we previously developed a procedure
for the reduction of azides to the corresponding amines by
employing FeCl3 in combination with NaI. However, in the
present-day context, the requirement for greener and effi-
cient Lewis acid promoters in organic transformations has
encouraged the development of environmentally friendly
methodologies.
Warangal 506 009, A.P. (India)
Fax : (+91)870-2439600
E-mail: chsrkuc@yahoo.co.in
[c] Dr. N. Shankaraiah, Prof. M. N. Eberlin
ThoMSon Mass Spectrometry Laboratory
University of Campinas, Unicamp (Brazil)
[d] Prof. L. Silva Santos
Laboratory of Asymmetric Synthesis
Chemistry Institute of Natural Resources
Talca University, Talca, P.O. Box 747 (Chile)
In recent years, the use of metal triflates such as Al-
ACHTNUTGRNEGU(N OTf)3, GdACHUTNGTRENN(UNG OTf)3, YtACHTNURGTEG(NNUN OTf)3, CuAHTCUNGTREN(NUNG OTf)2, and DyACHTNUGTNRUEGN(OTf)3 in
many organic transformations has grown significantly. The
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900853.
Chem. Eur. J. 2009, 15, 7215 – 7224
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7215

most prominent metal catalyst is aluminium triflate since it
is stable to air and moisture. It is used in Friedel–Crafts al-
kylation reactions[14a] and is a highly chemoselective hetero-
geneous catalyst for the dithioacetalization of carbonyl com-
pounds.[14b] Recently, it was found to be an efficient catalyst
for epoxide ring-opening,[14c,d] the esterification of carboxylic
acids with alcohols,[14e] thiol protection,[14f] the silylation of
alcohols and phenols,[14g] and it has also been used as a co-
catalyst in biodegradable polymerization reactions.[14h] Re-
cently, some facile methods for the acylation of alcohols,
phenols, and thiols have been developed in this laboratory
groups. Therefore we have previously reported some mild
and efficient azido reduction methods using a variety of re-
agent systems.[22] As a continuation of these efforts, and with
a view particularly to extending the applicability of NaI to
the reduction of aryl azides to the corresponding amino
compounds in a chemoselective manner, the reactions of
aryl azides in the presence of metal triflate catalysts and
NaI are described herein for the first time.
Optimization of the reaction conditions: To demonstrate the
generality of this method initially we investigated the scope
of these azido reductions under optimized reaction condi-
tions by using a variety of solvents, for example, CH2Cl2,
CH3CN, THF, MeOH, and EtOH, with the aim of increasing
the yields, shorten the reaction time, and to obtain a clean
product. Of the solvents tested, CH3CN was generally more
efficient than other solvents. Notably, the best conversions
and yields were achieved with CH3CN as solvent (up to
95% conversion, 90% yield in the reaction of 2a; Table 1).
The chemoselectivity of the azido reduction process was
also most efficient in CH3CN as solvent. The efficiency of
these solvents based on conversions and yields decreases in
the order CH3CN>CH2Cl2 >THF>MeOH>EtOH.
by using AlACHTUNGTRENNUNG
(OTf)3 as the catalyst.[15] This prompted us to de-
velop new methodologies involving metal triflates in combi-
nation with NaI for promoting different transformations,
which has led us to report a new protocol for the reduction
of aryl azides by employing metal triflate and NaI combina-
tions. In addition, the chemoselectivity of this reagent
system has also been examined for different types of sub-
strates.
Various mechanisms have been proposed for such metal-
assisted reduction of azides.[16,17] Comprehensive mechanistic
investigations usually require kinetic data gained by moni-
toring over long timescales, usually by UV, IR, or NMR
spectroscopy. However, these techniques are often not suita-
ble for the short timescales required for investigating transi-
ent species as unequivocal assignments of UV and IR bands
or NMR peaks and couplings, particularly for more complex
or transient structures, may be challenging and sometimes
unfeasible. 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, molecular analysis by mass spectrometry (MS)
has greatly benefited from the development of electrospray
ionization (ESI)[18] because molecules and supramolecules[19]
of high polarity, molecular complexity, and/or mass can be
easily ionized by ESI for investigation by MS. ESI is an in-
teresting “ion-fishing” technique because it gently transfers
preformed ions directly from solution to the gas phase. ESI-
MS (and its tandem version ESI-MS/MS) is rapidly becom-
ing the technique of choice for solution mechanistic studies
in chemistry and biochemistry[20] and in high-throughput
screening of homogeneous catalysis reactions.[21] In this con-
text, we were interested in employing the online ESI-MS
technique to trap and characterize the transient species that
Next, various metal triflates were examined and the re-
sults are summarized in Table 1. The soft Lewis acid metal
triflates tested were Al
(OTf)3, and Cu(OTf)2, in combination with NaI. In most
cases the yields were significantly improved when the reac-
tion was performed with Al(OTf)3 (20 mol%) as the catalyst
(Table 1, 78–92%). We also observed the chemoselective
formation of the desired products when Gd(OTf)3
ACHTUGNTRENNU(GN OTf)3, GdACHTUNRTGE(NGNUN OTf)3, YtACTHGUNTREN(NUGN OTf)3, Dy-
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
(20 mol%) was employed as the catalyst (Table 1, 52–75%).
Inferior results were obtained when other catalysts (Yt-
ACHUTNGREN(NUG OTf)3, 25%; DyACHTUNGTERN(NUGN OTf)3, 15%) were used, even with an
excess of the reagent (40–50 mol%) and prolonged reaction
times (12 h). However, a complicated mixture was obtained
when CuACTHNURTGENNG(U OTf)2 was used as the catalyst for this reaction.
Selective reduction of various aryl azido compounds: The
required azido starting materials (1a–l) were obtained ac-
cording to reported methods.[22b,c] Compounds 2a–l were
prepared from 1a–l in good-to-moderate yields (52–92%)
by using NaI (3 equiv) and AlACHTNUGTRENNUG(OTf)3 or GdACHTUNGTRENNUNG(OTf)3
(20 mol%) in CH3CN at ambient temperature for 10–45 min
(Table 1). These reactions were monitored by observing the
disappearance of the starting material, as indicated by TLC.
Note that reduction of aliphatic azido compounds 1b and 1c
fail to give the corresponding amines 2b and 2c despite the
are involved in the metal-assisted (Al
of aryl azido compounds.
ACHTUNGRTEN(NUGN OTf)3/NaI) reduction
Results and Discussion
use of excess reagents (1 equiv of AlACTHNGUTRENU(NG OTf)3 and 5 equiv of
NaI) and prolonged reaction times (24 h) under similar reac-
tion conditions (Table 1). Thus, it was concluded that this
methodology is exclusively applicable to the reduction of
aryl azides.
Interestingly, our results for 2j–l (70–92% yields; Table 1)
have revealed that the aromatic azido groups were reduced
chemoselectively when an aliphatic azido group is present in
the same substrate, with no trace of the corresponding ali-
Most recently, Marcantoni and co-workers[17] reported a ver-
satile method for aliphatic azido reductions using
CeCl3·7H2O (1.5 equiv)/NaI (9 equiv) at reflux for 24 h and
also studied the effect of microwave irradiation. However, it
is well known that a number of amines or imines decompose
at higher temperatures and in prolonged reactions. Some-
times they even dimerize in the presence of acid or ester
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Chem. Eur. J. 2009, 15, 7215 – 7224

Chemoselective Aromatic Azido Reduction
FULL PAPER
Table 1. Chemoselective reduction of aryl azides (1a–l) to the corresponding amines (2a–l) employing Al/Gd-
Therefore, we decided to apply
this chemoselective protocol to
the synthesis of C2-azido-substi-
tuted PBDs to probe its DNA-
binding ability and anticancer
activity. In our ongoing re-
search program we have been
involved in the development of
new methodologies in solution
as well as in solid-phase systems
for the synthesis of bioactive
natural products, including pyr-
ACHTUNGTRENNUNG
(OTf)3 (20 mol%) with NaI.[a]
Entry
Product
Al
(OTf)3: t [min]/
GdACTHNGUTREN(NUG OTf)3: t [min]/
yield[b,c] [%]
yield[b,c] [%]
2a
2b
2c
10/90
22/58
ND[d]
ND
ND
ND
rolobenzodiazepines[26]
fused quinazolinones.[27]
and
2d
2e
10/88
15/85
30/61
45/55
The functionalized imines
4a–f (42–88% yields) were pro-
duced by the reduction of sub-
stituted
(azido)prolinecarbaldehydes
3a–f in the presence of NaI
(3 equiv) and Al(OTf)3 or Gd-
(OTf)3 (20 mol%) at ambient
temperature for 30–75 min
(Table 2). The advantage of this
route is its ability to carry out a
chemoselective azido reduction
tandem cyclization for the syn-
thesis of this class of com-
pounds. Interestingly, the C-ring
azido-substituted PBDs 4d–f
were obtained in yields of 80–
2-azidobenzoyl-
AHCTUNGTRENNUNG
2 f
2g
2h
15/82
10/78
12/88
25/55
30/60
35/52
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
2i
2j
2k
2l
18/90
10/90
10/92
15/90
30/55
25/75
25/70
25/72
86% with Al
ACHTUNGTRENNUNG
and 55–68% with Gd
ACHTUNGTRENNUNG
[a] All reactions were conducted at room temperature with 0.5 mmol of 1a–l, 3.0 equiv of NaI, and 20 mol% (20 mol%; Table 2). This che-
of Al/GdACHTUNGTRENNUNG(OTf)3 in 2 mL of CH3CN for 10–45 min. [b] Isolated yields (purified by column chromatography).
moselective route gave im-
proved results compared with
previously reported methods
with respect to time and yields.
[c] All compounds were characterized by 1H NMR and IR spectroscopy and HRMS. [d] No product was de-
tected.
phatic amino products. Further, it was interesting to observe
that the azido derivative 1e with a carboxylic acid function-
ality fail not dimerize upon reduction using this reagent
system. In addition, with 2e, 2 f, and 2i (Table 1), even the
O-benzyl protection remained intact after the reduction pro-
cess. Moreover, most of these reactions with various sub-
strates provide good yields and clean products through a
facile work-up, as depicted in Table 1.
Encouraged by these results, this protocol was applied to
the synthesis of natural product DC-81 (4b) and benzylated
DC-81 (4c; Table 2) under similar reaction conditions.
During the course of our studies, this approach was also
employed in the preparation of PBD-5,11-diones. These
PBD-5,11-diones are important intermediates in the synthe-
sis of naturally occurring and synthetically modified PBD
imines, such as tomaymycin and chicamycin.[28] In this work,
we applied the same procedure as described earlier to the
reduction of substrates 5a–j to obtain the corresponding
PBD-5,11-diones 6a–j by an azido reduction tandem cycliza-
tion process. The results in Table 3 reveal that this proce-
In the light of these successful results, we became interest-
ed in applying this chemoselective method to the synthesis
of pyrroloACHTUNGTRENNUNG[2,1-c]ACHTUNGTRENNUNG[1,4]benzodiazepines (PBDs) and its deriva-
tives. It is well known that PBDs are a class of DNA-inter-
active potent antitumor antibiotics, gene regulators, and
DNA probes.[23] According to structure–activity relationship
(SAR) studies, C2-hydroxy substitution and C2 exo and
endo unsaturation plays an enormous role in enhancing the
DNA binding affinity and cytotoxicity of these compounds,
for example, naturally occurring chicamycin A and B,[24a] ne-
othramycin A and B,[24b] abbeymycin,[24c] and tomaymycin.[25]
dure gave improved yields of 75–90% with Al
ACHTUNGRTEN(NUNG OTf)3 and
50–75% with Gd(OTf)3 using NaI. Compounds 5 f–h were
AHCTUNGTRENNUNG
selectively reduced to the corresponding amines, which un-
derwent tandem cyclization reactions to afford 6 f–h in mod-
erate-to-excellent yields with Al
(OTf)3 (60–68%).
ACHTUNGRTEN(NUGN OTf)3 (80–90%) and Gd-
AHCTUNGTRENNUNG
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7217

A. Kamal, C. S. Reddy et al.
ies[33] because it transfers ions
directly from the solution to the
gas phase smoothly and effi-
ciently (no or little dissocia-
tion), thereby providing snap-
shots of the ion composition of
the reaction solutions. We have
used this technique extensively
to investigate the mechanisms
of some major reactions.[34–36]
Table 2. Chemoselective aryl azido reduction for the synthesis of PBD-imines 4a–f employing Al/GdACHTNUTRGNE(NUG OTf)3
(20 mol%) and NaI.[a]
Entry
4a
Product
Al
G
GdACTHNGUTREN(NUG OTf)3: t [min]/
yield[b,c] [%]
yield[b,c] [%]
30/88
45/50
To clarify the mechanism of
the reduction reactions and
provide experimental evidence
for the catalytic cycle proposed
in Scheme 1,[16] we investigated
the reduction of azides promot-
ed by CeCl3 by using mass spec-
trometry techniques. The reac-
tion mixture was electrosprayed
by the ESI source operated in
the positive ion mode, and the
cationic species were monitored
online by MS analysis. We also
monitored the reaction by ESI-
MS in the negative ion mode,
but no metal anions were de-
tected. ESI is known for its
ability to transfer ions to the
gas phase without inducing un-
desirable side-reactions. Indeed,
4b
45/75
30/80
30/85
35/86
40/80
75/42
50/45
60/68
65/60
60/55
4c
4d
4e
4 f
[a] All reactions were performed at ambient temperature with 0.5 mmol of 3a–f, 3.0 equiv of NaI, and
20 mol% of Al/GdACHTUNGTRENNUNG(OTf)3 in 2 mL of CH3CN for 30–75 min. [b] Isolated yields (purified by column chromatog-
raphy). [c] All the compounds were characterized by H/13C NMR and IR spectroscopy and HRMS.
1
Furthermore, it has been our long-term interest to explore
both the selective reduction of aryl azides and intramolecu-
lar azido reductive cyclization reactions. To undertake such
studies, the present chemoselective method was further ex-
tended to the synthesis of fused [2,1-b]quinazolinones. Re-
cently, vasicinone and its analogues were synthesized[29] and
evaluated for their bronchodilatory activity.[30] This class of
compounds, particularly deoxyvasicinone, is found in nature
and is reported to possess various pharmacological proper-
ties, such as antitumor[31] and antimycobacterial[32] activity,
and is used extensively in indigenous medicine for colds,
coughs, and asthma.[30]
The substituted azidobenzoyl precursors 7a–g were re-
duced by employing the same reagent system as described
earlier to afford the corresponding cyclized products 8a–g in
Scheme 1. Proposed mechanism for the conversion of aryl azides into
amines by using a) CeCl3,[16] and b) Al
(OTf)3/NaI based on an ESI(+)-
MS(/MS) analysis.
moderate-to-good yields using AlACHTUNGTERN(NUNG OTf)3 (82–95%) and Gd-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
Mechanistic studies: We monitored the reactions by ESI-
MS(/MS) experiments in an attempt to intercept ionic inter-
ACHTUNGTRENNUNG
mediates and thereby collect mechanistic information that
could allow optimization of the reaction conditions. By em-
ploying ESI(+)-MS, we monitored the reaction of the azide
1b with CeCl3·7H2O in MeCN, a reaction that was expected
to yield the amine 2b (Scheme 1). ESI-MS has been shown
to be a useful technique for carrying out mechanistic stud-
the ESI-MS spectra collected for such reactions are extraor-
dinarily clean and mechanistically enlightening. A number
of ions were detected that could be attributed to the species
shown in Figure 1. The isotopic patterns of the ions matched
those calculated for the suggested species, particularly those
containing multi-isotope elements such as iodine and nitro-
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Chemoselective Aromatic Azido Reduction
FULL PAPER
Table 3. Chemoselective aryl azido reduction with Al/Gd
(OTf)3
Table 4. Synthesis of fused quinazolinones 8a–g by an azido reduction
(20 mol%) for the synthesis of PBD-5,11-diones 6a–j.[a]
tandem cyclization process by using Al/GdACTHNGUTERNNUG
(OTf)3 (20 mol%).[a]
Entry
6a
6b
6c
Product
Al
(OTf)3: t [min]/
GdACTHNGUTREN(NUG OTf)3: t [min]/
yield[b,c] [%]
yield[b,c] [%]
Entry
Product
Al
E
GdACTHNGUTREN(NUG OTf)3:t [min]/
yield[b,c] [%]
yield[b,c] [%]
30/89
45/75
8a
30/95
40/55
30/84
35/82
35/90
40/77
30/90
35/80
32/86
45/79
50/75
45/65
50/62
55/65
75/55
60/62
50/68
55/60
70/50
75/55
8b
8c
8d
8e
30/92
35/95
40/88
40/90
45/50
55/38
45/50
40/62
6d
6e
6 f
8 f
8g
45/85
50/82
60/40
55/60
6g
6h
6i
[a] All reactions were performed at ambient temperature with 0.5 mmol
of 7a–g, 3.0 equiv of NaI, and 20 mol% of Al/Gd(OTf)3 in 2 mL of
CH3CN for 30–60 min. [b] Isolated yields (purified by column chromatog-
raphy). [c] All the compounds were characterized by 1H/13C NMR and
IR spectroscopy and HRMS.
AHCTUNGTRENNUNG
6j
nitrenoid species. It has been reported that azides can pro-
duce metal–nitrenoid species and our results show that the
the azido reduction of aromatic azides follows a similar
mechanism (Scheme 1b).[37–39] The mechanism in which the
metal azide compound is formed cannot be rationalized in a
straightforward way, however, a possible route to the nitre-
noid species involves metal azide dissociation with N2 loss
[a] All reactions were performed at ambient temperature with 0.5 mmol
of 5a–j, 3.0 equiv of NaI, and 20 mol% of Al/Gd(OTf)3 in 2 mL of
CH3CN for 30–75 min. [b] Isolated yields (purified by column chromatog-
raphy). [c] All the compounds were characterized by 1H/13C NMR and
IR spectrocopy and HRMS.
AHCTUNGTRENNUNG
followed by a ligand-exchange process with water to give
+
À
À
gen. The m/z values reported are those of the most abun-
dant isotopologue ions. The m/z 387 ion is likely to be the
species proposed by Marcantoni and co-workers.[17] ESI-(+
)-MS/MS shows that the species with m/z 387 dissociates by
loss of N2 and iodine to give PhCH2N=I+ with m/z 232. This
ion is therefore likely formed by the mechanism proposed in
Scheme 1a and is also sampled from solution.
species with m/z 330 [R N=AlOH+H] , m/z 440 [R N=
+
+
À
AlI+H] , and m/z 446 [R N=AlOTf+H] , as shown in
Figure 1b. Organic azides, depending on the experimental
conditions and the nature of the metal as well as the azide,
may react with the metal complex to give a metal–imido
À
species or a metal–azide adduct. The formation of a metal
nitrogen bond may occur by coordination of the terminal Ng
or Na atom or by oxidative addition of the azido group. To
predict the coordinating mode of the organic azide it is im-
portant to remember that the nitrogen in the a position is
more basic than the terminal unsubstituted one. A possible
mechanism that accommodates the features of the new reac-
Proposed mechanism: We then studied the reaction with Al-
ACHTUNGTRENNUNG(OTf)3. In the presence of aluminium complexes, it was
noted that azido compounds might give the corresponding
metal–azide adducts (not detected) prior to forming metal–
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7219

A. Kamal, C. S. Reddy et al.
Conclusions
We have reported a new cata-
lytic system for the chemoselec-
tive reduction of functionalized
aryl azides with concomitant
aliphatic azides by using a vari-
ety of metal triflates with
sodium iodide. Both the syn-
thetic and mechanistic aspects
of the reaction have been inves-
tigated and the formation of
some transient species has been
explained. This selective reduc-
tion of aryl azides to the corre-
sponding amines is interesting
and useful as it takes place in a
shorter time than previous
strategies and gives clean final
products in moderate-to-excel-
lent yields. This protocol is
clearly superior to previous
methods that used heavy metals
and hazardous reagents as well
as giving lower yields in longer
reaction times. Moreover, this
approach has been used for the
preparation of imine-containing
PBDs and their 5,11-diones as
well as bioactive fused quinazo-
linones by the intramolecular
azido reductive tandem cycliza-
tion process. Finally, we antici-
pate that this method may find
use in combinatorial library
synthesis due to its efficiency
and operational simplicity.
Figure 1. Online ESI(+)-MS spectra of a) the reaction of benzylamine with CeCl3/NaI and b) the reaction of
1b with Al(OTf)3/NaI. Note that several cationic N=Al intermediates are detected in this new protocol.
ACHTUNGTRENNUNG
tion is illustrated in Scheme 1b and is corroborated by the
data collected in the online ESI-MS experiments.
In other words, nonaromatic azido reduction reactions are
slower under triflate conditions and the products formed
from azides 1b and 1c were observed in very low yields. For
methyl 4-benzyloxy-5-methoxy-2-azidobenzoate (1i), we ob-
served a sharp decrease in the reaction rate, which indicates
that the presence of an electron-donating group on the
azide slows the reaction. This data is consistent with the
electrophilic behavior of the coordinated azide in the transi-
tion state, as expected. It is widely accepted that aryl azides
can generate metal–nitrene (imido) intermediates in the
presence of a suitable metal ion.[40] Structurally related iodo-
imine adducts have also been proposed on the basis of ki-
netic data as active intermediates in both the Mn/salen-cata-
lyzed sulfimidation of sulfides[39] and in the Mn/porphyrin-
catalyzed aziridination of olefins.[41] The collected data also
Experimental Section
General methods: Purchased chemical reagents were used without fur-
ther purification. Anhydrous THF, CH2Cl2, CH3CN, MeOH, EtOH, and
DMF to be 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. Infrared spectra were recorded on a Thermo Nicolet Nexus
670 and the wave numbers are expressed in cmÀ1. Melting points were
measured with an Eletrothermal apparatus. 1H and 13C NMR spectra
were recorded on Gemini 200, Avance 300, and Unity 400 spectrometers
using tetramethylsilane as the internal standard. Chemical shifts are re-
ported in parts per million (ppm) downfield from tetramethyl silane. Spin
multiplicities are described as s (singlet), brs (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 on a
Quattro-LC spectrometer (ESI); for molecular weights above 400 on an
LSIMS-VG-Autospec (FAB) spectrometer, and below 400 on a GC MS-
explains why when AlACHTNUGTRNEUNG(OTf)3 was used in the reaction with
subtrates containing aliphatic and aromatic azides, the reac-
tion took place selectively with the aromatic azides.
7220
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 7215 – 7224

Chemoselective Aromatic Azido Reduction
FULL PAPER
QP Zoloplus (Shimadzu) (EI-MS). The mechanistic studies were carried
out by using a Micromass Q-tof instrument. Column chromatography
was performed by using 100–200 mesh silica gel. TLC analyses were per-
formed with silica gel plates using iodine, KMnO4 and a UV lamp for vis-
ualization.
1302, 1231, 1175, 1061, 1023, 952, 869, 843, 784, 629, 448 cmÀ1; HRMS
(ESI): m/z: calcd. for C9H12NO4: 198.0766; found: 198.0774 [M+H]+·
.
Methyl 2-amino-4-benzyloxy-5-methoxybenzoate (2i): Brown solid; m.p.
131–1328C; 1H NMR (200 MHz, 258C, CDCl3, TMS): d=7.24–7.39 (m,
6H), 6.08 (s, 1H), 5.08 (s, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 1.26 ppm (d,
J=15.86 Hz, 2H); IR (KBr): n˜ =3468, 3356, 3030, 2947, 1676, 1617, 1587,
1560, 1514, 1462, 1426, 1384, 1303, 1258, 1200, 1170, 992, 872, 835, 740,
695 cmÀ1; HRMS (ESI): m/z: calcd. for C16H17NO4Na: 310.1055; found:
Procedure for the chemoselective reduction of aryl azide 1j to amine 2j:
NaI (0.031 g, 0.490 mmol) and AlACTHNUGTRENN(UG OTf)3 (0.015 g, 20 mol%) or GdACHTUNTGERN(NGUN OTf)3
(0.019 g, 20 mol%) were added to a stirred solution of 1j (0.050 g,
0.163 mmol) in CH3CN (2 mL) at ambient temperature. The combined
reaction mixture was stirred at the same temperature for 10 min and the
completion of the reaction was monitored by the disappearance of the
starting material, as indicated by TLC. Next, the solvent was removed
under reduced pressure and excess of NaI was quenched with saturated
sodium thiosulfate (Na2S2O3). The resulting product was extracted with
ethyl acetate (3ꢃ20 mL), washed with NaHCO3 solution (20 mL) and
brine (20 mL), and then dried over anhydrous Na2SO4. The final product
was further purified by short-length column chromatography through
silica gel (100–200 mesh) using ethyl acetate/hexane (8:10) as eluent to
310.1073 [M]+·
.
Methyl 2-amino-4-(4-azidobutyloxy)-5-methoxybenzoate (2k): Reddish
1
brown solid; m.p. 82–848C; H NMR (200 MHz, 258C, CDCl3, TMS): d=
7.22 (s, 1H), 6.04 (s, 1H), 3.98 (t, J=5.14 and 6.61 Hz, 2H), 3.82 (s, 3H),
3.76 (s, 3H), 3.37 (t, J=5.87 and 6.61 Hz, 2H), 1.74–1.95 ppm (m, 4H);
13C NMR (100 MHz, 258C, CDCl3, TMS): d=167.9, 154.0, 146.8, 140.6,
113.2, 102.1, 100.1, 67.8, 51.3, 51.1, 26.1, 25.7 ppm; IR (KBr): n˜ =3471,
3361, 2923, 2852, 2099, 1743, 1678, 1621, 1589, 1561, 1513, 1464, 1434,
1395, 1249, 1206, 1175, 864, 777 cmÀ1; HRMS (ESI): m/z: calcd. for
C13H18N4O4Na: 317.1225; found: 317.1218 [M]+·
.
give the desired compound 2j in good yields (90% with Al
ACHTUNGRTEN(NUNG OTf)3 and
Methyl 2-amino-4-(5-azidopentyloxy)-5-methoxybenzoate (2l): Reddish
brown solid; m.p. 102–1048C; 1H NMR (300 MHz, 258C, CDCl3, TMS):
d=7.22 (s, 1H), 6.06 (s, 1H), 3.95 (t, J=6.04 and 6.79 Hz, 2H), 3.83 (s,
3H), 3.77 (s, 3H), 3.29 (t, J=6.04 and 6.79 Hz, 2H), 1.82–1.91 (m, 2H),
1.51–1.73 ppm (m, 4H); 13C NMR (75 MHz, 258C, CDCl3, TMS): d=
187.3, 173.5, 166.0, 160.0, 132.5, 121.3, 119.4, 87.4, 75.8, 70.4, 47.7, 47.6,
42.4 ppm; IR (KBr): n˜ =3470, 3364, 2944, 2867, 2096, 1682, 1622, 1594,
1561, 1514, 1466, 1430, 1385, 1252, 1201, 1169, 1082, 1006, 887, 827,
765 cmÀ1; HRMS (ESI): m/z: calcd. for C14H20N4O4Na: 331.1382; found:
75% with Gd
ACHTUNGTRENNUNG
TMS): d=7.23 (s, 1H), 6.07 (s, 1H), 4.03 (t, J=6.04 Hz, 2H), 3.83 (s,
3H), 3.77 (s, 3H), 3.53 (t, J=6.04 and 6.79 Hz, 2H), 2.02–2.14 ppm (m,
2H); 13C NMR (75 MHz, 258C, CDCl3, TMS): d=187.8, 173.7, 166.6,
160.1, 133.0, 122.1, 120.2, 84.4, 76.2, 71.4, 67.2, 47.9 ppm; IR (KBr): n˜ =
3470, 3384, 2927, 2089, 1683, 1623, 1594, 1532, 1514, 1464, 1431, 1388,
1254, 1201, 1171, 1083, 1027, 971, 880, 828, 780, 628 cmÀ1; HRMS (ESI):
m/z: calcd. for C12H16N4O4Na: 303.1069; found: 303.1076 [M]+·
.
1-Amino-4-bromobenzene (2a): Brown solid; m.p. 60–628C; 1H NMR
(200 MHz, 258C, CDCl3, TMS): d=7.24 (d, J=8.72 Hz, 2H), 6.55 (d, J=
8.72 Hz, 2H), 3.67 ppm (brs, 2H); 13C NMR (50 MHz, 258C, CDCl3,
TMS): d=146.0, 131.8, 117.1, 109.0 ppm; IR (KBr): n˜ =3477, 3381, 3183,
1877, 1610, 1489, 1288, 1180, 1124, 1061, 833 cmÀ1; ESI (MS): m/z: 172
331.1389 [M]+·
(11aS)-1,2,3,11a-Tetrahydro-5H-pyrroloACTHNUTRGENN[GU 2,1-c]ACHUTNGTREN[NUNG 1,4]benzodiazepin-5-one
.
G
(4a): [a]2D5 =+343 (c=0.4 in CHCl3); 1H NMR (200 MHz, 258C, CDCl3,
TMS): d=8.05 (d, J=7.43 Hz, 1H), 7.79 (d, J=4.46 Hz, 1H), 7.53 (t, J=
6.69 Hz, 1H), 7.28–7.38 (m, 2H), 3.36–3.94 (m, 3H), 2.26–2.38, (m, 2H),
[M+H]+·
.
2.02–2.16 ppm (m, 2H); MS (EI): m/z: 200 [M]+·
.
1-Amino-4-chlorobenzene (2d): White solid; m.p. 70–718C; 1H NMR
(300 MHz, 258C, CDCl3, TMS): d=7.12 (d, J=8.87 Hz, 2H), 6.63 (d, J=
8.87 Hz, 2H), 3.67 ppm (brs, 2H); 13C NMR (75 MHz, 258C, CDCl3,
TMS): d=116.5, 123.7, 129.5, 144.8 ppm; IR (KBr): n˜ =3477, 3375, 3198,
1880, 1618, 1509, 1288, 1180, 1079, 1015, 647, 546 cmÀ1; ESI (MS): m/z:
DC-81 (4b): [a]2D5 =+281 (c=0.02 in CHCl3) {lit.:[42] [a]D =+135 (c=0.2
in CHCl3)}; 1H NMR (400 MHz, 258C, CDCl3, TMS): d=7.67 (d, J=
4.41 Hz, 1H), 7.52 (s, 1H), 6.90 (s, 1H), 3.96 (s, 3H), 3.42–3.87 (m, 3H),
2.12–2.32 (m, 2H), 1.81–2.10 ppm (m, 2H); MS (EI): m/z: 246 [M]+·
.
127 [M+H]+·
.
A
ACHTUNGTRENNUNG[2,1-c]-
AHCTUNGTRENNUNG
2-Amino-3-benzyloxybenzoic acid (2e): Brown solid; m.p. 141–1428C;
1H NMR (400 MHz, 258C, CDCl3, TMS): d=7.47 (d, J=9.29 Hz, 1H),
7.26–7.36 (m, 5H), 6.86 (d, J=8.80 Hz, 1H), 6.72 (brs, 1H), 6.49 (t, J=
7.82 and 8.31 Hz, 1H), 5.64 (brs, 1H), 5.00 ppm (s, 2H); 13C NMR
(50 MHz, 258C, CDCl3, TMS): d=174.4, 173.1, 146.1, 142.4, 136.6, 128.2,
123.6, 115.0, 114.5, 109.6, 76.9, 70.7, 22.6 ppm; IR (KBr): n˜ =3491, 3348,
3064, 3029, 2922, 2866, 1673, 1612, 1577, 1463, 1399, 1275, 1214, 1158,
(400 MHz, 258C, CDCl3, TMS): d=7.50 (d, J=2.97 Hz, 1H), 7.08–7.42
(m, 6H), 6.74 (s, 1H), 4.98–5.15 (m, 2H), 3.87 (s, 3H), 3.38–3.80 (m, 3H),
2.09–2.26 (m, 2H), 1.81–2.01 ppm (m, 2H); MS (EI): m/z: 336 [M]+.
ACHUTNGREN(NUG 2S,11aS)-2-Azido-1,2,3,11a-tetrahydro-5H-pyrroloHCATUNGTRENN[UGN 2,1-c]-
A
MeOH); 1H NMR (200 MHz, 258C, [D6]DMSO, TMS): d=7.55–7.60 (d,
J=6.01 Hz, 1H), 7.15–7.25 (m, 2H), 6.90–7.00 (m, 1H), 6.75–6.80 (m,
1H), 4.25–4.30 (m, 1H), 3.90–4.00 (m, 2H), 3.50–3.60 (m, 1H), 3.20–3.30
(m, 1H), 2.20–2.30 ppm (m, 1H); IR (KBr): n˜ =3311, 2103, 1618, 1448,
1211, 1145, 638 cmÀ1; HRMS (EI): m/z: calcd. for C12H11N5O: 241.0963;
1087, 1041, 902, 845, 796 cmÀ1
C14H13NO3Na: 266.0793; found: 266.0796 [M]+·
; HRMS (ESI): m/z: calcd. for
.
1-Amino-4-benzyloxy-3-chlorobenzene (2 f): White solid; m.p. 57–588C;
1H NMR (300 MHz, 258C, CDCl3, TMS): d=7.47 (d, J=7.46 Hz, 2H),
7.40 (t, J=7.46 Hz, 2H), 7.29 (t, J=7.47 Hz, 1H), 6.81 (d, J=8.76 Hz,
1H), 6.77 (d, J=3.27 Hz, 1H), 6.52 (dd, J=8.72 and 3.12 Hz, 1H), 5.11
(s, 2H), 3.46 ppm (brs, 2H); 13C NMR (75 MHz, 258C, CDCl3, TMS):
d=146.9, 141.5, 138.8, 128.4, 128.3, 127.5, 124.3, 116.9, 117.2, 113.9,
72.1 ppm; IR (KBr): n˜ =3409, 3301, 3208, 3061, 3032, 2911, 2859, 1627,
1509, 1272, 1225, 1012, 921, 855, 747, 696 cmÀ1; (ESI) MS: m/z: 234
found: 241.0966 [M]+·
AHCTUNGTERG(NNUN 2S,11aS)-2-Azido-8-benzyloxy-7-methoxy-1,2,3,11a-tetrahydro-5H-
[1,4]benzodiazepin-5-one (4e): M.p. 122–1248C; [a]D23
pyrroloACHTNUTRGENN[UG 2,1-c]ACHUTNGTRENNUNG =
À158 (c=0.5 in MeOH); 1H NMR (300 MHz, 258C, [D6]DMSO, TMS):
d=7.63 (d, J=7.28 Hz, 1H), 7.33–7.52 (m, 6H), 6.98 (s, 1H), 5.02 (s,
2H), 4.22–4.27 (m, 1H), 4.10–4.15 (m, 1H), 3.99 (s, 3H), 3.88 (m, 1H),
3.52 (m, 1H), 2.28 ppm (m, 2H); IR (KBr): n˜ =3322, 2842, 2098, 1622,
[M+H]+·
.
1528, 1452, 1209, 1148, 647 cmÀ1; ESI (MS): m/z: 378 [M+H]+·
Methyl 5-amino-2-chlorobenzoate (2g): Yellow semi-liquid; 1H NMR
(200 MHz, 258C, CDCl3, TMS): d=7.22 (d, J=8.48 Hz, 1H), 7.16 (d, J=
3.32 Hz, 1H), 6.77 (dd, J=8.48 and 3.21 Hz, 1H), 3.96 (s, 3H), 3.77 ppm
(brs, 2H); 13C NMR (50 MHz, 258C, CDCl3, TMS): d=167.1, 146.7,
132.6, 131.1, 122.2, 119.2, 117.8, 52.9 ppm; IR (KBr): n˜ =3458, 3366, 3228,
3010, 2947, 2838, 1727, 1628, 1611, 1488, 1444, 1334, 1044, 988, 788,
G
A
MeOH); 1H NMR (400 MHz, 258C, [D6]DMSO, TMS): d=7.60 (d, J=
4.58 Hz, 1H), 7.38 (s, 1H), 6.94 (s, 1H), 4.23–4.28 (m, 1H), 4.11–4.17 (m,
1H), 4.00 (s, 3H), 3.92 (s, 3H), 3.72–3.80 (m, 1H), 3.55 (m, 1H), 2.91–
3.08 (m, 1H), 2.32 ppm (m, 1H); IR (KBr): n˜ =2928, 2847, 2103, 1621,
656 cmÀ1; (ESI) MS: m/z: 186 [M+H]+·
.
1512, 1448, 1210, 742, 642 cmÀ1; ESI (MS): m/z: 302 [M+H]+·
Methyl 2-amino-4-hydroxy-5-methoxybenzoate (2h): Off-white solid;
m.p. 148–1498C; 1H NMR (200 MHz, 258C, CDCl3, TMS): d=7.22 (s,
1H), 6.15 (s, 1H), 5.48 (brs, 2H), 3.84 (s, 3H), 3.83 ppm (s, 3H); IR
(KBr): n˜ =3410, 3304, 3000, 2958, 2850, 1670, 1598, 1576, 1508, 1446,
AHCTUNGTREGNU(NN 11aS)-2,3,5,10,11,11a-Hexahydro-1H-pyrroloACHTUNRTGEGUN[NN 2,1-c]ACTHNGUTREN[NUGN 1,4]benzodiazepine-
5,11-dione (6a): White solid; m.p. 218–2198C; [a]2D3 =+201 (c=1.0 in
MeOH); 1H NMR (200 MHz, 258C, CDCl3, TMS): d=9.22 (brs, 1H),
Chem. Eur. J. 2009, 15, 7215 – 7224
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7221

A. Kamal, C. S. Reddy et al.
7.96 (d, J=6.57 Hz, 1H), 7.46 (t, J=6.57 and 7.30 Hz, 1H), 7.21–7.28 (m,
1H), 7.03 (d, J=8.03 Hz, 1H), 4.05 (d, J=6.57 Hz, 1H), 3.75–3.86 (m,
1H), 3.51–3.65 (m, 1H), 2.71–2.82 (m, 1H), 1.98–2.08 ppm (m, 3H);
13C NMR (50 MHz, 258C, CDCl3, TMS): d=171.2, 163.3, 135.1, 132.2,
130.8, 124.3, 123.0, 121.0, 56.8, 46.8, 26.1, 23.2; IR (KBr): n˜ =3223, 2952,
2873, 1688, 1625, 1476, 1449, 1413, 1268, 1213, 1154, 1103 cmÀ1; HRMS
[a]2D5 =+411 (c=1 in MeOH); 1H NMR (300 MHz, 258C, CDCl3, TMS):
d=9.36 (brs, 1H), 7.28–7.40 (m, 6H), 6.59 (s, 1H), 5.08 (m, 2H), 4.28
(m, 1H), 4.10 (dd, J=6.79 and 7.55 Hz, 1H), 3.89 (s, 3H), 3.74–3.80 (dd,
J=7.55 and 5.28 Hz, 1H), 3.62 (d, J=12.84 Hz, 1H), 3.02 (d, J=
14.35 Hz, 1H), 2.25–2.34 ppm (m, 1H); 13C NMR (75 Hz, 258C, CDCl3,
TMS): d=170.8, 165.7, 151.8, 135.8, 129.9, 128.7, 128.3, 127.4, 117.9,
112.5, 105.7, 70.9, 57.9, 56.2, 56.0, 52.6, 30.6; IR (KBr): n˜ =3221, 2924,
2854, 2100, 1744, 1693, 1606, 1510, 1492, 1430, 1375, 1310, 1261, 1226,
1117, 1021, 873, 788, 753, 697, 643 cmÀ1; HRMS (ESI): m/z: calcd. for
(ESI): m/z: calcd. for C12H12N2O2Na: 239.0796; found: 239.0806 [M]+·
(11aS)-7,9-Dibromo-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c]-
ACHTUNGTRENNUNG[1,4]benzodiazepine-5,11-dione (6b): White solid; m.p. 162–1658C;
.
A
ACHTUNGTRENNUNG
[a]2D3 =+321 (c=1.0 in MeOH); 1H NMR (200 MHz, 258C, CDCl3 +
[D6]DMSO, TMS): d=9.05 (brs, 1H), 7.94 (d, J=1.84 Hz, 1H), 7.86 (d,
J=1.84 Hz, 1H), 4.00 (d, J=6.44 Hz, 1H), 3.71–3.81 (m, 1H), 3.44–3.58
(m, 1H), 2.70 (m, 1H), 1.99–2.03 ppm (m, 3H); 13C NMR (50 MHz,
258C, CDCl3, TMS): d=188.9, 182.3, 157.4, 152.9, 151.6, 149.4, 137.5,
135.5, 76.1, 67.0, 45.7, 42.8 ppm; HRMS (ESI): m/z: calcd. for
C20H19N5O4Na: 416.1334; found: 416.1332 [M]+·
(2R,11aS)-2-Hydroxy-2,3,5,10,11,11a-hexahydro-1H-pyrrolo
AHCTUNGTRENNUNG
[1,4]benzodiazepine-5,11-dione (6i): Semi-liquid; [a]2D3 =+252 (c=1.0,
.
A
ACHTUNGTRENN[UNG 2,1-c]-
MeOH); 1H NMR (200 MHz, 258C, CDCl3 +[D6]DMSO, TMS): d=
10.20 (brs, 1H), 7.85–8.00 (m, 1H), 7.40–7.50 (m, 1H), 7.08–7.26 (m,
2H), 4.60–4.70 (m, 1H), 4.40–4.55 (m, 1H), 4.10–4.26 (m, 1H), 3.85–3.95
(m, 1H), 3.50–3.62 (m, 1H), 2.78–2.95 (m, 1H), 2.00–2.10 ppm (m, 1H);
13C NMR (50 MHz, 258C, CDCl3 +[D6]DMSO, TMS): d=169.6, 165.0,
135.3, 131.2, 128.2, 125.4, 123.4, 120.5, 67.1, 54.7, 53.3, 33.8 ppm; HRMS
C12H10N2O2NaBr2: 394.9006; found: 394.9002 [M]+·
(11aS)-7,8-Dimethoxy-2,3,5,10,11,11a-hexahydro-1H-pyrrolo
[1,4]benzodiazepine-5,11-dione (6c): White solid; m.p. 178–1808C;
.
A
ACHTUNGTRENN[UNG 2,1-c]-
ACHTUNGTRENNUNG
[a]2D3 =+303 (c=1.0 in MeOH); 1H NMR (400 MHz, 258C, CDCl3,
TMS): d=8.71 (brs, 1H), 7.42 (s, 1H), 6.48 (s, 1H), 4.03–4.10 (m, 1H),
3.93 (s, 3H), 3.90 (s, 3H), 3.72–3.82 (m, 1H), 3.52–3.65 (m, 1H), 2.70–
2.78 (m, 1H), 1.98–2.06 ppm (m, 3H); 13C NMR (50 MHz, 258C, CDCl3,
TMS): d=190.6, 184.8, 171.6, 165.7, 149.3, 138.5, 131.4, 123.3, 96.5, 76.3,
75.6, 66.7, 45.6, 43.0 ppm; HRMS (ESI): m/z: calcd. for C14H16N2O4:
(ESI): m/z: calcd. for C12H12N2O3Na: 255.0745; found: 255.0751 [M]+·
.
AHCTUNGTERG(NNUN 2R,11aS)-8-Benzyloxy-7-methoxy-2-hydroxy-2,3,5,10,11,11a-hexahydro-
1H-pyrrolo
[2,1-c]
E
(6j):
Semi-liquid;
[a]2D3 =À42 (c=0.5, MeOH); 1H NMR (200 MHz, 258C, CDCl3, TMS):
d=10.11 (brs, 1H), 7.43 (s, 1H), 7.32 (m, 5H), 6.51 (s, 1H), 5.01 (s, 2H),
4.31 (m, 1H), 4.05 (m, 1H), 3.81 (s, 3H), 3.60–3.65 (m, 2H), 1.90–1.98
(m, 2H), 1.21 ppm (m, 1H); 13C NMR (75 MHz, 258C, CDCl3, TMS): d=
172.1, 166.3, 152.8, 146.7, 138.1, 131.2, 129.9, 119.4, 112.7, 108.5, 80.1,
277.1188; found: 277.1184 [M]+·
(11aS)-8-Benzyloxy-7-methoxy-2,3,5,10,11,11a-hexahydro-1H-pyrrolo
c][1,4]benzodiazepine-5,11-dione (6d): White solid; m.p. 172–1738C;
.
G
ACHTUNGTNER[NUNG 2,1-
ACHTUNGTRENNUNG
70.2, 68.9, 56.9, 55.3, 40.3, 38.2 ppm; ESI (MS): m/z: 369 [M+H]+·
.
[a]2D3 =+239 (c=1.0 in MeOH); 1H NMR (200 MHz, 258C, CDCl3,
TMS): d=8.81 (s, 1H), 7.26–7.40 (m, 6H), 6.49 (s, 1H), 5.10 (s, 2H), 4.00
(d, J=6.44 Hz, 1H), 3.91 (s, 3H), 3.47–3.78 (m, 2H), 2.63–2.71 (m, 1H),
1.90–2.05 ppm (m, 3H); 13C NMR (50 MHz, 258C, CDCl3, TMS): d=
170.8, 165.0, 149.4, 146.6, 135.7, 129.4, 128.5, 128.0, 127.1, 119.4, 112.3,
105.8, 76.9, 76.6, 708, 56.7, 56.1, 47.2, 26.1, 23.5 ppm; IR (KBr): n˜ =3356,
2962, 2928, 2844, 1679, 1636, 1601, 1519, 1441, 1288, 1177, 1121, 1022,
1,2,3,9-TetrahydropyrroloACTHNUGTRNEUNG[2,1-b]quinazolin-9-one (8a): White solid; m.p.
104–1068C; 1H NMR (300 MHz, 258C, CDCl3, TMS) d=8.24 (dd, J=1.5
and 8.3 Hz, 1H), 7.57–7.70 (m, 2H), 7.38–7.52 (m, 1H), 4.16–4.21 (t, J=
7.5 Hz, 2H), 3.12–3.18 (t, J=7.5 Hz, 2H), 2.24–2.34 ppm (m, 2H);
HRMS (EI): m/z: calcd. for C11H10N2O: 186.0793; found: 186.0789 [M]+·
.
6-Methyl-1,2,3,9-tetrahydropyrrolo
G
883, 756, 697 cmÀ1
375.1320; found: 375.1333 [M]+·
(11aS)-8-Hydroxy-7-methoxy-2,3,5,10,11,11a-hexahydro-1H-pyrrolo
c][1,4]benzodiazepine-5,11-dione (6e): White solid; m.p. 254–2558C;
; HRMS (ESI): m/z: calcd. for C20H20N2O4Na:
1
1018C; H NMR (200 MHz, 258C, CDCl3, TMS): d=8.03 (s, 1H), 7.51 (s,
2H), 4.20 (t, J=7.52 Hz, 2H), 3.20 (t, J=7.85 Hz, 2H), 2.50 (s, 3H),
2.34 ppm (q, J=7.31 and 7.83 Hz, 2H); EI (MS): m/z: 200 [M]+·
.
A
ACHTUNGTNER[NUNG 2,1-
ACHTUNGTRENNUNG
6-Benzyloxy-7-methoxy-1,2,3,9-tetrahydropyrroloACTHNUGTRNEUNG[2,1-b]quinazolin-9-one
[a]2D5 =+276 (c=0.5 in MeOH); 1H NMR (200 MHz, 258C, CDCl3,
TMS): d=7.80 (brs, 1H), 7.40 (s, 1H), 6.50 (s, 1H), 6.00–6.10 (brs, 1H),
4.00–4.10 (m, 1H), 3.95 (s, 3H), 3.70–3.80 (m, 1H), 3.55–3.65 (m, 1H),
2.70–2.80 (m, 1H), 1.90–2.10 ppm (m, 3H); 13C NMR (50 MHz, 258C,
CDCl3, TMS): d=175.1, 170.1, 155.1, 149.5, 135.8, 122.5, 117.0, 112.8,
61.5, 60.7, 51.7, 30.7, 28.2 ppm; IR (KBr): n˜ =2960, 2925, 2843, 1683,
(8c): White solid; m.p. 157–1588C; 1H NMR (200 MHz, 258C, CDCl3,
TMS): d=7.53 (s, 1H), 7.25–7.46 (m, 5H), 7.00 (s, 1H), 5.22 (s, 2H), 4.16
(t, J=7.34 Hz, 2H), 3.99 (s, 3H), 3.10 (t, J=7.34 and 8.08 Hz, 2H), 2.18–
2.34 ppm (m, 2H); 13C NMR (50 MHz, 258C, CDCl3, TMS): d=176.8,
173.1, 168.4, 164.5, 155.4, 148.0, 147.4, 146.7, 133.3, 128.3, 125.0, 115.6,
89.9, 75.3, 65.7, 51.6, 49.1, 39.1, 31.5 ppm; IR (KBr): n˜ =2955, 2931, 2849,
1662, 1611, 1501, 1453, 1401, 1371, 1288, 1261, 1175, 1137, 1076, 1028,
846, 777 cmÀ1; HRMS (ESI): m/z: calcd. for C19H18N2O3Na: 345.1225;
1631, 1607, 1521, 1438, 1284, 1204, 1173, 1115, 1060, 1025, 884, 757 cmÀ1
HRMS (ESI): m/z: calcd. for C13H14N2O4: 263.1031; found: 263.1040
[M+H]+·
(2S,11aS)-2-Azido-2,3,5,10,11,11a-hexahydro-1H-pyrrolo
[1,4]benzodiazepine-5,11-dione (6 f): M.p. 217–2208C; [a]2D3 =+596 (c=1
;
.
found: 345.1200 [M]+·
6,7,8,9-Tetrahydro-11H-pyridinoACTHNUGTENR[NUG 2,1-b]quinazolin-11-one (8d): M.p. 96–
.
A
ACHTUNGTRENN[UNG 2,1-c]-
ACHTUNGTRENNUNG
in MeOH); 1H NMR (200 MHz, 258C, CDCl3 +[D6]DMSO, TMS): d=
10.20 (s, 1H), 7.85–95 (d, J=10.32 Hz, 1H), 7.40–7.45 (m, 1H), 7.10–7.20
(m, 2H), 4.25–4.35 (m, 1H), 4.05–4.15 (m, 1H), 3.80–3.95 (dd, J=6.21
and 13.70 Hz, 1H), 3.60–3.70 (m, 1H), 3.00–3.10 (m, 1H), 2.25–2.40 ppm
(m, 1H); 13C NMR (50 MHz, 258C, CDCl3 +[D6]DMSO, TMS): d=
169.5, 164.8, 135.5, 131.5, 129.8, 124.4, 123.2, 120.4, 56.9, 55.5, 14.29 ppm;
988C; 1H NMR (200 MHz, 258C, CDCl3, TMS) d=8.21 (d, J=8.0 Hz,
1H), 7.70 (t, J=7.4 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.41 (t, J=7.40 Hz,
1H), 4.07 (t, J=6.04 Hz, 2H), 3.06 (t, J=6.45 Hz, 2H), 1.90–2.10 ppm
(m, 4H); HRMS (EI): m/z: calcd. for C12H12N2O: 200.0944; found:
200.0932 [M]+·
.
3-Methyl-6,7,8,9-tetrahydro-11H-pyridinoACTHUNTGRENNG[U 2,1-b]quinazolin-11-one (8e):
IR (KBr): n˜ =2933, 2107, 1689, 1617, 1451, 1383, 1213, 1046, 750 cmÀ1
HRMS (EI): calcd. for C12H11N5O2: 257.0912; found: 257.0917 [M]+·
(2S,11aS)-2-Azido-8-hydroxy-7-methoxy-2,3,5,10,11,11a-hexahydro-1H-
pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione (6g): M.p. 116–1188C;
;
1H NMR (200 MHz, 258C, CDCl3, TMS): d=8.01 (s, 1H), 7.55 (s, 2H),
4.12 (t, J=5.07 Hz, 2H), 3.08 (t, J=5.0 Hz, 2H), 2.51 (s, 3H), 1.90–
.
ACHTUNGTRENNUNG
2.20 ppm (m, 4H); EI (MS): m/z: 214 [M]+·
7,8,9,10-TetrahydroazepinoACHTNUGTRNE[GUN 2,1-b]quinazolin-12(6H)-one (8 f): M.p. 96–
.
A
ACHTUNGTRENNUNG
[a]2D3 =+399 (c=1 in MeOH); 1H NMR (200 MHz, 258C, CDCl3, TMS):
d=10.10 (brs, 1H), 7.28 (s, 1H), 6.62 (s, 1H), 4.32 (m, 1H), 4.06 (dd, J=
6.79 and 2.26 Hz, 1H), 3.87 (s, 3H), 3.48 (d, J=12.83 Hz, 1H), 3.62 (d,
J=12.84 Hz, 1H), 3.02 (d, J=14.35 Hz, 1H), 2.25–2.34 ppm (m, 1H); IR
(KBr): n˜ =3448, 2925, 2853, 2105, 1732, 1681, 1628, 1497, 1425, 1355,
1271, 1215, 1116, 1023, 875, 790, 755, 696, 663, 634 cmÀ1; HRMS (ESI):
988C; 1H NMR (200 MHz, 258C, CDCl3, TMS): d=8.25 (d, J=8.04 Hz,
1H), 7.70 (t, J=7.46 Hz, 1H), 7.66 (d, J=8.08 Hz, 1H), 7.44 (t, J=
7.42 Hz, 1H), 4.43 (d, J=6.05 Hz, 2H), 3.03 (d, J=6.42 Hz, 2H),
1.81 ppm (s, 6H); EI (MS): m/z: 214 [M]+·
.
3-Methyl-7,8,9,10-tetrahydroazepino
M.p. 68–708C; H NMR (200 MHz, 258C, CDCl3, TMS): d=8.02 (s, 1H),
[2,1-b]quinazolin-12(6H)-one (8g):
m/z: calcd. for C13H13N5O4Na: 326.0865; found: 326.0871 [M]+·
(2S,11aS)-2-Azido-8-benzyloxy-7-methoxy-2,3,5,10,11,11a-hexahydro-1H-
pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione (6h): M.p. 173–1758C;
.
1
7.43 (s, 2H), 4.35 (d, J=5.06 Hz, 2H), 3.05 (d, J=6.44 Hz, 2H), 2.47 (s,
3H), 1.80 ppm (s, 6H); EI (MS): m/z: 228 [M]+·
.
ACHTUNGTRENNUNG
A
U
7222
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 7215 – 7224

Chemoselective Aromatic Azido Reduction
FULL PAPER
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