High-yielding synthesis of Nefopam analogues (functionalized benzoxazocines) by sequential one-pot cascade operations

Article abstract of DOI:10.1039/b910397j

An efficient amine-/ruthenium-catalyzed three-step process for the synthesis of Nefopam analogues was achieved through combinations of cascade enamine amination/iso-aromatization/allylation and diene or enyne metathesis as key steps starting from functionalized Hagemann's esters. In this communication, we discovered the application of ruthenium-catalysis on olefins containing free amines without in situ formation of salts.

Full text of DOI:10.1039/b910397j

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COMMUNICATION
www.rsc.org/obc | Organic & Biomolecular Chemistry
High-yielding synthesis of Nefopam analogues (functionalized
benzoxazocines) by sequential one-pot cascade operations†
Dhevalapally B. Ramachary,* Vidadala V. Narayana, M. Shiva Prasad and Kinthada Ramakumar
Received 27th May 2009, Accepted 23rd June 2009
First published as an Advance Article on the web 3rd July 2009
DOI: 10.1039/b910397j
An efficient amine-/ruthenium-catalyzed three-step process
for the synthesis of Nefopam analogues was achieved
through combinations of cascade enamine amination/iso-
aromatization/allylation and diene or enyne metathesis as key
steps starting from functionalized Hagemann’s esters. In this
communication, we discovered the application of ruthenium-
catalysis on olefins containing free amines without in situ
formation of salts.
technology triggered a burst of activity in the synthesis of a
huge variety of differently substituted heterocycles. In a similar
manner, reactions were performed via a combination of multi-
component and multi-catalysis approaches in one pot, generating
desired targets efficiently in a single reaction vessel without the
need to purify at each step.3 A particularly attractive green cascade
process occurs when two or more sequential reactions are mediated
by a catalytic amount of a simple amine. The catalytic ability of a
secondary amine (3a) to function as a catalyst for cascade enamine
amination/iso-aromatization (EA/IA) reactions has led to several
examples where combinations of these transformations provide
efficient new entries into useful o-hydroxydiarylamine 4 products
(Scheme 1).3f
During our studies on amine-catalyzed cascade EA/IA
reactions,3f we noted that functionalized o-hydroxydiarylamines
4 can serve as suitable starting materials for the generation of
Nefopam analogues via O-allylation, N-allylation and ring closing
metathesis (RCM) as key processes (Scheme 1). Unfortunately,
olefin metathesis, however, is known to be incompatible with free
amines due to catalyst inhibition by the basic nitrogen, although
the ammonium salts have been shown to undergo metathesis.4
Furthermore, there have been reports of ring-closing metathesis
of secondary and tertiary free amines protonated in situ to
form six-membered heterocycles, as well as a report of RCM
of a tertiary free amine to form a seven-membered ring under
acidic conditions, but they required a higher catalyst loading
(20 mol%).5
Herein, we discovered a novel and green technology for
the three-step synthesis of highly substituted benzoxazocines
using amine/potassium carbonate/sodium hydride/ruthenium-
catalysis through cascade enamine amination/iso-aromati-
zation/O-allylation (EA/IA/A), N-allylation, and diene or enyne
metathesis as key steps starting from commercially available Hage-
mann’s esters 1, nitrosobenzenes 2, allyl bromide, secondary amine
3a and Grubbs 1st and 2nd generated ruthenium catalysts 3b/3c,
an approach we call “multi-catalysis approach to heterocycles”
(Scheme 1). In this communication, we present for the first time
the RCM reaction of olefins containing free amines without in situ
salt formation.
We initiated our studies on the combination of a cascade
EA/IA reaction, O-and N-allylations and diene metathesis as
key steps for the synthesis of highly substituted 5,6-dihydro-2H-
benzo[b][1,4]oxazocine 7aa starting from Hagemann’s ester 1a
and nitrosobenzene 2a as shown in Table 1. Piperidine/K2CO3-
catalyzed cascade EA/IA/A reaction of 1a, 2a and allyl bro-
mide furnished the monoene amine 5aa in 93% yield. But the
same reaction under pyrrolidine/K2CO3-catalysis furnished the
monoene amine 5aa in 75% yield (result not shown in Table 1).
Drug-like highly substituted heterocycles are of considerable
importance in a variety of industries. As such, the development of
new and more general green methods for their preparation is of
significant interest.1 Especially, oxygen- and nitrogen-containing
heterocycles have attracted considerable attention as a result of
their biological activity and their presence in a variety of natural
and unnatural products.1 Thus, the diversity-oriented synthesis
of oxygen- and nitrogen-containing heterocycles represents an
important task because of the widespread occurrence of such
structural motifs and their use as building blocks. For example,
functionalized benzoxazocines and pharmaceutically acceptable
salts thereof, may be useful as analgesic agents and for the
treatment of emesis, depression, posttraumatic stress disorders,
attention deficit disorders, obsessive compulsive disorders, sexual
dysfunction and centrally acting skeletal muscle relaxants (see
eqn (1)).1g–o Herein, we report for the first time the organocat-
alytic approach to the high yielding synthesis of functionalized
benzoxazocines from a three-step sequence via “combination of
amine-/ruthenium-catalysis”.
(1)
Recently olefin metathesis of hetero-dienes and enynes catalyzed
by Grubbs’ catalysts provided a general route to a variety of
heterocycles in good yields.2 The advent of olefin metathesis
School of Chemistry, University of Hyderabad, Hyderabad-500 046, India.
E-mail: ramsc@uohyd.ernet.in; Fax: +91-40-23012460
† Electronic supplementary information (ESI) available: Experimental
procedures and analytical data (1H NMR, 13C NMR and HRMS) for
all new compounds. CCDC reference numbers 637091 and 637092. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/b910397j
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Scheme 1 Synthesis of Nefopam analogues via a three-step sequence.
In a similar manner, cascade EA/IA/A reaction of 1a, 2a
and allyl bromide under the combination of other amines like
glycine, proline, morpholine or benzylamine with K2CO3 is not
superior compared to piperidine/K2CO3-catalysis (results not
shown in Table 1). Further NaH-promoted N-allylation of cascade
EA/IA/A product 5aa furnished the diene amine 6aa in 85% yield.
Interestingly, RCM reaction of free diene amine 6aa using Grubbs’
1st generation catalyst 3b in CH2Cl2 at 25 ◦C for 8 h furnished the
highly functionalized 5,6-dihydro-2H-benzo[b][1,4]oxazocine 7aa
in 85% yield; but the same reaction with Grubbs’ 2nd generation
catalyst 3c furnished the 7aa in 75% yield (Table 1). The technical
advantage of these reactions is that the ruthenium-catalysis is
performed on free diene amines without the need for in situ salt
formation. With the optimized reaction conditions in hand, the
scope of the three-step synthesis of 7 was investigated with various
Hagemann’s esters 1a–o and nitrosobenzene 2a. As summarized
in Table 1, a series of Hagemann’s esters 1a–o were transferred
into highly substituted 5,6-dihydro-2H-benzo[b][1,4]oxazocines
7aa–oa in 33 to 67% overall yields via piperidine-/ruthenium-
catalysis from a three-step sequence. Unfortunately, we were
not able to recycle the ruthenium-catalyst 3b in these reactions,
because the reaction mixture was completely homogenous in
dichloromethane solution.
tion/decarboxylation reactions.3l For example, monoene amine
5ka furnished with moderate yield (61%) from ethyl acetoac-
etate, 4-chlorobenzaldehyde, nitrosobenzene 2a, and allyl bromide
under piperidine- and K2CO3-catalysis through cascade Knoeve-
nagel/Michael/aldol condensation/decarboxylation and cascade
enamine amination/isoaromatization/O-allylation reactions in
one pot (see Table 1). Further we were interested in investigating
the RCM reaction on triene amine 6pa to test the regioselectivity.
Compound 6pa was prepared from a Claisen rearrangement
of 5ka in DMF at 180 ◦C for 18 h followed by O- and
N-allylation with allyl bromide under NaH-catalysis in one pot
to furnish the triene amine 6pa in good yield, which on further
RCM reaction under 3b-catalysis furnished the benzo[b]oxepine
7¢pa with 60% yield6 and benzoxazocine 7pa with 40% yield as
shown in Table 1. The structure and regiochemistry of oxazocines
7aa–pa was confirmed by NMR analysis and also finally confirmed
by X-ray structure analysis on 7ha (Fig. 1).7 Functionalized
oxazocines 7 have shown many pharmaceutical applications like
noradrenaline, serotonin reuptake inhibitors for treatment of pain
and emesis, neurokinin receptor antagonists, anti-inflammatory
activity and anti-depressive activity.1g–o This three-step synthetic
strategy will have a great impact on the synthesis of a diversity-
oriented library of substituted oxazocines to find suitable drug
molecules.
Interestingly, monoene amines 5 can be synthesized directly
from two equivalents of ethyl acetoacetate and aldehyde under
piperidine-catalysis followed by in situ reaction with nitrosoben-
zene 2a and allyl bromide to furnish 5 with moderate to
good yields. So, for the synthesis of Hagemann’s ester 1a–p
library, we utilized piperidine-catalyzed condensation of ethyl
acetoacetate with different aldehydes in EtOH at 80 ◦C for
5–8 h through cascade Knoevenagel/Michael/aldol condensa-
With the success of a three-step synthesis of highly function-
alized 5,6-dihydro-2H-benzo[b][1,4]oxazocines 7, we continued
our investigation of the generation of 3,4,5,6-tetrahydro-2H-
benzo[b][1,4]oxazocines 8 via sequential Pd/C-mediated hydro-
genation of 7 through a one-pot synthesis due to a structural
similarity with Nefopam. The results in Scheme 2 demonstrate
the broad scope of this novel methodology covering a sequential
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Table 1 Three-step synthesis of Nefopam analogues via combination of amine-/potassium carbonate-/sodium hydride-/ruthenium-catalysisa
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Table 1 (Contd.)
◦
Reagents and conditions: (a) Ph–N O (0.5 equiv.), 3a (5 mol%), DMF (0.3 M), 25 C, 1 h; K2CO3 (5 equiv.), H2C CHCH2Br (3 equiv.), 25 ◦C, 24 h;
a
=
=
(b) NaH (3 equiv.), H2C CHCH2Br (2 equiv.), DMF (0.1 M), 25 ◦C, 2–5 h; (c) CH2Cl2 (0.05 M), 3b (5 mol%), 25 ◦C, 8–12 h; bYield representing from
=
5ka via two steps; cCH2Cl2 (0.05 M), 3c (5 mol%), 25 ◦C, 4 h; dHighly substituted benzo[b]oxepine 7¢pa furnished as a byproduct in 60% yield (see ref. 6).
Fig. 1 X-Ray crystal structure of 7ha.
amination/iso-aromatization/O-propargylation (EA/IA/P), N-
allylation, cascade RCM/DA reactions (see Scheme 3). Hage-
mann’s ester 1a was converted into highly functionalized tetra-
cyclic endo-product 12aa with >78% de in a stereoselec-
tive manner with 46% overall yield through a sequence of
amine/K2CO3-catalyzed cascade EA/IA/P, NaH-promoted
N-allylation, ruthenium-promoted enyne RCM followed by heat-
Scheme 2 Sequential combination of Ru- and Pd-catalysis in one pot for
promoted Diels–Alder (DA) reaction with 1-phenyl-pyrrole-2,5-
dione in one pot as shown in Scheme 3. Generality of the amine-
/K2CO3-/NaH-/Ru-catalyzed stereoselective sequential one-pot
cascade EA/IA/P, A and RCM/DA reactions was further con-
firmed by two more examples using a different Hagemann’s ester
1o and dienophile to furnish the expected highly functionalized
compound 12oa in 13.2% overall yield with >99% de and
compound 14aa in 22% overall yield, respectively, as shown in
Scheme 3. The structure and stereochemistry of oxazocines 12–14
the synthesis of 3,4,5,6-tetrahydro-2H-benzo[b][1,4]oxazocines 8.
combination of Ru- and Pd-catalysis to take place in one pot with
a good yield.8
After successful demonstration of a high yielding three-step
synthesis for the benzo[b][1,4]oxazocines 7 and 8, we further
extended the three-step synthesis into the construction of more
functionalized molecules via a combination of cascade enamine
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=
Scheme 3 General application of three-step chemistry in the synthesis of he◦terocycles. Reagents and conditions: (a) Ph–N O (0.5 equiv.), 3a (5 mol%),
DMF (0.5 M), 25 ◦C, 1 h; K2CO3 (3 equiv.), HC CCH2Br (2 equiv.), 25 C, 24 h; (b) NaH (3 equiv.), H2C CHCH2Br (2 equiv.), DMF (0.5 M),
≡
=
0
◦C → 25 ◦C, 3–6 h; (c) CH2Cl2 (0.05 M), 3b (5 mol%), 25 ◦C, 12 h; (d) N-phenylmaleimide (1.2 equiv.), C6H5CH3 (0.16 M), 110–120 ◦C, 21 h; (e)
diethyl acetylenedicarboxylate (1.2 equiv), C6H5CH3 (0.16 M), 120–140 ◦C, 21 h; (f) DMF (1.0 M), 190 ◦C, 6–8 h; (g) K2CO3 (2 equiv.), HC CCH2Br
(1.5 equiv.), DMF (0.5 M), 25 ◦C, 24 h.
≡
was confirmed by NMR analysis and also finally confirmed by
X-ray structure analysis on 12aa (Fig. 2).7 For the pharmaceutical
applications, a diversity-oriented library of tetra-cyclic com-
pounds 12 could be generated by using our three-step sequence
reactions.
With the success of a sequential three-step synthesis of
highly functionalized heterocycles 12–14 based on the benzo[b]-
[1,4]oxazocines 7 platform, we continued our investigation into
the generation of highly functionalized heterocycles 18oa and
19oa based on 3-vinyl-2,5-dihydro-benzo[b]oxepines 17oa through
a combination of cascade EA/IA/A, Claisen rearrangement,
O-propargylation, enyne RCM followed by DA reaction. The
results in Scheme 3 demonstrate the broad scope of this novel
methodology covering a structurally diverse group of Hagemann’s
esters 1 and nitrosobenzene 2a.
Claisen rearrangement of 5oa in DMF at 190 ◦C for 6–8 h
furnished the expected phenol 15oa in 50% yield, which on
O-propargylation with propargyl bromide and K2CO3 fur-
nished the enyne amine 16oa in 80% yield. Direct treatment
of enyne amine 16oa with Grubbs’ 1st generation catalyst 3b
generated the expected highly functionalized 3-vinyl-2,5-dihydro-
benzo[b]oxepine 17oa in good conversion as shown in Scheme 3,
which on in situ treatment with 1-phenyl-pyrrole-2,5-dione in
toluene at 110–120 ◦C for 21 h furnished the highly functionalized
tetra-cyclic endo-product 18oa with 64% de in a stereoselective
manner with 22% overall yield.
In summary, we have developed three-step sequential multi-
catalysis chemistry for the synthesis of highly substituted drug-
like heterocycles 7, 8, 12, 13, 14, 18 and 19 from simple starting
materials via EA/IA/A, EA/IA/P, C,N,O-allylations, Claisen
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Fig. 2 X-Ray crystal structure of 12aa.
rearrangement, diene RCM, enyne RCM and Diels–Alder re-
actions. The multi-catalysis strategy proceeds in good yields
with high selectivity using piperidine/K2CO3/NaH/ruthenium-
complex as the catalysts. Further work is in progress to utilize
novel multi-catalysis reactions in synthetic chemistry.
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Acknowledgements
We thank DST and CSIR (New Delhi) for support of this
project. VVN, MSP and KR thank CSIR (New Delhi) for their
research fellowships. We thank Dr Pallepogu Raghavaiah for
X-ray structural analysis.
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7 Crystal structure data for 7ha: C26H25NO3, Mr = 399.47, monoclinic,
˚
space group P21/c, a = 14.2321(13), b = 13.8619(13), c = 11.2976(11) A,
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3
˚
free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html
or from the Cambridge Crystallographic Data Centre, 12, Union
Road, Cambridge CB21EZ, UK; fax: (+44)1223-336-033; or
mailto:deposit@ccdc.cam.ac.uk.
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a
= 90, b = 105.460(2), g = 90◦, V = 2148.2(4) A , T
=
298(2) K, 22021 reflections collected. Crystal structure data for 12aa:
C32H30N2O5, Mr = 522.58, monoclinic, space group P21/n, a =
˚
12.9791(7), b = 15.0018(8), c = 13.9935(8) A, a = 90, b = 91.827(1), g =
◦
3
˚
90 , V = 2723.3(3) A , T = 298(2) K, 19684 reflections collected. CCDC-
637091 for 7ha and CCDC-637092 for 12aa contains the supplementary
crystallographic data for this paper. These data can be obtained
3378 | Org. Biomol. Chem., 2009, 7, 3372–3378
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