Mild and efficient synthesis of benzo-fused seven- and eight-membered ring lactams: A convenient approach to biologically interesting chemotypes

Article abstract of DOI:10.1080/00397911.2011.643439

A general and efficient method for the synthesis of benzo-fused 7- and 8-membered ring lactams via the Beckmann rearrangement of cyclic oximes is presented. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file. Copyright Taylor & Francis Group, LLC.

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Mild and Efficient Synthesis of Benzo-
Fused Seven- and Eight-membered Ring
Lactams: A Convenient Approach to
Biologically Interesting Chemotypes
Jayne L. Kenwright a , Warren R. J. D. Galloway a , Lars Wortmann b
& David R. Spring a
a Department of Chemistry, University of Cambridge, Cambridge,
United Kingdom
b Bayer Schering Pharma AG, Berlin, Germany
Accepted author version posted online: 05 Jun 2012.Version of
record first published: 06 Mar 2013.
To cite this article: Jayne L. Kenwright , Warren R. J. D. Galloway , Lars Wortmann & David R.
Spring (2013): Mild and Efficient Synthesis of Benzo-Fused Seven- and Eight-membered Ring Lactams:
A Convenient Approach to Biologically Interesting Chemotypes, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 43:11, 1508-1516
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Synthetic Communications1, 43: 1508–1516, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.643439
MILD AND EFFICIENT SYNTHESIS OF BENZO-FUSED
SEVEN- AND EIGHT-MEMBERED RING LACTAMS: A
CONVENIENT APPROACH TO BIOLOGICALLY
INTERESTING CHEMOTYPES
Jayne L. Kenwright,1 Warren R. J. D. Galloway,1
Lars Wortmann,2 and David R. Spring1
1Department of Chemistry, University of Cambridge, Cambridge,
United Kingdom
2Bayer Schering Pharma AG, Berlin, Germany
GRAPHICAL ABSTRACT
Abstract A general and efficient method for the synthesis of benzo-fused 7- and 8-membered
ring lactams via the Beckmann rearrangement of cyclic oximes is presented.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Lactam; medium ring; methodology
INTRODUCTION
The importance of medium-ring lactams (Seven- to 10-membered)[1] in organic
chemistry is exemplified by their presence in a large number of biologically active
and pharmaceutically relevant molecules.[2] One therapeutically important class of
compounds incorporating this motif is the benzo-fused medium ring lactams.
Numerous compounds based around a benzo-fused seven-membered lactam ring
core (commonly referred to as a benzazepinone motif) have been found to demon-
strate interesting biological properties (Fig. 1). For example, benzazepril (1) is
an angiotensin converting enzyme inhibitor, L-692428 (2) is a growth hormone
secretago,[3] and the structurally related compound alsterpaullone (3) is a cyclin-
dependent kinase inhibitor.[4]
Received November 2, 2011.
Address correspondence to David R. Spring, Department of Chemistry, University of Cambridge,
Lensfield Road, Cambridge, CB2 1EW, UK. E-mail: spring@ch.cam.ac.uk
1508

EFFICIENT SYNTHESIS OF BENZO-FUSED LACTAMS
1509
Figure 1. Some examples of biologically active compounds based around a benzo-fused seven-membered
lactam ring core (highlighted in bold).
Despite the interesting biological properties associated with seven-membered
benzo-fused lactams, compounds containing the equivalent eight-membered ring
systems are relatively scarce. Consequently, benzo-fused eight-membered ring
lactams (indeed, medium-ring lactams in general) are underrepresented in current
small-molecule libraries.[1,5] This relative paucity of compounds can be attributed
primarily to synthetic difficulties.[1,2] Thus, there is a need for the development of
efficient methods of broad utility for the synthesis of benzo-fused eight-membered
ring lactams so that the biological usefulness of this structural moiety can be
investigated and exploited further. Herein we describe a general procedure for the
synthesis of benzo-fused seven- and eight-membered ring lactams via the Beckmann
rearrangement of oximes under mild conditions. Additionally, we describe sub-
sequent synthetic manipulations of the products, which allow the generation of
further compound diversity; this may be valuable for the exploration of biological
activity space around the lactam core and the delineation of possible structure–
activity relationships in any future biological studies.
DISCUSSION
The direct lactamization of acyclic precursors is arguably the most concep-
tually straightforward approach to medium-ring lactams,[2] but it is both kinetically
and thermodynamically challenging, typically requiring the use of dilute reaction
conditions or carefully designed substrates.[1,2,6,7] Ring closure by other methods
(e.g., C-C bond formation) generally necessitates elaborate synthetic precursors,[6]
and the formation of unsaturated lactams by olefin metathesis can proceed with
unpredictable levels of geometrical selectivity.[2] The use of cycloadditions is
generally restricted to the synthesis of seven-membered lactam ring systems.[2] Ring

1510
J. L. KENWRIGHT ET AL.
expansion of cyclic ketones by nitrogen insertion eschews some of the difficulties
associated with the direct closure of acyclic precursors and has attracted significant
attention as a method for the synthesis of medium-ring lactams.[2] One commonly
used nitrogen-insertion process is the Beckmann rearrangement of cyclic oximes.[2,8]
There are numerous examples of medium-ring lactams of various sizes generated
by this reaction, including benzo-fused systems (generally isolated examples of
primarily seven-membered lactams of the benzazepinone family).[9] However, a wide
range of different reaction conditions have been reported for these processes, with no
one set showing a truly broad utility; optimization of reaction conditions (catalyst,
temperature, concentration) is usually required on a case-by-case basis.[2] Often very
harsh conditions (e.g., high reaction temperatures and very acidic and dehydrating
reaction media) are needed, which limit substrate functional group tolerability
and thus the structural diversity and synthetic manipulability of the resulting
products.[2,10] In addition, the regioselectivity of Beckmann-type rearrangements of
cyclic oximes can be somewhat variable.[2,11] In theory, the reaction is stereospecific
if a geometrically defined oxime is used.[11] However, isomerization of the oxime start-
ing material can occur under some rearrangement conditions, leading to a mixture of
amide products.[2,11,12] Secondary cleavage reactions can also complicate the progress
of the reaction.[11] We therefore sought the use of relatively mild reaction conditions
for the Beckmann rearrangement process that could be exploited to generate of
a range of benzo-fused seven- and eight-membered ring lactams, amenable to further
modification, with predictably high levels of regioselectivity. Initial optimization
studies focused upon the formation of the seven-membered benzo-fused lactam
(a 1-benzazepin-2-one) 4 via the Beckmann rearrangement of oxime E-5 (Table 1).
Treatment of commercially available ketone 6 with hydroxylamine hydrochlo-
ride and pyridine in ethanol furnished the desired E-isomer 5 (with no evidence for
the formation of the corresponding Z-isomer). Lactam formation from geometri-
cally-pure E-5 was then attempted using three different sets of reaction conditions
previously employed in Beckmann rearrangements (conditions A–C, Table 1). The first
two sets of conditions (conditions A and B, Table 1) involved the use of catalytic cyan-
uric chloride.[13] Only under conditions A was there any evidence for the formation of
Table 1. Optimization of conditions for the synthesis of lactam 4
Conditions
Observations
A, cyanuric chloride, ZnCl2, MeCN, rt UPLCa indicated a small amount of 4 had formed
after 7 days of reaction time, but this could not be isolated.
B, cyanuric chloride, DMF, rt
UPLCa indicated essentially no consumption of starting
material after 7 days of reaction time.
93% isolated yield of 4.
C, TsCl, pyridine, CH2Cl2, reflux, 4 h
aUPLC, ultraperformance liquid chromatography; rt, room temperature; h, hour.

EFFICIENT SYNTHESIS OF BENZO-FUSED LACTAMS
1511
the desired product, but the quantity was negligible and it could not be isolated. The
third set of reaction conditions examined (conditions C, Table 1) involved the use of
tosyl chloride and pyridine. It is commonly believed that under such conditions the
oxygen of the oxime is tosylated, creating a better leaving group and thereby accelerat-
ing the rate of the rearrangement process.[14] Pleasingly, an excellent isolated yield of 4
was obtained under reaction conditions C. In addition, there was no evidence for the
formation of the lactam resulting from alkyl rather than aryl migration, which implies
that there is no geometrical scrambling of the oxime functionality under these reaction
conditions.
With optimized conditions in hand, the rearrangement of various other
commercially available oximes was examined to explore the substrate scope of the
methodology (Table 2). Pleasingly, several seven- and eight-membered benzo-fused
lactams (7–11) could be accessed. Gratifyingly, in all cases only a single amide pro-
duct was observed, suggesting that there is no scrambling of oxime geometry under
the relatively mild reaction conditions. Both substituted and unsubstituted aromatic
ring systems were tolerated, and it also was proved possible to carry out the
rearrangement process on an oxime substituted at the a-position to generate the
novel phenyl-substituted benzo-fused lactam derivative 10.
In addition, the structurally novel nitrogen-linked biaryl eight-membered ring
lactam 12 could be generated (Fig. 2). Although the isolated product yield was very
low, this nevertheless represents a significant result. The isolated yield of 12 was only
6% (1.4-mmol scale). Efforts are currently under way to improve the yield of this pro-
cess and apply the methodology to the synthesis of other nitrogen-linked biaryl
medium ring lactams. Though numerous compounds based around a seven-membered
nitrogen-linked biaryl scaffold have been found to demonstrate interesting biological
properties, there are relatively few example of the synthesis of the analogous
eight-membered ring lactam scaffold.[15] Synthetic access to this very rare class of com-
pound will allow the biological properties of this potentially valuable structural motif
to be investigated further.
Having established a robust method for the synthesis of benzo-fused lactams,
we were interested in creating additional compound diversity by scaffold decoration
around the lactam core. To this end we investigated arylation reactions on the amide
nitrogen. Under copper catalysis it proved possible to couple a range of aryl iodides
onto both seven- and eight-membered benzo-fused lactams to generate several struc-
turally novel derivatives (15–18, Scheme 1).
In summary, we have reported a convenient, efficient, and general method for
the synthesis of benzo-fused seven- and eight-membered ring lactams by the Beck-
mann rearrangement of cyclic oximes. The process is technically simple, proceeds
under relatively mild conditions with compete regioselectivity, and forms biologically
interesting products that are generally difficult to synthesize by other methods. The
biological activities of the compounds disclosed in this report are currently being
evaluated. A full account of the results of our screening experiments will be reported
in due course. In addition, several structurally novel N-arylated derivatives were
prepared, demonstrating the capability to carry out structural elaboration around
the lactam core.
Overall, the work herein reported represents a convenient approach to
benzo-fused eight-membered ring lactams, a biologically interesting chemotype that

1512
J. L. KENWRIGHT ET AL.
Table 2. Synthesis of benzo-fused medium ring lactamsa
Entry
Time (h)
Product
Yield (%)
1
2
95
2
2
87
3
48
27
4
5
12
48
87
21
aSee Supporting Information for synthesis of oxime substrates; equiv, equivalents; h, hour.
is underrepresented in current small-molecule collections. The enrichment of screen-
ing libraries with compounds of this sort will allow the sampling of previously
untapped regions of chemical space, which may thus facilitate the discovery of novel
biologically active small-molecule agents. As such, we anticipate that this method-
ology will prove especially valuable in the diversity-oriented synthesis of structurally
diverse small-molecule collections.[18]

EFFICIENT SYNTHESIS OF BENZO-FUSED LACTAMS
1513
Figure 2. Structurally novel nitrogen-linked biaryl eight-membered ring lactam 12 was generated. The
isolated yield of 12 was only 6% (1.4-mmol scale). Efforts are currently under way to improve the yield
of this process and apply the methodology to the synthesis of other nitrogen-linked biaryl medium ring
lactams. Some examples of biologically active compounds based around a nitrogen-linked biaryl lactam
scaffold (highlighted in bold) are also shown: 13 is a potent Chk1 inhibitor,[16] and Dibenzepin (14) is
an antidepressant that has been shown to also have activity as a defibrillatory agent.[17]
Scheme 1. Synthesis of arylated lactam derivatives. In the case of compound 18, 4 equivalents of aryl
iodide were used, with a total reaction time of 2 h; equiv, equivalents; h, hour.

1514
J. L. KENWRIGHT ET AL.
EXPERIMENTAL
General Procedure for Oxime Synthesis
The protocol was adapted from the method of Learmonth et al.[19] with the
following modifications: Pyridine (1.75 equiv) was added to a stirring solution of
ketone (1 equiv) and hydroxylamine hydrochloride (2 equiv) in EtOH. The reaction
mixture was heated at reflux overnight before removing the solvent under reduced
pressure. The crude product was purified using flash chromatography.
General Procedure for the Beckmann Rearrangement
Pyridine (4 equiv) was added to a stirring solution of oxime (1 equiv) and TsCl
(1.5 equiv) in CH2Cl2, and the reaction mixture was heated at reflux until complete
consumption of starting material (as indicated by thin-layer chromatography, TLC).
The reaction mixture was diluted with CH2Cl2 and washed with saturated aqueous
copper(II) sulfate solution (ꢀ3). The organic layers were combined, dried over
MgSO4, and concentrated under reduced pressure to give the product. The crude
product was purified using flash chromatography.
General Procedure for Amide Arylation
A microwave tube was charged with amide (1 equiv), aryl halide (2 equiv),
potassium tert-butoxide (2 equiv), ethane-1,2-diamine (1 equiv), CuI (0.5 equiv),
and dioxane and was irradiated for 1 h at 175 ꢁC. EtOAc was added to the reaction
mixture and washed with water (ꢀ2). The organic layer was dried over Na2SO4,
filtered, and concentrated under reduced pressure. The crude product was purified
using flash chromatography.
Analytical Data for Compound 8
Mp 157.1–158.6 ꢁC (EtOAc-petroleum ether, 1:1); Rf ¼ 0.35 (SiO2; EtOAc-
=
petroleum ether, 1:1); IR: 3177 (N-H), 3047, 2943, 2931, 2853, 1651s (C O), 1602,
1578, 1493, 1450, 1439, 1431, 1394, 1349, 1338, 1312, 1253, 1196, 1159, 1140,
1102 cmꢂ1
;
1H NMR (500 MHz, d6-DMSO, 373 K) 9.09 (1H, s, br, NH),
7.31–7.27 (1H, m, aryl H), 7.24–7.17 (2H, m, aryl H), 7.07–7.03 (1H, m, H5),
2.64–2.54 (2H, m, H11), 2.01–1.93 (2H, m, H8), 1.80–1.67 (4H, m, H9 and H10);
13C NMR (125 MHz, d6-DMSO, 373 K) 175.03 (C7), 139.45 (C6), 137.61 (C1),
130.97 (CH), 127.16 (CH), 127.03 (CH), 125.48 (CH), 33.05 (CH2), 31.18 (CH2),
29.90 (CH2), 24.79 (CH2); HRMS (ESIþ) m=z [MþH]þ calcd. for C11H14NOþ:
176.1075; found 176.1084.
ACKNOWLEDGMENTS
The authors thank Bayer Schering, the EPSRC, and Newman Trust for funding.
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