Concise copper-catalyzed synthesis of tricyclic biaryl ether-linked aza-heterocyclic ring systems

Article abstract of DOI:10.1021/ol4025259

A new method for the synthesis of tricyclic biaryl ether-linked ring systems incorporating seven-, eight-, and nine-membered ring amines is presented. In the presence of catalytic quantities of copper(I), readily accessible acyclic precursors undergo an intramolecular carbon-oxygen bond-forming reaction facilitated by a templating chelating nitrogen atom. The methodology displays a broad substrate scope, is practical, and generates rare and biologically interesting tricyclic heteroaromatic products that are difficult to access by other means.

Full text of DOI:10.1021/ol4025259

ORGANIC
LETTERS
2013
Vol. 15, No. 21
5448–5451
Concise Copper-Catalyzed Synthesis
of Tricyclic Biaryl Ether-Linked
Aza-Heterocyclic Ring Systems
Paola Mestichelli,† Matthew J. Scott,† Warren R. J. D. Galloway,† Jamie Selwyn,†
Jeremy S. Parker,‡ and David R. Spring*,†
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2
1EW, U.K., and AstraZeneca, Pharmaceutical Development, Charter Way,
Silk Road Business Park, Macclesfield, Cheshire SK10 2NA, U.K.
spring@ch.cam.ac.uk
Received September 5, 2013
ABSTRACT
A new method for the synthesis of tricyclic biaryl ether-linked ring systems incorporating seven-, eight-, and nine-membered ring amines is presented. In
the presence of catalytic quantities of copper(I), readily accessible acyclic precursors undergo an intramolecular carbonÀoxygen bond-forming reaction
facilitated by a “templating” chelating nitrogen atom. The methodology displays a broad substrate scope, is practical, and generates rare and biologically
interesting tricyclic heteroaromatic products that are difficult to access by other means.
Tricyclic aza-hetereocyclic ring systems incorporating
a biaryl ether motif are present in a number of biologically
active and pharmaceutically relevant compounds and thus
constitute very attractive synthetic targets. For example,
the dibenzooxazepinones1 and dibenzooxazepines2 have
been shown to exhibit significant biological activities
(Figure 1). The dibenz[b,g][1,5]oxazocines, which contain
a tricyclic biaryl ether-linked ring system incorporating
an eight-membered ring amine, are comparatively much
less well studied, but some are known to be CNS active and
are used for the treatment of pain and/or inflammation.3
Despite these interesting biological properties, examples
are relatively rare; analogous compounds containing
seven- and nine-membered amine ring systems are extremely
scarce. Consequently, compounds of this sort (indeed, seven-
nine membered cyclic biaryl ethers in general) are under-
represented in current small molecule screening libraries.
This can mainly be attributed to synthetic difficulties; for
example, there are notable problems associated with medium
ring synthesis, with medium ring biaryl scaffolds representing
especially challenging targets.4,5 Overall, there are a lack of
† University of Cambridge.
‡ AstraZeneca, Pharmaceutical Development.
(1) For examples, see: (a) Wang, L.; Sullivan, G. M.; Hexamer, L. A.;
Hasvold, L. A.; Thalji, R.; Przytulinska, M.; Tao, Z.; Li, G.; Chen, Z.;
Xiao, Z.; Gu, W.; Xue, J.; Bui, M.; Merta, P.; Kovar, P.; Bouska, J. J.;
Zhang, H.; Park, C.; Stewart, K. D.; Sham, H. L.; Sowin, T. J.;
Rosenberg, S. H.; Lin, N. J. Med. Chem. 2007, 50, 4162. (b) Klunder,
J. M.; Hargrave, K. D.; West, M.; Cullen, E.; Pal, K.; Behnke, M. L.;
Kapadia, S. R.; McNeil, D. W.; Wu, J. C.; Chow, G. C. J. Med. Chem.
1992, 35, 1887. (c) Lu, S. M.; Maggi, C. A.; Gensini, M.; Bigioni, M.;
Parlani, M.; Giolitti, A.; Fratelli, M.; Valli, C.; Terao, M.; Garattini, E.
ACS Med. Chem. Lett. 2010, 1, 411. For Sintamil, see, for example: (d)
David, J.; Grewal, R. S. Indian J. Exp. Biol. 1974, 12, 225.
(2) For examples, see: (a) Jiang, X. L.; Lee, G. T.; Prasad, K.; Repic,
O. Org. Process Res. Dev. 2008, 12, 1137. (b) Sakaki, J.; Konishi, K.;
Kishida, M.; Gunji, H.; Kanazawa, T.; Uchiyama, H.; Fukaya, H.;
Mitani, H.; Kimura, M. Bioorg. Med. Chem. Lett. 2007, 17, 4808. (c)
Ebisawa, M.; Umemiya, H.; Ohta, K.; Fukasawa, H.; Kawachi, E.;
Christoffel, G.; Gronemeyer, H.; Tsuji, M.; Hashimoto, Y.; Shudo, K.;
Kagechika, H. Chem. Pharm. Bull 1999, 47, 1778. For Loxapine, see for
example: (d) Chakrabarti A.; Bagnall, A. M.; Chue, P.; Fenton, M.;
Palaniswamy, V.; Wong, W.; Xia, J. Loxapine for schizophrenia.
Cochrane Database of Systematic Reviews 2007, Issue 4, Art. No.
CD001943.
(3) (a) Ouyang, X.; Chen, Z.; Liu, L.; Dominguez, C.; Kiselyove,
A. S. Tetrahedron 2000, 56, 2369. (b) Ouyang, X.; Kiselyove, A. S.
Tetrahedron Lett. 1999, 40, 5827. See, for example: (c) Ohgog, T.;
Tanaka, S.; Fujimoto, M.; Kitahara, A. Yakugaku Zassi 1977, 97, 24.
(d) Tanaka, S.; Hashimoto, K. 6-substituierte 6,7-dihydro-5H-dibenzo
b.g. 1.5 Oxazocine und Thiazocine und Verfahren zu deren Herstellung.
Ger. Offen. DE 2044508, May 1971. (e) Joergensen, T. K.; Andersen, K. E.;
Andersen, H. S.; Hohlweg, R.; Madsen, P.; Olsen, U. B. Novel Heterocyclic
Compounds. WO 9631497 A1, October 1996.
r
10.1021/ol4025259
Published on Web 10/17/2013
2013 American Chemical Society

efficient, concise, and flexible strategies toward diversely
substituted dibenz[b,g][1,5]oxazocines and equivalent biaryl
ethers with seven- and nine-membered ring amines. New
methodology of broad utility for the synthesis of these
scaffolds is needed so that their biological usefulness can be
investigated and exploited further.
same mechanistic blueprint could be applied to a carbonÀ
oxygen bond formation manifold, which would enable
access to oxygen-linked biaryl oxazacine systems 3b from
acyclic precursors 4b. The validity of this approach had
been established in our previous study; the synthesis of one
oxygen-linked medium ring biaryl ether was accomplished
by direct cyclization of a phenolic acyclic precursor using
a slightly modified version of the optimized reaction
conditions employed for the synthesis of nitrogen-linked
biaryls.6 However, the yield of the desired cyclic product
was extremely low, which clearly limited the utility of this
method.
Scheme 1. Mechanistic Blueprint for the Copper(I)-Catalyzed
N- and O-Linked Biaryl Cyclization Processa
Figure 1. Examples of biologically active compounds based
around O-linked medium-ring biaryl scaffolds. Loxapine2d
(a dibenzooxazepine) is used in the treatment of schizophrenia,
and Sintamil1d (a dibenzooxazepinone) has antidepressive activity.
Compounds 1 and 2 are dibenz[b,g][1,5]oxazocines; 1 has anti-
depressive activity3d, and 2 has potential for the treatment of pain
and/or inflammation.3e
Recently, we reported the development of a novel
copper-catalyzed strategy for the synthesis of medium ring
nitrogen-linked biaryl systems 3a (Scheme 1).6 Our ap-
proach was based around the direct N-arylation of acyclic
precursors of the general form 4a, which incorporated
a “templating” aliphatic nitrogen atom in addition to
an aniline nitrogen and aryl bromide. Our mechanistic
hypothesis is that both the aniline nitrogen and aliphatic
templating nitrogen atom bind to the copper atom, form-
ing a species, 5a, in which the copper metal is incorporated
in a chelate with the substrate. This ligation is followed
by oxidative addition to the aryl halide, forming 6a,
and subsequent reductive elimination yields the cyclized
product. The presence ofthe templating nitrogen atom was
found to be crucial for cyclization.7 We envisaged that the
a The “templating” aliphatic nitrogen atom is circled. Possible ancilliary
ligands omitted for clarity.
Herein we describe the development of a new, concise,
and efficient protocol of broad applicability for the pre-
paration of a range of compounds based around rare and
biologically interesting tricyclic biaryl ether-linked scaf-
folds incorporating seven-, eight-, and nine-memberedring
amines.8 Application of this methodology should allow
the sampling of attractive regions of chemical space that
are under-exploited in current drug discovery efforts.9
Initial optimization studies were directed toward the
ring-closure of acyclic precursor 7, readily generated by
a three-step sequence (Scheme 2). Reductive amination
of (2-bromo)benzylamine 8 and salicylaldehyde 9 led to
the formation of amine 10. Subsequent treatment of this
crude product material with formaldehyde yielded cyclic
hemiaminal 11, and reduction in acid provided 7 in a high
overall yield, with chromatography required only at the
final stage.10 This proved to be a general and robust route
to a wide variety of cyclization substrates (see the Supporting
Information).
(4) (a) Rousseau, G. Tetrahedron 1995, 51, 2777. (b) Surry, D.; Su, X.;
Fox, D. J.; Franckevicius, V.; Macdonald, S. J. F.; Spring, D. R. Angew.
Chem., Int. Ed. 2005, 44, 1870. (c) Surry, D. S.; Spring, D. R. Chem. Soc.
Rev. 2005, 2589. See also ref 6.
(5) Selected examples of the main strategies used for the formation of
dibenz[b,g][1,5]oxazocines from acyclic precursors: Reaction of primary
amines with biaryl ethers disubstituted with alkyl bromides: (a) Tanaka,
S.; Hashimoto, K.; Tanaka, S.; Hashimoto, K. Yakugaku Zassi 1973, 93,
1003. (b) Tanaka, S.; Hashimoto, K.; Wantanabe, H. Chem. Pharm.
Bull. 1973, 21, 1683. (c) Tanaka, S.; Hashimoto, K. US Patent 3803143,
April 1974.Intramolecular amide formation in biaryl ethers followed by
amine reduction: (d) Lieb, F.; Eiter, K. Liebigs Ann. Chem 1976, 93, 203.
Intramolecualr SNAr reaction of aliphatic amines: ref 3a,3b.
(8) A similar chelate effect for enabling medium-ring biaryl synthesis
using carbonÀhydrogen coupling has previously been reported; see:
Pintori, D. G.; Greaney, M. F. J. Am. Chem. Soc. 2010, 133, 1209.
(9) For recent dicussions of chemical space coverage and bioactive
molecule discovery, see: (a) Galloway, W. R. J. D.; Isidro-Llobet, A.;
Spring, D. R. Nature Commun. 2010, 1, 80. (b) Eberhadt, L.; Kumar, K.;
Waldmann, H. Curr. Drug Targets 2011, 12, 1531.
(6) Kenwright, J. L.; Galloway, W. R. J. D.; Blackwell, D. T.; Isidro-
Llobet, A.; Hodgkinson, J.; Wortmann, L.; Bowden, S. D.; Welch, M.;
Spring, D. R. Chem.;Eur. J. 2011, 17, 2981.
(7) It was proposed that internal co-ordination of the diamine moiety
to the copper (I) catalyst yields a highly reative copper chelate bringing
the aryl halide bond into close proximity to the reactive copper metal
which may facilitate the subsequent oxidative addition step; chelation
may also stabilize the postulated copper (III) intermediate so formed,
lowering the energy barrier associated with its generation. See ref 6.
(10) Wei, H.; Yin, L.; Luo, H.; Li, X.; Chan, A. S. C. Chirality 2011,
23, 222.
Org. Lett., Vol. 15, No. 21, 2013
5449

Scheme 2. Synthesis of Substrate 5 and Cyclization to 6a
Scheme 3. Scope of Substrates for the Formation of Substituted
N-Methylated Dibenz[b,g][1,5]oxazocines
A selection of solvents, copper salts, bases, and 1,3-
dicarbonyl ligands were screened for the cyclization of 7 to
form 12.11 The optimized conditions used a combination of
copper(I) iodide, 2,6-tetramethylheptanedione (TMHD),12
cesium carbonate, sodium ascorbate, and sodium sulfate in
acetonitrile at a substrate concentration of 0.2 M,13 heated
under microwave irradiation (sealed tube, under nitrogen)
at 120 °C (Scheme 2).14
With these optimized conditions established, the cycli-
zation of various other acyclic precursors was examined
(Scheme 3). Electron donation (13 and 14) and electron
withdrawal (15) were well tolerated in the halide portion
of the substrates. With regard to the phenolic portion,
an electron-withdrawing nitro group ortho to the reac-
tive phenolic oxygen was tolerated (19). Different halogen
atoms could also be successfully incorporated into the
product scaffolds (16À18, 20). These provide possible syn-
thetic handles for postcyclization elaboration around the
biaryl core via other transition-metal-catalyzed processes.
Large groups placedortho tothe coupling oxygendid bring
about a drop in yield (e.g., 21). However, copper-catalyzed
carbonÀoxygen bond formation is known to be more
challenging with ortho-substituted coupling partners.
We next examined the synthesis of different sized
oxazacines bearing a biaryl ether motif. Pleasingly,
seven-membered derivative 22 could be generated from
substrate 23 in a high yield (Scheme 4).15 Nine-membered
rings (24 and 25) could also be obtained using the opti-
mized conditions (from 26 and 27 respectively), albeit with
a reduced yield (Scheme 4). Heterocyclic functionality
was incorporated into one product, 25, further demon-
strating the value of the methodology in the context of the
generating pharmaceutically relevant products.
The attempted ring closing of secondary amine 10 to 28
failedundertheoptimizedcyclizationconditions. However
we have developed an alternative route to 28 (Scheme 5).
An allyl group is easily appended to the secondary nitrogen
of 10 to give 29. Cylization then proceeded smoothly to
generate 30. The allyl group was removed in high yield using
Wilkinson’s catalyst, thus furnishing 28. The amine of 28
provides a handle for further functionalization around the
biaryl core.
(11) See the Supporting Information for details regarding the opti-
mization studies.
(12) The use of this ligand in the formation of diaryl ethers has
previously been reported. See, for example: Buck, E.; Song, Z. J.;
Tschaen, D.; Dormer, P. G.; Volante, R. P.; Reider, P. J. Org. Lett.
2002, 4, 1623.
Wehypothesizethat the success of these cyclization reac-
tions is due to the presence of a “templating” nitrogen
atom in the acyclic substrates, which chelates the copper
catalyst and thereby facilitates ring-closure. Consequently,
it was expected that acylation of the templating nitrogen
would diminish the reactivity of the system, since the
lone pair of electrons could then be delocalized into the
carbonyl bond and thus would not be as available for
co-ordination toa copper species. Indeed, itwas found that
(13) There was no evidence of any competitive intermolecular cou-
plings, despite the relatively high concentration used. Medium ring
formations from acyclic precursors frequently require the use of more
dilute reaction conditions. See ref 6 and references cited therein.
(14) The reaction of 7 to 12 (Scheme 2) proceeds in 74% yield at 80 °C
in the absence of both the sodium ascorbate and sodium sulfate.
Microwave heating to 120 °C and addition of sodium ascorbate were
both shown to increase the yield of this reaction. Further research into
the basis for this effect is ongoing. The addition of sodium sulfate was
found to have a minimal impact upon the maximum yield obtained for
this cyclization. However, in the absence of sodium sulfate, the yields for
this process were found to be quite variable and observed to change with
the age of the cesium carbonate base used. This effect was ascribed to the
variable moisture content of the base, and the addition of sodum sulfate
(which presumably acts as a drying agent) was found to improve the
reliability of the reaction.
(15) As seven-membered ring formation is often faster than for
equivalent eight-membered rings, we sought confirmation that the
aliphatic chelating nitrogen was still playing a part in facilitating the
cyclization process. To that end we synthesized an all carbon equivalent
of the acyclic precursor leading to 24 and subjected it to the optimized
cyclization conditions. As expected, there was no evidence for the
formation of the corresponding cyclic product (see the Supporting
Information for synthesis details).
5450
Org. Lett., Vol. 15, No. 21, 2013

N-Boc protected substrate 31 would not cyclize under our
optimized conditions (Scheme 6).16
Scheme 6. “Remote Activation” by an Exocyclic Tethera
Scheme 4. Formation of Biaryl Ethers Incorporating Seven- and
Nine-Membered Ring Aminesa
a Optimized reaction conditions: CuI (5 mol %), TMHD (10 mol %),
Cs2CO3 (2 equiv), sodium ascorbate (10 mol %), sodium sulfate (2 equiv),
CH3CN, 120 °C, microwave, 5 h.
a Optimized reaction conditions: CuI (5 mol %), TMHD (10 mol %),
Cs2CO3 (2 equiv), sodium ascorbate (10 mol %), sodium sulfate (2 equiv),
CH3CN, 120 °C, microwave, 5 h.
Scheme 5. Synthesis of Dibenz[b,g][1,5]oxazocine with Free
c
Secondary Amine GroupaÀ
“remote activation” concept could be leveraged in the synth-
esis of alternative series of oxidized dibenzoxazocine-type
scaffolds, extending the scope of the cyclization strategy.
In conclusion, we have developed a new, concise, and
general protocol for the synthesis of compounds based
around tricyclic biaryl ether-linked scaffolds incorporating
seven-, eight-, and nine-membered ring amines, including
the dibenz[b,g][1,5]oxazocines class of heterocycles. The
process displays a broad substrate scope, uses an inexpen-
sive copper catalyst, and generates rare and biologically
interesting heteroaromatic products that would be difficult
to synthesize by other methods. We envisage that this
approach should prove useful for the exploration of hitherto
under-investigated scaffolds and thereby the discovery of
new molecules of medicinal interest. Compounds synthesized
in this program are currently being screened for biological
activity. Further mechanistic investigation is underway in
our laboratories to clarify the activating effect of the “tem-
plating” nitrogen. The results of these studies will be reported
in due course.
a Optimized reaction conditions: CuI (5 mol %), TMHD (10 mol %),
Cs2CO3 (2 equiv), sodium ascorbate (10 mol %), sodium sulfate (2 equiv),
CH3CN, 120 °C, microwave, 5 h. b Yield of 29 over two steps from 8 and 9
(Scheme 2). c Wilkinson’s cat. = chlorotris(triphenylphosphine)rhodium(I).
We decided to investigate whether addition of a further
amine could restore reactivity (Scheme 6).
Acknowledgment. We thank AstraZeneca, the EU,
EPSRC, BBSRC, MRC, and Wellcome Trust for funding.
Gratifyingly, exocyclic amine functionality tethered via
an aliphatic linkage to the linear substrate (compound 32)
allowed successful cyclization to form 33. We propose that
this exocyclic tether is flexible enough to bind the copper. It is
striking that this proposed 11-membered chelate is able to
so dramatically affect the coupling process. Conceivably, this
Supporting Information Available. Experimental pro-
cedures, characterization data, and 1H and 13C NMR spec-
tra.This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Similar obervations were made during our studies into the
synthesis of nitrogen-linked medium-ring biaryls (see ref 6).
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 21, 2013
5451