Oxidative C-H bond functionalization and ring expansion with TMSCHN2: A copper(I)-catalyzed approach to dibenzoxepines and dibenzoazepines

Article abstract of DOI:10.1002/anie.201411726

Tricyclic dibenzoxepines and dibenzazepines are important therapeutic agents for the pharmaceutical industry and academic research. However, their syntheses are generally rather tedious, requiring several steps that involve a Wagner-Meerwein-type rearrangement under harsh conditions. Herein, we present the first copper(I)-catalyzed oxidative C-H bond functionalization and ring expansion with TMSCHN₂ to yield these important derivatives in a facile and straightforward way. Cut a long story short: Tricyclic dibenzoxepines and dibenzazepines are important therapeutic agents for pharmaceuticals, but their syntheses are generally rather tedious. A copper(I)-catalyzed oxidative C-H bond functionalization and ring expansion sequence with TMSCHN₂ has been developed to yield these important derivatives in a facile and straightforward way.

Full text of DOI:10.1002/anie.201411726

Angewandte
Chemie
DOI: 10.1002/anie.201411726
Synthetic Methods
À
Oxidative C H Bond Functionalization and Ring Expansion with
TMSCHN2: A Copper(I)-Catalyzed Approach to Dibenzoxepines and
Dibenzoazepines**
Tobias Stopka, Leyre Marzo, Mercedes Zurro, Simon Janich, Ernst-Ulrich Wꢀrthwein,
Constantin G. Daniliuc, Josꢁ Alemꢂn,* and Olga Garcꢃa MancheÇo*
Dedicated to Professor Josꢁ Luis Garcꢃa Ruano on the occasion of his retirement
Abstract: Tricyclic dibenzoxepines and dibenzazepines are
important therapeutic agents for the pharmaceutical industry
and academic research. However, their syntheses are generally
rather tedious, requiring several steps that involve a Wagner–
Meerwein-type rearrangement under harsh conditions. Herein,
À
we present the first copper(I)-catalyzed oxidative C H bond
functionalization and ring expansion with TMSCHN2 to yield
these important derivatives in a facile and straightforward way.
D
ibenzo[b,f]xepine and dibenzo[b,f]azepine derivatives (I,
Figure 1) are important therapeutic agents, which present
a broad spectrum of pharmaceutical properties. For example,
derivatives II–V are used for the treatment of depression in
some countries.[1] Moreover, derivatives such as metapramine
(II) also present analgesic properties,[2] whereas opipramol
(V) shows an anxiolytic profile.[3] Besides other activities,
some of these tricyclic structures are known as receptor
antagonists (VI). Oxcarbazepine (OXC, Trileptal, VII) rep-
resents the first narrow-spectrum antiepileptic drug (AED)
and more recently was used as a monotherapy for the
treatment of partial seizures in adults.[4]
Figure 1. Biologically active dibenzoxepines and dibenzazepines.
Despite the great importance of these types of hetero-
cycles, there is a lack of simple, mild, and direct synthetic
[*] T. Stopka, M. Zurro,[+] Dr. S. Janich, Prof. E.-U. Wꢀrthwein,
Dr. C. G. Daniliuc, Prof. O. G. MancheÇo[+]
Organisch-Chemisches Institut, Universitꢁt Mꢀnster
48149 Mꢀnster (Germany)
L. Marzo, Dr. J. Alemꢂn
Departamento de Quꢃmica Orgꢂnica (Mꢄdulo 01)
Universidad Autꢄnoma de Madrid
Cantoblanco, 28049-Madrid (Spain)
E-mail: jose.aleman@uam.es
[+] New address: Institut fꢀr Organische Chemie, Universitꢁt Regens-
burg, 93053 Regensburg (Germany)
E-mail: olga.garcia-mancheno@chemie.uni-regensburg.de
Scheme 1. Classical and present approach for the synthesis of dibenz-
oxepines and dibenzazepines I.
[**] The Deutscher Akademischer Austauschdienst (DAAD) supported
this work within the DAAD-PPP Spanien exchange programme
(project 710838). The Deutsche Forschungsgemeinschaft (DFG)
and the Fonds der Chemischen Industrie (FCI) are acknowledged
for generous support. L.M. thanks the DFG within the SFB 858 for
a predoctoral stay fellowship. Financial support from Spanish
Government (CTQ-2012-12168) is gratefully acknowledged. J.A.
thanks the MICINN for a “Ramon y Cajal” contract and L.M. for
a predoctoral fellowship. TMS=trimethylsilyl.
methods for their preparation.[5] The classical synthesis of
dibenzoxepines and dibenzazepines are so far based on
multistep processes (Scheme 1). In these approaches several
steps are required for the introduction of a CH2-LG (LG =
leaving group) unit at the benzylic position of xanthenes or
acridanes using stoichiometric reagents[6] as well as harsh
conditions for the Wagner–Meerwein rearrangement with
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201411726.
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a large excess (or even as a solvent) of strong acids under
heating (typically 140–2008C). These features limited the
preparation of new related tricyclic derivatives with broad
substitution patterns, which have been shown to be extremely
important to modulate their biological activity.[7]
Based on these precedents and driven by the need to
develop more general and straightforward methods, we
À
change to the nonprotic peroxide (PhCO2)2 gave a promising
29% yield (entry 5). To improve the properties and stability
of the copper catalyst, different P and N ligands (for full
screening see the Supporting Information) were assayed
(entries 6–11). From the set of tested ligands (20 mol%), the
bidentate bpy provided the best reactivity (entry 10), which
was improved when 30 mol% was used (entry 11). Thus, the
À
proposed
a
direct C H functionalization approach
challenging C H “activation”, insertion, and rearrangement
(Scheme 1). From the recent advances in copper-catalyzed
reactions of diazo compounds, we hypothesized that those
would be the appropriate reagents for functionalization of the
sequence led to the dibenzoxepine 3a in a good 55% yield,
with 41% of the starting material 1a recovered.
Under these optimized conditions, the scope of the
reaction with different substituted xanthene and acridane
derivatives 1 was investigated (Table 2). Different electron-
donating (MeO, 3b) and electron-withdrawing groups (F, 3c)
as well as bulkier substituents such as a fused phenyl group
(3d) were tolerated under these conditions. Nitrogen-con-
taining compounds were next explored. The substitution of
the oxygen by a nitrogen atom in 1e, which possesses
a phenylamino group, led to a significant improvement in
the yield (75%, 3e). Considering that most of the bioactive
dibenzazepines contain an N-alkyl substitution, the methyl-
and benzylacridanes 1 f and 1g[12] were investigated. The
reaction proceeded satisfactorily, with an enhanced yield of
74% for the N-Me derivative 3 f.[13] The reaction tolerated
different substitution with varied electronic properties,
C H bond.[8] Therefore, we chose trimethylsilyldiazomethane
À
(TMSCHN2), which already possess a silicon leaving group
that might also facilitate or promote the in situ rearrangement
to the tricyclic backbone of the desired products (I). Herein,
À
we present a copper-catalyzed mild oxidative C H bond
functionalization and ring-expansion process for the straight-
forward preparation of dibenzoxepines and dibenzazepines
from simple starting materials.
We started our screening with commercially available
xanthene (1a) and TMSCHN2 (2) in the presence of 10 mol%
Cu(OTf)2, which would be reduced in situ by 2 to the
presumed active CuI species[9] (Table 1, entry 1). However,
Table 1: Optimization of the reaction of 1a with TMSCHN2.[a]
Table 2: Scope of the Cu(OTf)2-catalyzed reaction.[a,b]
Entry[a] Ligand (mol%)
Additive (1.2 equiv) Yield [%][b]
1
2
3
4
–
–
–
–
–
–
T+BF4
traces
traces
7
À
tBuOOH
DDQ
5
6
7
–
(PhCO2)2
(PhCO2)2
(PhCO2)2
29
30
39
TMEDA (20)
BINAP (20)
8
1,10-phenanthroline (20) (PhCO2)2
44
9
10
11
tpy (20)
bpy (20)
bpy (30)
(PhCO2)2
(PhCO2)2
(PhCO2)2
41
50
55
[a] Conditions: 1a (0.2 mmol), 2 (0.48 mmol), (PhCO2)2 (0.24 mmol),
Cu(OTf)2 (10 mol%), and ligand in MeCN (2.0 mL) at RT for 18 h under
argon. [b] Yield of isolated product. T+BF4À =2,2,6,6-tetramethylpiper-
idine-1-oxoammonium tetrafluoroborate. BINAP=2,2’-bis(diphenyl-
phosphino)-1,1’-binaphthyl. tpy=2,2’,2’’-terpyridine. bpy=2,2’-bipyri-
dine.
under these conditions no formation of the desired product 3
occurred and only starting material could be detected in the
NMR spectrum. Driven by our experience in the oxidative
functionalization of benzylic C H bonds,[10] we decided to add
À
an oxidant to the reaction media to facilitate the nucleophilic
attack at this position. Although the TEMPO oxoammonium
[a] Conditions: 1 (0.2 mmol), 2 (0.48 mmol), (PhCO2)2 (0.24 mmol),
Cu(OTf)2 (10 mol%), and bpy (30 mol%) in MeCN (2.0 mL) at RT for
18 h under argon. [b] Yields are of isolated products. [c] Reaction on
a 5.0 mmol scale. [d] Reaction in the presence of KF (1.1 equiv). [e] 45%
of 1h recovered. [f] Along with an inseparable by-product.
À
salt T+BF4 and tBuOOH gave no results, the use of DDQ
(2,3-dichloro-5,6-dicyano-1,4-benzoquinone) allowed the iso-
lation of the desired product 3a (confirmed by X-ray
analysis,[11] see Table 1) in low yield (entries 2–4). The
2
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thereby providing the tricyclic compounds 3i–m in compara-
bly good yields. Moreover, the less-reactive N-Boc-protected
acridine 1h could also be employed, thus providing an easy
entry for late deprotection towards a broader scope of
substituted derivatives 3. On the other hand, 9-methyl-
substituted acridine showed no reactivity under the standard
conditions and 1n was recovered almost quantitatively. In
addition, the sulfur derivative 1o also gave the tricyclic thio
compound 3o, but in a lower yield. Finally, the reaction was
scaled-up to 5 mmol for xanthene 1a and acridine 1 f, which
led to 3a and 3 f in good yields (65% and 60%, respectively).
The synthetic applicability of the developed method was
demonstrated by the further derivatization of 3 (Scheme 2).
intermediate A, which can undergo a ring expansion driven
by the exclusion of a nitrogen molecule via the cationic
intermediates B and C. To confirm that the carbocation is an
intermediate, compound 7a was synthesized and isolated
following known procedures[19] and treated with trimethyl-
silyldiazomethane (2). The ring-expansion product 3 was then
obtained,[20] thereby excluding the participation of carbene
species and indicating that 7 is the key intermediate in this
transformation. Good evidence for the described mechanism
was confirmed by labeling experiments (Scheme 3, bottom).
Thus, a 1.8:1 mixture of products [D]-3b and [D]-3b’ were
obtained, which was in accordance with the higher electron
donation of the methoxy-substituted aromatic ring of [D2]-1b.
To achieve a better understanding of the unexpected ring-
expansion process, high-level density functional theory cal-
culations in the gas phase were performed. Using the
gaussian09 program package,[21] the geometries of the
involved compounds and intermediates were optimized with
the B3LYP/6-311 + G(d,p) method.[22] The corresponding
energies were subsequently refined by calculations at the
B2PLYP-D3/def2-TZVP level of theory, including zero-point
corrections (Figure 2). The high-energy carbocation 7 reacts
with 2 to give the more stable intermediate A,[23] which
evolves to the cyclopropane B through an exothermic intra-
molecular SN2-type reaction involving the exclusion of N2 as
a leaving group. A ring expansion takes place to deliver
a tricyclic carbocation, which adopts the strained conforma-
tion C when starting from the energetically most favorable
conformer of A. Then, C relaxes quickly by ring inversion to
give C’. Elimination of the silicon group delivers the final
product 3 with concomitant formation of trimethylsilylben-
zoate (8). This silyl ester by-product 8 was detected by GC-
MS and NMR spectroscopy.
Scheme 2. Derivatization of 3 to important biological products.
DEAD=diethyl azodicarboxylate, PCC=pyridinium chlorochromate.
Thus, the synthesis of the amino derivative 5a with analgesic
properties[2b] and an important precursor of cularine-type
alkaloids was carried out.[14] Moreover, compound 6 f, an
analogue of the potent central nervous system agent oxcar-
bazepine, was also synthesized from 3 f by a simple two-step
hydroboration and oxidation sequence.[15]
In conclusion, an intermolecular copper(I)-catalyzed
À
oxidative C H bond functionalization and ring expansion
The proposed mechanism is outlined in Scheme 3. The
sequence with TMSCHN2 has been developed. The reaction
initially formed Cu(bpy)2 complex[16] is
reduced in situ by the diazoalkane
reagent to an active CuI species[9] that
À
catalyzed the reductive O O bond cleav-
age of the peroxide at room temperature
to form the PhCO2C radical and the
corresponding CuII-carboxylate spe-
cies.[17] In agreement with Klussman and
co-workers as well as other authors,[18] the
oxidation of the benzylic position of
compounds of general structure 1 takes
place next through a two-electron radical
oxidation (HC abstraction and further
oxidation with the regenerated CuII) to
afford carbocation 7. The reaction was
inhibited by the addition of typical rad-
ical scavengers such as BHT (butylated
hydroxytoluene) and TEMPO (2,2,6,6-
tetramethylpiperidine N-oxyl), thus sug-
gesting the participation of a radical
intermediate in the formation of 7.
Next, this carbocation (7) reacts with
the diazo compound 2 to generate an Scheme 3. Mechanistic proposal and labeling experiment.
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Figure 2. DFT (B2PLYP-D3/def2-TZVP//B3LYP/6-311+G(d,p)) reaction energy profile in the gas phase. The relative energies [kcalmolÀ1] are based
on the sums of the respective total energies Etot of all species, including nitrogen.
Stachulski, Org. Lett. 2011, 13, 5592 – 5595; for a ring-closing
metathesis approach, see g) T. Matsuda, S. Sato, J. Org. Chem.
2013, 78, 3329 – 3335, and references therein.
proceeds with high selectivity to form tricyclic dibenzoxe-
pines and dibenzazepines, which are important therapeutic
agents.
[6] For selected examples, see a) K. Chiba, H. Tagaya, M. Karasu, T.
Ono, M. Kugiya, Chem. Lett. 1990, 39 – 42; b) T. Storz, E.
Vangrevelinghe, P. Dittmar, Synthesis 2005, 2562 – 2570; see also
Ref. [4f].
Received: December 5, 2014
Published online: && &&, &&&&
[7] Y. Wu, J. P. Sanderson, J. Farrell, N. S. Drummond, A. Hanson,
E. R. Bowkett, N. G. Berry, A. V. Stachulski, S. E. Clarke, W. J.
Pichler, M. Piromohamed, B. K. Park, D. J. J. Naisbitt, J. Allergy
Clin. Immunol. 2006, 118, 233 – 241.
[8] X. Zhao, Y. Zhang, J. Wang, Chem. Commun. 2012, 48, 10162 –
10173.
À
Keywords: C H functionalization · copper · heterocycles ·
ring expansion · TMSCHN2
.
[9] For practical and stability issues, Cu(OTf)2 was used as the stable
CuI precursor. Moreover, CuOTf proved to be less efficient than
Cu(OTf)2 (see the Supporting Information). For the reduction of
CuII(OTf)2 to CuI with CH2N2, see R. G. Salomon, J. K. Kochi, J.
Am. Chem. Soc. 1973, 95, 3300 – 3310.
[10] See, for example: a) H. Richter, R. Frçhlich, C. G. Daniliuc, O.
Garcꢃa MancheÇo, Angew. Chem. Int. Ed. 2012, 51, 8656 – 8660;
Angew. Chem. 2012, 124, 8784 – 8788; b) H. Richter, R. Rohl-
mann, O. Garcꢃa MancheÇo, Chem. Eur. J. 2011, 17, 11622 –
11627; c) H. Richter, O. Garcꢃa MancheÇo, Eur. J. Org. Chem.
2010, 4460 – 4467.
[1] For a general chapter on this topic, see a) J. M. Vela, H.
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Antipsychotics, Anxiolytics: From Chemistry and Pharmacology
to Clinical Application, Weinheim, Wiley-VCH, 2007, p. 248; for
the biological properties of metapramine, see b) A. M. Bouger-
olle, G. Dordain, J. A. Berger, A. Eschalier, Life Sci. 1992, 50,
161 – 168; for opipramol, see c) H.-J. Mçller, H. P. Volz, L. W.
Reimann, K.-D. Stoll, J. Clin. Psychopharmacol. 2001, 21, 59 –
65; for maroxepine/eresepine, see d) S. Bischoff, A. Vassout, A.
Delini-Stula, P. Waldmeier, Pharmacopsychiatry 1986, 19, 306 –
307.
[11] See the Supporting Information for the X-ray crystal structure
data of 3a (CCDC 1001790 contains the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.).
[12] 1 f can also be prepared in large amounts from N-methylacri-
done by reduction with BH3 or LiAlH4: a) J. Shi, X. Zhang, D. C.
Neckers, J. Org. Chem. 1992, 57, 4418 – 4421; b) A. Mustafa, W.
Asker, M. E. El-Din Sobhy, J. Am. Chem. Soc. 1955, 77, 5121 –
5124. See also the Supporting Information.
[2] a) A. Michael-Titus, J. Costentine, Pain 1987, 31, 391 – 400; b) K.
Kawai, Nippon Yakurigaku Zasshi 1960, 56, 971 – 983.
[3] W. E. Mꢁller, B. Siebert, G. Holoubek, C. Gentsch, Pharmacop-
sychiatry 2004, 37, 189 – 197.
[4] a) M. M. Kalis, N. A. Huff, Clin. Ther. 2001, 23, 680 – 700; b) S.
Shorvon, Seizure 2000, 9, 75 – 79.
[5] For selected examples based on the Wagner–Meerwein rear-
rangement, see a) R. J. Stolle, Prakt. Chem. Naturforsch. 1922,
105, 137 – 148; b) J. Martinet, A. Dansette, Bull. Soc. Chim. Fr.
1929, 45, 101 – 109; c) F. A. Anet, P. M. G. Bavin, Canadian J.
Chem. 1957, 35, 1084 – 1087; d) M. S. Newman, W. H. Powell, J.
Org. Chem. 1961, 26, 812 – 815; e) Z. Razavi, F. McCapra,
Luminescence 2000, 15, 239 – 244; f) E.-C. Elliott, E. R. Bowkett,
J. L. Maggs, J. Bacsa, B. K. Park, S. L. Regan, P. M. OꢂNeill, A. V.
[13] Dibenzazepine 3 f was obtained under the standard conditions in
67% yield, which was improved to 74% by using of 1.1 equiv of
KFas an additive. This effect was not observed for 3e (NPh) and
3g (NBn).
4
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[14] A. Garcia, L. Castedo, D. Domꢃnguez, Tetrahedron 1995, 51,
8585 – 8598.
[19] See, for example: S. Sugawara, S. Kojima, Y. Yamamoto, Chem.
Commun. 2012, 48, 9735 – 9737.
[15] A Scifinder survey revealed more than 2471 biological studies on
this structure: a) N. Kaniwa, Y. Saito, Ther. Adv. Drug. Saf. 2013,
4, 246; b) E. Kaiser, C. Prasse, M. Wagner, K. Broeder, T. A.
Ternes, Environ. Sci. Technol. 2014, 48, 10208 – 10216; c) D. Kim,
J.-H. Seo, E. Joo, L. Yeon, W. Hyang, W. C. Shin, S. B. Hong,
Clin. Neuropharmacol. 2014, 37, 100 – 107; synthetic approaches
to oxcarbazepines: d) K. Hirpara, K. Jesunadh, M. K. Sharma,
C. H. Khanduri, PCT Int. Appl. WO 2014049550A1 20140403,
2014, and references therein.
[16] The expected in situ formed precatalyst Cu(bpy)2·(OTf)2 was
preformed by reaction of a 1:2 mixture of Cu(OTf)2 and bpy.
This complex was used under standard conditions, and the same
result (3a, 55%) was obtained as with the preformed and in situ
catalyst (see the Supporting Information).
[17] J. K. Kochi, Organometallic Mechanisms and Catalysis: The Role
of Reactive Intermediates in Organic Processes, Academic Press,
New York, 1978, chap. 4, pp. 50 – 83.
[18] See, for example: a) A. Pintꢄr, A. Sud, D. Sureshkumar, M.
Klussmann, Angew. Chem. Int. Ed. 2010, 49, 5004 – 5007; Angew.
Chem. 2010, 122, 5124 – 5128; b) F. Benfatti, M. Guiteras Cap-
devila, L. Zoli, E. Benedetto, P. G. Cozzi, Chem. Commun. 2009,
5919 – 5921; c) B. Zhang, S.-K. Xiang, L.-H. Zhang, Y. Cui, N.
Jiao, Org. Lett. 2011, 13, 5212 – 5215; d) B. Zhang, Y. Cui, N. Jiao,
Chem. Commun. 2012, 48, 4498 – 4500.
[20] 7a was synthesized from 1a by hydride abstraction with
Ph3CSbCl6. The isolated rather unstable carbocation 7a was
immediately treated with 2 to give 3a in good yield. However,
the one-pot reaction with the trityl cation and 2 led to 3a only in
trace amounts (< 5%) (see the Supporting Information).
[21] Gaussian09 (RevisionB.01), M. J. Frisch et al., Gaussian, Inc.,
Wallingford CT, 2010.
[22] A. D. Becke, J. Chem. Phys. 1993, 98, 5648 – 5652.
[23] Intermediate A is conformationally highly flexible in terms of
À
rotation about the initially formed C C bond. The three possible
conformers present almost degenerate energy levels in the gas
phase (B2PLYP-D3/def2-TZVP + ZPE//B3LYP/6-311 + G(d,p)
(see below). Both the relative most stable one A1 and the
slightly less favorable A2 can serve as entry points to similar
reaction paths which are equally feasible, but comprise diaste-
reomeric intermediates. For brevityꢂs sake, only the path starting
from A1 is presented. See the Supporting Information for
a complete overview of the examined pathways.
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Communications
Synthetic Methods
T. Stopka, L. Marzo, M. Zurro, S. Janich,
E.-U. Wꢁrthwein, C. G. Daniliuc,
J. Alemꢂn,*
O. G. MancheÇo*
&&&& — &&&&
À
À
Oxidative C H Bond Functionalization
and Ring Expansion with TMSCHN2: A
Copper(I)-Catalyzed Approach to
Cut a long story short: Tricyclic dibenz-
oxepines and dibenzazepines are impor-
tant therapeutic agents for pharmaceut-
icals, but their syntheses are generally
rather tedious. A copper(I)-catalyzed oxi-
dative C H bond functionalization and
ring expansion sequence with TMSCHN2
has been developed to yield these
important derivatives in a facile and
straightforward way.
Dibenzoxepines and Dibenzoazepines
6
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Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!