Late stage Pd-catalyzed C-H bond functionalization: A powerful tool for the one step access to arylated Cyproheptadine and cyclobenzaprine derivatives

Article abstract of DOI:10.1016/j.catcom.2019.105716

The reactivity of Cyproheptadine and Cyclobenzaprine in Pd-catalyzed arylation via C-H bond functionalizations was investigated. From Cyproheptadine using aryl bromides as aryl sources and 5 mol% of a palladium catalyst, the C10-arylated Cyproheptadine derivatives were regioselectively obtained. The highest yields were obtained with electron-rich aryl bromides, but the reaction tolerated useful functional groups on the aryl bromide such as dimethylamino, methoxy, hydroxyl, alkyl, aryl, fluoro, chloro and trifluoromethyl. Cyclobenzaprine was also reactive under the same reaction conditions.

Full text of DOI:10.1016/j.catcom.2019.105716

Accepted Manuscript
Late stage Pd-catalyzed C-H bond functionalization: A powerful
tool for the one step access to arylated Cyproheptadine and
cyclobenzaprine derivatives
Dhieb Atoui, Haoran Li, Ridha Ben Salem, Thierry Roisnel, Elsa
Caytan, Jean-François Soulé, Henri Doucet
PII:
S1566-7367(19)30178-5
https://doi.org/10.1016/j.catcom.2019.105716
105716
DOI:
Article Number:
Reference:
CATCOM 105716
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
23 April 2019
27 May 2019
28 May 2019
Please cite this article as: D. Atoui, H. Li, R.B. Salem, et al., Late stage Pd-catalyzed C-H
bond functionalization: A powerful tool for the one step access to arylated Cyproheptadine
and cyclobenzaprine derivatives, Catalysis Communications, https://doi.org/10.1016/
j.catcom.2019.105716
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ACCEPTED MANUSCRIPT
Late stage Pd-catalyzed C-H bond functionalization: A
powerful tool for the one step access to arylated
Cyproheptadine and Cyclobenzaprine derivatives
a,b
a
b,*
a
a
Dhieb Atoui , Haoran Li , Ridha Ben Salem , Thierry Roisnel , Elsa Caytan , Jean-
a,*
a,*
François Soulé jean-francois.soule@univ-rennes1.fr, and Henri Doucet
ridhabensalem@yahoo.fr; henri.doucet@univ-rennes1.fr
a
Univ Rennes, CNRS, ISCR-UMR 6226, F-35000 Rennes, France
b
Laboratoire de Chimie Organique LR 17ES08, Université de Sfax, Faculté des Sciences de Sfax, Route de la
Soukra km 4, 3038 Sfax, Tunisia
*
Corresponding author.

ACCEPTED MANUSCRIPT
Abstract— The reactivity of Cyproheptadine and Cyclobenzaprine in Pd-catalyzed arylation via C-H bond func-
tionalizations was investigated. From Cyproheptadine using aryl bromides as aryl sources and 5 mol% of a pal-
ladium catalyst, the C10-arylated Cyproheptadine derivatives were regioselectively obtained. The highest yields
were obtained with electron-rich aryl bromides, but the reaction tolerated useful functional groups on the aryl
bromide such as dimethylamino, methoxy, hydroxyl, alkyl, aryl, fluoro, chloro and trifluoromethyl. Cycloben-
zaprine was also reactive under the same reaction conditions. © 2019 Elsevier Science. All rights reserved
Keywords: palladium, C-H bond functionalization, Cyproheptadine, Cyclobenzaprine, aryl bromides

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1
. Introduction
The dibenzo[a,d][7]annulene unit (Fig 1, top) can be found in several drugs. For example, Cyproheptadine is
used to treat allergic reactions and cyclical vomiting syndrome; whereas Cyclobenzaprine is employed as
muscle relaxer medication to relieve skeletal muscle spasms (Fig. 1, bottom). Moreover, Cyproheptadine might
be useful for breast cancer treatment [1,2]. Amitriptyline, which can be prepared by reduction of the C =C
11
10
double bond of Cyclobenzaprine [3], is one of the most efficient drugs used in the treatment of depression (Fig.
, bottom) [4]. Therefore, the development of a methodology employing the so-called late stage C-H bond
1
functionalization allowing the easy access in one step to a wide variety of derivatives of these drugs containing
useful functional groups has potential in pharmaceutical chemistry.
Figure 1 Structures of 5H-dibenzo[a,d][7]annulene, Cyproheptadine, Cyclobenzaprine and Amitriptyline
2
During the last decades, the metal-catalyzed C–H bond functionalization of a broad range of the sp C-H bonds
[
5-14] including cyclic alkenes [15-21] were demonstrated to be extremely effective for the access to sophisti-
cated structures. With cyclic alkenes, in general the reaction likely proceed via a Heck type mechanism. How-
ever, as the Heck type -H elimination step is not possible with these substrates – as the hydrogen involved in
the -hydride elimination process is anti with respect to the Pd-C bond – , a syn ’-hydride elimination may
occur in some cases [22]. These methodologies are very attractive in terms of late-stage functionalization as it
does not require the preparation of an organometallic or a boron derivative of one of the coupling partners. A
few examples of metal-catalyzed C–H bond functionalization of the C4-position of dibenzo[a,d][7]annulene
units have been reported [23-26]. For example, in 1996, Dyker described one example of C4-functionalization
of a 5-methylene-5H-dibenzo[a,d][7]annulene via Pd-catalysis (Scheme 1, a) [23]. In 2017, Yu et al. reported

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conditions for the intermolecular C4-acylation of 5H-dibenzo[a,d][7]annulen-5-one with 2-oxo-2-phenylacetic
acid using 5 mol% Pd(OAc) catalyst (Scheme 1, b) [24]. In 2016, Nakamura, Ilies et al. methylated the C4-
2
position of 5H-dibenzo[a,d][7]annulen-5-one with AlMe using a Fe-catalyst [25], and very recently, Sundara-
3
raju et al. described conditions for the Co-catalyzed C4-alkylation of this annulen-5-one with a maleimide [26].
Scheme 1 Pd-catalyzed C-H bond functionalizations of dibenzo[a,d][7]annulene units and of Cyproheptadine
and Cyclobenzaprine.
To our knowledge, the Pd-catalyzed C-H bond functionalization of Cyproheptadine and Cyclobenzaprine has
not yet been described and needed to be investigated. Herein, we report on the reactivity of Cyproheptadine and
Cyclobenzaprine in palladium-catalyzed arylations via a C-H bond functionalization using a variety of aryl
bromides as the aryl source.
2
. Results and discussion
First, we examined the reactivity of Cyproheptadine in Pd-catalyzed direct arylation in the presence
KOAc as base using DMA as the solvent (Table 1), as we had previously observed that these reaction
conditions allowed the coupling of fulvene, acenaphthylene or dibenzo[b,f]azepine derivatives with aryl
bromides [11,12]. Reactions performed with 5 mol% Pd(OAc) or PdCl (MeCN) as the catalysts at
2
2
2
1
50 °C during 16 or 48 h using 4-bromotoluene as the aryl source regioselectively afforded the C10-

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arylated Cyproheptadine
Cyproheptadine were observed by GC/MS analysis of the crude mixtures. Then, the influence of a set
of phosphine ligands on the reaction was examined. Higher yields in were obtained with PPh and
dppb than with the electron-rich PCy ligand (Table 1, entries 4-7). The use of PdCl(C H )(dppb) [27]
1 in 17-27% yields (Table 1, entries 1- 3). No arylations at other positions of
1
3
3
3
5
as the catalyst afforded
CsOAc, NaOAc or DBU) and other solvents (DMF, NMP and xylene), afforded
ble 1, entries 9-16). Using a shorter reaction time (16 h instead of 48 h), was obtained in a similar
yield; whereas after 4 h the yield in dropped to 34% due to a partial conversion of 4-bromotoluene
Table 1, entries 17 and 18).
PdCl(C H )(dppb) catalyst afforded
1 in a higher yield of 41% (Table 1, entry 8). Other bases (K CO , Cs CO ,
2 3 2 3
1
in lower yields (Ta-
1
1
(
The use of 4-iodotoluene instead of 4-bromotoluene with
in only 11% yield, and the formation of a large amount of 4,4'-
1
3
5
dimethyl-1,1'-biphenyl due to the homo-coupling of 4-iodotoluene was observed (Table 1, entry 19).
On the other hand, with 4-chlorotoluene as aryl source, product
conversion of this aryl chloride (Table 1, entry 20).
1 was obtained in 19% due to a poor

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Table 1. Influence of the reaction conditions on the coupling of Cyproheptadine with 4-bromotoluene
Entry
Catalyst (mol%)
Pd(OAc)2
Solvent
DMA
Base
Yield (%)
1
2
3
4
5
6
7
8
9
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
24
17
27
20
a
a
Pd(OAc)2
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMF
NMP
xylene
DMA
DMA
DMA
DMA
PdCl (MeCN)
2
2
Pd(OAc) / 2 PPh
2
3
a
Pd(OAc) / 2 PCy
6
2
3
a
a
Pd(OAc) / dppe
14
24
41
0
2
Pd(OAc) / dppb
2
PdCl(C H )(dppb)
3
5
PdCl(C H )(dppb)
K CO3
2
3
5
1
1
1
1
1
1
1
1
1
1
2
0
1
2
3
4
5
6
7
8
9
0
PdCl(C H )(dppb)
Cs CO3
0
3
5
2
PdCl(C H )(dppb)
CsOAc
NaOAc
DBU
5
3
5
PdCl(C H )(dppb)
8
3
5
a
PdCl(C H )(dppb)
5
3
5
PdCl(C H )(dppb)
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
0
3
5
PdCl(C H )(dppb)
5
3
5
PdCl(C H )(dppb)
0
3
5
a
PdCl(C H )(dppb)
39
34
11
19
3
5
b
PdCl(C H )(dppb)
3
5
a,c
a,d
PdCl(C H )(dppb)
3
5
PdCl(C H )(dppb)
3
5
Conditions: Catalyst (0.05 equiv.), Cyproheptadine (1 equiv.), 4-bromotoluene (2 equiv.), base (3 equiv.), 48 h,
a
b
c
d
1
50 °C, isolated yields of 1. 16 h. 4 h. From 4-iodotoluene. From 4-chlorotoluene.

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Then, the scope of the coupling of Cyproheptadine with a set of aryl bromides in the presence of 5
mol% PdCl(C H )(dppb), KOAc as the base in DMA at 150 °C was investigated (Scheme 2). No for-
3
5
mation of the desired product
2
was detected with the highly electron-deficient 4-bromobenzonitrile.
were obtained for the reactions with the less electron-
Conversely, low yields in the target products
3-5
deficient 4-bromobenzotrifluoride, 4-bromochlorobenzene and 4-bromofluorobenzene, although com-
plete conversions of these aryl bromides were observed. With these three aryl bromides, the formation
of large amounts of aryl bromide homo-coupling products and unidentified degradation products was
observed by NMR analysis of the crude mixtures. Higher yields were obtained for the reactions with
electron-neutral or -rich aryl bromides. From bromobenzene, the C10-phenyl substituted Cyprohepta-
dine
6
was obtained in 51% yield. Aryl bromides bearing tert-butyl, phenyl or methoxy para-
in 45-72% yields. Even 4-bromo-N,N-dimethylaniline was
substituents afforded the target products
7-9
reactive providing the product 10 in 38% yield. The structure of 10 was confirmed by X-ray analysis.
From a 4-bromobiphenyl bearing a free OH group, the desired product 11 was obtained in moderate
yield. Interestingly, the OH group remained untouched allowing further transformations. The low reac-
tivity of electron-poor aryl halides compared to electron-rich aryl halides had already been observed for
related Pd catalyzed reactions [28].
The reactivity of four meta-substituted aryl bromides was also examined. Again, the “quite strong”
electron-withdrawing substituent CF on the aryl bromide led to the coupling product 12 a in lower
3
yield than the chloro-, methyl- and methoxy-substituted aryl bromides which afforded the products 13
in 41-63% yields. Unprotected 6-bromo-2-naphthol and the more hindered 2-bromotoluene, 1-
bromonaphthalene and 1-bromo-4-fluoronaphthalene were also found to be useful substrates for this
reaction, as the products 16 19 were obtained in 34-55% yields. Finally, the dimethoxy-substituted aryl
bromide, 4-bromoveratrole provided the C10-arylated Cyproheptadine derivative 20 in 34% yield.
-
1
5
-

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Scheme 2 Palladium-catalyzed C10-arylations of Cyproheptadine.
By contrast, the direct arylation of Cyclobenzaprine with 1-bromo-4-tert-butylbenzene produced an
equimolar mixture of the two regioisomeric compounds 21a and 21b in 42% yield (Scheme 3).

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Scheme 3 Palladium-catalyzed direct arylations of Cyclobenzaprine.
These two regioisomers were separated by silica gel column chromatography, and the structures of 21a
and 21b were assigned by NMR analysis. Relevant spatial proximities (determined by NOESY experi-
ments) are shown in figure 2 (see supporting information for more details). Structure of 21a is supposed
to be twisted since a correlation is seen between protons from the aryl of tBu-aryl group and N-methyl.
It can be seen from the X-ray solid structure of 10 that the NMe -aryl group and the methyl-piperidine
2
moiety are located on the same side of the tricyclic part. For 21a, methyl-piperidine is replaced by a
N,N-dimethylethanamine unit which is likely to be much more flexible.
Figure 2 Relevant NOESY correlations observed for compounds 21a and 21b
In summary, we report here the first method allowing to prepare C10-arylated Cyproheptadine derivatives. As
this method employs the so-called late-stage C-H bond functionalization methodology, no preparation of specif-
ic starting materials is required allowing an easy tuning of the steric and electronic properties of the introduced

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aryl group. Moreover, these arylation were performed using the air-stable PdCl(C H )(dppb) catalyst precursor
3
5
associated to KOAc as inexpensive base, and tolerated useful functional groups on the aryl bromide such as di-
methylamino, methoxy, hydroxyl, alkyl, aryl, fluoro, chloro and trifluoromethyl. We also describe the catalytic
C10/C11-arylation of Cyclobenzaprine. In the course of this reaction an equimolar mixture of the two regioi-
somers which could be separated by column chromatography was formed. Such late-stage functionalizations of
important drugs should allow a fast screening of the influence of aryl groups at C10-position on their biological
properties. This work should also lead to the development of new synthetic pathways by functionalizing the
C10/C11 positions of these drugs through the use of different coupling partners.

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*Highlights




First regioselective arylations at the C10-position of Cyproheptadine
One step access to Cyproheptadine congeners
Good functional group tolerance
Air and moisture tolerant Pd-catalyst
Graphical abstract