A straightforward access to guaiazulene derivatives using palladium-catalysed sp2 or sp3 C-H bond functionalisation

Article abstract of DOI:10.1039/c3cc42226g

A novel palladium-catalysed direct arylation of guaiazulenes with a variety of aryl bromides is reported. Both sp² and sp³ C-H bonds have been functionalised, as the nature of the cation of the base was found to allow the control of the regioselectivity of the arylation giving rise to C2 or C3 arylated guaiazulenes and also to 4-benzylguaiazulenes.

Full text of DOI:10.1039/c3cc42226g

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A Straightforward Access to Guaiazulene Derivatives using Palladium-
View Article Online
Catalysed sp2 or sp3 C-H Bond Functionalisation
Liqin Zhao,a Christian Bruneau,a Henri Doucet*a
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
First published on the web Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
5
55 straightforward modification of the nature of the substituents and
hence of the properties of the resulting guaiazulene derivatives.
A novel palladium-catalysed direct arylation of guaiazulene with a
variety of aryl bromides is reported. Both sp2 and sp3 C-H bonds
have been functionalised, as the nature of the cation of the base
Previous work11
10 was found allow the control of the regioselectivity of the arylation
giving rise to C2 or C3 arylated guaiazulenes and also to 4-
benzylguaiazulenes. The reaction tolerates various substituents
such as formyl, acetyl, propionyl, fluoro, trifluoromethyl, fluoro or
even chloro on the aryl bromide.
Pd(OAc)2 5 mol%
X
R
+
K2CO3 (8 equiv.), DMF,
100 or 140 °C, 72 h
H
5 or 30 equiv.
X
I
R
H
Yield (%)
13*
* 2 equiv. Bu4NBr
Cl NO2 16
15
Azulene and also guaiazulene that feature the azulene skeleton
(Fig. 1) are both constituents of pigments in the lactarius indigo
mushrooms. They are also present in some corals and in
chamomile oil. Guaiazulene is used as a cosmetic color additive
(blue colour) and as a drug against ulcer. It also provides anti-
This work
H
sp2 activations
H
a
Ar
Ar
[Pd]
base
or
or
+
ArBr
20 inflammatory and pain relief benefits, and is used treating skin
irritation caused by over-exposure to the sun. Guaiazulene is also a
strong antioxidant, an antiviral and has been shown to be effective
in suppressing both warts and cold sores. Because of its rose-like
scent, it is used as a fragrance in some formulations. It is also
25 employed as a volatile dye. Due to these multiple uses, the
discovery of simple access to guaiazulene derivatives would be
very useful.1
H
H
b
c
sp3 activation
Ar
Scheme 1
Azulenes display unique structural and electronic properties.2,3
Their large dipole moment arises from the electron drift from its
30 seven-membered ring to its five-membered ring, which leads to its
aromatic delocalization energy being 5 times lower than that of
benzene.3
As guaiazulenes present several type of sp2 and sp3 C-H bonds,
60 their reactivities towards palladium-catalysed direct arylation were
unpredictable. We now (i) report on the influence of the reaction
conditions for the palladium-catalysed direct coupling of aryl
bromides with guaiazulene, and (ii) show the scope of the sp2 or
sp3 functionalization of guaiazulene.
C1
C2
C3
C4
65
Keeping in mind the reaction conditions employed for the direct
arylation of heteroaromatics in our previous works,6 we initially
examined the influence of the nature of base and their cation for
the coupling of guaiazulene with 4-bromobenzonitrile using 2
mol% PdCl(C3H5)(dppb) as catalyst and DMAc as solvent (Table
Azulene
Guaiazulene
Figure 1 Structures of Azulene and Guaiazulene
35 As guaiazulene does not present any reactive function, its
modification requires the activation of C-H bonds. The palladium-
catalysed direct arylation or vinylation of heteroaromatics has
recently emerged as a very powerful method for the preparation of
70 1). The use of K2CO3 as base did not result in the formation of the
target coupling products (Table 1, entry 1); whereas, Cs2CO3
afforded a mixture of the coupling products 1b and 1c in 33:67
ratio (Table 1, entry 2). On the other hand, the use of mixtures of
bases: CsOAc + K2CO3 or Cs2CO3 led to a complete modification
75 of the regioselectivity of the arylation with an exclusive sp3 C-H
bond functionalization5,8-10 of the seven membered ring methyl
substituent to give 4-benzylguaiazulene 1a in 61% or 67% yields
(Table 1, entries 3, 5 and 6). It should be noted that the
intermolecular sp3 palladium-catalysed arylations of unactivated C-
80 H bonds without participation of a directing group are quite
scarce.5c,10 A similar selectivity was observed for the reactions
performed in DMF, diethyl carbonate or cyclopentyl methyl ether,
but with a low productivity in carbonate and ether solvents (Table
1, entries 7-9). CsOAc as the only base also gave quite selectively
85 isomer 1a (Table 1, entry 10). On the other hand, the use of KOAc
/ K2CO3 or KOAc / Cs2CO3 as mixtures of bases led to a mixture of
1b and 1c without formation of 1a showing the crucial role of
cations in the reaction (Table 1, entries 11 and 12).12
substituted (hetero)aromatics.4-10
However, there are still
40 limitations for these reactions in terms of substrate scope. If the
coupling of various aryl halides with heteroarenes has been largely
described, on the other hand, the coupling of azulenes with aryl
halides via palladium-catalysed C-H bond functionalization has
attracted much less attention, as only two examples of such
45 reaction have been described (Scheme 1, top). It has been reported
by Dyker and co-workers that the direct arylation at C1 of azulene
with iodobenzene or 4-chloronitrobenzene proceeded in quite low
yields using 5 mol% Pd(OAc)2 catalyst.11 For these coupling
reactions 5-30 equiv. of aryl halide were employed.
50 The palladium-catalysed direct arylation would allow the
preparation of arylated guaiazulenes in only one step, with low
amount of wastes, which represent a considerable advantage
(Scheme 1, bottom). In addition, such couplings are expected to
present a high functional group tolerance, which would allow a
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Journal Name, [year], [vol], 00–00 | 1

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Table 1. Influence of the reaction conditions for palladium-catalysed direct coupling of 7-isopropyl-1,4-dimethylazulene (guaiazulene)
with 4-bromobenzonitrile.
View Article Online
CN
H
+
+
[Pd]
+
Br
CN
H
CN
base
H
1a
1b
1c
CN
Entry
1
2
3
4
5
6
7
8
Catalyst (mol %)
Base (equiv.)
K2CO3 (4)
Cs2CO3 (4)
Solvent
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMF
Ratio 1a:1b:1c
-
Conv. (%)
Yield (%)
61 of 1a
67 of 1a
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (0.5)
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (2)
Pd(OAc)2 (10)
100
64
0:33:67
100:0:0
92:8:0
100:0:0
100:0:0
100:0:0
100:0:0
100:0:0
96:4:0
0:25:75
0:30:70
0:31:69
0:15:85
0:18:82
0:53:47
0:47:53
0:20:80
0:19:81
0:18:82
CsOAc (4) + K2CO3 (4)
CsOAc (4) + K2CO3 (4)
CsOAc (4) + Cs2CO3 (4)
CsOAc (1) + K2CO3 (1)
CsOAc (4) + K2CO3 (4)
CsOAc (4) + K2CO3 (4)
100
100
100
100
100
10
diethyl carbonate
9
CsOAc (4) + K2CO3 (4) cyclopentyl methyl ether
9
60
10
11
12
13
14
15
16
17
18
19
20
CsOAc (4)
KOAc (4) + K2CO3 (4)
KOAc (4) + Cs2CO3 (4)
KOH (4) + K2CO3 (4)
KOAc (8)
DMAc
DMAc
DMAc
DMAc
DMAc
NMP
ethylbenzene
xylene
DMAc
100
100
43
100
100
100
55
100
100
100
51 of 1c
38 of 1b
KOAc (8)
KOAc (8)
KOAc (8)
KOAc (8)
KOAc (8)
KOAc (8)
Pd(OAc)2 (2) / PCy3 (4)
Pd(OAc)2 (2) / dppe (4)
DMAc
DMAc
Conditions: catalyst: [Pd], 7-isopropyl-1,4-dimethylazulene (1.5 mmol), 1-bromobenzonitrile (1 mmol), under argon, 16 h, 150 °C, GC and NMR
5 conversions, isolated yields.
Then, in order to favour the formation of 1b and 1c, we employed
KOAc as the only base. No formation of 1a was detected, and a
bromobenzaldehyde and 4-bromopropiophenone. Higher yields of
67% and 68% in 4a and 5a were obtained from ethyl 4-
mixture of 1b and 1c was obtained in a 15:85 ratio (Table 1, entry 40 bromobenzoate and 4-(trifluoromethyl)bromobenzene. The desired
14). This difference of selectivity might be due to the higher
10 solubility of CsOAc. A similar selectivity was observed in NMP;
whereas, a less polar solvent such as ethylbenzene gave 1b and 1c
in a 53:47 ratio (Table 1, entries 15 and 16). A similar influence of
coupling products 6a and 7a were also obtained using 4-
bromochlorobenzene and 4-fluorobromobenzene as the coupling
partners. It should be noted that no cleavage of the C-Cl bond was
observed in the course of the reaction with 4-bromochlorobenzene
the nature of the solvent on the regioselectivity of the arylation of 45 allowing further transformations. Lower yield in 8a and 9a were
3-substituted furans has already been reported.13 A minor
15 influence of the nature of the catalyst on the regioselectivity of this
reaction was observed (Table 1, entries 18-20).
obtained from the electron rich, 4-bromotoluene and 4-tert-
butylbromobenzene due to the formation some unidentified side-
products. Then, we examined the reactivity of a few meta-
substituted aryl bromides. Again, the best results were obtained
In all cases, the first step of the catalytic cycle is certainly the
oxidative addition of the aryl bromide to Pd(0) to afford a Pd(II) 50 with the trifluoromethyl- and chloro-substituted bromobenzenes to
intermediate. The arylation which takes place at the electron-rich
20 C3 position to form 1c in DMAc suggests an electrophilic aromatic
substitution mechanism from an electrophilic cationic Pd-species,
although a concerted-metallation-deprotonation mechanism is also
give 12a and 13a in 71% and 69% yields, respectively; whereas,
moderate yields of 11a and 14a were obtained with 3-
bromoacetophenone or 3-bromotoluene. 2-Bromofluorobenzene
was also found to be a suitable substrate for this reaction to give
possible.11,14 The non-polar solvent ethylbenzene certainly favours 55 15a in 63% yield. Finally, the reactivity of 3-bromopyridine was
neutral Pd-species and therefore an Heck type mechanism with
25 formation of a Pd-C bond at C3 and arylation at C2 to form 1b.13
The 4-benzylguaiazulene 1a more likely result from formation of
an allyl-palladium intermediate such as A (Scheme 2). The higher
base concentration in solution due to the better solubility of CsOAc
compared to KOAc might favour this reaction pathway.15,16 The
30 Pd-catalysed activation of benzylic C-H bonds has already been
reported.9b
examined. The desired 4-benzylguaiazulene 17a was obtained in
61% yield.
H
PdCl(C3H5)(dppb)
2 mol%
R
Br
R
4-CHO
4-COEt
+
R
CsOAc, K2CO3,
DMAc, 150 °C
H
2a-17a
Product
2a
Yield (%)
45
46
3a
4-CO2Et 4a
67
4-CF3
4-Cl
4-F
4-Me
4-tBu
3-CN
5a
6a
7a
8a
9a
10a
68
66
52
42
48
54
Ar
Ar
Pd
Pd
16a 45%
A
Ar
OAc
Scheme 2
3-COMe 11a
51
3-CF3
3-Cl
3-Me
2-F
12a
13a
14a
15a
71
69
54
63
Using CsOAc/K2CO3 as bases (Table 1, entry 3), the scope of the
35 sp3 C-H bond functionalisation was examined using various aryl
bromides (Scheme 3). Moderate yields of 45% and 46% in 2a and
3a were obtained by coupling of guaiazulene with 4-
N
17a 61%
Scheme 3 Palladium-catalysed direct sp3 arylation of guaiazulene
2
|
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This journal is © The Royal Society of Chemistry [year]

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60
65
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As the C2-arylation of guaiazulene was also possible using KOAc
as the base in ethylbenzene (Table 1, entry 15), the scope of this
coupling was also examined (Scheme 4). The use of less electron-
deficient aryl bromides than 4-bromobenzonitrile led to b isomers
in higher regioselectivities. From 4-chlorobromobenzene or 4-
fluorobromobenzene, products 6b and 7b were obtained in 77%
regioselectivities and in 53% and 51% yields, respectively. Similar
regioselectivities in favour of the formation of the C2-arylated
guaiazulene were observed with 3- or 4-bromotoluene or
10 bromobenzene to give 8b, 14b and 18b in 54-56% yields. The
reactivity of electron-rich 3-bromotoluene for C3-arylation of
guaiazulene was also examined using KOAc as the base in DMAc
(Scheme 4). Product 14c was obtained in a lower selectivity of
63% and in 38% yield, as compared to the reaction with the
15 electron-poor 4-bromobenzonitrile which gave 1c in 51% yield
(Table 1, entry 13).
5
70
75
H
7. A. Ohta, Y. Akita, T. Ohkuwa, M. Chiba, R. Fukunaga, A. Miyafuji, T.
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+
PdCl(C3H5)(dppb)
2 mol%
R
80
c
b
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bonds with aryl halides: (a) T. Niwa, H. Yorimitsu and K. Oshima,
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H
KOAc,
ethylbenzene,
150 °C
+
Major
Product
6b
7b
8b
14b
18b
14c
R
R
ratio b:c
Yield of b (%)
53
51
56
54
56
38 of c*
R
4-Cl 77:23
4-F 77:23
4-Me 70:30
3-Me 76:24
Br
85
H
75:25
* DMAc as the solvent
3-Me 37:63
Scheme 4 Palladium-catalysed direct sp2 C2- or C3-arylation of
guaiazulene
90
20 In summary, we have demonstrated that both the sp2 and sp3 direct
arylations of guaiazulene are possible when appropriate reaction
conditions are employed. The use of a mixture of CsOAc/K2CO3
selectively promotes the sp3 direct arylation at C4-Me of
guaiazulene to give 4-benzylguaiazulenes; whereas KOAc in
25 DMAc led quite selectively to the C3 arylated compounds and
KOAc in ethylbenzene to the C2 arylated guaiazulenes. These
conditions offer routes for fast and direct access to arylated
guaiazulenes. It should be noted that this protocol is applicable to
a range of functions, including reactive ones, on the aryl bromide.
30 Such functional group tolerance allows the easy modification of
these derivatives, a strategy enabling the tuning of their properties.
95
100
105
110
115
120
125
Acknowledgment. We are grateful to the “Chinese Scholarship
Council” for a grant to Z. L.
Notes and references
35 a Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Université
de Rennes 1 "Organométalliques: Matériaux et Catalyse", 35042 Rennes
Cedex, France. Tel: 33 (0)2 23 23 63 84; E-mail: henri.doucet@univ-
rennes1.fr.
† Electronic Supplementary Information (ESI) available: procedures; NMR
40 data for all compounds. See DOI: 10.1039/b000000x/
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without palladium catalyst did not show any incorporation of
deuterium.
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