Aryl norbornanes and analogues via palladium-catalyzed hydroarylation with arenediazonium tetrafluoroborates

Article abstract of DOI:10.1055/s-2008-1078051

The palladium-catalyzed hydroarylation of arenediazonium tetrafluoroborates with norbornene derivatives and analogues in the presence of Pd(OAc) ₂ and i-Pr₃SiH in THF affords hydroarylation products containing the added aryl unit in the exo position in good to high yields. The reaction tolerates a variety of useful functional groups and can be performed as a one-pot procedure generating the arenediazonium salt in situ. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078051

2
508
LETTER
Aryl Norbornanes and Analogues via Palladium-Catalyzed Hydroarylation
with Arenediazonium Tetrafluoroborates
A
G
ryl
N
orbornane
s
a
via Palladiu
b
m-Catalyzed
r
Hydroa
i
rylatio
e
n with
A
ren
l
ediaz
o
e
nium Salts Bartoli, Sandro Cacchi,* Giancarlo Fabrizi, Antonella Goggiamani
Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi ‘La Sapienza’, P. le A. Moro 5, 00185 Rome, Italy
Fax +39(06)49912780; E-mail: sandro.cacchi@uniroma1.it
Received 18 June 2008
X
X
Pd cat.
reducing agent
Abstract: The palladium-catalyzed hydroarylation of arenediazo-
nium tetrafluoroborates with norbornene derivatives and analogues
ArN2+BF4–
Ar
+
R
R
in the presence of Pd(OAc) and i-Pr SiH in THF affords hydroary-
2
3
R
R
lation products containing the added aryl unit in the exo position in
good to high yields. The reaction tolerates a variety of useful func-
tional groups and can be performed as a one-pot procedure generat-
ing the arenediazonium salt in situ.
1
2
3
Scheme 1
Key words: norbornene, palladium, hydroarylation, arenediazoni-
um salts
norbornene derivatives have also been described.14 The
extension of this chemistry to arenediazonium salts would
widen significantly its synthetic scope. Herein we report
the results of this study.
Because of their higher reactivity, their availability from
inexpensive anilines, the utilization of mild conditions,
and the absence of added bases in several applications,
The reaction of dimethyl bicyclo[2.2.1]hept-5-ene-2,3-di-
carboxylate (1a, R = CO Me; X = CH ) and p-acetyldi-
2
2
azobenzene tetrafluoroborate (2a) was chosen as the mod-
el system for our initial investigation of this hydroaryla-
tion process. Phosphine-free conditions were selected on
the basis of the known detrimental effect of phosphine
ligands in many palladium-catalyzed reactions of arenedi-
arenediazonium salts represent an attractive alternative to
aryl halides or triflates in palladium-catalyzed reactions.1
They have been widely utilized in Mizoroki–Heck reac-
2
3
4
tions. Suzuki–Miyaura, and Stille cross-couplings as
2
a,5
well as carbonylation reactions, the synthesis of sulfin-
ic acids and boronic esters have also been reported.
However, a number of applications still remain a chal-
15
6
7
azonium salts and our results in the hydroarylation of
8
alkynes. Utilization of formate anions as the reducing
1
agent (commonly used in the hydroarylation of nor-
bornene derivatives with aryl iodides or triflates) did not
afford the desired hydroaylation product. Apparently, for-
mate anions tend to favor several side processes, includ-
ing the reduction of the arylpalladium intermediates and
the olefinic double bond. For example, no evidence of hy-
droarylation product formation was obtained using
lenging target. Only recently, the first synthetically use-
ful palladium-catalyzed alkyne-based reaction of
arenediazonium tetrafluoroborates has been described by
us. In particular, we have shown that arenediazonium tet-
rafluoroborates can be used as aryl partners in the hy-
8
droarylation of internal alkynes. Hydroarylation products
have been isolated in good to high yields under mild con-
ditions with very high stereoselectivity and, with an asym-
metrically disubstituted alkyne such as ethyl
phenylpropynoate, the regioselectivity was found to be
comparable to that observed with aryl iodides.
HCOOK and Pd(OAc) in THF or DMF at 0 °C to room
2
temperature, acetophenone and 4 being formed in 19–
5
5% and 1–9% yields, respectively. Therefore, we
switched to the more selective trialkylsilanes. The influ-
ence of several trialkylsilanes on the reaction outcome as
well as that of temperature and the excess of arenediazo-
nium salts have been investigated. The results of our
screening study are summarized in Table 1.
On the basis of these results, we decided to study the fea-
sibility of a hydroarylation process involving hindered
olefinic systems such as norbornenes and analogues
(
Scheme 1). Indeed, the hydroarylation of norbornenes
9
,10
Under a variety of conditions the reduction product 4,
most probably formed by a palladium-catalyzed reaction,
was isolated in significant yields. No evidence of com-
pound 4 formation was obtained when the reaction was
carried out omitting the palladium catalyst. Notably, the
with aryl halides and triflates has proved to be an effec-
tive method for the synthesis of bicyclo[2.2.1]heptanes
and related compounds with an aryl substituent in the exo
1
1
position. It has been used in the total synthesis of the po-
1
2
tent nonopiate analgesic alkaloid epibatedine, a com-
pound isolated from the skin of the Ecuadorian frog,
Epipedobates tricolor, as well as in different approaches
utilization of Ph SiH, which gave the highest yields in the
3
hydroarylation of alkynes, led to the formation of 3a only
1
6
1
2b,13
in 26% yield (Table 1, entry 5). Compound 4 was isolat-
to its analogues.
Enantioselective hydroarylations of
ed as the main product even with Me PhSiH, Oct SiH, and
2
3
Et SiH (Table 1, entries 6–8). Formation of acetophenone
was also observed (Table 1, entries 1, 7–9). Switching to
3
SYNLETT 2008, No. 16, pp 2508–2512
Advanced online publication: 12.09.2008
DOI: 10.1055/s-2008-1078051; Art ID: G19808ST
x
x
.x
x
.2
0
0
8
i-Pr SiH yielded 3a as the main product. However, com-
3
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Aryl Norbornanes via Palladium-Catalyzed Hydroarylation with Arenediazonium Salts
2509
Table 1 The Influence of the Trialkylsilane, Temperature, and Ex-
cess of Arenediazonium Salt on the Palladium-Catalyzed Hydroary-
lation of Dimethyl Bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate (1a)
Table 2 Palladium-Catalyzed Hydroarylation of Dimethyl Bicy-
clo[2.2.1]hept-5-ene-2,3-dicarboxylate 1a with Arenediazonium
Salts 2a
a
with p-Acetyldiazobenzene Tetrafluoroborate (2a)
Entry Arenediazonium salt 2
Time (h) Yield (%)b,c of 3
Pd(OAc)2, R3SiH
+
–
1
2
3
4
5
6
7
8
9
0
1
2
3
4-AcC H N BF
4
2a
2b
2c
2d
2e
2f
0.67
3
3a
3b
3c
3d
3e
3f
73
73
86
78
86
73
75
85
92
56
19d
80
28e
+
–
6
4
2
+
ArN2 BF4
THF
CO2Me
CO2Me
+
2
–
–
4-MeOC H N BF
6
4
4
4
1
a
2a
+
2
2-MeOC H N BF
2
6
4
Ar
+
+BF
4
–
2
CO2Me
CO Me
2
4-ClC
6
H
4
N
2
CO2Me
2
CO Me
+
–
4
4-MeC H N BF
1
6
4
2
Ar = p-AcC6H4
3a
4
+
–
4-MeO CC H N BF
4
1.5
0.5
3
2
6
4
2
EntryTrialkyl- 2a
Temp Time (h) Yield (%)b Yield (%)b
+
–
4-O NC H N BF
2g
2h
2i
3g
3h
3i
2
6
4
2
4
silane
(equiv) (°C)
of 3a
of 4
+
–
4
4-NCC H N BF
6
4
2
1
2
3
4
5
6
7
i-Pr SiH
4
2
2
0 to 15
1
71c
–
3
+
2
–
2,4-Me C H N BF
4
1.5
3.5
20
1.5
7
2
6
3
i-Pr SiH
0 to 15 0.67
73
20
36
34
72
85
58
93
3
+
–
1
1
1
2-Me-4-FC H N BF
4
2j
3j
6
3
2
i-Pr SiH
r.t.
3.5
2
48d
3
+
–
4-IC H N BF
4
2k
2l
3k
3l
6
4
2
i-Pr SiH 1.1
0 to 15
44
3
+
–
PhN BF
2
4
Ph SiH
1.2
0 to 15 0.67
0 to 15 0.5
0 to 15 1.5
26
3
+
–
1
2-BrC H N BF
4
2m
3m
6
4
2
Me PhSiH 2
Tracese
17f,g
–h
2
a
Reactions were carried out under argon on a 0.5 mmol scale using 1
equiv of 1a, 2 equiv of 2, 2 equiv of i-Pr SiH, 0.05 equiv of Pd(OAc)
in 4 mL of anhyd THF at 0 °C to 15–25 °C.
Yields are given for isolated products.
Compound 4 was formed in variable amounts ranging from traces
entries 5, 8, 9) to 35% yield (entries 10 and 13).
The reduction–hydroarylation derivative 7 was isolated in 10%
Oct SiH
2
2
3
3
2
8
a
Et SiH
0–15
1
b
3
c
Unless otherwise stated, reactions were carried out under argon on a
.5 mmol scale using 1 equiv of 1a, 2 equiv of 2a, 2 equiv of R SiH,
.05 equiv of Pd(OAc) in 4 mL of anhyd THF.
Yields are given for isolated products.
Acetophenone was isolated in 29% yield.
Compound 1a was recovered in 11% yield.
Acetophenone was isolated in 40% yield.
Acetophenone was isolated in 20% yield.
Compound 1a was recovered in 14% yield.
Acetophenone was isolated in 35% yield.
(
0
3
d
0
2
b
yield.
e
c
d
e
f
The reduction–hydroarylation derivative 7 was isolated in 6% yield.
Table 3 Palladium-Catalyzed Hydroarylation of Norbornene 1b
g
h
with Arenediazonium Salts 2a
ArN2+BF4–
Ar
+
pound 4 was still isolated in significant yields under the
conditions shown in Table 1, entries 3 and 4. The best re-
sult in terms of yield, reaction time, and excess of arene-
diazonium salt was obtained when the reaction was
1
b
2
5
b
Entry Arenediazonium salt 2
Time (h) Yield (%) of 5
+
–
1
2
3
4-AcC H N BF
4
2a 6
5a
5b
5f
94
93
86
80
carried out using 2 equiv of i-Pr SiH and 2 equiv of p-
6
4
2
3
acetyldiazobenzene tetrafluoroborate 2a at 0–15 °C (see
experimental section; Table 1, entry 2). Consequently,
these conditions were employed when the procedure was
extended to include other benzenediazonium salts
+
–
4-MeOC H N BF
4
2b 2.5
6
4
2
+
–
4-MeO CC H N BF
4
2f
4
2
6
4
2
+
–
4
2-ClC H N BF
4
2n 5
5n
6
4
2
(
Table 2) and bicyclic derivatives such as norbornene (1b,
a
Reactions were carried out under argon on a 0.5 mmol scale using 1
equiv of 1b, 2 equiv of 2, 2 equiv of i-Pr SiH, 0.05 equiv of Pd(OAc)
in 4 mL of anhyd THF at 0 °C to 15–25 °C.
Yields are given for isolated products.
R = H, X = CH ; Table 3) and dimethyl 7-oxa-bicy-
2
3
2
clo[2.2.1]hept-5-ene-2,3-dicarboxylate (1c, R = CO Me,
2
1
7
X = O; Table 4).
b
Hydroarylation products were isolated in moderate to
high yields as single stereoisomers. The exo stereochem-
18
substituents such as chloro, cyano, ester, keto, and nitro
groups (frequently, the latter tend to give decomposition
products in palladium-catalyzed reactions ). Arenediazo-
nium tetrafluoroborates containing ortho substituents can
also be used (Table 2, entries 3, 9 and 10; Table 3, entry
istry of 3a was assigned by NOESY experiments. That
of the other hydroarylation derivatives was assigned
based on this data and all the previous work on this type
of chemistry. The reaction tolerates a variety of useful
15
Synlett 2008, No. 16, 2508–2512 © Thieme Stuttgart · New York

2
510
G. Bartoli et al.
LETTER
Table 4 Palladium-Catalyzed Hydroarylation of Dimethyl 7-Oxa-
NH2
Ac
bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate (1c) with Arenediazoni-
1. t-BuNO2, BF3⋅OEt2, THF, –15 °C to r.t.
2. 1a, Pd(OAc) , i-Pr SiH, THF, 0 to 20 °C
um Salts 2a
2
3
O
O
Ac
+
–
Ar
+
ArN2 BF4
CO2Me
CO2Me
CO2Me
CO2Me
+
1
c
2
6
CO2Me
CO2Me
CO2Me
CO2Me
b
Entry Arenediazonium salt 2
Time (h) Yield (%) of 6
3a 64%
4 8%
+
–
1
2
3
4-CNC H N BF
2h 1.5
6h
6d
6o
6n
84
91
85
93
Scheme 2
6
4
2
4
+
–
4-ClC H N BF
2d 1.25
6
4
2
4
Table 5 Palladium-Catalyzed Reaction of Norbornadiene with
+
–
3,4,5-MeOC H N BF
4
2o
2n
2.25
3
p-Acetyldiazobenzene Tetrafluoroborate (2a)a
6
2
2
+
–
4
2-ClC H N BF
6 4 2 4
Pd(OAc)2, i-Pr3SiH
a
+
2a
Reactions were carried out under argon on a 0.5 mmol scale using 1
equiv of 1c, 2 equiv of 2, 2 equiv of i-Pr SiH, 0.05 equiv of Pd(OAc)
THF, 0 to 15 °C
3
2
in 4 mL of anhyd THF at 0 °C to 15–25 °C.
b
Yields are given for isolated products.
Ar
+
Ar
Ar
+
Ar
4
; Table 4, entry 4). The low yields observed with iodo
8
9
10
and bromo derivatives (Table 2, entries 11 and 13) are
most probably due to the competitive oxidative addition
of carbon–halogen bonds to Pd(0) species generating
arylpalladium intermediates which can undergo several
side reactions. Although we have not investigated this
point in detail, this notion is strongly supported by the fact
that the reaction of p-iodo- or o-bromodiazobenzene tet-
rafluoroborate with 1a affords 7 (Figure 1), very likely
formed via reduction of arylpalladium halide intermedi-
ates (before and/or after the carbopalladation step). Chlo-
roarenediazonium tetrafluoroborates, however, can be
selectively converted into the corresponding chloroaryl
derivatives in high yields (Table 2, entry 4; Table 3, entry
Entry 2a
Norbor- Time Yield (%)b Yield (%)b Yield (%)b
(
equiv) nadiene (h) of 8
equiv)
of 9
of 10
(
1
2
3
2
1
1
1
1
2
3
5
18 traces
38
–
25
–
5
5
5
20
40
10
–
–
4
–
–
a
Reactions were carried out under argon on a 0.5 mmol scale using 2
equiv of i-Pr SiH, 0.05 equiv of Pd(OAc) in 4 mL of anhyd THF.
3
2
b
Yields are given for isolated products.
4
; Table 4, entry 4).
The hydroarylation of norbornene derivatives can be per-
leads to lower yields, most probably because of the forma-
tion of multiple insertion products..
1
9,20
formed generating the diazonium salt in situ.
tocol was attempted with p-aminoacetophenone and 1a
Scheme 2). The corresponding hydroarylation product
a was isolated in 64% yield along with minor amount of
This pro-
A possible rationale to account for the formation of the
hydroarylation products, depicted in Scheme 3 for nor-
bornene, involves (a) a stereoselective addition of the ini-
tially formed s-arylpalladium complex A to the carbon–
carbon double bond, (b) the reaction of the resultant car-
bopalladation adduct B with trialkylsilane to give the
alkylpalladium hydride intermediate C, (c) a reductive
elimination step which affords the hydroarylation deriva-
tive and regenerates the active palladium catalyst. The
mechanism based on the cross-coupling of arylpalladium
complexes with norbornyltrialkylsilanes formed via a hy-
drosilylation step appears to be flawed by the fact that
alkylfluorosilanes in the presence of fluoride anions are
usually required to perform palladium-catalyzed cross-
coupling reactions.21
(
3
the reduction derivative 4. The starting norbornene deriv-
ative was recovered in 19% yield.
The hydroarylation of norbornadiene was also investigat-
ed. However, while an excess of arenediazonium tetra-
fluoroborate was generally used in the reaction of
norbornene derivatives and analogues, with norborna-
diene it seems that a 1:3 excess of the hindered olefin is
necessary to obtain the desired exo-aryl derivative in ac-
ceptable yield, at least with our model system (Table 5,
entry 3). Increasing further the amount of norbornadiene
Ph
In conclusion, we have shown that arenediazonium salts
can be efficiently used as aryl donors in the palladium-cat-
alyzed hydroarylation of norbornenes and analogues to
give exo-arylated derivatives in good to high yields. The
CO2Me
CO2Me
7
Figure 1
Synlett 2008, No. 16, 2508–2512 © Thieme Stuttgart · New York

LETTER
Aryl Norbornanes via Palladium-Catalyzed Hydroarylation with Arenediazonium Salts
2511
(
3) For some recent references, see: (a) Peyroux, E.; Berthiol,
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+
–
ArN2 BF4
Ar
(
Pd(0)
N2
–
Eur. J. 2004, 10, 2681. (c) See also: Gallo, V.; Mastrorilli,
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Ar
+
ArN2 BF4
A
C
(
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BF3
–
R3SiH
BF4 Pd
Ar
B
(
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one-pot process generating the arenediazonium salt in
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4
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Correia, C. R. D.; Eberlin, M. N. Angew. Chem. Int. Ed.
(16) When 1a was subjected to the reaction conditions reported in
Table 1 (entry 5) omitting Pd(OAc) no reduction product 4
2
2
was formed suggesting that the reduction of 1a to 4 proceeds
through a palladium-catalyzed process.
2
004, 43, 2514; corrigendum: Angew. Chem. Int. Ed. 2004,
(
17) Typical Procedure for the Palladium-Catalyzed Hydro-
arylation of Norbornene Derivatives with Arenediazo-
nium Tetrafluoroborates – Hydroarylation of 1a with 2a
43, 4389. (k) Masllorens, J.; Bouquillon, S.; Roglans, A.;
Hénin, F.; Muzart, J. J. Organomet. Chem. 2005, 690, 3822.
l) Garcia, A. L. L.; Carpes, M. J. S.; Montes de Oca, A. C. B.;
(
(
Table 2, entry 1)
To a stirred solution of 1a (105.1 mg, 0.50 mmol) and
Pd(OAc) (5.6 mg, 0.025 mmol) in anhyd THF (4.0 mL), 2a
dos Santos, M. A. G.; Santana, C. C.; Correia, C. R. D.
J. Org. Chem. 2005, 70, 1050. (m) Artuso, E.; Barbero, M.;
Degani, I.; Dughera, S.; Fochi, R. Tetrahedron 2006, 62,
2
(233.8 mg, 1.0 mmol) was added at r.t. under argon. The
3146. (n) Pastre, J. C.; Correia, C. R. D. Org. Lett. 2006, 8,
reaction mixture was cooled in an ice bath. Then, i-Pr SiH
1657. (o) Perez, R.; Veronese, D.; Coelho, F.; Antunes,
3
(
205 mL, 1.0 mmol) was added and the reaction mixture was
O. A. C. Tetrahedron Lett. 2006, 47, 1325.
stirred at 15 °C for 40 min under argon (the reactor was
protected from light with aluminum film). After this time,
the mixture was diluted with EtOAc, washed with H O,
2
Synlett 2008, No. 16, 2508–2512 © Thieme Stuttgart · New York

2
512
G. Bartoli et al.
LETTER
(20) Palladium-Catalyzed Hydroarylation of 1a with 2a
dried over Na SO , and concentrated under reduced
2
4
pressure. The residue was purified by chromatography on
Generated In Situ
silica gel [n-hexane–EtOAc, 90:10 (v/v)] to afford 120.8 mg
A solution of BF ·OEt (140 mL, 1.1 mmol) in anhyd THF (1
3
2
(
73% yield) of 3a, mp 64–66 °C. IR (KBr): 2968, 1735, 1198
mL) was cooled at –15 °C and p-aminoacetophenone (135.1
mg, 1 mmol) was added. Then, tert-butyl nitrite (160 mL, 1.3
mmol) in 1 mL of the same solvent was added dropwise to
the rapidly stirred reaction solution over a period of 10 min.
Following complete addition, the temperature of the solution
was maintained at –15 °C for 10 min and subsequently
allowed to warm to 5 °C in an ice-water bath over a period
of 20 min. Then, the reaction mixture was warmed to r.t. and
stirred at the same temperature till the starting p-amino-
acetophenone was converted into p-acetylbenzenediazo-
nium tetrafluoroborate. The reaction mixture was cooled in
–
1 1
cm . H NMR (400 MHz, CDCl ): d = 7.89 (d, J = 8.2 Hz,
2
3
H), 7.38 (d, J = 8.2 Hz, 2 H), 3.70 (s, 6 H), 3.64 (t, J = 7.4
Hz, 1 H), 3.19 (ddd, J = 11.7 Hz, J = 4.5 Hz, J = 1.4 Hz, 1
1
2
3
H), 2.99 (dd, J = 11.8 Hz, J = 3.7 Hz, 1 H), 2.75–270 (m, 1
1
2
H), 2.73–2.58 (m, 1 H), 2.13 (ddd, J = 11.1 Hz, J = 8.8 Hz,
1
2
J = 3.7 Hz, 1 H), 1.74–1.65 (m, 2 H), 1.42–1.26 (m, 1 H).
3
3
1
C NMR (100.6 MHz, CDCl ): d = 197.9, 172.9, 172.6,
3
1
51.9, 134.9, 128.5, 127.5, 51.7, 51.5, 47.7, 46.2, 45.9, 41.6,
4
0.2, 37.5, 33.2, 26.6. MS: m/z (relative intensity) = 330 (12)
+
[
M ], 298 (10), 270 (57), 185 (232), 43 (100).
(
18) NOESY experiments on 3a: for selected H–H interactions,
see Figure 2.
an ice bath and 1a (105.1 mg, 0.50 mmol), Pd(OAc) (5.6
2
mg, 0.025 mmol), i-Pr SiH (205 mL, 1.0 mmol), and of
3
anhyd THF (2 mL) were added. The reaction mixture was
allowed to warm to 20 °C and stirred at that temperature for
6 h under argon (the reactor was protected from light with
aluminum film). After this time, the mixture was diluted
m
H
H
H
m
w
with EtOAc, washed with H O, dried over Na SO , and
concentrated under reduced pressure. The residue was
purified by chromatography on silica gel [n-hexane–EtOAc,
s
2
2
4
H
H
w: weak; m: medium; s: strong
90:10 (v/v)] to afford 106.3 mg (64% yield) of 3a.
(
21) (a) Hatanaka, Y.; Hiyama, T. Tetrahedron Lett. 1990, 31,
Figure 2
2719. (b) Hatanaka, Y.; Hiyama, T. J. Am. Chem. Soc. 1990,
112, 7783.
(
19) Doyle, M. P.; Bryker, W. J. J. Org. Chem. 1979, 44, 1572.
Synlett 2008, No. 16, 2508–2512 © Thieme Stuttgart · New York