Palladium-catalyzed double activation and arylation of 2° and 3° C(sp3)-H bonds of the norbornane system: Formation of a C-C bond at the bridgehead carbon and bridgehead quaternary stereocenter

Article abstract of DOI:10.1055/s-0033-1341242

Pd-catalyzed activation and direct arylation of both 2° and the bridgehead 3° (sp³) C-H bonds and an unprecedented C-C bond formation at the bridgehead carbon of the norbornane system are reported. The assembly of bridgehead-substituted norbornane frameworks having contiguous stereocenters was accomplished. X-ray crystal structure analysis of representative molecules unambiguously established the stereochemistry.

Full text of DOI:10.1055/s-0033-1341242

LETTER
▌1395
3
letter
Palladium-Catalyzed Double Activation and Arylation of 2° and 3° C(sp )–H
Bonds of the Norbornane System: Formation of a C–C Bond at the Bridgehead
Carbon and Bridgehead Quaternary Stereocenter
Arylation of 2° and 3° C–H Bonds of Norbornanes
Ramarao Parella, Srinivasarao Arulananda Babu*
Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Manauli P.O., Sector 81, SAS Nagar,
Mohali, Knowledge City, Punjab 140306, India
Fax +91(172)2240266; E-mail: sababu@iisermohali.ac.in
Received: 19.02.2014; Accepted after revision: 25.03.2014
In light of the above developments, we wanted to examine
Abstract: Pd-catalyzed activation and direct arylation of both 2°
one of the most challenging reactions of organic chemis-
try, ‘bridgehead-substitution’ via C–H activation of the
bridgehead 3° C(sp3)–H bond of norbornane systems. To
and the bridgehead 3° (sp3) C–H bonds and an unprecedented C–C
bond formation at the bridgehead carbon of the norbornane system
are reported. The assembly of bridgehead-substituted norbornane
frameworks having contiguous stereocenters was accomplished. X- the best of our knowledge there is only one report3k deal-
ray crystal structure analysis of representative molecules unambig-
uously established the stereochemistry.
ing with two examples related to the C–H functionaliza-
tion of bridgehead 3° C(sp3)–H bonds of the norbornane-
Key words: arylation, bridgehead substitution, C–H activation,
diastereoselectivity, palladium, stereoselective synthesis
type systems. The direct arylation of the bridgehead 3°
C(sp3)–H bond of norbornanes, using 8-aminoquinoline
and 2-thiomethylaniline as auxiliaries, which were devel-
oped by Daugulis, form the basis of this work. Herein, we
The chemistry of bridgehead-substituted bridged bicyclic report an auxiliary-aided, Pd-catalyzed sequential activa-
frameworks (bridged rings) has a long and esteemed his- tion and arylation of 2° C(sp3)–H and the bridgehead 3°
tory.1,2 Notably, functional group transformation at a C(sp3)–H bonds and an unprecedented C–C bond forma-
bridged center and the generation of an quaternary bridge- tion at the bridgehead carbon of the norbornane frame-
head carbon of bridged bicyclic compounds is among the work (Scheme 1).
most challenging and fascinating of research topics. There
To examine the C–H functionalization of 2° C(sp3)–H
has been a substantial number of studies on reactions at
bonds and ‘bridgehead substitution’ via C–H activation of
the bridgehead center of several bridged bicyclic sys-
the bridgehead 3° C(sp3)–H bond, we prepared substrate
tems.1,2 Apart from the celebrated substitution reactions at
endo-N-(quinolin-8-yl)bicyclo[2.2.1]heptane-2-carbox-
amide (1a) from endo-bicyclo[2.2.1]heptane-2-carboxyl-
the bridgehead carbon of bridged bicyclic compounds,
there exist versatile routes1,2 that can be used to assemble
ic acid and an auxiliary (e.g., 8-aminoquinoline). To
bridgehead-substituted bicyclic frameworks, including
arrive at the best reaction conditions and solvents, we then
bridgehead enolate chemistry1i,j and Diels–Alder reac-
performed a series of reactions, listed in Table 1, that in-
volved Pd-catalyzed C–H arylation of the substrate 1a
tion.1a–h
The development of novel C–C bond-forming protocols (endo) with 1-iodo-4-methylbenzene (2a). The reaction of
and functionalization of organic molecules with stereo- a mixture of substrate 1a (endo), aryl iodide 2a and
control are persistent goals of organic chemists. In recent AgOAc, either in the presence or absence of the Pd(OAc)2
years, transition-metal-catalyzed, and especially Pd-cata- catalyst (10 mol%), in toluene at 110 °C did not give the
lyzed functionalization of C–H bonds has emerged as a product in good yield (Table 1, entries 1 and 2). We next
powerful tool in organic synthesis.3–6 In this context, the performed the C–H arylation of substrate 1a with 2a in the
Pd-catalyzed, auxiliary-aided C–H functionalization of presence of Ag2CO3 as a halide-removing agent, instead
sp3 C–H bonds initiated by Daugulis, Yu, and other of AgOAc, in toluene at 110 °C. In this reaction, we were
groups is evolving as a very convenient tactic.3–6 Excel- pleased to observe the formation of product 3a (65%; Ta-
lent papers on the Pd-catalyzed, auxiliary-directed C–H ble 1, entry 3) via the direct bis-arylation of both 2°
activation of 1° and 2° sp3 C–H bonds have been pub- C(sp3)–H (endo) and the bridgehead 3° C(sp3)–H bonds
lished. Recently, we reported an auxiliary-enabled, Pd- and an unprecedented C–C bond formation at the bridge-
catalyzed direct C–H arylation of 2° sp3 C–H bonds of head center of the norbornane system 1a.
small rings such as cyclopropane and cyclobutane.4k,l To
The C–H functionalization of substrate 1a with 1-iodo-4-
methylbenzene (2a) in the presence of Ag2CO3 and
Pd(OAc)2 catalyst (10 mol%) in tert-butanol gave the
product 3a with slightly improved yield (70%; Table 1,
the best of our knowledge only a few reports exist that
deal with metal-catalyzed C–H functionalization of 3° sp3
C–H bonds.6
entry 4). When only 5 mol% Pd(OAc)2 catalyst was used,
product 3a was obtained in 60% yield (Table 1, entry 5).
The Pd-catalyzed C–H arylation of 1a with 2a in the pres-
ence of various additives such as K2CO3, Na2CO3, KOAc,
SYNLETT 2014, 25, 1395–1402
Advanced online publication: 29.04.2014
DOI: 10.1055/s-0033-1341242; Art ID: st-2014-d0142-l
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1396
R. Parella, S. A. Babu
LETTER
popular ways to generate
bridgehead substitution
R
R
C
one of the
challenging
reactions
R
FG
FG
Diels–Alder (or)
substitution
chemistry
R1
R2
R4
R1
R3
R3
C–C bond
construction
2
R4 R
5 R3
4 R2
R
R
available examples
OMe
recent works by Chen's group
HO
N
O
activation of 2° C(sp3)–H of
norbornanes using
H
HN
O
picolinic acid based auxiliary
H
N
N
N
auxiliary
H
OMe
O
bridgehead
3° sp3 CH
this work
consecutive activation of
2° & bridgehead 3° C(sp3)–H
Ar–I
Pd(II)/Ag(I)
Ar
H
H
unprecedented bridgehead
C–H arylation
H
COR
Ar
COR
direct mono and diarylation
highly diastereoselective
H
endo 2° sp3 CH
R =
C–C bond formation
at the bridgehead carbon
HN
auxiliary
N
Scheme 1 Theme of this work
and PhI(OAc)2 gave product 3a in 24–30% yields (Table ization of substrate 1a, only the bisarylated product 3a
1, entries 6–9). Use of other palladium catalysts such as (Scheme 2, entries 1–3) was observed. The reaction of
PdCl2, Pd(TFA)2, Pd(MeCN)2Cl2 and Pd(PPh3)4 were in- substrate 1a with 1.5 equivalent of aryl iodide (2a) gave
effective (Table 1, entries 10–13). The reaction of 1a with bisarylated product 3a (6%) and monoarylated product 4a
2a in the presence of Ag2CO3 and the Pd(OAc)2 catalyst (40%; Scheme 2, entry 4). The reaction of substrate 1a
(10 mol%) in other solvents such as MeCN, 1,2-DCE, 1,4- with 1.0 or 0.5 equivalent of 1-iodo-4-methylbenzene (2a)
dioxane, EtOH, AcOH, and tert-amyl alcohol failed to af- in tert-butanol selectively gave the monoarylated norbor-
ford product 3a with improved yields (Table 1, nane system 4a in 57 and 32% yield, respectively
entries 14–19). The Pd-catalyzed C–H arylation of sub- (Scheme 2, entries 5 and 6). In these reactions, we did not
strate 1a with bromobenzene (2b) or chlorobenzene (2c) get the other expected product 4a′, which convincingly in-
did not furnish any product (Table 1, entries 20 and 21).
dicated that arylation of the 2° C(sp3)–H bond is easier
than the bridgehead 3° C(sp3)–H bond of norbornanes.
Under the optimized reaction conditions (Table 1,
entries 3 and 4), the Pd-catalyzed Ag-promoted C–H ary- We then extended the scope of this protocol by exploiting
lation of 1a (1 equiv) with 1-iodo-4-methylbenzene (2a; 4 the optimized reaction conditions that provided the selec-
equiv) afforded product 3a through the direct bis-aryla- tive formation of the monoarylated compound 4a
tion of both 2° C(sp3)–H (endo) and bridgehead 3° (Scheme 2, entry 5). We performed several reactions us-
C(sp3)–H bonds of the norbornane framework of 1a. Re- ing a range of aryl iodides as the coupling partner in the
alistically, under the experimental conditions, one would Pd-catalyzed, auxiliary-aided selective C–H arylation of
expect the formation of both the mono- and bis-arylated the 2° C(sp3)–H (endo) bond of the norbornane system 1a,
products 4a, 4a′, and 3a (Table 1). However, we did not which gave the corresponding monoarylated norbornane
observe either of the monoarylated products 4a or 4a′ un- frameworks 4b–f in 49–73% yield (Scheme 2) with a high
der the reaction conditions shown in Table 1.
degree of stereoselectivity.
We decided to study further the reaction conditions and The above reactions involving substrate 1a indicated that
determine the number of equivalents of aryl iodide re- the auxiliary, 8-aminoquinoline, attached to the norbor-
quired to produce only the monoarylated product 4a or 4a′ nane system assists in the Pd-catalyzed dual activation of
(Scheme 2).7b By employing 2–4 equivalents of 1-iodo-4- both 2° C(sp3)–H (endo) and the bridgehead 3° C(sp3)–H
methylbenzene (2a) in the Pd-catalyzed C–H functional- bonds of substrate 1a. Under the optimized reaction con-
Synlett 2014, 25, 1395–1402
© Georg Thieme Verlag Stuttgart · New York

LETTER
Arylation of 2° and 3° C–H Bonds of Norbornanes
1397
ditions, the C–H arylation of other substrates 1b–h, pre- respective auxiliaries attached to the norbornane system
pared by using various substrates and auxiliaries, were did not direct the C–H activation of the norbornane ring.
ineffective (Scheme 3). The reason for this may be that the The arylation of norbornene system 1f,7a which is struc-
Table 1 Optimization of Reaction Conditions
Me
H
+
H
N
H
N
N
H
O
Me
4a'
N
(not obtained)
N
H
O
1a (0.25 mmol)
(endo)
H
H
H
PdL2
+
N
Ag salt (y mmol)
solvent (3 mL)
36 h, 80–110 °C
N
H
N
O
H
O
X
Me
+
2a; X = I
2b; PhBr
2c; PhCl
(1 mmol)
Me
Me
3a
(endo, endo)
4a
(endo, endo)
(not obtained)
Entry
Catalyst (mol%)
Oxidant/halide removing agent Solvent
(y mmol)
Temp
(°C)
Yield of 3a
(%)
1
2
none
AgOAc (0.55)
AgOAc (0.55)
Ag2CO3 (0.25)
Ag2CO3 (0.25)
Ag2CO3 (0.25)
K2CO3 (0.25)
Na2CO3 (0.25)
KOAc (0.25)
toluene
toluene
toluene
110
110
110
85
0
5
Pd(OAc)2 (10)
3
Pd(OAc)2 (10)
65
70
60
0
Pd(OAc)2 (10)
4
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
MeCN
5
Pd(OAc)2 (5)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
PdCl2 (10)
85
6
85
7
85
0
8
85
24
30
25
26
0
9
PhI(OAc)2 (0.25)
Ag2CO3 (0.25)
Ag2CO3 (0.25)
Ag2CO3 (0.25)
Ag2CO3 (0.25)
Ag2CO3 (0.25)
Ag2CO3 (0.25)
Ag2CO3 (0.25)
Ag2CO3 (0.25)
Ag2CO3 (0.25)
Ag2CO3 (0.25)
Ag2CO3 (0.25)
Ag2CO3 (0.25)
85
10
11
12
13
14
15
16
17
18
19
20a
21b
85
Pd(TFA)2 (10)
Pd(CH3CN)2Cl2 (10)
Pd(PPh3)4 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
85
85
85
0
80
11
9
1,2-DCE
1,4-dioxane
EtOH
80
100
80
15
54
0
AcOH
110
100
85
t-AmylOH
t-BuOH
t-BuOH
40
0
85
0
a 1-Bromobenzene (2b) was used instead of 2a; the corresponding product was not obtained.
b 1-Chlorobenzene (2c) was used instead of 2a; the corresponding product was not obtained.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1395–1402

1398
R. Parella, S. A. Babu
LETTER
turally similar to the substrate 1a, did not furnish any new The generality and scope of this protocol involving the
product under the experimental conditions. The use of 1h, Pd-catalyzed, auxiliary-directed activation and direct ary-
which is similar to substrate 1a, in the Pd-catalyzed C–H lation of 2° and bridgehead 3° C(sp3)–H bonds and an un-
arylation reaction also failed to afford any arylated prod- precedented C–C bond formation at the bridgehead center
uct. We are investigating new reactions using these sub- of the norbornane system were elaborated (Scheme 5).
strates and the results will be published in due course.
Under the optimized reaction conditions, the production
of a wide range bisarylated norbornane frameworks 3a–g
(45–81%) and 5a–g (23–50%) from the direct arylation of
2° C(sp3)–H (endo) and bridgehead 3° C(sp3)–H bonds of
substrates 1a and 1i was accomplished by employing sev-
eral substituted aryl iodides containing electron-with-
drawing or electron-donating groups (Scheme 5).7b,8–10
Double heterocyclic substitutions on the norbornane sys-
tem 1a through direct C–H functionalization using 2-io-
dothiophene, successfully gave the expected product 3h
(78%; Scheme 5). All the reactions furnished the products
3a–h and 5a–g as single diastereomers through selective
incorporation of various aryl groups at the endo 2°
C(sp3)–H and bridgehead 3° C(sp3)–H positions of the
To develop other working auxiliaries attached to the nor-
bornane framework, we then carried out Pd-catalyzed ar-
ylation of substrate 1i (endo), prepared from an auxiliary
[e.g., 2-(methylthio)aniline] with various aryl iodides
(Scheme 4). By employing the optimized reaction condi-
tions, the Pd-catalyzed selective C–H activation and ary-
lation of an endo 2° C(sp3)–H bond of substrate 1i gave
the monoarylated norbornane systems 6a–c in 32–36%
yield with high stereoselectivity (Scheme 4).7b The yields
of the products 6a–c were lower than the products 4a–f,
which is perhaps due to the difference in the abilities of
the respective auxiliaries (attached to the substrates 1i and
1a) to assist the Pd-catalyzed C–H activation reactions.
H
H
Me
N
N
H
O
Me
H
1a (0.25 mmol)
(endo)
Pd(OAc)2
(10 mol%)
H
H
+
N
N
Ag2CO3
(0.25 mmol)
t-BuOH (3 mL)
24–36 h, 85 °C
N
N
H
H
H
O
O
I
Me
+
+
N
N
H
O
2a
(1 mmol)
4a'
(not obtained)
Me
Me
4a
3a
(endo, endo)
(endo, endo)
entry
1a (mmol)
2a (mmol)
ratio 1a:2a
3a yield (%)
4a yield (%)
1
2
3
4
5
6
1.0
1:4
70
50
36
6
0
0.25
0.25
0.25
0.25
0.25
0.25
1:3
0.75
0.5
0
1 : 2
1:1.5
1:1
0
0.375
0.25
0.125
40
57
32
0
1:0.5
0
H
H
H
H
H
H
N
H
N
N
N
N
H
O
N
O
H
O
Me
OMe
4a; 57% (36 h)
4b; 73% (36 h)
4c; 65% (36 h)
H
H
H
H
H
H
N
N
N
H
O
N
H
O
N
N
H
O
S
Ac
4d; 49% (36 h)
CN
4e; 58% (36 h)
4f; 61% (73 °C, 24 h)
Scheme 2 Mono- and bis-C–H functionalization of 1a
Synlett 2014, 25, 1395–1402
© Georg Thieme Verlag Stuttgart · New York

LETTER
Arylation of 2° and 3° C–H Bonds of Norbornanes
1399
3° sp3 C–H
activation of
H
O
(7)th C–H from auxiliary N
H
4
3
H
7
(or)
6
5
N
2
(7')th C–H from auxiliary N
H
N
1
N
7'
N
H
O
H
1a
H
2° sp3 C–H
H
H
H
H
N
HN
N
O
OMe
N
H
O
O
N
1d
1b
1c
H
H
N
H
H
H
O
N
N
N
N
N
N
H
H
O
O
1f
1e
O
1g
N
H
H
HN
O
N
1h
Scheme 3 The role of the auxiliary and other bicyclic compounds
norbornane systems 1a and 1i. The stereochemistry of tems 1a and 1i. Therefore, we envisaged the introduction
representative products 4a, 3d, 5d, and 7b were assigned of a different aryl group at the bridgehead carbon and ex-
on the basis of X-ray crystal structure analysis (Figure amined the prospect of this unprecedented ‘bridgehead
1).7b,11
carbon substitution’ via C–H activation (Scheme 6).7b To
this end, we carried out a series of reactions with the aim
of achieving exclusive activation of the bridgehead 3°
C(sp3)–H bond and C–C bond formation at the bridgehead
carbon.
In the reactions shown in the Table 1, Scheme 2, and
Scheme 5 (products 3a–h and 5a–g), similar aryl groups
were incorporated at the endo 2° C(sp3)–H as well as at the
bridgehead 3° C(sp3)–H positions of the norbornane sys-
H
I
H
H
Pd(OAc)2 (10 mol%)
+
N
N
Ag2CO3 (0.25 mmol)
t-BuOH (3 mL)
SMe
SMe
R
H
H
O
O
2
1i (0.25 mmol)
(endo)
36 h, 85 °C
(0.5 mmol)
R
6a–c
(endo, endo)
H
H
H
N
N
N
SMe
SMe
H
H
SMe
O
O
H
O
6a; 36%
CN
Ac
6b; 32%
6c; 32%
Scheme 4 Mono C–H arylation of the 2° C(sp3)–H (endo) bond of the norbornane framework of 1i
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1395–1402

1400
R. Parella, S. A. Babu
LETTER
R
H
H
Pd(OAc)2 (10 mol%)
I
H
auxiliary
auxiliary
+
N
Ag2CO3 (0.25 mmol)
t-BuOH (3 mL)
24–36 h, 85 °C
N
H
O
R
H
O
1a/1i (0.25 mmol)
(endo)
2
(1 mmol)
R
(endo, endo)
Me
Me
CN
Me
H
N
H
H
H
N
H
O
N
N
H
N
N
N
H
N
O
O
H
O
3b
81% (24 h)
Me
Me
CN
Me
3a; 68%
3c
3d
(gram-scale
55% (24 h)
65% (24 h)
reaction yield)
Br
OMe
COCH3
S
H
N
H
N
H
H
N
H
O
N
N
N
N
N
H
H
H
O
O
O
S
3h
78% (73 °C, 24 h)
Br
Ac
OMe
3e
3f
3g
46% (24 h)
62% (24 h)
45% (36 h)
R
O2N
MeO
OMe
H
N
OMe
H
H
SMe
H
O
N
N
SMe
H
O
H
O
MeS
NO2
5b
32% (24 h)
MeO
OMe
R
5c; R = H; 43% (30 h)
5d; R = Ac; 40% (36 h)
5e; R = OMe; 50% (24 h)
5f; R = CN; 33% (24 h)
5g; R = Me; 35% (24 h)
OMe
5a
23% (36 h)
Scheme 5 Double C–H arylation of norbornanes 1a and 1i
We treated several endo substituted norbornane systems, In summary, we have presented our work on the Pd-cata-
with the generalized structure 4, with a variety of aryl io- lyzed concurrent activation and arylation of 2° and bridge-
dides and heteroaryl iodide (Scheme 6). These reactions head 3° C(sp3)–H bonds of norbornane systems and an
successfully gave the respective novel bridgehead-arylat- unprecedented ‘formation of C–C bond at the bridgehead
ed norbornane systems 7a–h (32–50%) through C–H ac- carbon and bridgehead quaternary stereocenter via the C–
tivation of the bridgehead 3° C(sp3)–H bond followed by H activation’. Novel bridgehead-substituted norbornane
C–C bond formation at the bridgehead carbon. The prod- frameworks having contiguous stereocenters were assem-
ucts 7a–h were obtained in low to moderate yields, which bled. Further work is in progress to demonstrate the utility
suggested that the C–H functionalization of the bridge- of this protocol.
head 3° C(sp3)–H bond is a relatively difficult reaction.
Synlett 2014, 25, 1395–1402
© Georg Thieme Verlag Stuttgart · New York

LETTER
Arylation of 2° and 3° C–H Bonds of Norbornanes
1401
References and Notes
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Figure 1 X-ray crystal structures of products 4a, 3d, 5d and 7b
Acknowledgment
We thank IISER-Mohali for funding and the NMR, HRMS and X-
ray facilities of IISER-Mohali. R.P. is thankful to CSIR, New Delhi,
for a fellowship.
(2) (a) Kraus, G. A.; Hon, Y.-S.; Thomas, P. J.; Laramay, S.;
Liras, S.; Hanson, J. Chem. Rev. 1989, 89, 1591.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
(b) Paquette, L. A. Chem. Soc. Rev. 1995, 24, 9. (c) Harmata,
M.; Wacharasindhu, S. Synthesis 2007, 23. (d) Wendeborn,
S.; Nussbaumer, H.; Schaetzer, J.; Winkler, T. Synlett 2010,
1966. (e) Grimme, W.; Bertsch, A.; Flock, H.; Noack, T.;
R
H
I
H
Pd(OAc)2 (10 mol%)
H
+
N
Ag2CO3 (0.25 mmol)
t-BuOH (3 mL)
36 h, 85 °C
R
N
N
H
O
N
2
H
O
(1 mmol)
R
R
7a–h
(endo, endo)
4 (0.25 mmol)
(endo, endo)
Me
OMe
O
O
H
N
H
H
H
N
N
H
N
H
O
N
N
H
N
O
O
N
H
O
S
S
7c; 33%
Me
S
7d; 32%
CN
S
7a; 43%
7b; 37%
S
S
H
H
H
H
N
H
N
N
H
N
H
N
H
O
N
N
N
O
O
O
7g; 37%
Me
7f; 33%
Ac
OMe
7e; 38%
7h; 50%
Scheme 6 C–H arylation of the bridgehead C–H bond of 4
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1395–1402

1402
R. Parella, S. A. Babu
LETTER
Krauthäuser, S. Synlett 1998, 1175. (f) Slowinski, F.; Ayad,
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(7) For a paper dealing with norbornene-type systems with the
palladium catalyst, see: (a) Malacria, M.; Maestri, G. J. Org.
Chem. 2013, 78, 1323. (b) The stereochemistry was assigned
based on X-ray crystal structures of 4a, 3d, 5d, and 7b and
the similarity in the NMR spectral pattern.
(8) General procedure for the direct C–H arylation of
norbornane systems and the preparation of 3a–h, 5a–g,
and 7a–h: A solution of bridged bicyclic framework 1a, 1i
or 4 (0.25 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol, 10
mol%), aryl iodide (1 mmol), and Ag2CO3 (68.9 mg, 0.25
mmol) in anhydrous t-BuOH (3 mL) was heated at an
appropriate temperature and for an appropriate time (73–
85 °C, 24–36 h; see the respective tables or schemes for
specific examples) under a nitrogen atmosphere. After the
reaction period, the reaction mixture was diluted with EtOAc
and concentrated in vacuum. Purification of the resulting
reaction mixture by column chromatography (silica gel,
100−200 mesh) furnished the corresponding bisarylated
bicyclo[2.2.1]heptane-2-carboxamides.
(9) Analytical data of 3a: Following the general procedure
described above, 3a was obtained after purification by
column chromatography on silica gel (EtOAc–hexanes,
30:70). Yield: 70% (78 mg); brown solid; mp 172–174 °C
(MeOH–hexanes, 1:1). FTIR (KBr): 3401, 1629, 1521,
1322, 667 cm–1. 1H NMR (400 MHz, CDCl3): δ = 9.27 (br s,
1 H), 8.63 (dd, J = 7.2, 1.6 Hz, 1 H), 8.57 (dd, J = 4.2,
1.6 Hz, 1 H), 8.07 (dd, J = 8.2, 1.6 Hz, 1 H), 7.47–7.34 (m,
5 H), 7.18 (d, J = 8.0 Hz, 2 H), 7.09 (d, J = 8.0 Hz, 2 H), 7.01
(d, J = 8.0 Hz, 2 H), 3.88 (dd, J = 11.0, 2.8 Hz, 1 H), 3.57
(dd, J = 11.0, 1.3 Hz, 1 H), 2.90–2.85 (m, 1 H), 2.80 (br s,
1 H), 2.32 (s, 3 H), 2.30–2.26 (m, 2 H), 2.23 (s, 3 H), 1.93
(dd, J = 9.5, 1.6 Hz, 1 H), 1.83–1.77 (m, 2 H). 13C NMR (100
MHz, CDCl3): δ = 170.3, 147.6, 141.2, 138.2, 137.6, 136.0,
135.7, 134.9, 134.6, 129.0, 128.6, 128.2, 127.7, 127.3,
127.1, 121.3, 120.9, 116.2, 58.0, 56.2, 49.2, 46.5, 41.6, 29.6,
23.9, 21.1, 21.0. HRMS (ESI): m/z [M + H]+ calcd for
C31H31N2O: 447.2436; found: 447.2444.
(10) Analytical data of 3b: Following the general procedure
described above, 3b was obtained after purification by
column chromatography on silica gel (EtOAc–hexanes,
30:70). Yield: 81% (84 mg); white solid; mp 135–137 °C
(MeOH–hexanes, 1:1). FTIR (KBr): 3300, 1668, 1587,
1321, 1021 cm–1. 1H NMR (400 MHz, CDCl3): δ = 9.30
(br s, 1 H), 8.63 (dd, J = 7.2, 1.9 Hz, 1 H), 8.56–8.55 (m,
1 H), 8.06 (dd, J = 8.3, 1.8 Hz, 1 H), 7.52–7.49 (m, 1 H),
7.46–7.07 (m, 12 H), 3.92 (dd, J = 13.6, 1.4 Hz, 1 H), 3.63
(dd, J = 13.6, 1.4 Hz, 1 H), 2.92–2.86 (m, 2 H), 2.36–2.31
(m, 2 H), 1.96 (dd, J = 9.4, 1.6 Hz, 1 H), 1.86–1.78 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 170.0, 147.7, 144.1, 140.7,
138.2, 136.0, 134.5, 128.3, 128.1, 127.8, 127.7, 127.3,
127.2, 126.3, 125.6, 121.3, 120.9, 116.1, 58.0, 56.5, 49.5,
46.4, 41.4, 29.6, 23.8. HRMS (ESI): m/z [M + H]+ calcd for
C29H27N2O: 419.2123; found: 419.2123.
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(11) The crystallographic data have been deposited at the
Cambridge Crystallographic Data Centre: CCDC-982495
(4a), CCDC-982494 (3d), CCDC-982496 (5d), and CCDC-
982497 (7b). These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Synlett 2014, 25, 1395–1402
© Georg Thieme Verlag Stuttgart · New York