Synthesis of anti-2,7-disubstituted norbornadienes

Article abstract of DOI:10.1055/s-0028-1083352

Synthesis of a variety of anti-2,7-disubstituted norborna- dienes was achieved by palladium- and iron-catalyzed cross- coupling reactions of the anti-tert-butoxynorbornadien-2-yl triflate. While the palladium-catalyzed coupling reactions could only genera

Full text of DOI:10.1055/s-0028-1083352

PAPER
609
Synthesis of anti-2,7-Disubstituted Norbornadienes
S
ynthesis of anti-2
a
, 7-Disubsti
v
tuted Norbor
i
nadien
n
es C. Tsui, Paul Le Marquand, Anna Allen, William Tam*
Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, Department of Chemistry, University of Guelph,
Guelph, ON, N1G 2W1, Canada
Fax +1(519)8244120 (ext. 52268); E-mail: wtam@uoguelph.ca
Received 6 August 2008; revised 19 September 2008
7
1
7
Z
Abstract: Synthesis of a variety of anti-2,7-disubstituted norborna-
dienes was achieved by palladium- and iron-catalyzed cross-
coupling reactions of the anti-tert-butoxynorbornadien-2-yl triflate.
While the palladium-catalyzed coupling reactions could only gener-
ate coupling products with aryl and alkynyl groups, the iron-cata-
lyzed coupling reactions have a much broader scope and provide
efficient synthesis of anti-2,7-disubstituted norbornadienes with at-
tached primary, secondary and tertiary alkyl groups, cycloalkyl
groups with various ring sizes, as well as vinyl, aryl and alkynyl
groups.
4
3
5
Y
3
6
2
2
2
X
X
3
1
2
4
7
7
Z
Z
5
X
2
2
2
X
X
X
5
6
7
Figure 1 Norbornadiene and derivatives
Key words: bicyclic compounds, cross-coupling, catalysis, palla-
dium, iron
tadiene and an alkyne. Since unactivated alkynes are poor
dienophiles in Diels–Alder cycloadditions, the variety of
substituted norbornadienes that could be synthesized
using this approach is rather limited – substrates usually
contain at least one electron-withdrawing group such as
an ester, an amide, or a cyano group.18 We have recently
reported the synthesis of a variety of 2-substituted (3) and
2,3-disubstituted norbornadienes (4) by three different
methods. Double lithium–halide exchange of 2,3-dibro-
monorbornadiene (8), followed by trapping with various
electrophiles, produced a variety of substituted norborna-
dienes 9 [X and Y being primary alkyl groups, silyl
groups, Cl, Br, I, R3Sn, COOR, R1R2C(OH);
Scheme 1].15d
Bicyclo[2.2.1]hepta-2,5-diene (1; Figure 1), commonly
known as norbornadiene (NBD), was first reported in the
literature in 1951.1 Its structural characteristics include a
bridged, bicyclic framework, two isolated double bonds
that are homoconjugated through space,2 and two distinct
faces (exo and endo). The rigid bicyclic structure of NBD
results in a significant strain energy of 32.3 kcal/mol.3 In
many cases the release of this strain energy accounts for
the ability of NBD to participate in a variety of reactions.
Substituted norbornadienes are important compounds.
They have been used as key intermediates for the synthe-
sis of natural products such as prostaglandin endoperox-
ides PGH2 and PGG2,4 cis-Trikentrin B,5 and b-santalol.6
Chiral 2,5-disubstituted norbornadienes 5 have recently
been used as chiral ligands in asymmetric catalysis.7 Pho-
tochemical valence isomerization between norborna-
dienes and quadricyclanes is of interest for solar energy
storage and has demonstrated the efficiency and switching
potential of these reversible systems.8,9 This photochemi-
cal isomerization reaction has recently been investigated
as an optical waveguide utilizing photoinduced refractive
index changes,10 as a photochromic system potentially ap-
plicable to data storage,11 and as light-driven, carrier-
mediated, active transport across a membrane against a
concentration gradient.12
1. t-BuOK, n-BuLi
2. BrCH2CH2Br
3
Br
ArB(OH)2,
Pd2(dba)3, t-Bu3P
CsF, THF
2
Br
1
8
1. t-BuLi, THF
2. X+
3. t-BuLi, THF
4. Y+
R
Ar
Pd(PPh3)4
CuI, Et3N
Ar
11
R
Y
X
10
9
R
Scheme 1 Previous synthesis of 2-substituted and 2,3-disubstituted
norbornadienes
Synthetic methods for the construction of 7-substituted
norbornadienes 2,13 2-substituted norbornadienes 3,14,15
2,3-disubstituted norbornadienes 4,14–17 and 2,5-disubsti-
tuted norbornadienes 5,7 have been developed in the liter-
ature. Traditionally, substituted norbornadienes can be
synthesized by Diels–Alder reactions between cyclopen-
Palladium-catalyzed Sonogashira couplings of 2,3-dibro-
monorbornadiene (8) with terminal alkynes yielded nor-
bornadiene-2,3-diynes 10,16 and palladium-catalyzed
Suzuki couplings of 8 with aryl boronic acids afforded
2,3-diarylnorbornadienes 11.17 These studies significantly
broadened the variety of substituted norbornadienes that
cannot otherwise be prepared by the Diels–Alder method-
SYNTHESIS 2009, No. 4, pp 0609–0619
x
x
.
x
x
.2
0
0
9
Advanced online publication: 02.02.2009
DOI: 10.1055/s-0028-1083352; Art ID: M04308SS
© Georg Thieme Verlag Stuttgart · New York

610
G. C. Tsui et al.
PAPER
ology. However, to the best of our knowledge, no system- A successful synthesis of the anti-tert-butoxynorborna-
atic method has been reported in the literature for the dien-2-yl triflate (20) is shown in Scheme 4. Hydrobora-
synthesis of anti-2,7-disubstituted norbornadienes 7 tion–oxidation of 7-tert-butoxynorbornadiene 16, which
(Figure 1). In this paper, we report our investigation into is commercially available and can be synthesized on large
the synthesis of anti-2,7-disubstituted norbornadienes 7 scale in a single step using norbornadiene 1 following lit-
by palladium- and iron-catalyzed coupling reactions.
erature procedure,13c gave the alcohol 17 as the only regio-
and stereoisomer, in 72% yield. However, the hydrobora-
tion step required a very long time (14 days) to go to com-
pletion. Alternatively, a less time-consuming, two-step
oxymercuration–demercuration of 16 could be used to
give alcohol 17. Oxymercuration of 7-tert-butoxynorbor-
nadiene (16) afforded the acetate 18 in 78% yield and sub-
sequent demercuration using sodium amalgam (6% Na/
Hg) provided the alcohol 17 in 70% yield. After testing a
variety of oxidation conditions for the oxidation of alco-
hol 17 to ketone 19, Swern oxidation [DMSO, (COCl)2,
Et3N, CH2Cl2, –78 °C] was found to give the highest yield
(90%) of ketone 19. Although attempts to convert ketone
19 into a lithiated norbornadiene 15 by a Shapiro reaction
(Scheme 3) were unsuccessful, the target anti-tert-but-
oxynorbornadien-2-yl triflate (20) could be synthesized in
good yield (Scheme 4). Several conditions have been used
to convert ketone 19 into the anti-tert-butoxynorborna-
dien-2-yl triflate 20. The use of potassium hexamethyldi-
silazide (KHMDS) as the base and N-phenyl triflamide
(PhNTf2) as the triflating agent gave the triflate 20 in 94%
yield.
Although it is possible to synthesize 2,7-disubstituted nor-
bornadienes by deprotonation of 7-disubstituted norbor-
nadienes 2, inseparable mixtures of the syn and anti
products are often obtained (Scheme 2).19 Thus, it is not a
good method for the selective synthesis of anti-2,7-disub-
stituted norbornadienes 7.
Z
Z
Z
1. t-BuOK, n-BuLi
2. MeI
+
X
2
X
syn-6
anti-7
Z
Yield (%)
syn-6/anti-7
Ot-Bu
50
40
75
73
2.3:1
1.3:1
1:3
OMOM
OTBS
OTIPS
1:9
(data taken from ref. 19)
Scheme 2 Deprotonation of 7-substituted norbornadienes
Our synthetic plan for the selective synthesis of anti-2,7-
disubstituted norbornadienes 7 is shown in Scheme 3. 7-
Substituted norbornadienes 2 can be prepared according
to literature procedures.13 Hydroboration–oxidation or
oxymercuration–demercuration of 7-substituted norbor-
nadienes 2 should produce alcohol 12. Oxidation of 12
would produce ketone 13, which can be converted into the
corresponding triflate 14. Metal-catalyzed coupling
would generate our desired anti-2,7-disubstituted norbor-
nadienes 7. Alternatively, ketone 13 can be converted into
the lithiated norbornadiene 15 by a Shapiro reaction via
the corresponding tosylhydrazone.20 Trapping the lithi-
ated norbornadiene 15 with various electrophiles would
provide the desired anti-2,7-disubstituted norbornadienes
7.
t-BuO
t-BuO
t-BuO
1. 9-BBN, THF,
25 °C, 14 d
[O]
OH
2. H2O2, NaOH,
25 °C, 4 h
16
17
19
22%
O
(72%)
CrO3•2py:
Hg(OAc)2,
THF, 25 °C,
12 h
CrO3, H2SO4: 45%
TPAP, NMO: 55%
Dess–Martin: 58%
Na/Hg
NaOH
(70%)
t-BuO
PCC:
65%
90%
(78%)
HgCl
OAc
Swern:
18
t-BuO
t-BuO
LDA, Tf2O:
12%
19
23%
28%
33%
75%
94%
20
NaHMDS, Tf2O:
KHMDS, Tf2O:
LDA, PhNTf2:
O
OTf
Z
Z
NaHMDS, PhNTf2:
KHMDS, PhNTf2:
OH
2
1
12
Scheme 4 Synthesis of anti-tert-butoxynorbornadien-2-yl triflate
(20)
Z
With the anti-tert-butoxynorbornadien-2-yl triflate (20) in
hand, palladium-catalyzed Suzuki coupling reactions21
were investigated (Table 1). Optimization of the reactions
was carried out using phenylboronic acid (Table 1, entries
1–12) in tetrahydrofuran. Of the five different palladium
catalysts tested, palladium(II) acetate gave the best result
(entries 1–5) and, among the six phosphine ligands tested,
tricyclohexylphosphine provided the highest yield in the
coupling reaction (entries 5–10). The use of different
bases showed little effect, however potassium fluoride
Z
Z
13
O
14
15
OTf
Li
Z
7
X
Scheme 3 Synthetic plan
Synthesis 2009, No. 4, 609–619 © Thieme Stuttgart · New York

PAPER
Synthesis of anti-2,7-Disubstituted Norbornadienes
611
Table 1 Palladium-Catalyzed Suzuki Coupling Reactions of Triflate 20
t-BuO
t-BuO
Pd catalyst, phosphine
base, THF, 65 °C
RB(OH)2
+
20
21
OTf
R
R
Entry
1
Catalysta
Phosphineb
none
Basec
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
K2CO3
KF
Product
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21b
21c
–
Yield (%)d
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Pd(PPh3)4
PdCl2(PPh3)2
PdCl2(PhCN)2
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
28
35
42
68
74
4
2
none
3
t-Bu3P
t-Bu3P
t-Bu3P
n-Bu3P
Ph3P
4
5
6
7
5
8
(MeO)3P
BINAPe
Cy3P
5
9
4
10
11
12
13
14
15
16
17
80
75
90
86
84
0
Cy3P
Cy3P
4-MeO-C6H4
4-AcC6H4
n-Bu
Cy3P
KF
Cy3P
KF
Cy3P
KF
i-Pr
Cy3P
KF
–
0
Cy
Cy3P
KF
–
0
a 5 mol% of the Pd catalyst was used.
b 10 mol% of the monodentate phosphine ligand was used.
c 3–4 equiv of base was used.
d Isolated yield after column chromatography.
e 5 mol% BINAP was used.
t-BuO
seemed to work best (entries 10–12). The use of solvents
such as pentane, toluene, and 1,2-dichoroethane gave
much lower yields. On the other hand, the use of N,N-di-
methylformamide or dioxane gave yields comparable
with those obtained using tetrahydrofuran. Electron-rich
and electron-deficient benzene rings work equally well in
the coupling reactions, giving the coupling products in
good yields (entries 13 and 14). However, the use of pri-
mary or secondary alkyl boronic acids did not afford any
coupling products (entries 15–17). Thus, this palladium-
catalyzed Suzuki coupling reaction method will only al-
low the production of anti-2,7-disubstituted norborna-
dienes 21 with R = aryl groups. Synthesis of an anti-2,7-
disubstituted norbornadiene 21d, with R = an alkyne, is
t-BuO
Pd(PPh3)4, CuI, Et3N
Ph
, DMF, 55 °C
20
21d
OTf
(75%)
Ph
Scheme 5 Synthesis of anti-2,7-disubstituted norbornadiene 21d
norbornadienes. In 1945, Kharasch and co-workers
reported the first iron-catalyzed alkenylation of Grignard
reagents.23a,b Kochi and co-workers improved the proce-
dures and studied the mechanism of the reaction in 1971
but the yields of the reactions were low and not conve-
nient for preparative applications.23c,d More recently in
1998, Cahiez reported that the use of N-methyl-2-pyrroli-
dinone (NMP) or N,N’-dimethylpropylene urea (DMPU)
as a co-solvent, which greatly improved the yields of iron-
catalyzed alkenylations of Grignard reagents; alkenyl
chlorides, bromides and iodides as well as alkenyl phos-
possible using
a
palladium-catalyzed Sonogashira
coupling22 (Scheme 5).
The limitations of the above palladium-catalyzed cou-
pling reactions lead us to explore other alternative
methods for the synthesis of anti-2,7-disubstituted
Synthesis 2009, No. 4, 609–619 © Thieme Stuttgart · New York

612
G. C. Tsui et al.
PAPER
phates have also been used successfully.24b In 2004,
Fürstner extended Cahiez’s conditions to include alkenyl
triflates as successful substrates in iron-catalyzed alkeny-
lations of Grignard reagents.24f,g More importantly, the
successful use of alkyl Grignard nucleophiles were report-
ed in these studies on iron-catalyzed alkenylations. This is
significant since we would like to employ such an ap-
proach for the synthesis of anti-2,7-disubstituted norbor-
nadienes 21 with alkyl groups as an alternative to the
unsuccessful palladium-catalyzed couplings (Table 1 en-
tries 15–17). This methodology has been successfully ap-
plied to synthesize biologically active natural products
such as muscopyridine,25 latrunculin,26 and the immuno-
suppressive agent FTY720.27
Table 2 Effect of Solvent
t-BuO
t-BuO
t-BuO
Fe(acac)3, solvent
+
CyMgCl, –25 °C
30 min
OTf
16
20
21e
Cy
Entrya Solvent
Yield (%)b
Coupling
Reduced Recovered
product 21e product 16 20
1
2
Et2O
22
66
15
62
75
44
8
4
26
0
THF
5
3
DME
9
50
0
4
NMP
4
We began our study on iron-catalyzed coupling reactions
using the anti-tert-butoxynorbornadien-2-yl triflate (20).
In the presence of five equivalents of cyclohexylmagne-
sium chloride (CyMgCl) and Fe(acac)3 (10 mol% in Et2O)
at –25 °C, the desired coupling product 21e was formed in
22% isolated yield, accompanied with 4% of the reduced
product 16 and 26% of the unreacted starting triflate 20
(Table 2, entry 1). This result was very exciting since in
all of our previous studies (Scheme 1, Table 1 and
Scheme 5), we were only able to form carbon–carbon
bonds between the alkenyl carbon (C2) of norbornadiene
with an sp-hybridized carbon (Scheme 1, 10, and
Scheme 5, 21d), with an sp2-hybridized carbon
(Scheme 1, 11, and Table 1), and with an sp3-hybridized
carbon of a primary alkyl group (Scheme 1, 9). However,
we were never able to synthesize substituted norborna-
dienes with R = secondary alkyl groups (e.g. i-Pr or cy-
cloalkyl) or tertiary alkyl groups (e.g. t-Bu) using
previous methods (Scheme 1). To the best of our knowl-
edge, this is the first example of the synthesis of an anti-
5
DMPU
2
0
6
DMF
5
10
62
76
0
7
Et3N
7
8
TMEDA
5
0
9
THF/NMP (1:3)
THF/NMP (1:1)
THF/NMP (3:1)
THF/DMPU (1:3)
THF/DMPU (1:1)
THF/DMPU (3:1)
81
72
70
70
66
62
3
10
11
12
13
14
5
0
10
4
0
0
6
0
11
0
a Using CyMgCl (5 equiv) and Fe(acac)3 (10 mol%).
b Isolated yield after column chromatography.
2,7-disubstituted norbornadiene with a secondary alkyl To determine the effect of different iron catalysts on the
group attached to C2 (the alkenyl carbon) of the norborna- coupling reaction, several catalysts that were reported in
diene.
the literature to be active in iron-catalyzed coupling reac-
tions were screened (Table 3). The catalysts Fe(dpm)3,
Fe(dbm)3 and catalyst 22 were prepared by literature pro-
cedures.24e,28 All iron catalysts tested afforded the desired
coupling product 21e in moderate to good yields. The
commercially available, air-stable Fe(acac)3 catalyst
seems to be the best choice with respect to high yields and
ease of handling.
To optimize the yield of the iron-catalyzed coupling reac-
tion, an investigation into the effect of solvent, different
iron catalysts, different Grignard halides and reaction
temperature was carried out (Tables 2– 4). Solvent plays
an important role in iron-catalyzed coupling reactions.24
Based on the various solvent systems reported in the liter-
ature for iron-catalyzed coupling reactions,24 a wide range
of ether, amide and amine based solvents were screened The effect of reaction temperature on the iron-catalyzed
(Table 2). The use of THF, NMP, DMPU and THF/NMP coupling reaction is shown in Table 4. Reaction tempera-
or THF/DMPU mixed solvents gave the desired coupling tures above 0 °C led to decomposition of the starting tri-
product 21e in >60% isolated yields (entries 2, 4, 5 and 9– flate and lower yields of the desired coupling product 21e
14) and, in all cases, a small amount of the undesired re- were observed. Although the reaction seemed to work at
temperatures as low as –40 °C (little reaction was ob-
served for temperatures below –40 °C), –25 °C gave the
duced product 16 was also isolated. The highest yield
(81%) of the desired coupling product 21e was obtained
when THF/NMP (1:3) was used as solvent (entry 9). It best results among all the temperature tested (entries 1–5).
was interesting to observe that a decrease in the amount of
The effect of different Grignard halides on the iron-cata-
NMP used in the THF/NMP solvent mixture led to a de-
lyzed coupling reaction is shown in Table 5. Decrease in
crease in the yield of the desired coupling product 21e but
the yield of the desired coupling product 21e and increase
increase in the yield of the undesired reduced product 16
in the yield of the undesired reduced product 16 was ob-
(compare entries 9–11 and entries 12–14).
Synthesis 2009, No. 4, 609–619 © Thieme Stuttgart · New York

PAPER
Synthesis of anti-2,7-Disubstituted Norbornadienes
613
Table 3 Effect of Different Iron Catalystsa
Table 5 Effect of Different Halides of the Grignard Reagenta
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
Fe catalyst
Fe(acac)3
THF/NMP (1:3)
THF/NMP (1:3)
+
+
CyMgCl, –25 °C
OTf
CyMgX, –25 °C
30 min
OTf
16
16
20
21e
20
21e
30 min
Cy
Cy
Entry
Catalyst
Yield (%)b
Entry
X
Yield (%)b
Coupling product 21e Reduced product 16
Coupling product 21e
Reduced product 16
1
2
3
4
5
Fe(acac)3 81
FeCl3 74
3
5
9
6
9
1
2
3
Cl
Br
I
81
73
65
3
4
7
Fe(dpm)3 65
Fe(dbm)3 70
a Using CyMgX (5 equiv) and Fe(acac)3 (10 mol%).
b Isolated yield after column chromatography.
22
61
a Using CyMgCl (5 equiv) and 10 mol% of catalyst.
b Isolated yield after column chromatography.
flate 20 not only worked well with cycloalkyl Grignard re-
agents, it also worked well with acyclic primary,
secondary and even tertiary-alkyl groups (entries 6–9),
giving the anti-2,7-disubstituted norbornadienes with
R = i-Pr, n-Bu, s-Bu, t-Bu groups in good yields (50–
75%). The use of vinyl, aryl and alkynyl Grignard re-
agents in the iron-catalyzed coupling reaction of triflate
20 also afforded the corresponding anti-2,7-disubstituted
norbornadienes in good yields (61–76%, entries 10–12).
In some cases, apart from the formation of a small amount
of the reduced product 16 (entries 1–8), a mixture of the
homo-coupled products 23a and 23b was also obtained in
5–10% yield (entries 2 and 7–9).
H
H
N
N
Fe
Cl
O
O
t-Bu
O
O
t-Bu
R
R
t-Bu
t-Bu
R = Me (acac, acetoacetonato)
R = t-Bu (dpm, dipivaloylmethio)
R = Ph (dbm, dibenzoylmethio)
22
Table 4 Effect of Reaction Temperaturea
A proposed mechanism for the iron-catalyzed cross-
coupling reactions between anti-tert-butoxynorborna-
dien-2-yl triflate (20) and cyclobutylmagnesium chloride,
which accounts for the formation of coupling product 21g,
the reduced product 16, and the homo-coupled products
23a and 23b, is shown in Scheme 6. It has been proposed
that the active catalyst in iron-catalyzed coupling reac-
tions using Grignard reagents is an ‘Fe-Inorganic Grig-
nard reagent, Fe-IGR’, [Fe(MgX)2].24c,e–g,k,28 Based on the
proposed formation of a Fe-IGR, four equivalents of Grig-
nard are required to generate this active cluster for every
equivalent of Fe precatalyst. Reduction of the Fe(acac)3
precatalyst with the Grignard reagent produced the active
catalyst – the Fe-IGR. Oxidative insertion of the Fe-IGR
into the anti-tert-butoxynorbornadien-2-yl triflate (20)
would give intermediate 24. Addition of the Grignard re-
agent to 24 would afford 25. Reductive elimination of 25
would provide the coupling product 21g and regenerate
the Fe-IGR active catalyst. With alkyl groups containing
a b-hydrogen, b-hydride elimination is possible and iron-
hydride 26 would be formed. Reductive elimination of 26
would give the reduced product 16. On the other hand, in-
termediate 24 could react with triflate 20 to form 27,
which would undergo reductive elimination to give the
homo-coupled products 23a and 23b.
t-BuO
t-BuO
t-BuO
Fe(acac)3
THF/NMP (1:3)
+
CyMgCl, Temp,
OTf
30 min
16
20
21e
Cy
Entry
Temp (°C) Yield (%)b
Coupling product 21e Reduced product 16
1
2
3
4
5
–40
–25
0
70c
81
73
60
43
4
2
5
7
7
25
40
a Using CyMgCl (5 equiv) and Fe(acac)3 (10 mol%).
b Isolated yield after column chromatography.
c 15% of the starting triflate 20 was recovered.
served when the halide of the Grignard reagent was
changed from Cl to Br to I.
To explore the scope of the iron-catalyzed cross-coupling
reactions of triflate 20, various Grignard reagents
(RMgX) were employed and the results are shown in
Table 6. Various cycloalkyl magnesium halides under-
went the reaction, giving the corresponding cross-cou-
pling products in moderate to good yields (50–81%,
entries 1–5). This iron-catalyzed coupling reaction of tri-
In conclusion, we have investigated the palladium- and
iron-catalyzed cross-coupling reactions of anti-tert-but-
oxynorbornadien-2-yl triflate (20) with boronic acids and
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614
G. C. Tsui et al.
PAPER
t-BuO
Table 6 Iron-Catalyzed Cross-Coupling of Triflate 20 and Various
t-BuO
Grignard Reagents (RMgX)a
Fe(acac)3
MgCl
t-BuO
t-BuO
t-BuO
MgCl
Fe(acac)3
20
24
OTf
Fe
Ln
THF/NMP (1:3)
+
RMgX, –25 °C
30 min
t-BuO
OTf
21
20
16
R
t-BuO
MgCl
Entry
R
X
Yield (%)b
20
OTf
Ot-Bu
Coupling
product 21
Reduced
product 16
25
t-BuO
Fe
Ln
H
β-hydride
reductive
elimination
elimination
1c
2c
3c
4
cyclopropyl
cyclobutyl
cyclopentyl
cyclohexyl
cycloheptyl
i-Pr
Br
Cl
Cl
Cl
Br
Cl
Br
Cl
Cl
Br
Br
Br
50 (21f)
55 (21g)
68 (21h)
81 (21e)
66 (21i)
75 (21j)
65 (21k)
55 (21l)
50 (21m)
65 (21n)
76 (21a)
60 (21d)
4
Fe
Ln
27
t-BuO
t-BuO
8d
5
Ot-Bu
H
26
Fe
21g
t-BuO
Ln
3
23a and 23b
5
5
t-BuO
6
3
16
5d
4d
0d
0
H
7
n-Bu
Scheme 6 Proposed mechanism
8c
9
s-Bu
t-Bu
All reactions were carried out in an atmosphere of dry nitrogen at
ambient temperature unless otherwise stated. Standard column
chromatography was performed on 230–400 mesh silica gel using
standard flash column chromatography techniques.29 Analytical
thin-layer chromatography (TLC) was performed on Merck pre-
coated silica gel 60 F254 plates. All glassware was either oven-dried
(120 °C) or flame dried under an inert atmosphere of dry nitrogen.
Infrared spectra were taken on a Bomem MB-100 FTIR spectropho-
tometer. 1H and 13C NMR spectra were recorded on Bruker Avance-
300, 400 or 600 MHz spectrometers. Chemical shifts for 1H NMR
spectra are reported in parts per million (ppm) from TMS with the
residual proton resonance as the internal standard (CHCl3: d = 7.26
ppm). Chemical shifts for 13C NMR spectra are reported in parts per
million (ppm) from TMS with the solvent as the internal standard
(CDCl3: d = 77.0 ppm). Unless stated otherwise, commercial re-
agents were used without purification. Solvents were purified by
distillation under dry nitrogen: THF and Et2O from potassium/ben-
zophenone; DME from CaH2; DMPU, DMSO, TMEDA and Et3N
from 4 Å molecular sieves. The catalysts Fe(dpm)3, Fe(dbm)3 and
Fe-catalyst 22 were prepared by literature procedures.24e,28 All the
Grignard reagents (commercially available or prepared as follows)
were titrated according to literature procedures before use.30
10
11
12
vinyl
Ph
0
0
Ph
a Using RMgX (5 equiv) and Fe(acac)3 (10 mol%).
b Isolated yield after column chromatography.
c Reactions carried out at 0 °C.
d 5–10% of the homo-coupled products 23a and 23b were also ob-
tained.
Ot-Bu
Ot-Bu
t-BuO
t-BuO
23a
23b
with Grignard reagents. The palladium-catalyzed cou-
pling reactions provide an efficient method for the synthe-
sis of anti-2,7-disubstituted norbornadienes 21 with
R = aryl and alkynyl groups. The iron-catalyzed coupling
reactions have a much broader scope and provide efficient
synthesis of anti-2,7-disubstituted norbornadienes 21
with R = primary, secondary and tertiary alkyl groups, cy-
cloalkyl groups with various ring sizes, as well as vinyl,
aryl and alkynyl groups. These studies are important not
only because efficient synthesis of a variety of anti-2,7-
disubstituted norbornadienes has been developed, but also
because the capability of this methodology to form car-
bon–carbon bonds between the alkenyl carbon (C2) of
norbornadiene with a sp3-hybridized carbon of a second-
ary alkyl group (e.g. i-Pr or cycloalkyl) or tertiary alkyl
group (e.g. t-Bu) by using iron-catalyzed cross-coupling
reactions which cannot be achieved using previous meth-
ods (Scheme 1).
anti-exo-7-tert-Butoxybicyclo[2.2.1]hept-5-en-2-ol (17);
Hydroboration–Oxidation Procedure
9-BBN dimer (11.4 g) was dissolved in THF (180 mL) and the re-
sulting solution was added via a cannula to a solution of 7-tert-but-
oxynorbornadiene (16; 14.0 g, 85.2 mmol) in THF (170 mL) at
25 °C. The reaction mixture was stirred for 14 d and was monitored
by TLC. H2O (150 mL) and aq NaOH (5 M, 60 mL) were added at
0 °C then H2O2 (30%, 130 mL) was added dropwise at 0 °C. The re-
action mixture was stirred at 25 °C for 5 h then quenched with aq
HCl (100 mL). The mixture was extracted with Et2O (4 × 500 mL)
and the combined organic layers were washed with sat. aq NaHCO3
(2 × 500 mL) and brine (2 × 500 mL), and dried over anhydrous
Na2SO4. The solvent was removed by rotary evaporation and the
crude product was purified by flash chromatography (hexanes–
EtOAc, 4:1) to provide alcohol 17 as a colorless oil (11.2 g, 72%).
Synthesis 2009, No. 4, 609–619 © Thieme Stuttgart · New York

PAPER
Synthesis of anti-2,7-Disubstituted Norbornadienes
615
Oxymercuration–Demercuration Procedure
the combined organic layers were washed sequentially with sat.
NaHCO3 (200 mL), H2O (200 mL) and brine (200 mL) and dried
over anhydrous Na2SO4. The solvent was removed by rotary evap-
oration and the crude product was purified by flash chromatography
(hexanes–EtOAc, 9:1) to provide the triflate 20.
Hg(OAc)2 (20.7 g, 64.9 mmol) was slowly added over 45 min to a
flame-dried flask containing 7-tert-butoxynorbornadiene (16; 8.92
g, 54.3 mmol) in THF (125 mL). The mixture was stirred at r.t. for
12 h, quenched with NaCl (15.1 g, 258 mmol) and stirred vigorous-
ly for 30 min. After quenching with H2O (100 mL), the aqueous lay-
er was extracted into CH2Cl2 (3 × 150 mL), and the combined
organic layers were washed with brine (2 × 100 mL) and dried
(MgSO4). The solvent was removed by rotary evaporation and the
crude product was purified by flash chromatography (hexanes–
EtOAc, 4:1) to provide compound 18 (19.5 g, 78%) as a colorless
oil.
Yield: 6.25 g (94%); pale-yellow oil; Rf = 0.54 (hexanes–EtOAc,
9:1).
1H NMR (300 MHz, CDCl3): d = 6.67 (br s, 2 H), 6.20 (dd, J = 4.0,
1.4 Hz, 1 H), 4.14 (s, 1 H), 3.43–3.42 (m, 1 H), 3.37–3.36 (m, 1 H),
1.16 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 162.8, 138.2, 135.4, 122.8, 118.5
(q, 1JC–F = 321 Hz), 103.9, 74.6, 56.8, 54.0, 28.1.
Compound 18 was subjected to demercuration without character-
ization. Sodium amalgam (6% w/w Na/Hg, 199 g) was added to a
flame-dried flask containing the above mercuric chloride 18 in
NaOH (2.5 M, 400 mL) and the reaction mixture was stirred for 18
h. The reaction was quenched with H2O (400 mL), extracted into
Et2O (4 × 400 mL), and the combined organic layers were washed
with H2O (1 L), brine (1 L) and dried (MgSO4). The solvent was re-
moved by rotary evaporation and the crude product was purified by
flash chromatography (hexanes–EtOAc, 4:1) to provide alochol 17.
HRMS: m/z [M + H]+ calcd for C12H16O4SF3: 313.0721; found:
313.0733.
Pd-Catalyzed Suzuki Coupling (Table 1); General Procedure A
Inside an inert atmosphere (Ar) glove box, triflate 20 (1.0 equiv),
THF (~0 8 M), boronic acid (1.2 equiv), KF (3.6 equiv), Cy3P (10
mol%) and Pd(OAc)2 (5 mol%) were added to an oven-dried vial
containing a stirrer bar. After sealing the vial with a screw cap, the
reaction mixture was taken out of the glove box and heated to 65 °C
for 6–12 h. The crude product was purified by flash chromatogra-
phy.
Yield: 5.44 g (70%); colorless oil; Rf = 0.18 (hexanes–EtOAc, 4:1).
1H NMR (400 MHz, CDCl3): d = 6.17 (dd, J = 5.6, 2.6 Hz, 1 H),
5.93 (dd, J = 5.6, 2.8 Hz, 1 H), 4.29 (br s, 1 H), 3.78 (dm, J = 7.5
Hz, 1 H), 3.00 (m, 1 H), 2.71 (br s, 1 H), 2.67 (br s, 1 H), 1.61 (dd,
J = 12.5, 7.9 Hz, 1 H), 1.40 (dt, J = 12.5, 2.7 Hz, 1 H), 1.19 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 136.1, 129.2, 86.2, 73.5, 70.2, 55.1,
45.7, 34.0, 28.2.
anti-7-tert-Butoxy-2-phenylnorbornadiene (21a) (Table 1, entry
12)
Synthesized according to general procedure A, using triflate 20
(65.8 mg, 0.211 mmol), THF (1.0 mL), phenylboronic acid (31.1
mg, 0.255 mmol), KF (46.5 mg, 0.801 mmol), Cy3P (5.0 mg, 0.018
mmol) and Pd(OAc)2 (2.5 mg, 0.011 mmol). The crude product was
purified by flash chromatography (hexanes–EtOAc, 19:1) to pro-
vide norbornadiene 21a.
HRMS: m/z calcd for C11H18O2: 182.1307; found: 182.1311.
anti-7-tert-Butoxybicyclo[2.2.1]hept-5-en-2-one (19)
DMSO (5.0 mL, 70.4 mmol) was added to a flame-dried flask con-
taining oxalyl chloride (3.2 mL, 36.6 mmol) and CH2Cl2 (50 mL) at
–78 °C (dry-ice/acetone bath). After 5 min, alcohol 17 (5.61 g, 30.7
mmol) in CH2Cl2 (30 mL) was added slowly to the reaction mixture
via a cannula. The reaction mixture was stirred at –78 °C for 30 min
then freshly distilled Et3N (20 mL, 144 mmol) was added to the re-
action mixture at –78 °C. The reaction was stirred at –78 °C for 15
min and at r.t. for 2 h. The reaction mixture was quenched with sat.
NH4Cl (100 mL), and the aqueous layer was extracted with Et2O
(3 × 100 mL). The combined organic layers were washed sequen-
tially with H2O (100 mL) and brine (100 mL), and dried over
MgSO4. The solvent was removed by rotary evaporation and the
crude product was purified by flash chromatography (hexanes–
EtOAc, 9:1) to provide ketone 19.
Yield: 45.6 mg (90%); white solid; Rf = 0.36 (hexanes–EtOAc,
19:1).
IR (neat): 3068, 2974, 2932, 1601, 1491, 1446, 1389, 1363, 1302,
1227, 1199, 1186, 1103 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.47–7.49 (m, 2 H), 7.34–7.42 (m,
2 H), 7.26–7.31 (m, 1 H), 6.88 (d, J = 3.1 Hz, 1 H), 6.77–6.78 (m,
1 H), 6.71–6.72 (m, 1 H), 4.04 (s, 1 H), 3.86 (br s, 1 H), 3.61 (br s,
1 H), 1.23 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 152.9, 137.7, 136.3, 135.7, 132.1,
128.5, 127.2, 124.7, 102.4, 73.8, 56.5, 56.2, 28.4.
HRMS: m/z [M + H]+ calcd for C17H21O: 241.1592; found:
241.1586.
Yield: 4.97 g (90%); colorless oil; Rf = 0.51 (hexanes–EtOAc, 9:1).
1H NMR (300 MHz, CDCl3): d = 6.50 (dd, J = 5.4, 2.6 Hz, 1 H),
5.97 (dd, J = 5.5, 2.9 Hz, 1 H), 4.23 (s, 1 H), 3.12–3.09 (m, 2 H),
2.07–1.93 (m, 2 H), 1.18 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 211.0, 139.3, 125.2, 89.5, 74.3,
62.6, 46.9, 38.1, 28.2.
HRMS: m/z [M + H]+ calcd for C11H17O2: 181.1229; found:
181.1223.
anti-7-tert-Butoxy-2-(4-methoxyphenyl)norbornadiene (21b)
(Table 1, entry 13)
Synthesized according to general procedure A, using triflate 20
(73.7 mg, 0.236 mmol), THF (1.0 mL), 4-methoxyphenylboronic
acid (43.4 mg, 0.286 mmol), KF (52.1 mg, 0.897 mmol), Cy3P (5.0
mg, 0.018 mmol) and Pd(OAc)2 (2.5 mg, 0.011 mmol). The crude
product was purified by flash chromatography (hexanes–EtOAc,
39:1) to provide norbornadiene 21b.
Yield: 54.9 mg (86%); white solid; Rf = 0.24 (hexanes–EtOAc,
39:1).
anti-7-tert-Butoxynorbornadien-2-yl Triflate (20)
KHMDS (0.5 M in toluene, 64.0 mL, 32.0 mmol) was added to a
flame-dried flask containing ketone 19 (3.83 g, 21.3 mmol) and
THF (100 mL) at –78 °C (dry-ice/acetone bath) under N2. The reac-
tion mixture was stirred at –78 °C for 3 h and at 0 °C for 15 min.
PhNTf2 (10.9 g, 31.9 mmol) dissolved in THF (20 mL) was added
via a cannula at 0 °C and the resulting mixture was stirred at 25 °C
for 12 h. The reaction mixture was quenched with sat. NaHCO3 (50
mL), the aqueous layer was extracted with Et2O (3 × 100 mL), and
1H NMR (300 MHz, CDCl3): d = 7.40–7.32 (m, 2 H), 6.92–6.83 (m,
2 H), 6.74–6.62 (m, 3 H), 3.96 (s, 1 H), 3.81 (s, 3 H), 3.76 (br s,
1 H), 3.52 (br s, 1 H), 1.17 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 159.0, 152.4, 137.9, 136.0, 129.6,
128.7, 125.9, 113.9, 102.2, 73.7, 56.6, 56.0, 55.3, 28.4.
HRMS: m/z calcd for C18H22O2: 270.1620; found: 270.1624.
Synthesis 2009, No. 4, 609–619 © Thieme Stuttgart · New York

616
G. C. Tsui et al.
PAPER
anti-7-tert-Butoxy-2-(4-acetylphenyl)norbornadiene (21c)
(Table 1, entry 14)
were washed with sat. NaHCO3, H2O and brine, dried over anhyd-
rous MgSO4, filtered, and concentrated using rotary evaporation.
The crude product was purified by column chromatography
(EtOAc–hexane) to give the product.
According to general procedure A, using triflate 20 (70.9 mg, 0.227
mmol), THF (1.0 mL), 4-acetoxyphenylboronic acid (42.7 mg,
0.260 mmol), KF (45.3 mg, 0.780 mmol), Cy3P (4.7 mg, 0.017
mmol) and Pd(OAc)2 (2.4 mg, 0.011 mmol). The crude product was
purified by flash chromatography (hexanes–EtOAc, 9:1) to provide
norbornadiene 21c.
anti-7-tert-Butoxy-2-cyclohexylnorbornadiene (21e) (Table 6,
entry 4)
Synthesized according to general procedure C, using triflate 20
(54.1 mg, 0.173 mmol), Fe(acac)3 (6.1 mg, 0.017 mmol), THF (0.24
mL), NMP (0.73 mL) and cyclohexylmagnesium chloride (1.71 M
in Et2O, 0.50 mL, 0.86 mmol). The crude product was purified by
column chromatography (hexanes–EtOAc, 49:1) to provide norbor-
nadiene 21e.
Yield: 54.1 mg (84%); yellow solid; Rf = 0.24 (hexanes–EtOAc,
9:1).
1H NMR (300 MHz, CDCl3): d = 7.96–7.87 (m, 2 H), 7.52–7.43 (m,
2 H), 7.02–6.96 (m, 1 H), 6.75–6.61 (m, 2 H), 3.98 (s, 1 H), 3.82 (br
s, 1 H), 3.59 (br s, 1 H), 2.59 (s, 3 H), 1.17 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 197.4, 152.1, 140.2, 137.5, 136.3,
135.7, 135.6, 128.7, 124.7, 102.6, 73.9, 56.5, 56.4, 28.3, 26.5.
Yield: 34.5 mg (81%); colorless oil; Rf = 0.46 (hexanes–EtOAc,
19:1).
IR (neat): 3070, 2974, 2929, 2872, 2860, 1617, 1466, 1362 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.53–6.59 (m, 2 H), 6.01–6.02 (m,
1 H), 3.72 (br s, 1 H), 3.31 (br s, 1 H), 3.22 (br s, 1 H), 2.04–2.10
(m, 1 H), 1.61–1.81 (m, 4 H), 1.13 (s, 9 H), 0.97–1.33 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 160.4, 138.1, 136.8, 128.4, 102.3,
73.4, 57.3, 54.9, 39.8, 31.1, 31.0, 28.3, 26.4, 26.11, 26.07.
HRMS: m/z calcd for C19H22O2: 282.1620; found: 282.1624.
anti-7-tert-Butoxy-2-phenylethynylnorbornadiene (21d)
(Scheme 5)
Inside an inert atmosphere (Ar) glove box, a solution of triflate 20
(50.2 mg, 0.161 mmol) in DMF (0.75 mL) was added using a pipette
to an oven-dried vial containing Pd(PPh3)4 (5.3 mg, 0.0048 mmol)
and CuI (7.5 mg, 0.039 mmol). Et3N (34 mL, 0.24 mmol) was then
added followed by phenyl acetylene (21 mL, 0.19 mmol). After the
vial was sealed with a screw cap, the reaction mixture was taken out
of the glove box and heated to 55 °C for 2.5 h. The crude product
was purified by flash chromatography (hexanes–EtOAc, 9:1) to
provide norbornadiene 21d.
HRMS: m/z [M + H]+ calcd for C17H27O: 247.2062; found:
247.2057.
anti-7-tert-Butoxy-2-cyclopropylnorbornadiene (21f) (Table 6,
entry 1)
Synthesized according to general procedure C, using triflate 20
(54.2 mg, 0.174 mmol), Fe(acac)3 (6.0 mg, 0.017 mmol), THF (0.23
mL), NMP (0.70 mL) and cyclopropylmagnesium bromide (0.5 M
in THF, 1.6 mL, 0.80 mmol). The crude product was purified by
column chromatography (hexanes–EtOAc, 19:1) to provide norbor-
nadiene 21f.
Yield: 32.1 mg (75%); colorless oil; Rf = 0.61 (hexanes–EtOAc,
9:1).
1H NMR (400 MHz, CDCl3): d = 7.37 (dd, J = 7.8, 1.8 Hz, 2 H),
7.24 (m, 1 H), 7.22 (d, J = 1.8 Hz, 2 H), 6.82 (dd, J = 3.6, 1.0 Hz,
1 H), 6.65–6.63 (m, 1 H), 6.51–6.49 (m, 1 H), 3.90 (s, 1 H), 3.47 (br
s, 1 H), 3.44 (br s, 1 H), 1.09 (s, 9 H).
Yield: 17.8 mg (50%); colorless oil; Rf = 0.33 (hexanes–EtOAc,
19:1).
13C NMR (100 MHz, CDCl3): d = 144.2, 136.8, 136.5, 134.6, 131.3,
1H NMR (400 MHz, CDCl3): d = 6.58 (dd, J = 4.9, 2.9 Hz, 1 H),
6.54 (dd, J = 4.9, 2.8 Hz, 1 H), 6.09 (d, J = 3.1 Hz, 1 H), 3.75 (s,
1 H), 3.32 (br s, 1 H), 2.94 (br s, 1 H), 1.60–1.53 (m, 1 H), 1.13 (s,
9 H), 0.71–0.65 (m, 2 H), 0.47–0.46 (m, 2 H).
128.3, 128.1, 123.4, 103.3, 96.1, 85.9, 74.0, 60.7, 56.3, 28.3.
HRMS: m/z calcd for C19H20O: 264.1514; found: 264.1517.
Preparation of Non-Commercially Available Grignard
Reagents: General Procedure B
13C NMR (75 MHz, CDCl3): d = 156.7, 138.3, 136.4, 128.9, 102.2,
73.4, 55.6, 55.1, 28.3, 12.2, 5.4, 4.6.
Cut pieces (2–3 mm) of freshly sanded Mg (3.0–4.5 equiv) were
added to an oven-dried flask that was subsequently equipped with a
condenser and purged with nitrogen. The total amount of Et2O em-
ployed in the Grignard preparation was 1.0 M with respect to the to-
tal amount of halide (1.0 equiv). Initially, sufficient Et2O was added
to barely cover the Mg pieces followed by a portion of the halide
(0.05–0.10 equiv) and a single crystal of iodine. The mixture was re-
fluxed without stirring for at least 10 min following the disappear-
ance of the iodine color. Half of the remaining Et2O was added to
the refluxing reaction and stirring was commenced, while the other
half of the Et2O was employed to dilute the remaining halide. The
dilute halide was added dropwise at a slow enough rate to result in
gentle refluxing. Following the addition, the reaction was refluxed
for 1.5–3.0 h before being titrated according to the literature30 and
employed in the Fe-catalyzed coupling reactions.
HRMS: m/z [M + H]+ calcd for C14H21O: 205.1592; found:
205.1596.
anti-7-tert-Butoxy-2-cyclobutylnorbornadiene (21g) (Table 6,
entry 2)
The Grignard reagent cyclobutylmagnesium chloride was prepared
according to general procedure B, with Mg (73.0 mg, 3.00 mmol),
Et2O (3.0 mL), I2 (one crystal) and cyclobutyl chloride (0.27 mL,
3.0 mmol). According to general procedure C, the freshly prepared
and titrated Grignard reagent (0.94 M, 2.66 mL) was added to a
mixture of triflate 20 (78.1 mg, 0.250 mmol), Fe(acac)3 (8.6 mg,
0.024 mmol), THF (0.23 mL) and NMP (0.76 mL). The crude prod-
uct was purified by column chromatography (hexanes–EtOAc,
49:1) to provide norbornadiene 21g.
Yield: 29.9 mg (55%); colorless oil; Rf = 0.31 (hexanes–EtOAc,
19:1).
Fe-Catalyzed Cross-Coupling Reactions (Table 6); General
Procedure C
IR (neat): 3069, 2974, 2865, 1561, 1472, 1388, 1362, 1226, 1200,
1179, 1100 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.58 (br s, 2 H), 6.04–6.05 (m,
1 H), 3.76 (s, 1 H), 3.33–3.34 (m, 1 H), 3.188–3.191 (m, 1 H), 3.10
(quin, J = 7.8 Hz, 1 H), 2.06–2.12 (m, 2 H), 1.77–1.95 (m, 4 H),
1.14 (s, 9 H).
To a solution of triflate 20 (1.0 equiv) in THF/NMP (1:3, 1.0 mL)
was added Fe(acac)3 (10 mol%) under nitrogen, and reaction mix-
ture was cooled to –25 °C. The Grignard reagent (5 equiv) was add-
ed dropwise and the reaction mixture was stirred at –25 °C for 30
min. The reaction was quenched with HCl (1 M, 1.0 mL) at –25 °C
and extracted with Et2O (3 × 2.0 mL). The combined organic layers
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Synthesis of anti-2,7-Disubstituted Norbornadienes
617
13C NMR (75 MHz, CDCl3): d = 158.9, 138.0, 136.6, 128.6, 102.5,
73.4, 56.9, 55.0, 36.7, 28.3, 26.9, 26.8, 18.4.
(hept, J = 6.8 Hz, 1 H), 1.14 (s, 9 H), 1.02 (d, J = 6.7 Hz, 3 H), 1.94
(d, J = 6.8 Hz, 3 H).
HRMS: m/z [M + H]+ calcd for C15H23O: 219.1749; found:
219.1755.
13C NMR (75 MHz, CDCl3): d = 161.4, 138.1, 136.7, 128.1, 102.3,
73.4, 57.3, 54.9, 30.1, 28.4, 20.5, 20.4.
HRMS: m/z [M + H]+ calcd for C14H23O: 207.1749; found:
207.1754.
anti-7-tert-Butoxy-2-cyclopentylnorbornadiene (21h) (Table 6,
entry 3)
Synthesized according to general procedure C, using triflate 20
(51.4 mg, 0.165 mmol), Fe(acac)3 (7.4 mg, 0.021 mmol), THF (0.23
mL), NMP (0.70 mL) and cyclopentylmagnesium chloride (1.65 M
in Et2O, 0.48 mL, 0.80 mmol). The crude product was purified by
column chromatography (hexanes–EtOAc, 49:1) to provide norbor-
nadiene 21h.
anti-7-tert-Butoxy-2-butylnorbornadiene (21k) (Table 6, entry
7)
The Grignard reagent n-butylmagnesium bromide was prepared ac-
cording to general procedure B, with Mg (80.3 mg, 3.31 mmol),
Et2O (3.0 mL), I2 (one crystal) and n-butyl bromide (0.50 mL, 4.73
mmol). According to general procedure C, the freshly prepared and
titrated Grignard reagent (1.1 M, 1.05 mL) was added to a mixture
of triflate 20 (55.3 mg, 0.177 mmol), Fe(acac)3 (6.1 mg, 0.017
mmol), THF (0.23 mL) and NMP (0.76 mL). The crude product was
purified by column chromatography (hexanes–EtOAc, 49:1) to pro-
vide norbornadiene 21k.
Yield: 26.2 mg (68%); colorless oil; Rf = 0.30 (hexanes–EtOAc,
19:1).
IR (neat): 3069, 2971, 2867, 1472, 1452, 1361, 1199, 1095 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.57–6.58 (m, 2 H), 6.02–6.04 (m,
1 H), 3.75 (s, 1 H), 3.30–3.32 (m, 1 H), 3.17–3.18 (m, 1 H), 2.62
(quin, J = 7.6 Hz, 1 H), 1.51–1.67 (m, 4 H), 1.20–1.41 (m, 4 H),
1.14 (s, 9 H).
Yield: 25.2 mg (65%); colorless oil; Rf = 0.41 (hexanes–EtOAc,
19:1).
IR (neat): 3070, 2974, 2929, 2872, 1466, 1362, 1226, 1180, 1120
cm–1.
1H NMR (400 MHz, CDCl3): d = 6.58 (br s, 2 H), 6.04–6.06 (m,
1 H), 3.78 (s, 1 H), 3.30–3.32 (m, 1 H), 3.13–3.14 (m, 1 H), 2.15–
2.20 (m, 2 H), 1.35–1.42 (m, 2 H), 1.26–1.33 (m, 2 H), 1.14 (s,
9 H), 0.89 (t, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 155.5, 138.0, 136.6, 130.1, 102.5,
73.4, 58.6, 55.2, 31.4, 29.5, 28.4, 22.4, 13.9.
HRMS: m/z [M + H]+ calcd for C15H25O: 221.1905; found:
221.1910.
13C NMR (75 MHz, CDCl3): d = 158.9, 138.0, 136.7, 128.5, 103.4,
73.4, 57.7, 54.9, 41.6, 30.7, 30.4, 28.4, 25.2, 25.1.
HRMS: m/z [M + H]+ calcd for C16H25O: 233.1905; found:
233.1910.
anti-7-tert-Butoxy-2-cycloheptylnorbornadiene (21i) (Table 6,
entry 5)
The Grignard reagent cycloheptylmagnesium chloride was pre-
pared according to general procedure B, with Mg (83.3 mg, 3.42
mmol), Et2O (3.0 mL), I2 (one crystal) and cycloheptyl bromide
(0.45 mL, 3.3 mmol). According to general procedure C, the freshly
prepared and titrated Grignard reagent (0.89 M, 2.18 mL) was add-
ed to a mixture of triflate 20 (56.7 mg, 0.182 mmol), Fe(acac)3 (8.3
mg, 0.023 mmol), THF (0.23 mL) and NMP (0.76 mL). The crude
product was purified by column chromatography (hexanes–EtOAc,
49:1) to provide norbornadiene 21i.
anti-7-tert-Butoxy-2-sec-butylnorbornadiene (21l) (Table 6,
entry 8)
Synthesized according to general procedure C, using triflate 20
(50.1 mg, 0.160 mmol), Fe(acac)3 (6.8 mg, 0.019 mmol), THF (0.23
mL), NMP (0.70 mL) and sec-butylmagnesium chloride (1.91 M in
Et2O, 0.42 mL, 0.80 mmol). The crude product was purified by col-
umn chromatography (hexanes–EtOAc, 49:1) to provide norborna-
diene 21l as an inseparable ~1:1 mixture of two diastereoisomers.
Yield: 31.2 mg (66%); colorless oil; Rf = 0.31 (hexanes–EtOAc,
19:1).
IR (neat): 3070, 297, 2929, 2872, 1562, 1466, 1388, 1362, 1226,
1200, 1180, 1099 cm–1.
Yield: 19.3 mg (55%); colorless oil; Rf = 0.23 (hexanes–EtOAc,
19:1).
1H NMR (400 MHz, CDCl3): d = 6.55–6.58 (m, 2 H), 5.98–5.99 (m,
1 H), 3.73 (s, 1 H), 3.30–3.33 (m, 1 H), 3.176–3.179 (m, 1 H), 2.62–
2.31 (m, 1 H), 1.21–1.79 (m, 12 H), 1.13 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 161.0, 137.9, 136.8, 127.8, 102.2,
73.4, 57.8, 54.8, 41.7, 32.5, 32.3, 28.4, 28.23, 28.18, 26.5 (×2).
IR (neat): 2971, 2931, 2872, 1458, 1362, 1179 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.54–6.58 (m, 2 H), 6.03–6.05 (m,
1 H), 3.75 (s, 0.5 H), 3.74 (s, 0.5 H), 3.31–3.32 (m, 1 H), 3.21 (br s,
0.5 H), 3.19 (br s, 0.5 H), 2.18–2.29 (m, 1 H), 1.39–1.50 (m, 1 H),
1.20–1.36 (m, 1 H), 1.14 (s, 9 H), 0.98 (d, J = 6.9 Hz, 1.5 H), 0.96
(d, J = 6.8 Hz, 1.5 H), 0.82 (t, J = 7.4 Hz, 1.5 H), 0.80 (t, J = 7.4 Hz,
1.5 H).
HRMS: m/z [M + H]+ calcd for C18H29O: 261.2218; found:
261.2222.
anti-7-tert-Butoxy-2-isopropylnorbornadiene (21j) (Table 6,
entry 6)
13C NMR (75 MHz, CDCl3): d = 159.9, 159.7, 137.9, 137.8, 136.8,
129.5, 129.3, 102.4, 102.2, 73.4, 56.9, 56.6, 55.0, 54.9, 37.1, 37.0,
28.4, 27.5, 18.4, 17.6, 11.8, 11.6.
HRMS: m/z [M + H]+ calcd for C15H25O: 221.1905; found:
221.1908.
Synthesized according to general procedure C, using triflate 20
(56.2 mg, 0.180 mmol), Fe(acac)3 (6.4 mg, 0.0176 mmol), THF
(0.25 mL), NMP (0.70 mL) and isopropylmagnesium chloride (1.76
M in THF, 0.50 mL, 0.88 mmol). The crude product was purified by
column chromatography (hexanes–EtOAc, 49:1) to provide norbor-
nadiene 21j.
anti-7-tert-Butoxy-2-tert-butylnorbornadiene (21m) (Table 6,
entry 9)
Yield: 27.8 mg (75%); colorless oil; Rf = 0.38 (hexanes–EtOAc,
19:1).
Synthesized according to general procedure C, using triflate 20
(93.0 mg, 0.298 mmol), Fe(acac)3 (10.5 mg, 0.0298 mmol), THF
(0.46 mL), NMP (1.4 mL) and tert-butylmagnesium chloride (0.77
M in THF, 1.95 mL, 1.5 mmol). The crude product was purified by
column chromatography (hexanes–EtOAc, 49:1) to provide norbor-
nadiene 21m.
IR (neat): 3070, 2972, 2933, 2869, 1461, 1388, 1362, 1199, 1180,
1101 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.57–6.58 (m, 2 H), 6.01–6.03 (m,
1 H), 3.73 (s, 1 H), 3.30–3.33 (m, 1 H), 3.20–3.24 (m, 1 H), 2.42
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618
G. C. Tsui et al.
PAPER
Yield: 32.7 mg (50%); colorless oil; Rf = 0.31 (hexanes–EtOAc,
19:1).
(0.93 M in THF, 0.91 mL, 0.85 mmol). The crude product was pu-
rified by column chromatography (hexanes–EtOAc, 49:1) to pro-
vide norbornadiene 21d.
IR (neat): 3057, 2962, 2870, 1723, 1681, 1598, 1494, 1448, 1301,
1278, 1222 cm–1.
Yield: 26.1 mg (60%); colorless oil; Rf = 0.61 (hexanes–EtOAc,
9:1).
1H NMR (400 MHz, CDCl3): d = 6.56–6.57 (m, 2 H), 5.99–6.00 (m,
1 H), 3.69 (br s, 1 H), 3.30–3.33 (m, 2 H), 1.14 (s, 9 H), 1.02 (s,
9 H).
1H NMR (400 MHz, CDCl3): d = 7.37 (dd, J = 7.8, 1.8 Hz, 2 H),
7.24 (m, 1 H), 7.22 (d, J = 1.8 Hz, 2 H), 6.82 (dd, J = 3.6, 1.0 Hz,
1 H), 6.65–6.63 (m, 1 H), 6.51–6.49 (m, 1 H), 3.90 (s, 1 H), 3.47 (br
s, 1 H), 3.44 (br s, 1 H), 1.09 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 144.2, 136.8, 136.5, 134.6, 131.3,
128.3, 128.1, 123.4, 103.3, 96.1, 85.9, 74.0, 60.7, 56.3, 28.3.
13C NMR (100 MHz, CDCl3): d = 164.3, 137.9, 136.9, 127.0, 102.1,
73.3, 55.9, 54.7, 32.8, 28.3, 28.0.
HRMS: m/z [M + H]+ calcd for C15H25O: 221.1905; found:
221.1911.
HRMS: m/z calcd for C19H20O: 264.1514; found: 264.1517.
anti-7-tert-Butoxy-2-vinylnorbornadiene (21n) (Table 6, entry
10)
7-tert-Butoxynorbornadiene Dimers (23a and 23b) (Table 6,
entries 2, 7–9)
Synthesized according to general procedure C, the undesired homo-
coupling side product 7-tert-butoxynorbornadiene dimers (23a and
23b, ~1:1) were obtained as a white solid in 5–10% yield.
Synthesized according to general procedure C, using triflate 20
(37.8 mg, 0.121 mmol), Fe(acac)3 (4.7 mg, 0.0136 mmol), THF
(0.23 mL), NMP (0.70 mL) and vinylmagnesium bromide (0.83 M
in THF, 0.78 mL, 0.65 mmol). The crude product was purified by
column chromatography (hexanes–EtOAc, 49:1) to provide norbor-
nadiene 21n.
Mp 145–147 °C; Rf = 0.14 (hexanes–EtOAc, 19:1).
IR (neat): 2964, 2876, 1689, 1448, 1331, 1167, 1127, 1074 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.65–6.67 (m, 1 H), 6.61–6.63 (m,
1 H), 6.53 (s, 2 H), 6.31–6.34 (m, 2 H), 3.91 (s, 1 H), 3.79 (s, 1 H),
3.43–3.44 (m, 3 H), 3.40 (s, 1 H), 1.16 (s, 9 H), 1.12 (s, 9 H).
Yield: 15.0 mg (65%); colorless oil; Rf = 0.43 (hexanes–EtOAc,
19:1).
IR (neat): 3071, 2975, 2934, 2872, 1623, 1389, 1362, 1200, 1183,
1101 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.61–6.64 (m, 1 H), 6.56–6.58 (m,
1 H), 6.48 (dd, J = 17.4, 10.6 Hz, 1 H), 6.38 (d, J = 3.2 Hz, 1 H),
5.24 (d, J = 17.3 Hz, 1 H), 5.06 (d, J = 10.5 Hz, 1 H), 3.85 (s, 1 H),
3.59 (br s, 1 H), 3.43 (br s, 1 H), 1.15 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 149.5, 149.3, 137.9, 137.8, 136.2,
136.1, 130.3, 130.2, 101.9, 73.7, 55.9, 55.8, 55.7, 55.5, 28.4.
HRMS: m/z calcd for C22H30O2: 326.2246; found: 326.2243.
13C NMR (100 MHz, CDCl3): d = 152.6, 137.7, 136.1, 135.9, 132.4,
112.4, 102.2, 73.7, 55.8, 54.0, 28.4.
Acknowledgment
This work was supported by the Merck Frosst Centre for Therapeu-
tic Research, Natural Sciences and Engineering Research Council
of Canada (NSERC), and Boehringer Ingelheim (Canada) Ltd. P.L.
and A.A. thank NSERC for providing postgraduate scholarships
(PGS M and CGS M).
HRMS: m/z [M + H]+ calcd for C13H19O: 191.1436; found:
191.1433.
anti-7-tert-Butoxy-2-phenylnorbornadiene (21a) (Table 6, entry
11)
Synthesized according to general procedure C, using triflate 20
(51.5 mg, 0.165 mmol), Fe(acac)3 (6.3 mg, 0.018 mmol), THF (0.23
mL), NMP (0.76 mL) and phenylmagnesium bromide (0.95 M in
THF, 0.93 mL, 0.88 mmol). The crude product was purified by col-
umn chromatography (hexanes–EtOAc, 49:1) to provide norborna-
diene 21a.
References
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Yield: 30.1 mg (76%); colorless oil; Rf = 0.36 (hexanes–EtOAc,
19:1).
IR (neat): 3068, 2974, 2932, 1601, 1491, 1446, 1389, 1363, 1302,
1227, 1199, 1186, 1103 cm–1.
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anti-7-tert-Butoxy-2-phenylethynylnorbornadiene (21d) (Table
6, entry 12)
Synthesized according to general procedure C, using triflate 20
(50.5 mg, 0.162 mmol), Fe(acac)3 (6.2 mg, 0.018 mmol), THF (0.23
mL), NMP (0.76 mL) and phenylacetylenemagnesium bromide
Synthesis 2009, No. 4, 609–619 © Thieme Stuttgart · New York

PAPER
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Synthesis of anti-2,7-Disubstituted Norbornadienes
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Synthesis 2009, No. 4, 609–619 © Thieme Stuttgart · New York