Nickel-catalyzed cycloisomerization of enynes: catalyst generation via C-H activation of carbene ligands

Article abstract of DOI:10.1016/j.tet.2008.03.071

The combination of Ni(0) and an N-heterocyclic carbene acts as a precatalyst for the cycloisomerization of enynes to afford 1,3-dienes. During the course of the reaction, a nickel hydride is formed from oxidative addition of the ortho C-H on the carbene ligand. Deuterium labeling studies are presented. Crown Copyright

Full text of DOI:10.1016/j.tet.2008.03.071

Tetrahedron 64 (2008) 6870–6875
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Nickel-catalyzed cycloisomerization of enynes: catalyst generation
via C–H activation of carbene ligands
y
*
Thomas N. Tekavec , Janis Louie
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, UT 84112-0850, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The combination of Ni(0) and an N-heterocyclic carbene acts as a precatalyst for the cycloisomerization
of enynes to afford 1,3-dienes. During the course of the reaction, a nickel hydride is formed from oxi-
dative addition of the ortho C–H on the carbene ligand. Deuterium labeling studies are presented.
Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
Received 15 January 2008
Received in revised form 17 March 2008
Accepted 19 March 2008
Available online 22 March 2008
Table 1
1. Introduction
Ligand screening for enyne cycloisomerizationa
During the development of Ni/NHC (NHC¼N-heterocyclic car-
bene) catalyst systems for various cycloaddition reactions,1 we
found that the Ni(COD)2/NHC system was capable of catalyzing the
cycloisomerization of enyne 1 to diene 2 (Eq. 1). While this reaction
is typically performed with ‘noble’ metals (Pd, Ru, Rh, Ir),2 we were
intrigued with the possibility of accessing the highly versatile 1,3-
diene with a more economical Ni catalyst.3 As a key component of
the Diels–Alder reaction, 1,3-dienes of varying complexity are
important compounds.4 We now report the combination of Ni and
an NHC ligand catalyzes the cycloisomerization of enynes. We also
present evidence that suggests that catalyst generation occurs
through C–H activation of the bound NHC ligand.
Entry
NHC
Conversionb
(%) of 1
Yieldb
(%) of 2
1
2
3
4
5
6
7
8
IDTB
IPr
IMes
SIDTB
SIPr
26
38
52
13
40
52
100
100
30
20
20
0
0
0
SIMes
IAd
0
0
IiBu
a
Reaction conditions: 5 mol % NI(COD)2, 10 mol % NHC, 0.1 M 1, rt.
Uncorrected GC yield based on naphthalene internal standard.
b
optimization with IDTB led to general reaction conditions that
employed 5 mol % Ni(COD)2, 10 mol % IDTB, and enyne concentra-
tions of 0.1 M in toluene at 60 ꢀC (Table 2).
2. Results and discussion
Initially, we discovered the formation of moderate amounts of 2
as a side product in Ni/IPr catalyzed cycloadditions of 1 and
ketones.1e Furthermore, reactions run with 1 alone led to relatively
clean conversion to 2. In an effort to further enhance yields, a series
of NHC ligands in combination with Ni(COD)2 were evaluated
for catalytic activity in the cycloisomerization of 1 (Table 1).5 In-
terestingly, 1,3-diene (2) formation was only observed in reactions
involving N-aryl-imidazol-2-ylidene ligands (entries 1–3). IDTB
gave the best yield-to-conversion ratio (entry 1). Reactions run
with the saturated NHC analogs failed to produce any of the desired
product (entries 4–6). Although reactions with N-alkyl ligands
displayed high enyne conversions, only substrate oligomerization
occurred6 and no 1,3-diene was obtained. Ultimately, further
E
5 mol% Ni(COD)2
10 mol% NHC
E
E
E
E
E
toluene, rt
ð1Þ
E
E
1 E = CO2Et
2
A cursory examination of the substrate scope under optimized
conditions showed that a variety of enynes participated in the re-
action. Substituent groups at the terminal position of the alkyne of
varying lengths were tolerated well as Me, Et, and nPr substituted
enynes (Table 2, entry 1) produced the corresponding dienes in ex-
cellent yields. The reaction of a more sterically demanding substrate
i
such as the Pr substituted enyne (7) also gave excellent diene for-
mation. The synthesisof a five-membered ring was also successful as
demonstrated by the formation of 9 in good yield (entry 2).
Based on the previously reported Pd catalyzed process, two
general mechanisms for cycloisomerization are depicted in
* Corresponding author. Tel.: þ1 801 581 7309; fax: þ1 801 581 8433.
E-mail address: louie@chem.utah.edu (J. Louie).
Present address: Nalco Energy Services LP.
y
0040-4020/$ – see front matter Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.071

T.N. Tekavec, J. Louie / Tetrahedron 64 (2008) 6870–6875
6871
Table 2
10 mol% Ni(COD)2
20 mol%
Scope of enyne cycloisomerizationa
t-Bu
t-Bu
E'
E'
E'
Entry
Enyne
Product
Yieldb,c
(%)
E'
E'
N
N
E'
E'
D
D
ð2Þ
IDTB
toluene, 60 °C
t-Bu
t-Bu
E'
EtO2C
EtO2C
EtO2C
EtO2C
1-d
2-d
1
1
95% D incorporation
80% D incorporation
65% yield
R
1
2
1 R¼Me
3 R¼Et
5 R¼nPr
7 R¼iPr
2
4
6
8
90
92
97
99
It seemed likely that protium incorporation in 2-d1 arose from
the formation of a reactive Ni–H species (mechanism B). It was
possible that this species could originate from solvent activation.
However, reactions run with enyne 1 in deuterated toluene showed
no deuterium incorporation. Furthermore, the cycloisomerizations
are unaffected by protic additives, unlike many notable Pd cata-
lyzed enyne rearrangement reactions.3 For example, the addition of
water (either H2O or D2O) had no effect on protium incorporation.
An alternative route to a Ni–H species is the orthometalation of
the pendant NHC ligand (Scheme 2). Yet unlike the orthometalation
of Pd complexes to form Pd–H species,9,10 C–H oxidative addition
by Ni-complexes is rare.11,12 Nevertheless, when super stoichio-
metric amounts of Ni/IDTB were employed (200 mol % Ni(COD)2
and 400 mol % IDTB), a protium incorporation of 50% was observed
in the 1,3-diene product 2-d1.13 Thus, an increase in ligand (and
in catalyst) did indeed facilitate an increase in hydrogen
incorporation.
MeO2C
MeO2C
10
82
9
a
b
c
Reaction conditions: 5 mol % Ni(COD)2, 10 mol % IDTB, 0.1 M 1, 60 ꢀC, 1 h.
Isolated yield, average of two runs.
E/Z (>95:5) based on 1H NMR analysis of crude reaction mixture.
Scheme 1.2c In mechanism A, the enyne undergoes oxidative cou-
pling with the Ni0 catalyst to generate a metallacyclopentene. This
metallacyclopentene undergoes b-hydride elimination to generate
a vinyl nickel hydride. The vinyl nickel hydride then reductively
eliminates to yield the observed 1,3-diene. Alternatively, in mech-
anism B, the alkyne component of the enyne undergoes hydro-
metalation with a Ni–H complex to generate a vinyl nickel species.
The pendant olefin then inserts into the vinyl nickel bond thereby
forming an alkyl nickel species. b-Hydride elimination and
reductive elimination affords the observed 1,3-diene.
5 mol% Ni(COD)2
10 mol%
t-Bu
t-Bu
E'
E'
E'
E'
N
N
E'
E'
E'
E'
ð3Þ
D
D
D
D
IDTB-d
t-Bu
t-Bu
4
toluene, 60 °C
1
2
37%
H
Ni0
H
t-Bu
t-Bu
t-Bu
t-Bu
N
N
N
N
Ni0
NiII
H
t-Bu
t-Bu
Scheme 2. C–H activation of Ni/carbene complex.
t-Bu
t-Bu
Ni
H
Ni
H
H
Additionally, we reasoned that if orthometalation of the NHC
ligand was operative,14 then replacing the IDTB ligand with its
deuterium labeled analog IDTB-d4 would have a profound affect on
the cycloisomerization reaction.15 The IDTB-d4 ligand was prepared
(>95% D incorporation) and evaluated as a ligand in Ni/NHC cata-
lyzed reactions. Importantly, no difference in yields was observed
between IDTB and IDTB-d4 when either of these ligands was
employed in our other [2þ2þ2] cycloaddition reactions (98 vs 96%,
respectively),1 suggesting that deuteration of the IDTB has a neg-
ligible effect on the steric and electronic properties of the NHC
ligand.16 In contrast, severely depressed yields were obtained in the
cycloisomerization of 2 run under otherwise identical conditions
(90% yield with IDTB vs 37% with IDTB-d4, Eq. 3).17 In addition,
subjecting 1-d1 to the Ni(0)/IDTB-d4 catalyst afforded 2-d1 in only
21% yield.
IDTB-d4 possesses a stronger Caryl–D bond relative to the Caryl–H
bond in IDTB.18 As such, generation of Ni–D is more difficult with
IDTB-d4 than generation of Ni–H from IDTB. Yet, in reactions
employing IDTB-d4, Ni–H can be formed, though in significantly
lower concentrations than in IDTB reactions (Scheme 3). Thus, in
a competition between diene formation, which is Ni–H catalyzed,
and oligomerization, which is Ni(0) catalyzed, lower Ni–H con-
centrations would lead to a diminished yield of 1a as observed in
Eq. 3. A similar yet less pronounced phenomenon is observed in
the Ni/IDTB catalyzed cycloisomerization of 1-d1. Moreover, the
Mechanism A
NiII
H
H
H
H
H
Ni
H
Ni
Mechanism B
Scheme 1. Proposed mechanisms for cycloisomerization.
In an effort to differentiate between the mechanisms proposed
in Scheme 1, the reaction of enyne 1-d1 (95% deuterium in-
corporation) was evaluated. If diene formation occurred through
mechanism A, no deuterium washing would be observed since the
deuterium would be shifted from the olefin to the alkyne of the
same molecule. Conversely, if diene product was formed through
mechanism B, any protium in the product would come from
a source other than the substrate. The reaction of enyne 1-d1 pro-
duced diene 2-d1 in 65% isolated yield (Eq. 2).7 However, only 80%
deuterium was incorporated in the product, which immediately
suggested that mechanism A was not the operative pathway.8

6872
T.N. Tekavec, J. Louie / Tetrahedron 64 (2008) 6870–6875
Ni/IDTB-d4 catalyzed reaction of 1-d1 is even more difficult than the
parent cycloisomerization (i.e., Eq. 1) and only a fraction of the
product yield is observed.
conditions: initial oven temperature: 100 ꢀC; temperature ramp
rate 50 ꢀC/min; final temperature: 300 ꢀC held for 7 min; detector
temperature: 250 ꢀC.
O
H
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
NH2
H
t-Bu
t-Bu
N
N
N
N
O
D
D
D
D
N
N
D
D
Ni0
D
NiII
cat. formic acid
t-Bu
t-Bu
t-Bu
t-Bu
D
t-Bu
11
t-Bu
t-Bu
t-Bu
O
H
t-Bu
D
H
H
n
N
N
Cl
HCl
H
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
N
N
N
N
D
D
D
12
D
D
D
Ni0
H
NiII
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
H
t
KO Bu
N
N
Scheme 3. Regeneration of a Ni–H from Ni(IDTB-d4).
t-Bu
t-Bu
IDTB
13
3. Conclusion
The combination of Ni(COD)2 and IDTB catalyzes the cyclo-
isomerization of enynes to synthetically valuable cyclic 1,3-dienes.
Deuterium labeling studies suggest that the active catalyst species
is a Ni–H species, which is generated via a rare Ni(0) C–H activation.
More extensive mechanistic studies are currently underway.
4.2. Preparation of (N,N0E,N,N0E)-N,N0-(ethane-1,2-diylidene)-
bis(2,5-di-tert-butylaniline) (11)
To a stirring solution of 2,5-di-tert-butyl aniline (13.95 g,
68 mmol) in 130 mL EtOH were added glyoxal (3.9 mL 34 mmol)
and four drops of formic acid. The resulting yellow solution was
stirred at room temperature for 2 h at which time a yellow pre-
cipitate formed. The mixture was stirred for an additional 12 h and
then cooled to ꢁ78 ꢀC. The cold mixture was then quickly filtered
and the collected yellow solids were washed with cold MeOH
(ꢁ78 ꢀC) until the filtrate ran clear. The yellow solid was dried in
vacuo to yield 11 (12.21 g, 83%). Mp: 186 ꢀC. 1H NMR (500 MHz,
CDCl3): d (ppm) 8.28 (s, 2H), 7.36 (d, J¼8.3 Hz, 2H), 7.26 (dd,
J1¼2.0 Hz, J2¼8.3 Hz), 6.87 (d, J¼2.0 Hz), 1.44 (s, 18H), 1.36 (s, 18H).
13C {1H} NMR (125 MHz, CDCl3): d (ppm) 158.8, 150.3, 150.2, 140.7,
126.2, 124.0, 116.2, 35.5, 34.7, 31.6, 30.7. IR (neat): 2959, 2872, 1608,
1554, 1262, 926, 880, 827 cmꢁ1. HRMS (FAB): calcd for C30H44N2
(Mþ) 432.3504, obsd 432.3468.
4. Experimental
4.1. General information
All reactions were conducted under an atmosphere of N2 using
standard Schlenk techniques or in an N2 filled glove box unless
otherwise noted. Toluene was dried over neutral alumina under N2
using a Grubbs type solvent purification system. THF was freshly
distilled from Na/benzophenone. Ni(COD)2 was purchased from
Strem and used without further purification. The IPr, SIPr, IMes,
SIMes, IAd, and ItBu ligands were prepared as previously reported.19
Sodium hydride was thoroughly washed with pentane and dried in
vacuo prior to use. The compounds 1-bromo-4-methylpentyne and
1-bromo-2-hexyne were prepared from the corresponding alcohols
by the method described by Brandsma.20 Enynes 1, 3, 5, 7, and 91e,21
as well as vinyl bromide 1422 and alkyne 171e were prepared by
known literature procedures. Glyoxal was purchased from Aldrich
Chemical Company as a 40 wt % solution in water. All other reagents
were purchased and used without further purification unless
otherwise noted.
4.3. Preparation of 1,3-bis(2,5-di-tert-butylphenyl)-1H-
imidazol-3-ium chloride (12)
A stirring suspension of bisimine 11 (6.43 g, 14.88 mmol) and
paraformaldehyde (447.0 mg, 14.88 mmol) in toluene (35 mL) was
heated at 80 ꢀC for 1 h. The solution was then cooled to room
temperature and HCl (5.6 mL, 22.3 mmol, 4 M in dioxane) was
added dropwise at a rate such that the previous drop had fully
dispersed before addition of the next drop. The resulting dark red/
brown solution was stirred at room temperature for 8 h and then
filtered. The collected solids were washed with cold THF (ꢁ78 ꢀC)
until the filtrate ran clear. The tan solid was further purified by
dissolving the solid in hot acetone and reprecipitating it by the
addition of hexanes. The beige solids were collected by vacuum
filtration, washed with Et2O (30 mL), and dried in vacuo to yield
crude imidazolium salt 12 (2.51 g, 35%). HRMS (FAB): calcd for
1H and 13C nuclear magnetic resonance spectra of pure com-
pounds were acquired at 500 and 125 MHz, respectively, unless
otherwise noted. All spectra are referenced to a singlet at 7.27 ppm
for 1H and to the center line of a triplet at 77.23 ppm for 13C. The
abbreviations s, d, dd, dt, dq, t, td, tq, q, qt, quint, sept, septd, septt,
m, br m, br d, br t, and br s stand for singlet, doublet, doublet of
doublets, doublet of triplets, doublet of quartets, triplet, triplet of
doublets, triplet of quartets, quartet, quartet of triplets, quintet,
septet, septet of doublets, septet of triplets, multiplet, broad mul-
tiplet, broad doublet, broad triplet, and broad singlet, in that order.
All 13C NMR spectra were proton decoupled. IR spectra were
recorded on a Bruker Tensor 27 FT-IR spectrometer. HRMS were
performed at the mass spectrometry facility at The University of
Utah.
C
31H45N2 (Mþ) 445.3583, obsd 445.3587.
4.4. Preparation of IDTB (13)
Gas chromatographies were performed on an Agilent 6890 gas
chomatograph with a 30 m HP-5 column using the following
In a glove box, imidazolium salt 7 (534.1 mg, 1.11 mmol) and
KOtBu (186.9 mg, 1.67 mmol) were weighed into a vial and

T.N. Tekavec, J. Louie / Tetrahedron 64 (2008) 6870–6875
6873
suspended in toluene (4 mL). The resulting suspension was stirred
at room temperature for 4 h and the solvent was removed in vacuo.
The solids were then suspended in 2 mL toluene and the excess
salts were precipitated by the addition of 7 mL pentane. The mix-
ture was then vacuum filtered and the collected solids were sub-
jected to the suspension, precipitation, filtration sequence two
more times. The collected filtrate was concentrated in vacuo to
yield IDTB as a beige solid (412.4 mg 84%). Analytically pure sample
could be obtained by cooling a saturated solution of IDTB in Et2O to
ꢁ40 ꢀC. Mp: decomp. 206 ꢀC. 1H NMR (500 MHz, C6D6): d 7.47 (d,
J¼8.3 Hz, 2H), 7.38 (d, J¼2.0 Hz), 7.27 (dd, J1¼2.0 Hz, J2¼8.3 Hz, 2H),
6.77 (s, 2H), 1.47 (s, 18H), 1.16 (s, 18H). 13C {1H} NMR (125 MHz,
C6D6): d (ppm) 221.4, 149.9, 144.0, 142.5, 129.0, 125.8, 123.0, 36.3,
34.5, 32.6, 31.5. HRMS (EI): calcd for C31H44N2 (MHþ) 445.3583,
obsd 445.3580.
cross-peaks were observed: H(4) with H(1) and H(3), H(5) with
H(6) and H(2), H(6) with H(5) and H(2). NOE summary: the fol-
lowing pertinent enhancements were observed: irradiation of H(4)
showed enhancement of H(3) and H(5); irradiation of H(5) showed
enhancement of H(4); irradiation of H(1) showed enhancement of
H(3); irradiation of H(3) showed enhancement of H(1).
4.8. Preparation of (E)-tetraethyl 4-butylidene-5-
methylenecyclohexane-1,1,2,2-tetracarboxylate (6)
The general procedure was used with enyne 5 (150.0 mg,
0.342 mmol), Ni(COD)2 (4.7 mg, 0.017 mmol), IDTB (15.2 mg,
0.0342 mmol), and 3.42 mL toluene. The reaction mixture was
purified by flash column chromatography on SiO2 eluting with 10%
EtOAc/hexanes to yield diene 4a (147.6 mg, 98%) as a sticky, pale
yellow oil. 1H NMR (500 MHz, CDCl3): d (ppm) 5.68 (t, J¼7.32 Hz,
1H), 5.02 (br s, 1H), 4.66 (br s, 1H), 4.27–4.16 (m, 8H), 3.05 (s, 2H),
2.97 (s, 2H), 2.06 (q, J¼7.32 Hz, 2H), 1.40 (sext, J¼7.32 Hz, 2H), 1.31–
1.23 (m, 12H), 0.92 (t, J¼7.32 Hz, 3H). 13C {1H} NMR (125 MHz,
CDCl3): d (ppm) 169.8, 169.7, 144.7, 133.8, 127.3, 110.4, 61.9, 61.7,
59.4, 59.3, 38.1, 32.0, 29.8, 22.9, 14.1, 14.008, 13.997. IR (neat): 2982,
2934, 2873, 1738, 1367, 1266, 1159, 1040, 865 cmꢁ1. HRMS (CI):
calcd for C23H35O8 (MHþ) 439.2332, obsd 439.2350. COSY sum-
mary: the following pertinent cross-peaks were observed: H(4)
with H(1) and H(3), H(5) with H(6) and H(2), H(6) with H(5) and
H(2). NOE summary: the following pertinent enhancements were
observed: irradiation of H(4) showed enhancement of H(3) and
H(5); irradiation of H(5) showed enhancement of H(4); irradiation
of H(1) showed enhancement of H(3); irradiation of H(3) showed
enhancement of H(1).
4.5. General procedure for the cycloisomerization of enynes
To a stirring solution of enyne in toluene (w0.4 M) at 60 ꢀC
was added the catalyst solution (Ni(COD)2 and IDTB, which was
previously equilibrated for at least 8 h at room temperature at a
concentration of w0.04 M). The resulting solution was stirred for
1 h at 60 ꢀC, cooled to room temperature, and quenched with the
addition of MeOH (0.5 mL). The crude mixture was then concen-
trated in vacuo and the residue was purified by flash column
chromatography on SiO2 to yield the 1,3-diene.
4.6. Preparation of (E)-tetraethyl 4-ethylidene-5-methylene-
cyclohexane-1,1,2,2-tetracarboxylate (2)
The general procedure was used with enyne 1 (200.0 mg,
0.4873 mmol), Ni(COD)2 (6.7 mg, 0.0244 mmol), IDTB (21.7 mg,
0.0588 mmol), and 4.87 mL toluene. The reaction mixture was
purified by flash column chromatography on SiO2 eluting with 10%
EtOAc/hexanes to yield diene 2 (191.2 mg, 96%) as a sticky, pale
yellow oil. 1H NMR (500 MHz, CDCl3): d (ppm) 5.75 (q, J¼6.83 Hz,
1H), 5.00 (br s, 1H), 4.66 (br s, 1H), 4.27–4.16 (m, 8H), 3.07 (s, 2H),
2.94 (s, 2H), 1.68 (d, J¼6.83, 3H), 1.27 (app. td, 12H). 13C {1H} NMR
(125 MHz, CDCl3): d (ppm) 169.9, 169.7, 144.7, 134.7, 121.4, 110.3,
61.9, 61.7, 59.6, 59.2, 38.1, 31.6, 14.0, 13.4. IR (neat): 2983, 2938,
2907, 1738, 1300, 1266, 1202, 1042, 865 cmꢁ1. HRMS (CI): calcd for
4.9. Preparation of (E)-tetraethyl 4-methylene-5-(2-methyl-
propylidene)cyclohexane-1,1,2,2-tetracarboxylate (8)
The general procedure was used with enyne 7 (150.0 mg,
0.342 mmol), Ni(COD)2 (4.7 mg, 0.0171 mmol), IDTB (15.2 mg,
0.0342 mmol), and 3.42 mL toluene. The reaction mixture was
purified by flash column chromatography on SiO2 eluting with 10%
EtOAc/hexanes to yield diene 8 (149.0 mg, 99%) as a sticky, pale
yellow oil. (1H NMR (500 MHz, CDCl3): d (ppm) 5.50 (d, J¼9.27 Hz,
1H), 5.02 (br s, 1H), 4.66 (br s, 1H), 4.27–4.16 (m, 8H), 3.05 (s, 2H),
2.99 (s, 2H), 2.59 (m, 1H), 1.31–1.23 (m, 12H), 0.97 (d, J¼6.83 Hz,
6H). 13C {1H} NMR (125 MHz, CDCl3): d (ppm) 169.9, 169.7, 144.7,
134.7,131.6,110.6, 61.9, 61.8, 59.45, 59.36, 38.1, 32.1, 26.8, 23.1,14.04,
14.02. IR (neat): 2982, 2961, 2907, 2869, 1738, 1267, 1234, 1202,
1040, 865 cmꢁ1. HRMS (CI): calcd for C23H35O8 (MHþ) 439.2332,
obsd 439.2335. COSY summary: the following pertinent cross-
peaks were observed: H(4) with H(1) and H(3), H(5) with H(6) and
H(2), H(6) with H(5) and H(2). NOE summary: the following per-
tinent enhancements were observed: irradiation of H(4) showed
enhancement of H(3) and H(5); irradiation of H(5) showed en-
hancement of H(4); irradiation of H(1) showed enhancement of
H(3); irradiation of H(3) showed enhancement of H(1).
C
21H31O8 (MHþ) 411.2019, obsd 411.2023. COSY summary: the
following pertinent cross-peaks were observed: H(4) with H(1) and
H(3), H(5) with H(6) and H(2), H(6) with H(5) and H(2). NOE
summary: the following pertinent enhancements were observed:
irradiation of H(4) showed enhancement of H(3) and H(5);
irradiation of H(5) showed enhancement of H(4); irradiation of
H(1) showed enhancement of H(3); irradiation of H(3) showed
enhancement of H(1).
4.7. Preparation of (E)-tetraethyl 4-methylene-5-propyl-
idenecyclohexane-1,1,2,2-tetracarboxylate (4)
The general procedure was used with enyne 3 (200.0 mg,
0.471 mmol), Ni(COD)2 (6.5 mg, 0.0236 mmol), IDTB (20.9 mg,
0.0471 mmol), and 4.71 mL toluene. The reaction mixture was
purified by flash column chromatography on SiO2 eluting with 10%
EtOAc/hexanes to yield diene 4 (189.5 mg, 95%) as a sticky, pale
yellow oil. 1H NMR (500 MHz, CDCl3): d (ppm) 5.66 (t, J¼7.32 Hz,
1H), 5.02 (br s, 1H), 4.67 (br s, 1H), 4.27–4.16 (m, 8H), 3.05 (s, 2H),
2.97 (s, 2H), 2.10 (quint, J¼7.32 Hz, 2H), 1.27 (app. td, 12H), 0.99 (t,
J¼7.32 Hz). 13C {1H} NMR (125 MHz, CDCl3): d (ppm) 169.9, 169.7,
144.7, 133.2, 129.1, 110.5, 61.9, 61.8, 59.5, 59.4, 38.2, 31.9, 21.1,
14.2, 14.07, 14.05. IR (neat): 2983, 2938, 2907, 1738, 1300, 1266,
1202, 1042, 865 cmꢁ1. HRMS (CI): calcd for C22H33O8 (MHþ)
425.2175, obsd 425.2164. COSY summary: the following pertinent
4.10. Preparation of (E)-dimethyl 3-ethylidene-4-methylene-
cyclopentane-1,1-dicarboxylate (10)
The general procedure was used with enyne 9 (150.0 mg,
0.669 mmol), Ni(COD)2 (9.2 mg, 0.0334 mmol), IDTB (29.7 mg,
0.0668 mmol), and 6.69 mL toluene. The reaction mixture was
purified by flash column chromatography on SiO2 eluting with 6%
EtOAc/hexanes to yield diene 5a (125.2 mg, 83%) as a pale yellow
oil. (1H NMR (500 MHz, CDCl3): d (ppm) 5.94 (qt, J1¼2.4 Hz,
J2¼7.3 Hz, 1H), 5.23 (s, 1H), 4.81 (s, 1H), 3.73 (s, 6H), 3.01 (t,
J¼2.0 Hz, 2H), 2.98 (s, 2H), 1.71 (d, J¼7.3 Hz, 3H). 13C {1H} NMR
(125 MHz, CDCl3): d (ppm) 172.1, 145.3, 137.0, 117.0, 102.8, 57.7, 53.0,

6874
T.N. Tekavec, J. Louie / Tetrahedron 64 (2008) 6870–6875
41.7, 37.7, 15.0. IR (neat): 2956, 2917, 2855, 1737, 1436, 1248, 1202,
1073, 880 cmꢁ1. HRMS (CI): calcd for C12H17O4 (MHþ) 225.1127,
obsd 225.1098.
t-Bu
NH2
t-Bu
NH2
DCl, D2O
EtOD
D
t-Bu
t-Bu
D
Br
HO
PBr3
1) NaH
2) t-BuLi
3) D2O
HO
O
18
D
Br
14
H
D
H
t-Bu
t-Bu
O
15
16
N
N
cat. formic acid
D
D
E'
E'
D
D
E'
E'
H
t-Bu
t-Bu
E'
E'
1) NaH
E'
E'
19
D
2) 16
O
t-Bu
t-Bu
H
H n
N
N
17
1-d
Cl
1
D
D
DCl
D
D
D
t-Bu
t-Bu
4.11. Preparation of deuterated enyne 1-d1
20
To a stirring suspension of NaH (2.412 g, 100.5 mmol) in
Et2O (250 mL) was added vinyl bromide 14 dropwise (10.59 g,
77.27 mmol). The resulting brown solution was stirred at room
temperature for 1 h. The solution was then cooled to ꢁ78 ꢀC and
tBuLi was added dropwise. The resulting pale yellow solution was
warmed to ꢁ10 ꢀC for 2 h and then cooled to ꢁ78 ꢀC at which time
D2O (20.00, 1000 mmol) was added. The reaction mixture was
warmed to room temperature and stirred for an additional 2 h. The
reaction mixture was then quenched by the addition of saturated
NH4Cl solution (50 mL) and the two phases were separated. The
aqueous phase was extracted with Et2O (3ꢂ10 mL) and the col-
lected organics were washed with brine (15 mL), and dried with
MgSO4. The mixture was concentrated via careful distillation
through a Vigreux column. The concentrate was further purified
via fractional distillation through a Vigreux column. The fraction
boiling from 46 ꢀC to 94 ꢀC was collected to yield the crude alcohol
15 as a colorless oil (2.2147 g, 49%). To a stirring solution of PBr3
(1.35 mL, 14.2 mmol) in Et2O (15 mL) was added crude alcohol 15
(2.10 g, 35.5 mmol) dropwise at 0 ꢀC. The resulting solution was
stirred at 0 ꢀC for 1 h and then carefully quenched by the addition of
brine (7 mL). The layers were separated and the organics were
washed with a saturated solution of NaHCO3 (3ꢂ5 mL), brine
(5 mL), and dried over MgSO4. The volatiles were carefully removed
via distillation through a Vigreux column. Crude allyl bromide 16
was obtained as yellow oil (1.9712 g, 46%). To a stirring suspension
of NaH (194.4 mg, 8.100 mmol) in 18 mL THF was added tetra-ester
17 (1.000 g, 2.702 mmol) in 2 mL THF. The resulting solution was
stirred at room temperature for 1 h at which time crude allyl bro-
mide 16 (1.000 g, 8.197 mmol) was added in a single portion via
syringe. The flask was the equipped with a reflux condenser and
the mixture was stirred at reflux until no starting material was
observed by GC analysis (w36 h). The mixture was then cooled to
room temperature and quenched with 20 mL of saturated NH4Cl
solution. The layers were separated and the aqueous layer was
extracted with Et2O (3ꢂ10 mL). The combined organics were
washed with brine (10 mL), dried over Na2SO4, and concentrated in
vacuo to yield a yellow oil. The crude oil was purified by flash
column chromatography eluting with 15% EtOAc/hexanes pro-
ducing a yellow oil, which was then triturated with cold hexanes
to yield enyne 1-d1 (892.3 mg, 80%) as a white solid. The degree of
deuteration was w95% as determined by 1H NMR analysis. Mp:
67 ꢀC. 1H NMR (500 MHz, CDCl3): d (ppm) 5.10 (br s, 1H), 5.05 (br s,
1H), 4.31–4.12 (m, 8H), 3.07 (br s, 2H), 2.85 (br s, 2H), 1.75 (t,
J¼2.4 Hz, 3H), 1.31–1.25 (m, 12H). 13C {1H} NMR (125 MHz, CDCl3):
d (ppm) 169.2, 161.1, 133.7 (t, J¼24.0 Hz), 119.0, 78.1, 74.8, 62.5, 62.3,
61.9, 61.7, 36.1, 22.8, 14.01, 13.99, 3.8. IR (neat): 3458, 2984, 1739,
1446, 1214, 1042, 923 cmꢁ1. HRMS (CI): calcd for C21H30DO8 (MHþ)
412.2082, obsd 412.2078.
t-Bu
t-Bu
t
KO Bu
N
N
D
D
D
D
t-Bu
t-Bu
IDTB-d
4
21
4.12. Preparation of deuterated aniline (18)
The following is modification of a published procedure.23 To a N2
flushed thick walled bomb with a Teflon screw top were added 2,5-
di-tert-butylaniline (10.0 g, 48.7 mmol), DCl (10 mL, 20 mmol, 2 N
in D2O), D2O (20 mL), and EtOD (20 mL). The flask was sealed and
heated at 105 ꢀC for 3 days at which time the flask was cooled to
room temperature and the solvents were removed in vacuo. The
flask was flushed with N2 and DCl (10 mL, 20 mmol), D2O (20 mL),
and EtOD (20 mL) were added. The flask was resealed and heated to
105 ꢀC for 5 days. The flask was cooled to room temperature and the
solvents were removed in vacuo. The flask was flushed with N2 and
DCl (10 mL, 20 mmol), D2O (20 mL), and EtOD (40 mL) were added.
The flask was resealed and heated to 105 ꢀC for another 5 days. The
flask was cooled to room temperature and the reaction mixture was
quenched by the addition of 2 N NH4OH to pH 10. The mixture was
then extracted with Et2O (3ꢂ75 mL) and the collected organics
were washed with brine (20 mL) and then dried with MgSO4. The
volatiles were removed in vacuo to yield 18 as an off-white solid
(8.93 g, 89%). The degree of deuteration was >95% at the ortho and
para positions as determined by H NMR analysis. Mp: 104 ꢀC 1H
1
NMR (500 MHz, CDCl3): d (ppm) 7.18 (s, 1H), 3.98 (br s, 2H), 1.42 (s,
9H), 1.29 (s, 9H). 13C {1H} NMR (125 MHz, CDCl3): d (ppm)
149.9, 144.2, 131.1, 126.4, 115.7 (t, J¼23.8 Hz), 115.0 (t, J¼22.9 Hz),
34.2, 34.1, 31.5, 29.9. IR (neat): 3470, 2957, 2872, 1620, 1548, 1470,
792 cmꢁ1. HRMS (CI): calcd for C14H21D2N (Mþ) 207.1956, obsd
207.1966.
4.13. Preparation of deuterated bisimine (19)
The procedure was identical to the procedure used in the syn-
thesis of bisimine 11 using deuterated aniline 18 (7.038 g,
33.94 mmol), glyoxal (1.95 mL, 17.0 mmol), and formic acid (four
drops) in 65 mL EtOH. The bisimine 19 was isolated as a yellow solid
in 93% yield. Mp: 182 ꢀC. 1H NMR (500 MHz, CDCl3): d (ppm) 8.28 (s,
2H), 1.44 (s, 18H), 1.35 (s, 18H). 13C {1H} NMR (125 MHz, CDCl3):
d (ppm) 158.8, 150.2, 150.1, 140.7, 126.1, 123.7 (t, J¼22.4 Hz), 115.9 (t,
J¼20.6 Hz), 35.5, 34.6, 31.5, 30.7. IR (neat): 2959, 2872, 1612, 1539,
1362, 1265, 909, 873 cmꢁ1. HRMS (CI): calcd for C30H41D4N2 (MHþ)
437.3834, obsd 437.3845.

T.N. Tekavec, J. Louie / Tetrahedron 64 (2008) 6870–6875
6875
4. Reviews: (a) Takao, K.; Munakata, R.; Tadano, K. Chem. Rev. 2005, 105, 4779; (b)
Winkler, J. D. Chem. Rev. 1996, 96, 167; Recent reports: (c) Nicolaou, K. C.;
Harrison, S. T. Angew. Chem., Int. Ed. 2006, 45, 3256; (d) Leduc, A. B.; Kerr, M. A.
Eur. J. Org. Chem. 2007, 237; (e) Pandey, S. K.; Orellana, A.; Greene, A. E.; Poisson,
J.-F. Org. Lett. 2006, 8, 5665; (f) Crimmins, M. T.; Brown, B. H.; Plake, H. R. J. Am.
Chem. Soc. 2006, 128, 1371; (g) Caussanel, F.; Wang, K.; Ramachandran, S. A.;
Deslongchamps, P. J. Org. Chem. 2006, 71, 7370.
4.14. Preparation of deuterated imidazolium salt (20)
The procedure was identical to the procedure used in the
synthesis of imidazolium salt 12 using bisimine 19 (6.500 g,
14.88 mmol), paraformaldehyde (447.0 mg, 14.88 mmol), and
DCl (1 M in Et2O, 22.3 mL, 22.3 mmol) in 35 mL toluene. The
crude imidazolium salt 20 was isolated as a light tan solid in 42%
yield. HRMS (FAB): calcd for C31H40D5N2 (Mþ) 450.3897, obsd
450.3923.
5. IDTB¼1,3-bis(2,5-di-tert-butylphenyl)-imidazol-2-ylidene; IPr¼1,3-bis(2,6-di-
isopropylphenyl)-imidazol-2-ylidene;
IMes¼1,3-bis(2,4,6-trimethylphenyl)-
imidazol-2-ylidene; SIDTB¼1,3-bis(2,5-di-tert-butylphenyl)-4,5-dihydroimid-
azolin-2-ylidene; SIPr¼1,3-bis(2,5-diisopropylphenyl)-4,5-dihydroimidazolin-
2-ylidene; SIMes¼1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazolin-2-yl-
idene; IAd¼1,3-diadamantylimidazol-2-ylidene; ItBu¼1,3-di-tert-butylimid-
azol-2-ylidene.
4.15. Preparation of IDTB-d4 (21)
6. The oligomerization of alkynes is a predominant side reaction that is catalyzed
by Ni(0)/NHC complexes. See Ref 1.
7. The depressed yield of 2 arises from an increased difficulty to undergo b-D
elimination (the last step of either mechanism A or B).
8. All efforts to recover the ITDB ligand after the cycloaddition led to intractable
mixtures.
9. Reviews: (a) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731; (b)
Naota, T.; Takaya, H.; Murahashi, S.-I. Chem. Rev. 1998, 98, 2599; (c) Dyker, G.
Angew. Chem., Int. Ed. 1999, 38, 1699.
10. Stylianides, N.; Danopoulos, A. A.; Pugh, D.; Hancock, F.; Zanotti-Gerosa, A.
Organometallics 2007, 26, 5627.
11. Theoretical calculations show that C–H activation is endothermic for Ni-com-
plexes in comparison with the analogous Pt-complexes. Reinhold, M.; McGrady,
J. E.; Perutz, R. N. J. Am. Chem. Soc. 2004, 126, 5268.
12. C–H activation by Ni(0) species: (a) Keen, A. L.; Johnson, S. A. J. Am. Chem. Soc.
2006, 128, 1806; (b) Brunkan, N. M.; Brestensky, D. M.; Jones, W. D. J. Am. Chem.
Soc. 2004, 126, 3627; (c) van der Boom, M. E.; Liou, S.-Y.; Shimon, L. J.;
Ben-David, Y.; Milstein, D. Inorg. Chim. Acta 2004, 357, 4015.
The procedure used was identical to the procedure used in the
synthesis of the IDTB carbene (13) using deuterated imidazolium
salt 20 (508 mg, 1.04 mmol) and KOtBu (176 mg, 1.57 mmol) in 4 mL
toluene. The title compound was isolated as a beige solid in 24%
yield. Analytically pure sample could be obtained by cooling a sat-
urated solution of the carbene in Et2O to ꢁ40 ꢀC. Mp: decomp.
206 ꢀC. 1H NMR (500 MHz, C6D6): d 7.47 (s, 2H), 6.77 (s, 2H), 1.48 (s,
18H), 1.16 (s, 18H). 13C {1H} NMR (125 MHz, C6D6): d (ppm) 221.4,
149.2, 143.5, 141.9, 125.0 (t, J¼23.3 Hz), 122.5, 35.8, 33.9, 32.1,
31.0. HRMS (EI): calcd for C31H40D4N2 (MHþ) 449.3834, obsd
449.3837.
Acknowledgements
13. Product yields were identical to reactions run with 1 and superstoichiometric
amounts of Ni(COD)2 and IDTB.
14. It is interesting to note that N-alkyl NHC ligands do not facilitate the cyclo-
isomerization. This may be due to a decreased propensity for orthometallation
relative to NHC ligands that possess easily oxidizable ortho-aromatic C–H
bonds (such as IDTB) or benzylic C–H bonds (such as IPr and IMes).
15. For a review of bond activation reactions with NHC’s, see: Crudden, C. M.; Allen,
D. P. Coord. Chem. Rev. 2004, 248, 2247. For recent examples of C–H activation:
[Ir]: (a) Hanasaka, F.; Tanabe, Y.; Fujita, K.; Yamaguchi, R. Organometallics 2006,
25, 826; (b) Corbera´n, R.; Sanau´ , M.; Peris, E. Organometallics 2006, 25, 4002; (c)
We gratefully acknowledge Merck, NSF (Career Award), the
NIH-NIGMS, and the Alfred P. Sloan Foundation for supporting this
research.
Supplementary data
´
´
Corberan, R.; Sanau, M.; Peris, E. J. Am. Chem. Soc. 2006, 128, 3974; (d) Scott, N.
M.; Pons, V.; Stevens, E. D.; Heinekey, D. M.; Nolan, S. P. Angew. Chem., Int. Ed.
2005, 44, 2512; [Rh]: (e) Huang, J.; Stevens, E. D.; Nolan, S. P. Organometallics
2000, 19, 1194; (f) Scott, N. M.; Dorta, R.; Stevens, E. D.; Correa, A.; Cavallo, L.;
Nolan, S. P. J. Am. Chem. Soc. 2005, 127, 3516; [Ru]: (g) Cabeza, J. A.; del Rio, I.;
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.03.071.
References and notes
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Miguel, D.; Sanchez-Vega, M. G. Chem. Commun. 2005, 3956.
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IDTB-d4 solution were essentially identical.
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Ni–H is formed in both reactions but in different and immeasurable amounts.
Furthermore, Ni(0) catalyzed enyne oligomerization is
reaction in IDTB-d4 reactions.
a competitive side
18. For examples of kinetic isotope effect used to partition between two products
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