Doubly coarctate-stabilized carbenes: Synthetic and computational studies

Article abstract of DOI:10.1021/jo3020374

Isoindazoles joined by an ethynyl linker to either a phenyltriazene or a phenyldiazene moiety were synthesized, and their subsequent reactivity was examined. Computations suggest that these molecules could rearrange at moderate temperatures via carbene intermediates that are doubly stabilized by coarctate conjugation. The experimental results corroborate the calculations, as the transient carbene can either be trapped with oxygen or undergo ring-opening to afford a rearranged product. Additional calculations illustrate some design principles that might lead to stable carbenes that are the global minimum on the coarctate hypersurface.

Full text of DOI:10.1021/jo3020374

Article
pubs.acs.org/joc
Doubly Coarctate-Stabilized Carbenes: Synthetic and Computational
Studies
Brian S. Young,† Rainer Herges,‡ and Michael M. Haley*,†
†Department of Chemistry, University of Oregon, Eugene, Oregon 97403-1253, United States and
‡Institut fur Organische Chemie, Universitat Kiel, 24098 Kiel, Germany
̈
̈
S
* Supporting Information
ABSTRACT: Isoindazoles joined by an ethynyl linker to either a
phenyltriazene or a phenyldiazene moiety were synthesized, and their
subsequent reactivity was examined. Computations suggest that these
molecules could rearrange at moderate temperatures via carbene
intermediates that are doubly stabilized by coarctate conjugation. The
experimental results corroborate the calculations, as the transient
carbene can either be trapped with oxygen or undergo ring-opening
to afford a rearranged product. Additional calculations illustrate some
design principles that might lead to stable carbenes that are the global
minimum on the coarctate hypersurface.
Recent calculations showed that pyrazoles and arene-fused
pyrazoles (e.g., isoindazoles) strongly stabilize carbenes in the
5-position (e.g., 2) by as much as 16−17 kcal mol−1 over open-
chain model systems.8 We attributed this unusually large
stabilization of these heterocyclic singlet carbenes to “coarctate
conjugation”. The carbene is generated by a coarctate
cyclization, and therefore, part of the wave function of the
reactant mixes into the carbene wave function. This leads to a
significantly shorter bond length between the carbene center
and the neighboring carbon atom in the coarctate carbenes
compared to the corresponding phenyl and open-chain
analogues.8 By replacing the terminal acetylene proton in the
starting material (1) with a preformed isoindazole, as in
compounds 3 and 4, it might be possible to induce a cyclization
reaction where the resultant carbene 5 could be doubly
stabilized by coarctate conjugation (Scheme 2). In addition,
depending upon the nature of R1 and R2, it might be possible to
affect the ratio of 3 to 4 as they interconvert via 5. Herein we
present our computational and experimental results to address
both of these issues.9
INTRODUCTION
■
Over the past 12 years, we have been investigating the
isoindazole-forming cyclizations1 of hetero-ene−ene−yne sys-
tems.2 Early experiments focused on the cyclization of
o-ethynylphenyltriazenes (1a, Scheme 1), which required the
Scheme 1. Cyclization of Hetero-Ene−Ene−Ynes To Afford
Isoindazoyl Carbenes/Carbenoids
addition of a catalytic metal salt (typically CuCl) to stabilize the
carbene/carbenoid intermediate (2a).3 Computational and
experimental mechanistic studies indicated that the isoindazole
was formed through a concerted mechanism featuring a
“coarctate” transition state.4 A coarctate reaction is defined as
one in which two bonds are broken and two bonds are formed
in a single step.5 Interestingly, when the diethyltriazene moiety
was replaced with a phenyldiazene (1b), the coarctate
cyclization proceeded smoothly without the use of a carbene
stabilizer.6 DFT calculations revealed that the energy of
activation leading to the carbene intermediate (2b) was about
10 kcal mol−1 lower for the diazene compared to that of the
triazene, results consistent with the more facile cyclization of
the diazenes.6,7
RESULTS AND DISCUSSION
■
Computational Studies. Before performing any exper-
imental work, model systems 3a (R1 = R2 = NMe2), 3b (R1 =
R2 = Ph), and 3c (R1 = NMe2, R2 = Ph) were examined using
the Gaussian 0310 suite of programs to determine the energies
required to affect their cyclizations. Density functional theory
Special Issue: Howard Zimmerman Memorial Issue
Received: September 17, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo3020374 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
For the coarctate cyclization of diazene−ene−ynes, the
calculations for 3b predicted a transition state energy of 20.5
kcal mol−1 (Figure 1, right), which is 2.3−5.3 kcal mol−1 lower
than the barrier for 1b; the energy for intermediate 5b is
similarly lowered from 2b. Given the greater propensity of the
diazenes to cyclize,6,7 we anticipated that 3b might react readily
at ambient temperature and thus only obtain products derived
from 5b.
Scheme 2. Interconversion of 3 and 4 via Doubly Coarctate-
Stabilized Carbene 5
Asymmetric carbene 5c presents an interesting possibility.
Whereas carbenes 5a and 5b must revert back to 3a and 3b,
respectively, in the equilibrium between the two forms due to
symmetry of the intermediates, 5c can undergo ring-opening to
yield two different starting ethynylisoindazoles, either 3c or 4c.
From the energy diagram (Figure 2), a few key observations
and conclusions can be made. (1) Isoindazole 3c is 14 kcal
mol−1 higher in energy than 4c; therefore, 3c should be
targeted as its thermally induced rearrangement to more stable
4c should be possible while the reverse rearrangement should
not. (2) The energy barrier for the cyclization of 3c to its
corresponding carbene 5c is 23.2 kcal mol−1. This value is
comparable to diazene 1b, which has an energy of activation of
22.8 kcal mol−1 and required no catalyst to effect cyclization;
thus, 3c is also expected to cyclize without need of a catalyst.
(3) The energy barrier from 4c to 5c is 31.3 kcal mol−1. This is
comparable to the energy predicted to cyclize the N,N-dimethyl
version of triazene 1 at 33.7 kcal mol−1 and indicates that in
(DFT) calculations at the B3LYP level of theory11 and the 6-
31G* basis set once again were utilized as these have proven
useful in our previous studies. The calculations showed that the
coarctate cyclization of 3a has a transition-state energy of 33.7
kcal mol−1 (Figure 1, left), identical to the energy of activation
for the hypothetical NMe2-analogue of triazene−ene−yne 1a,
and similar energies for carbenes 2a and 5a;9b therefore, we
anticipated that 3a would cyclize to 5a under standard
isoindazole formation conditions (heating in 1,2-dichloro-
ethane (DCE) to 50 °C in the presence of excess CuCl),
which then could be trapped/intercepted by molecular oxygen
or an electron-rich alkene.
Figure 1. DFT (B3LYP/6-31G* + ZPE)-calculated relative energies of the reactants, transition states, and intermediates involved in the coarctate
cyclization of 3a (left) and 3b (right).
B
dx.doi.org/10.1021/jo3020374 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 2. DFT (B3LYP/6-31G* + ZPE)-calculated relative energies of the reactants, transition states, intermediates, and products involved in the
proposed conversion of 3c to 4c via carbene 5c.
addition to being more thermodynamically stable than 3c, 4c
would also be more kinetically stable.
tion reaction in oxygen-saturated DCE gave ketone 9 in 57%
yield. These results indicate that while the coarctate reaction of
3d was energetically favorable, the [2 + 1] cycloaddition with
DMB did not occur, likely due to the sterically hindered nature
of the carbene center; however, molecular oxygen was small
enough to intercept successfully the reactive intermediate.
For the synthesis of 3e and 3f, we elected to include methyl
groups in the starting materials. These provided the dual
benefits of reducing the complexity of the aromatic region of
Experimental Studies. Synthesis of 3d (R1 = R2 = NEt2)
began with a Corey−Fuchs reaction12 on known aldehyde 63a
to generate ethynylisoindazole 7 (Scheme 3). Sonogashira
cross-coupling with (2-iodophenyl)triazene 813 afforded target
molecule 3d. Based on the calculated activation energy for the
coarctate cyclization of 3a, we expected to be able to trap the
resulting carbene using 2,3-dimethyl-2-butene (DMB) as we
have previously shown; however, all attempts resulted in only
recovered starting material. Gratifyingly, repeating the cycliza-
1
the H NMR spectra due to the added N-phenyl groups while
at the same time giving clear spectroscopic handles in the alkyl
region to ascertain purity. MnO2-mediated oxidation of known
alcohol 106 gave aldehyde 11 (Scheme 4). Subjecting this
aldehyde to Corey−Fuchs conditions led to alkyne 12.
Unfortunately, Sonogashira cross-coupling of 12 to iodide
136 failed to provide the desired isomer 3e. While all starting
material was consumed, no identifiable products were
recovered. A plausible explanation is that the desired product
3e did form but that it readily rearranged to generate carbene
5e that subsequently reacted to generate several unidentifiable
products. This is consistent with our previous work involving
(2-ethynylphenyl)phenyldiazenes6 in which these molecules
would undergo coarctate cyclization under ambient conditions,
resulting in a number of unidentifiable products. All attempts to
intercept 5e or any reactive intermediates in this reaction were
unsuccessful.
Scheme 3. Synthesis and Coarctate Cyclization of 3d
We next focused on the asymmetrical structure 3f and the
potential rearranged product 4f. Isoindazole aldehyde 143a was
subjected to a Corey−Fuchs sequence to form alkyne 15
(Scheme 5), which was subsequently cross-coupled under
C
dx.doi.org/10.1021/jo3020374 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
ing tributylstannane of alkyne 15 was formed and cross-coupled
to iodide 13 under Stille conditions; again, the only product
isolated was 4f. While it appeared that 3f was simply not stable
and spontaneously rearranged to 4f, there still existed the
possibility that the Pd catalyst was facilitating the rearrange-
ment. While Cu(I) is usually utilized to perform our coarctate
cyclizations, other transition metals such as Rh(II) have been
used as well. To rule out Pd as the cause for the rearrangement,
a transition-metal-free strategy to form 3f was required. We
envisioned that a Colvin rearrangement14 of the appropriate
ketone 17 could be a viable way of producing 3f without the
use of transition metals (Scheme 6).13 Lithium−halogen
Scheme 4. Attempted Synthesis of 3e
Scheme 6. Transition-Metal-Free Attempt To Synthesize 3f
Scheme 5. Synthesis of 4f through Sonogashira and Stille
Cross-Coupling Reactions
exchange on 13 followed by nucleophilic attack on aldehyde
14 gave crude alcohol 18, which was smoothly oxidized to the
corresponding ketone 17 using MnO2. Finally, treatment of 17
with the Li salt of trimethylsilyldiazomethane induced a Colvin
rearrangement. Unfortunately, this also resulted in formation of
4f rather than 3f. Rearrangement inevitably occurs at room
temperature or lower even in the complete absence of
transition metals that could act as carbene stabilizers.
Computational Studies Revisited. In title systems 3 and
4 coarctate cyclization is coupled to coarctate ring-opening
proceeding via carbenes 5 (Scheme 2). Even though the
carbenes are stabilized by coarctate conjugation, they are short-
lived intermediates that cannot be isolated but only trapped
with oxygen. A straightforward way to stabilize the carbene, and
to make it the global minimum on the three-minimum reaction
hypersurface (ring closure, carbene, ring-opening) would be to
include the triple bond of the ene−ene−yne as part of a ring
system. Use of a medium-sized ring will enforce more strain
upon the overall system and thus destabilize the alkyne. The
molecule should then readily cyclize to the carbene form, which
is naturally bent and thus will relieve ring strain. To check this
hypothesis, we performed calculations on the hypothetical
cyclooctyne 19a and the corresponding carbene 20a, as well as
the phenyl substituted systems 19b and 20b (Figure 3). As
expected, upon bridging the isoindazole rings with ethyne and
methylene units forming an 8-membered ring, carbene 20a
becomes 25.6 kcal mol−1 more stable than ene−ene−yne 19a.
For the phenyl-substituted systems, carbene 20b is calculated to
be 11.9 kcal mol−1 more stable than cyclooctyne 19b. Both
carbenes are singlet ground states. It therefore appears that
coarctate stabilization in combination with ring strain could
provide a way to design stable carbenes that differ structurally
Sonogashira conditions with iodide 13. Surprisingly, the proton
NMR spectra of the resultant material strongly suggested that
the only characterizable product was 4f! Intentionally synthesiz-
ing 4f afforded definitive proof: cross-coupling alkyne 12 to
iodide 163a furnished a compound whose NMR data were
identical to those of the material formed in the previous
reaction. It appears that while 3f was formed in situ, it
immediately rearranged under the reaction conditions to form
4f.
Because Cu(I) salts effect coarctate cyclizations, we
hypothesized that the small amount of CuI used for the
Sonogashira reaction could have promoted the unwanted
rearrangement. To perform a Cu-free reaction, the correspond-
D
dx.doi.org/10.1021/jo3020374 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
was distilled from Na and benzophenone under N2. All purchased
reagents were used as received unless otherwise indicated.
Alkyne 7. PPh3 (0.893 g, 3.4 mmol) was added to a stirred solution
of CBr4 (0.565 g, 1.7 mmol) in DCM (10 mL) at 0 °C. To this was
added dropwise a solution of aldehyde 63a (0.185 g, 0.85 mmol) in
DCM (10 mL). The reaction mixture was warmed to rt and stirred
overnight. The mixture was filtered through a pad of silica with DCM,
and the solvent removed under reduced pressure to give the crude
1
dibromoalkene (0.274 g, 85%) as a waxy yellow solid: H NMR (300
MHz, CDCl3) δ 7.81 (dt, J = 8.7, 0.9 Hz, 1H), 7.77 (s, 1H), 7.70 (dt, J
= 8.7, 0.9 Hz, 1H), 7.36−7.29 (m, 1H), 7.20−7.14 (m, 1H), 3.28 (br s,
4H), 0.83 (t, J = 7.2 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 146.6,
131.3, 127.7, 126.4, 122.4, 122.3, 118.1, 116.9, 92.5, 52.7, 12.1.
To a stirred solution of dibromoalkene (0.274 g, 0.7 mmol) in dry
THF (25 mL) at −95 °C was added BuLi (1.4 mL, 2.5 M, 3.5 mmol)
dropwise. After 40 min, the reaction was quenched with satd aq
NH4Cl solution and extracted with DCM. The organic layer was dried
(MgSO4), filtered, and concentrated, and the crude product was
purified by preparative TLC (1:2 EtOAc/hexanes) to give alkyne 7
1
(0.097 g, 62%) as a pale yellow solid: mp 93−94 °C; H NMR (300
MHz, CDCl3) δ 7.73−7.71 (m, 1H), 7.70−7.68 (m, 1H), 7.36−7.33
(m, 1H), 7.20−7.15 (m, 1H), 3.81 (s, 1H), 3.33 (q, J = 7.2 Hz, 4H),
0.88 (t, J = 7.2 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 146.3, 126.9,
123.1, 122.4, 120.2, 118.2, 117.9, 87.6, 72.1, 53.0, 12.1; HRMS (EI+)
for C13H15N3 calcd 213.1266, found 213.1264.
Triazene 3d. A stirred mixture of iodide 813 (0.152 g, 0.5 mmol),
Pd(PPh3)4 (0.008 g, 0.007 mmol), CuI (0.003 g, 0.013 mmol), THF
(10 mL), and DIPA (20 mL) was purged with Ar for 45 min. A
solution of alkyne 7 (0.072 g, 0.34 mmol) in Ar-purged THF (10 mL)
was added via cannula, and the mixture was stirred overnight at 50 °C.
After cooling, the crude mixture was filtered through a pad of silica
(acetone), concentrated, and purified by preparative TLC (1:3
EtOAc/hexanes) to give 3d (0.070 g, 54%) as a pale yellow solid:
mp 109−110 °C; 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J = 8.4 Hz,
1H), 7.71 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.50 (d, J = 8.4
Hz, 1H), 7.37−7.28 (m, 2H), 7.18−7.08 (m, 2H), 3.91−3.78 (m, 4H),
3.34 (q, J = 7.2 Hz, 4H), 1.30 (br s, 6H), 0.93 (t, J = 7.2 Hz, 6H); 13C
NMR (150 MHz, CDCl3) δ 152.4, 146.3, 133.4, 129.6, 126.7, 124.8,
122.2, 122.0, 121.5, 120.7, 117.9, 117.8, 117.2, 98.5, 81.1, 52.7, 47.9,
19.3, 12.3; HRMS (ESI+) for C23H28N6 (M + H)+ calcd 389.2454,
found 389.2439.
Figure 3. Bridged systems 19a,b that are calculated to be more stable
in the carbene forms 20a,b.
from the more commonly utilized imidazole-based N-
heterocyclic carbenes.15
CONCLUSIONS
■
Molecules that can undergo coarctate cyclization to form
carbene intermediates, specifically, isoindazoles fused via an
ethynyl linker to either phenyldiazenes or diethyltriazenes, were
studied computationally and experimentally. DFT calculations
suggested that the isoindazoles fused to phenyldiazenes would
rearrange via carbenes at lower temperatures when compared
to their diethyltriazene counterparts; this was confirmed
experimentally. Both 3d and 4f are stable at room temperature,
with activation energies of coarctate cyclization of 33.4 and 33.7
kcal mol−1, respectively. It was shown that 3d can rearrange to a
carbene and be trapped by molecular oxygen in the presence of
CuCl, much like our previously observed triazene systems.
While 3e unfortunately degraded into multiple products, 3f was
presumably formed in situ and rearranged to 4f in modest yield.
Additional calculations indicate that modification of the
molecular framework by including the alkyne portion of these
molecules into a medium-sized ring would result in carbenes
that are the global minimum on the coarctate hypersurface.
Coarctate stabilization along with ring strain, then, could lead
to the development of novel stable carbenes that could be
interesting ligands of transition-metal compounds.
Ketone 9. A solution of 3d (0.02 g, 0.05 mmol) in DCM (20 mL)
was sparged with O2 for 30 min, CuCl (0.051 g, 0.5 mmol) was added,
and the mixture was stirred overnight at 50 °C. After cooling, the
crude mixture was filtered through a pad of silica (1:3 EtOAc/
hexanes), concentrated, and purified by preparative TLC (1:19
EtOAc/DCM) to give ketone 9 (0.012 g, 57%) as a yellow solid:
mp 145−146 °C; 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J = 9.0 Hz,
2H), 7.36−7.29 (m, 2H), 7.07−7.00 (m, 2H), 6.98−6.93 (m, 2H),
3.33 (q, J = 7.2 Hz, 8H), 0.89 (t, J = 7.2 Hz, 12H); 13C NMR (150
MHz, CDCl3) δ 173.1, 145.7, 133.7, 126.7, 124.7, 120.4, 120.3, 118.2,
52.4, 12.1; HRMS (ESI+) for C23H28N6O (M + H)+ calcd 405.2403,
found 405.2386.
Aldehyde 11. Isoindazole alcohol 106 (0.83 g, 3.5 mmol) was
dissolved in CHCl3 (50 mL), MnO2 (6.05 g, 70 mmol) was added, and
the reaction was stirred for 16 h. The crude reaction mixture was
filtered through Celite, and the solvent was removed under reduced
pressure to yield 11 (0.712 g, 87%) as an orange solid: mp 101−102
1
°C; H NMR (300 MHz, CDCl3) δ 10.06 (s, 1H), 8.06 (s, 1H), 7.79
(d, J = 9.0 Hz, 1H), 7.66−7.53 (m, 5H), 7.30 (dd, J = 9.0, 1.2 Hz, 1H),
2.51 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 180.1, 147.5, 138.9,
137.6, 131.6, 130.7, 130.0, 129.6, 126.5, 124.0, 119.5, 118.4, 22.2;
HRMS (EI+) for C15H12N2O calcd 236.0950, found 236.0956.
Alkyne 12. PPh3 (3.16 g, 12.1 mmol) was added to a stirred
solution of CBr4 (1.99 g, 6.0 mmol) in DCM (20 mL) at 0 °C. To this
solution was added dropwise a solution of aldehyde 11 (0.712 g, 3.0
mmol) in DCM (10 mL). The reaction mixture was warmed to rt and
stirred overnight. The mixture was filtered through a pad of silica with
DCM and the solvent removed under reduced pressure to give the
EXPERIMENTAL SECTION
■
General Information. 1H and 13C NMR spectra were recorded in
CDCl3 using a 300 (1H: 299.93 MHz, 13C: 75.42 MHz), 500 (1H:
500.11 MHz, 13C: 125.75 MHz), or 600 MHz (1H: 599.90 MHz, 13C:
150.88 MHz) spectrometer. Chemical shifts (δ) are expressed in ppm
relative to the residual chloroform (1H: 7.26 ppm, 13C: 77.16 ppm)
reference. High-resolution mass spectra were recorded on instruments
using either an electric/magnetic sector or a TOF analyzer. Dry THF
1
dibromoalkene (0.693 g, 59%) as a waxy yellow solid: H NMR (300
E
dx.doi.org/10.1021/jo3020374 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
MHz, CDCl3) δ 7.70 (d, J = 9.0 Hz, 1H), 7.66−7.45 (m, 7H), 7.20
(dd, J = 9.0, 1.2 Hz, 1H), 2.48 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ 148.1, 140.0, 132.7, 130.1, 129.5, 129.2, 129.0, 127.8, 125.3, 121.2,
119.7, 118.1, 95.1, 22.2.
mmol) dropwise. After the solution was stirred for 5 min, a solution of
aldehyde 14 in THF (1 mL) was added dropwise by syringe. The
reaction was warmed to 0 °C and stirred for 3 h at that temperature.
The reaction was quenched with satd aq NaHCO3 solution and
extracted three times with DCM. The organic layer was dried
(MgSO4), and the solvent was removed under reduced pressure to
give crude alcohol 18. Alcohol 18 was redissolved in CHCl3 (10 mL),
and excess MnO2 was added. After the reaction was stirred for 16 h,
the mixture was filtered through a pad of Celite and concentrated.
Purification by preparative TLC (1:2 EtOAc/hexanes) gave ketone 17
(0.062 g, 49%) as an orange oil: 1H NMR (300 MHz, CDCl3) δ 7.82−
7.77 (m, 2H), 7.62 (d, J = 8.7 Hz, 1H), 7.43−7.38 (m, 2H), 7.28−7.15
(m, 6H), 2.96 (br s, 4H), 2.49 (s, 3H), 2.47 (s, 3H), 0.63 (t, J = 7.2
Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 187.7, 152.2, 148.0, 144.8,
141.7, 140.5, 135.3, 133.6, 131.3, 131.1, 129.7, 128.9, 128.8, 123.0,
121.5, 120.0, 117.6, 117.6, 51.3, 22.2, 21.6, 12.0; HRMS (ESI+) for
C26H27N5O (M + H)+ calcd 426.2294, found 426.2300.
Triazene 4f via Colvin Rearrangement. To a solution of
(trimethylsilyl)diazomethane (0.07 mL, 2.0 M, 0.14 mmol) in THF (5
mL) cooled to −78 °C was added BuLi (0.05 mL, 2.5 M, 0.13 mmol).
The reaction mixture was stirred for 40 min, after which it was
transferred by cannula into a stirred, −78 °C solution of ketone 17
(0.042 g, 0.10 mmol) in dry THF (10 mL). After 1 h, the reaction was
quenched with satd aq NaHCO3 solution, diluted with Et2O, and
washed with brine. The organic layer was dried (MgSO4), filtered, and
concentrated. The product was purified by preparative TLC (1:2
EtOAc/hexanes) to give triazene 4f (0.012 g, 41%) as a pale yellow
solid. The spectroscopic data of this product matched those described
above for 4f.
To a stirred solution of dibromoalkene (0.693 g, 1.8 mmol) in dry
THF (25 mL) at −95 °C was added BuLi (3.5 mL, 2.5 M, 8.75 mmol)
dropwise. After 40 min, the reaction was quenched with satd aq
NH4Cl solution and extracted with DCM. The organic layer was dried
(MgSO4), and the crude product was concentrated and then purified
by preparative TLC (DCM) to give alkyne 12 (0.204 g, 50%) as a
purple solid: mp 66−67 °C; 1H NMR (300 MHz, CDCl3) δ 7.92 (d, J
= 7.8 Hz, 2H), 7.72 (d, J = 9.0 Hz, 1H), 7.58−7.41 (m, 4H), 7.21 (dd,
J = 9.0, 1.2 Hz, 1H), 3.80 (s, 1H), 2.47 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 147.7, 140.2, 133.5, 130.4, 129.1, 128.7, 126.9, 124.5, 118.2,
118.2, 116.2, 88.6, 72.9, 22.0; HRMS (EI+) for C16H12N2 calcd
232.1000, found 232.1005.
Alkyne 15. PPh3 (1.270 g, 4.8 mmol) was added to a stirred
solution of CBr4 (0.803 g, 2.4 mmol) in DCM (10 mL) at 0 °C. To
this solution was added dropwise a solution of aldehyde 14 (0.280 g,
1.2 mmol) in DCM (10 mL). The reaction mixture was warmed to rt
and stirred overnight. The mixture was filtered through a pad of silica
with DCM and the crude material was concentrated and then purified
by preparative TLC(1:3 EtOAc:hexanes) to give the corresponding
1
dibromide (0.396 g, 85%) as a waxy yellow semisolid: H NMR (300
MHz, CDCl3) δ 7.73 (s, 1H) 7.61 (d, J = 8.7 Hz, 1H), 7.55 (s, 1H),
7.18 (d, J = 8.7 Hz, 1H), 3.27 (s, 4H), 2.46 (s, 3H), 0.82 (t, J = 7.2 Hz,
6H); 13C NMR (150 MHz, CDCl3) δ 145.4, 131.9, 129.3, 127.8,
120.5, 117.8, 117.1, 92.2, 52.7, 22.2, 12.1.
To a stirred solution of dibromoalkene (0.390 g, 1.0 mmol) in dry
THF (25 mL) at −95 °C was added BuLi (2.0 mL, 2.5 M, 5.0 mmol)
dropwise. After 40 min, the reaction was quenched with satd aq
NH4Cl solution and extracted with DCM. The organic layer was dried
(MgSO4), filtered, and concentrated, and the crude product was
purified by preparative TLC (1:3 EtOAc/hexanes) to give 15 (0.146 g,
ASSOCIATED CONTENT
* Supporting Information
■
S
All computational details including Cartesian coordinates, total
energies, and imaginary frequencies for all computed structures
1
64%) as a pale yellow solid: mp 95−96 °C; H NMR (300 MHz,
1
as well as transition-state analysis; copies of H and 13C NMR
CDCl3) δ 7.61 (d, J = 8.9 Hz, 1H), 7.46 (s, 1H), 7.18 (d, J = 8.9 Hz,
1H), 3.79 (s, 1H), 3.32 (q, J = 7.2 Hz, 4H), 2.44 (s, 3H), 0.87 (t, J =
7.2 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 141.6, 129.3, 126.3,
119.1, 115.2, 114.9, 114.4, 83.9, 68.9, 49.5, 18.5, 8.6; HRMS (EI+) for
C14H17N3 calcd 227.1422, found 227.1413.
spectra for 3d, 4f, 7, 9, 11, 12, 15, and 17. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: haley@uoregon.edu.
■
Triazene 4f via Sonogashira Reaction/Rearrangement. A
stirred mixture of iodide 136 (0.085 g, 0.26 mmol), Pd(PPh3)4 (0.004
g, 0.004 mmol), CuI (0.002 g, 0.009 mmol), THF (10 mL), and DIPA
(20 mL) was purged with Ar for 45 min. A solution of alkyne 15
(0.050 g, 0.22 mmol) in Ar-purged THF (10 mL) was added via
cannula, and the mixture was stirred overnight at room temperature.
The crude mixture was filtered through a pad of silica (acetone),
concentrated, and purified by preparative TLC (1:3 EtOAc/hexanes)
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
1
to give 4f (0.044 g, 48%) as a pale yellow solid: mp 115−117 °C; H
We thank the National Science Foundation (CHE-1013022)
for continued support of this research as well as for support in
the form of instrumentation grants (CHE-0923589).
NMR (300 MHz, CDCl3) δ 8.08 (d, J = 7.5 Hz, 2H), 7.70 (d, J = 7.2
Hz, 1H), 7.59 (s, 1H), 7.55−7.49 (m, 2H), 7.44 (d, J = 7.2 Hz, 1H),
7.38 (d, J = 8.4 Hz, 1H) 7.28 (s, 1H), 7.2 (dd, J = 9.0, 1.2 Hz, 1H),
7.12 (dd, J = 8.4, 1.5 Hz, 1H), 3.75 (q, J = 7.2 Hz, 4H), 2.46 (s, 3H),
2.33 (s, 3H), 1.25 (br s, 6H); 13C NMR (150 MHz, CDCl3) δ 150.4,
147.9, 140.6, 134.5, 133.0, 132.5, 130.8, 130.3, 129.0, 128.2, 126.2,
124.4, 118.9, 118.3, 118.0, 117.2, 117.1, 99.7, 81.6, 47.1 (br), 21.9,
20.9, 19.5; HRMS (ESI+) for C27H27N5 (M + H)+ calcd 422.2345,
found 422.2328.
REFERENCES
■
(1) Young, B. S.; Herges, R.; Haley, M. M. Chem. Commun. 2012, 48,
9441−9455.
(2) Shirtcliff, L. D.; McClintock, S. P.; Haley, M. M. Chem. Soc. Rev.
2008, 37, 343−364.
(3) (a) Kimball, D. B.; Weakley, T. J. R.; Haley, M. M. J. Org. Chem.
2002, 67, 6395−6405. (b) Kimball, D. B.; Hayes, A. G.; Haley, M. M.
Org. Lett. 2000, 2, 3825−3827.
Triazene 4f via Direct Sonogashira Reaction. A stirred mixture
of iodide 16 (0.034 g, 0.10 mmol), Pd(PPh3)4 (0.003 g, 0.002 mmol),
CuI (0.001 g, 0.004 mmol), THF (10 mL), and DIPA (20 mL) was
purged with Ar for 45 min. A solution of alkyne 12 (0.025 g, 0.10
mmol) in Ar-purged THF (10 mL) was added via cannula, and the
mixture was stirred overnight at room temperature. The crude mixture
was filtered through a pad of silica (acetone), concentrated, and
purified by preparative TLC (1:3 EtOAc/hexanes) to give 4f (0.025 g,
56%) as a pale yellow solid. The spectroscopic data of this product
matched those described ealier for 4f.
(4) (a) Kimball, D. B.; Weakley, T. J. R.; Herges, R.; Haley, M. M. J.
Am. Chem. Soc. 2002, 124, 13463−13473. (b) Kimball, D. B.; Herges,
R.; Haley, M. M. J. Am. Chem. Soc. 2002, 124, 1572−1573.
(5) (a) Herges, R. Angew. Chem., Int. Ed. Engl. 1994, 33, 255−276.
(b) Herges, R. J. Chem. Inf. Comput. Sci. 1994, 34, 91−102.
(6) Shirtcliff, L. D.; Weakley, T. J. R.; Haley, M. M.; Kohler, F.;
Herges, R. J. Org. Chem. 2004, 69, 6979−6985.
Ketone 17. To a solution of iodide 13 (0.100 g, 0.3 mmol) in THF
(10 mL) cooled to −105 °C was added BuLi (0.13 mL, 2.5 M, 0.325
(7) Shirtcliff, L. D.; Hayes, A. G.; Haley, M. M; Kohler, F.; Hess, K.;
Herges, R. J. Am. Chem. Soc. 2006, 128, 9711−9721.
F
dx.doi.org/10.1021/jo3020374 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(8) Young, B. S.; Koehler, F.; Herges, R.; Haley, M. M. J. Org. Chem.
2011, 76, 8483−8487.
(9) Additional o-ethynylaryltriazene studies: (a) Shirtcliff, L. D.;
Haley, M. M.; Herges, R. J. Org. Chem. 2007, 72, 2411−2418.
(b) McClintock, S. P.; Forster, N.; Herges, R.; Haley, M. M. J. Org.
Chem. 2009, 74, 6631−6636. (c) McClintock, S. P.; Zakharov, L. N.;
Herges, R.; Haley, M. M. Chem.Eur. J. 2011, 17, 6798−6806.
(d) Young, B. S.; Marshall, J. L.; MacDonald, E.; Vonnegut, C. L.;
Haley, M. M. Chem. Commun. 2012, 48, 5166−5168.
(10) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.;
Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.;
Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.;
Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.;
Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J.
B.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev,
O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.;
Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.;
Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen,
W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision
B.04, Gaussian, Inc.: Pittsburgh, PA, 2003.
(11) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648−5652. (b) Lee,
C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785−789.
(12) Corey, E. J.; Fuchs, P. W. Tetrahedron Lett. 1972, 3769−3772.
(13) Kehoe, J. M.; Kiley, J. H.; English, J. J.; Johnson, C. A.; Petersen,
R. C.; Haley, M. M. Org. Lett. 2000, 2, 969−972.
(14) Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Perkin Trans. 1 1977,
869−874.
(15) (a) Droge, T.; Glorius, F. Angew. Chem., Int. Ed. 2010, 49,
̈
6940−6952. (b) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41,
1290−1309.
G
dx.doi.org/10.1021/jo3020374 | J. Org. Chem. XXXX, XXX, XXX−XXX