Phenanthrene-fused azo-ene-ynes: Synthesis of dibenzo[ f, h ]cinnoline and dibenzo[ e, g ]isoindazole derivatives

Article abstract of DOI:10.1021/jo201378t

The cyclization reactions of a phenanthreno-fused azo-ene-yne compound have been studied both experimentally and computationally. Experimental results show that this system is prone to dimerization, more so than previously studied naphthalene- and benzene-based analogues. Calculations reveal that pyrazoles and arene-fused pyrazoles strongly stabilize carbenes in the 5-position through coarctate conjugation, suggesting a stationary concentration of the carbenes/carbenoids during cyclization that is high enough for dimerization.

Full text of DOI:10.1021/jo201378t

NOTE
pubs.acs.org/joc
Phenanthrene-Fused Azo-ene-ynes: Synthesis of Dibenzo[f,h]cinnoline
and Dibenzo[e,g]isoindazole Derivatives
Brian S. Young,† Felix K€ohler,‡ Rainer Herges,*,‡ and Michael M. Haley*,†
†Department of Chemistry, University of Oregon, Eugene, Oregon 97403-1253, United States
‡Institut f€ur Organische Chemie, Universit€at Kiel, 24098 Kiel, Germany
S Supporting Information
b
ABSTRACT: The cyclization reactions of a phenanthreno-fused
azo-ene-yne compound have been studied both experimentally and
computationally. Experimental results show that this system is
prone to dimerization, more so than previously studied naphtha-
lene- and benzene-based analogues. Calculations reveal that pyr-
azoles and arene-fused pyrazoles strongly stabilize carbenes in the
5-position through “coarctate conjugation”, suggesting a stationary concentration of the carbenes/carbenoids during cyclization that
is high enough for dimerization.
uring the past decade, there has been increased interest in
the cyclization of “ene-ene-yne” compounds to produce
protected acetylene 9, which was then desilated to give terminal
acetylene 5 in 14% overall yield for the five steps.
D
aromatic heterocycles in high yields.1 Specifically, we have been
examining the dual reaction pathways of conjugated azo-ene-ynes
(e.g., 1, Scheme 1)2À6 in which a cinnoline (2) is formed under
thermal conditions via a pericyclic mechanism or an isoindazole
(3) is formed in the presence of a carbene-stabilizing transition-
metal salt via a coarctate mechanism.7 While we have expended
significant efforts exploring the scope and limitations of these reac-
tions,2À6,8À10 our synthetic and computational studies have focused
predominantly on benzo-fused heterocycles (a in Scheme 1).
Motivated by potential optical and electronic applications
of larger heteroaromatic compounds, we recently reported the
dual cyclization of naphtho-fused azo-ene-ynes.11 As anticipated,
naphthalene-based systems 1b and 1c afforded the desired
benzocinnolines 2b and 2c under thermal conditions (Scheme 1).
Addition of carbene/carbenoid stabilizers furnished the desired
isoindazolecarbaldehydes 3b,c; however, the unanticipated di-
mers 4b,c were also produced in low to moderate yield. Although
we have previously observed dimers based on 4a, they are
typically not generated under the “optimized” coarctate reaction
conditions.2c Formation of 4b,c could be suppressed by saturat-
ing the reaction mixture with O2 prior to the addition of the
transition-metal salt.11 To further explore the utility of our dual
cyclization methodology, we report herein the synthesis and
cyclization of phenanthrene-fused azo-ene-yne 5. This study will
illustrate a surprisingly high propensity for dimer formation via a
more stable carbene/carbenoid intermediate, results that are
corroborated computationally.
Thermolysis of 5 at 200 °C in o-dichlorobenzene (ODCB)
generated unknown dibenzo[f,h]cinnoline 1014 in 58% yield
(Scheme 3). Treatment of 5 with excess CuCl in O2-saturated
1,2-dichloroethane (DCE) gave dibenzo[e,g]isoindazolecarbaldehyde
11 at best in 17% yield along with a trans/cis mixture of dimer 12
as the major product in 38% isolated yield. Compound 12 was
the sole product (49%) when catalytic Rh2(OAc)4 was used to
effect the cyclization. A proton NMR spectrum of the crude
material showed that the trans dimer (alkene proton singlet at
8.37 ppm) was the major isomer initially along with a small
amount (∼6:1 trans/cis) of the cis dimer (singlet at 7.37 ppm);
however, attempted separation/purification resulted in partial
isomerization, leading to an inseparable 2:1 trans/cis mixture of
12.15 Interestingly, using CuCl with diphenyl sulfoxide (DPSO)
as the oxygen atom source16 afforded only aldehyde 11 in 62%
yield. Even when used in excess, CuCl represents a cheaper
alternative to the Ph3PAuCl/AgSbF6 catalytic system recently
reported by Toste et al. to mediate this transformation.16
The above experimental results suggest that upon expanding
the aromatic system from benzo to naphtho to phenanthro fusion,
there is an increasing propensity for the carbene/carbenoid to
dimerize rather than to react with O2 to form the aldehyde.
Seeking answers to these observations, we examined the reaction
computationally. The DFT-calculated energies (B3LYP/6-31G* +
ZPE) for the cyclizations of 1aÀc and 5 are shown in Table 1,
with a representative energy diagram given in Figure 1.17 While
the transition state energies are similar for the syn conforma-
tion of the coarctate reaction, both the anti conformer and the
pericyclic TS energies become smaller with increasing size of
the fused ring (ΔE ca. 3À4 kcal molÀ1). The differences are
The synthesis of starting triazene 5isshowninScheme2.Nitration
of commercially available 9-bromophenanthrene afforded 6, which
was subsequently reduced with iron powder in the presence of acetic
acid to give bromoaniline 7.12 Diazotization of 7 with BF3 Et2O
3
and t-BuONO followed by quenching with HNEt2 furnished
Received: July 2, 2011
Published: September 22, 2011
triazene 8.13 Sonogashira cross-coupling of 8 with TMSA afforded
r
2011 American Chemical Society
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NOTE
Scheme 1. Cyclization Reactions of Triazene-ene-ynes 1aÀc
Scheme 3. Cyclization of Phenanthrene-Fused Azo-ene-yne 5
Table 1. DFT (B3LYP/6-31G* + ZPE)-Calculated Energies
for the Cyclization Reactions of 1aÀc and 5
mechanism/orientation
Scheme 2. Synthesis of Phenanthrene-Fused Azo-ene-yne 5
1aaÀc
1ba,b
1ca,b
5a,b
pericyclic zwitterion
syn carbene
15.01
26.07
28.69
30.30
30.60
31.58
11.00
23.49
24.68
28.84
29.28
29.50
9.73
26.19
24.68
28.10
30.70
29.41
7.62
24.47
21.94
27.04
29.47
27.75
anti carbene
pericyclic TS
coarctate syn TS
coarctate anti TS
a kcal molÀ1 b NEt2 replaced by NMe2 in computations. Values are
.
c
2.14 kcal molÀ1 lower than in ref 6 as the reactive conformation is
defined as 0 in Figure 1.
nonannelated reference model systems (Figure 2) was calculated
using DFT (UB3LYP/6-31G*).
The hydrogenation energy of the carbenes to the correspond-
ing methyl derivatives was calculated to ascertain if there is a
significant thermodynamic stabilization associated with the
coarctate position of the carbene (Table 2). To elucidate the
nature of interaction with the neighboring π system, we com-
pared the hydrogenation of our pyrazole substituted title car-
benes (IaÀIIIa) with the corresponding open-chain compounds
(IbÀIIIb) and with the corresponding phenyl-, naphthyl-, and
phenanthryl-substituted systems (IcÀIIIc). Whereas the phenyl
and open-chain derivatives are triplet ground states, the hetero-
cyclic systems with the carbene center in the coarctate position
are singlet carbenes. The hydrogenation energies indicate that
the singlet state of the heterocyclic coarctate carbenes is strongly
stabilized. For example, the isoindazole ring system in IIa is able
to stabilize the singlet state of a neighboring carbene center
roughly 16À17 kcal molÀ1 more efficiently than a corresponding
open-chain π system ((E)-4-iminobut-2-en-2-amine, IIb) and
9À10 kcal molÀ1 more than a naphthyl group (IIc). Solvent effects
(polarizable continuum model, dichloromethane ε = 10.125,
Table 2) are small and do not change the relative stabilities.
We attribute the unusually large stabilization of our hetero-
cyclic singlet carbenes to “coarctate conjugation”. The carbene is
amplified in the intermediates, with the anti carbene and
zwitterion intermediates 6.7 and 7.4 kcal molÀ1, respectively,
lower in energy going from benzo to phenanthro fusion. A likely
explanation for the lower energies and thus increased stability is
the reduced aromaticity/delocalization of the fused bond. The
9,10-bond of phenanthrene is well-known to have appreciable
double bond character and often reacts like a typical alkene.
The unexpected tendency of the intermediate carbenes to
form dimers caused us to further investigate their electronic
structure and thermodynamic energetic stability. One hypothesis
was that the carbenes might be lower in energy, lasting longer in
solution and thus giving them more time to find another carbene
with which to dimerize. To probe this, a set of annelated and
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Figure 1. DFT (B3LYP/6-31G* + ZPE)-calculated energies for the dual cyclization pathways of 5.
Table 2. DFT (B3LYP/6-31G*)-Calculated SingletÀTriplet
Gap Energies (ΔEst), Hydrogenation Energies (ΔEhyd) of the
Carbenes, and HOMO Energies of the Hydrogenated Model
Compounds
carbene model
systemsa
CcarbeneÀCb ΔEhyd ΔEhyd,solv
ΔEst HOMOf
c
c,d
e
pyrazole carbenes
Ia (anti)
1.403
1.390
1.392
À99.37 À99.46
1.89 À6.31
2.93 À5.36
2.17 À5.58
IIa (anti)
À93.57 À93.66
À94.81 À96.71
IIIa (anti)
open chain analogues
Ib (syn)
1.438
1.446
1.424
À108.11 À108.31 À5.13 À5.15
À110.14 À110.47 À11.97 À4.63
À105.81 À106.62 À9.47 À4.85
IIb (syn)
IIIb (anti)
phenyl derivatives
Ic (anti)
1.432
1.423
1.405
À105.69 À104.09 À4.10 À6.40
À103.60 À102.34 À4.37 À5.67
À98.64 À98.74 À4.31 À5.75
IIc (anti)
IIIc (anti)
a An extensive conformational search including syn and anti conformations
of the carbenes was performed, and only the energetically most stable
conformers are included in this table. b Bond length (Å) between the carbene
center and the neighboring carbon atom. c The hydrogenation energies
(ΔEhyd, kcal molÀ1) were obtained computationally as the reaction energy of
the singlet carbenes with molecular hydrogen. d Hydration enthalpies in
solvent DCE calculated using a polarizable continuum model with ε = 10.125
Figure 2. Model analogues of the intermediate carbenes generated by
the coarctate cyclization of azo-ene-ynes.
generated by an endothermic, coarctate cyclization and therefore
part of the electronic wave function of the reactant mixes into the
carbene wave function, as depicted in terms of valence bond
structures in Figure 3.18 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 (CcarbeneÀC bond in Table 2).
It is well-known that the singlet states of carbenes with π
substituents are stabilized by an interaction of the carbene empty
p orbital (LUMO) and the HOMO (and other occupied π MOs)
of the π substituents, which also leads to shorter CcarbeneÀC
bonds. The strength of interaction increases with increasing
HOMO energy (decreasing LUMOÀHOMO energy difference).
as implemented in Gaussian09. e The singletÀtriplet gap (ΔEst, kcal molÀ1
)
is given as the relative energy of the T0 electronic state with respect to
the S0 singlet state of the corresponding geometry-optimized carbene.
f Energy (eV) of the highest occupied orbital in the hydrogenated carbene.
This mode of interaction, however, obviously does not account
for the significant stabilization of our coarctate carbenes, since we
make comparison with reference carbenes that are π substituted
as well. Moreover, the HOMO energies in the open-chain analogues
are significantly higher than those in the coarctate carbenes;
nevertheless, the CcarbeneÀC bonds are longer, and the stabiliza-
tion is lower.
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NOTE
150.6, 132.1, 130.6, 128.4, 128.3, 127.4, 127.1, 127.0, 126.4, 125.6, 124.9,
122.5, 122.4, 107.3, 102.4, 101.0, 48.9, 41.2, 14.1, 11.0, 0.2; HRMS (EI+) for
C23H27N3Si calcd 373.1974, found 373.1971.
Ethynyltriazene 5. A suspension of 9 (0.050 g, 0.134 mmol) and
K2CO3 (0.185 g, 1.34 mmol) in THF (5 mL) and MeOH (1 mL) was
stirred for 15 min. The solids were removed by filtration, and the solvent
was removed under reduced pressure. The crude material was dissolved
in EtOAc and washed with aq NH4Cl solution (2Â), H2O (3Â), and
brine (3Â). The organic layer was dried (MgSO4), filtered, and con-
centrated in vacuo to yield the free acetylene (0.036 g, 90%) as a yellow
solid: 1H NMR (300 MHz, CDCl3) δ 8.64 (dd, J = 11.9, 4.6 Hz, 2H),
8.50 (dd, J = 7.9, 1.6 Hz, 1H), 8.23 (dd, J = 8.3, 1.2 Hz, 1H), 7.72À7.55
(m, 4H), 3.92 (q, J = 6.9 Hz, 4H), 3.43 (s, 1H), 1.41 (t, J = 6.9 Hz, 6H);
13C NMR (75 MHz, CDCl3) δ 151.1, 132.1, 130.7, 128.4, 128.3, 127.5,
127.1, 126.9, 126.5, 125.7, 124.9, 122.5, 122.4, 106.1, 83.6, 81.1, 48.9, 41.4,
14.1, 11.1; HRMS (EI+) for C20H19N3 calcd 301.1579, found 301.1592.
Dibenzo[f,h]cinnoline 10. Triazene 5 (0.06 g, 0.2 mmol) was
dissolved in ODCB (8 mL) in a screwtop pressure reaction vessel. The
sealed vessel was placed in a preheated 200 °C sand bath. The reaction
was stirred overnight and then cooled to rt. Removal of solvent in vacuo
followed by preparative TLC (EtOAc) yielded cinnoline 10 (0.026 g,
58%) as a brown solid: 1H NMR (300 MHz, CDCl3) δ 9.56 (dd, J = 7.2,
2.1 Hz, 1H), 9.43 (d, J = 5.6 Hz, 1H), 8.62À8.47 (m, 3H), 8.38 (d, J = 5.6
Hz, 1H), 7.84À7.71 (m, 3H), 7.66 (dt, J = 6.9, 1.2 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 148.7, 148.2, 131.5, 131.2, 130.4, 130.2, 128.6,
128.3, 127.8, 126.1, 125.6, 125.2, 124.3, 123.6, 122.7, 118.4; UVÀvis
(CHCl3) λmax (ε) 258 (75,300), 280 (18,600) nm; HRMS (EI+) for
C16H10N2 calcd 230.0844, found 230.0845.
Figure 3. Mesomeric stabilization of a coarctate carbene, which is not
operative for the analogous six-membered ring aromatic carbenes.
Whereas the coarctate stabilization explains the unusual mode
of reaction (dimerization, reaction with oxygen) of our coarctate
carbenes, our calculations do not reproduce the higher propen-
sity for dimerization of the dibenzo[e,g]isoindazole system as
compared to the benzoisoindazole- and isoindazole-substituted
carbenes. Small differences in energies lead to relatively large shifts
in equilibria. Coordination to the catalyst and different activation
barriers for the carbene dimerization, which are not included in
our calculations, are likely responsible for the different reactivity of
the various arene-annelated isoindazole carbenes.
In conclusion, we have prepared the first examples of dibenzo-
[f,h]cinnoline and dibenzo[e,g]isoindazole derivatives and
shown that the carbene intermediates for the latter systems have
a strong propensity to dimerize. Calculations indicate that these
pyrazole-based carbenes are stabilized through coarctate con-
jugation. Given that we are mainly interested in monomeric species,
future efforts will focus on alternative pericyclic and coarctate
azo-ene-yne cyclization routes to access heteroacene-like structures.
Dibenzo[e,g]isoindazolecarbaldehyde 11. A mixture of 5
(0.025 g, 0.01 mmol), diphenyl sulfoxide (0.201 g, 0.1 mmol), and
CuCl (0.098 g, 0.1 mmol) in DCE (10 mL) was stirred at 50 °C for 2.5 h.
After cooling, the mixture was filtered through a short pad of silica and
thesolventremoved under reduced pressure. Preparative TLC(CH2Cl2)
yielded isoindazole 11 (0.016 g, 62%) as a tan solid: 1H NMR
(300 MHz, CDCl3) δ 10.69 (s, 1H), 9.60À9.54 (m, 1H), 8.69À8.57
(m, 3H), 7.73À7.62 (m, 4H), 3.68À3.54 (m, 2H), 3.35À3.21 (m, 2H),
0.95 (t, J = 7.1 Hz, 6H); 13C NMR (151 MHz, CDCl3) δ 183.1, 130.7,
130.0, 128.4, 127.8, 127.51, 127.48, 127.3, 126.4, 124.9, 123.3, 123.3,
115.9, 52.6, 12.1; UVÀvis (CHCl3) λmax (ε) 299 (1,840), 335
(1,270) nm; HRMS (EI+) for C20H19N3O calcd 317.1528, found
317.1523.
Dibenzo[e,g]isoindazole Dimer 12. A solution of 5 (0.030 g,
0.01 mmol) in DCE (10 mL) was purged with Ar for 45 min. Rh2OAc4
(0.0022 g, 0.005 mmol) was added and the mixture stirred at 50 °C for
90 min. After cooling, the mixture was filtered through a short pad of
silica and the solvent removed under reduced pressure, affording crude
dimer 12 as a 6:1 trans/cis mixture. Preparative TLC (1:9 EtOAc/
hexanes) yielded pure dimer 12 (0.015 g, 49%) as a 2:1 trans/cis
mixture. trans-12: 1H NMR (300 MHz, CDCl3) δ 8.79 (m, 2H), 8.61
(m, 6H), 8.39 (s, 2H), 7.65 (m, 4H), 7.55 (m, 4H), 3.60 (br s, 4H), 3.36
(br s, 4H), 1.05 (t, J = 7.2 Hz, 12H). trans-12 isomerized to the 2:1
mixture upon purification, thus precluding definitive 13C NMR data of
this isomer: UVÀvis (CHCl3) λmax (ε) 341 (22,500), 365 sh (19,700),
385 sh (15,500), 410 (7,260) nm; HRMS (EI+) for C40H38N6 calcd
602.3158, found 602.3171.
’ EXPERIMENTAL SECTION
General Methods. These have been described previously in ref 4.
Bromotriazene 8. To a flame-dried flask was added BF3 OEt2
3
(4.0 mL, 32.6 mmol) under an Ar atmosphere, and the flask was cooled
to À20 °C. A solution of 712 (2.22 g, 8.16 mmol) in dry THF (33 mL) was
added slowly such that the internal temperature stayed below À10 °C.
After complete addition, a solution of t-BuONO (3.4 mL, 28.6 mmol) in
dry THF (27 mL) was added dropwise. The reaction was stirred for an
additional 10 min at À20 °C and then warmed to 5 °C over a period of
20 min. Pentane was added, and the green precipitate that formed was
isolated by suction filtration. The solid was then added in one portion to
a stirred suspension of K2CO3 (5.64 g, 40.8 mmol) and HNEt2 (8.4 mL,
81.6 mmol) in DMF (150 mL) at 0 °C and stirred for 2 h. The reaction
was diluted with EtOAc and washed with aq NH4Cl solution (2Â) and
brine (5Â). The organic layer was dried (MgSO4) and filtered and the
solvent removed in vacuo. The crude material was purified by flash
chromatography (1:19 EtOAc/hexanes) to yield bromotriazene 8 (1.71 g,
59%) as a red solid: 1H NMR (300 MHz, CDCl3) δ 8.67 (t, J = 9.0 Hz,
2H), 8.51 (dd, J = 7.9, 1.3 Hz, 1H), 7.94 (dd, J = 8.2, 0.9 Hz, 1H), 7.73À
7.53 (m, 4H), 3.93 (br s, 4H), 1.42 (br s, 6H); 13C NMR (75 MHz,
CDCl3) δ 145.7, 131.3, 130.4, 129.7, 129.3, 128.2, 127.6, 127.0, 126.9,
126.2, 124.9, 122.9, 122.6, 113.5, 49.2, 41.6, 15.1, 11.6; HRMS (EI+) for
C18H18BrN3 calcd 355.0684, found 355.0667.
Silyltriazene 9. A mixture of 8 (0.83 g, 2.3 mmol), CuI (0.018 g, 0.09
mmol), and Pd(PPh3)2Cl2 (0.033 g, 0.045 mmol) was dissolved in THF
(11 mL) and HN-i-Pr2 (11 mL). The solution was purged with Ar for 45
min at rt after which TMSA (3.3 mL, 23.3 mmol) was added. The flask was
stirred overnight at 80 °C. After being cooled to rt, the mixture was run
through a short pad of silica and the solvent removed in vacuo. The crude
material was purified by flash chromatography (1:9 EtOAc/hexanes) to
yield the TMSethynyltriazene 9(0.641 g, 75%) as an orange solid: 1HNMR
(300 MHz, CDCl3) δ8.64 (dt, J= 6.0, 0.9 Hz, 2H), 8.48 (dd, J= 6.6, 1.5 Hz,
1H), 8.20 (dd, J = 8.1, 1.1 Hz, 1H), 7.71À7.53 (m, 4H), 3.93 (q, J = 7.0 Hz,
4H), 1.41 (t, J = 7.0 Hz, 6H), 0.31 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
’ ASSOCIATED CONTENT
S
Supporting Information. All computational details in-
b
cluding Cartesian coordinates, total energies, and imaginary
frequencies for all computed structures as well as transition state
analysis; copies of H and 13C NMR spectra for 5 and 8À12;
1
X-ray data for trans-12(CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
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NOTE
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: haley@uoregon.edu; rherges@oc.uni-kiel.de.
’ ACKNOWLEDGMENT
We thank the National Science Foundation (CHE-1013032)
for support of this research as well as for support in the form of
instrumentation grants (CHE-0639170 and CHE-0923589). We
thank Dr. Lev N. Zakharov for obtaining the X-ray structure of
trans-12. MS were obtained at the Mass Spectrometry Facilities
and Services Core of the Environmental Health Sciences Center,
Oregon State University, supported by Grant No. P30-ES00210,
National Institute of Environmental Health Sciences, National
Institutes of Health.
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(14) A SciFinder search claims that 10 is a known molecule
(Hughes, A. N.; Prankprakma, V. Tetrahedron 1966, 22, 2053–2058);
however, inspection of the original article reveals that the cinnoline in
the paper is actually dibenzo[f,h]phenanthro[9,10-c]cinnoline, not 10.
(15) An X-ray structure analysis confirmed that trans-12 was indeed
the major isomer and thus the source of the proton singlet at 8.37 ppm;
see the Supporting Information for structural details.
(16) Witham, C. A.; Mauleꢀon, P.; Shapiro, N. D.; Sherry, B. D.;
Toste, F. D. J. Am. Chem. Soc. 2007, 129, 5838–5839.
(17) In our model calculations, complexation with transition metals
salts (e.g., Cu(I), Rh(II)) was not included, as the computed transition-
state structures and the exact mechanism(s) under experimental condi-
tions become much more complicated; see ref 5 as an example.
(18) Similar effects were theoretically predicted in enediynes react-
ing to 1,4-benzynes via Bergman cyclization; see: Galbraith, J. M.;
Schreiner, P. R.; Harris, N.; Wei, W.; Wittkopp, A.; Shaik, S. Chem.—
Eur. J. 2000, 6, 1446–1454.
8487
dx.doi.org/10.1021/jo201378t |J. Org. Chem. 2011, 76, 8483–8487