On the Solvent-Dependent Bromination of Dihydroazulenes

Article abstract of DOI:10.1055/s-0035-1560823

Bromination of 1,8a-dihydroazulene-1,1-dicarbonitriles (DHA) followed by elimination of HBr was previously shown to be an important protocol for functionalizing these molecular photoswitches in the seven-membered ring (at C7). Here we show systematically

Full text of DOI:10.1055/s-0035-1560823

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, 450–454
letter
450
M. D. Kilde et al.
Letter
Synlett
On the Solvent-Dependent Bromination of Dihydroazulenes
Martin Drøhse Kilde
Søren Lindbæk Broman
Anders Kadziola
Br
unpolar
solvent
Br
NC
CN
X = EDG
or
X
Br2
NC
EWG
Mogens Brøndsted Nielsen*
CN
X
CS2
7 examples (yields >99%)
Department of Chemistry, University of Copenhagen,
Universitetsparken 5, 2100 Copenhagen Ø, Denmark
mbn@chem.ku.dk
CN
Br2
X
X: σp 0.23
bromination
controlled by
solvent polarity &
electronic
AcOH
_
<
polar
solvent
Br
5 examples (yields 53–95%)
character of X
Received: 04.09.2015
Accepted after revision: 29.09.2015
Published online: 13.11.2015
Previously, 2-phenyl-1,8a-dihydroazulene-1,1-dicarbo-
nitrile (DHA), a dihydro derivative of azulene, has proven to
act as a precursor for a 1-bromo-3-cyano-substituted azu-
lene, which by palladium-catalyzed reaction with alkynes
can give larger conjugated electron-accepting scaffolds.10
One problem with this procedure is that it cannot be uti-
lized for large-scale preparation of functionalized azulenes,
since the workup requires tedious chromatography.
DOI: 10.1055/s-0035-1560823; Art ID: st-2015-d0695-l
Abstract Bromination of 1,8a-dihydroazulene-1,1-dicarbonitriles
(DHA) followed by elimination of HBr was previously shown to be an im-
portant protocol for functionalizing these molecular photoswitches in
the seven-membered ring (at C7). Here we show systematically how
the outcome of the bromination reaction depends on the electronic
character of an aryl substituent at the C2 position of DHA, and the sol-
vent polarity as the reaction can lead to either the addition product or
to the corresponding 2-aryl-1-bromo-3-cyanoazulene.
The yellow-colored DHA is a photochromic molecule11
that can undergo a light-triggered ring-opening to the iso-
meric, red vinylheptafulvene (VHF), which in turn under-
goes a thermally induced cyclization back to the DHA
(Scheme 1). The back reaction of VHF to DHA is relatively
slow, but enhanced in polar solvents12 and systematically
sensitive to the electronic character of substituents placed
at position 2 and/or 7.12a,13 Hence, the rate of ring-closure
obeys linear free-energy relationships.13
During the past few years, addition of bromine to the
DHA under different conditions has proven to be an effec-
tive way to functionalize the DHA (1 → 2 → 3; Scheme 2),
but also to achieve new azulenes. Thus, in 2007,10 we
showed that an addition of Br2 over the C7–C8 double bond
of DHA in CH2Cl2 and treatment of the resulting dibromide
2f with Bu4NBr yielded 1-bromo-3-cyano-2-phenylazulene
4f. Shortly after, in 2009,14 we reported the regioselective
elimination of HBr upon treatment of the dibromide with
lithium hexamethyldisilazide (LiHMDS), yielding solely the
7-bromo-substituted DHA 3f. The procedure is though lim-
ited to the presence of phenyl or mostly electron-with-
drawing substituents on the 2-position.15 Thus, in terms of
Hammett σ values, para substituents on the phenyl should
have σp ≥ –0.17 (methyl). With the more electron-donating
Key words bromine, conjugation, elimination, solvent effects, cross-
coupling
Azulene (Scheme 1) is a nonbenzenoid aromatic mole-
cule with an intense blue color that can be varied depend-
ing on the nature and position of substituents on the two
fused rings.1–3 Azulene has a dipole moment of 1.0 D4 since
it has a tendency to form a stabilized tropylium cation to-
gether with a cyclopentadienyl anion.5 Due to these proper-
ties, derivatives of azulenes can be utilized for advanced
materials such as conducting polymers,6 nonlinear optical
(NLO) materials,7 charge-transfer complexes,8 and dye-sen-
sitized solar cells (DSSC).9 For example, the good electron
acceptor 2,4,6,8-tetracyanoazulene was shown by Hafner
and co-workers8 to form a charge-transfer complex with
tetrathiafulvalene.
8
AlCl3
or
light
7
NC
NC
CN
Ph
1
8a
CN
Ph
6
2
3a
3
5
4
Δ
azulene
DHA
VHF
methoxy substituent (corresponding to DHA 1h; σp,OMe
=
Scheme 1 Left: numbering of the azulene core. Right: dihydroazulene
(DHA)/vinylheptafulvene (VHF) photoswitch.
–0.27; Scheme 2) the procedure did not majorly yield the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 450–454

451
M. D. Kilde et al.
Letter
Synlett
dibromide 2h, but instead gave a mixture including the azu-
lene 4h and starting material. Bromination of 1h in the po-
lar solvent AcOH gave 4h in 53% yield.15
tution occurs at position 1.18 One recent, convenient proto-
col deserves particular attention, in which iodination of
azulene and heteroazulene derivatives can be achieved
with N-chlorosuccinimide/NaI.19
We believe that azulene formation upon the bromina-
tion of 1h (via an assumed initial attack at C3) in CH2Cl2 or
AcOH instead of bromination of the C7–C8 double bond
originates from the increased electron density at C3 due to
the electron-donating methoxy group.
Herein, we demonstrate a solvent-polarity dependence
in the bromination reaction of multiple DHA 1a–h with
electron-donating and electron-accepting groups on the 2-
position, providing either an extended scope for the syn-
thesis of 7,8-dibromo-substituted DHA 2 (important pre-
cursor for 7-bromo-substituted DHA 3) or the opportunity
for large-scale synthesis of 1-bromo-3-cyano-substituted
azulenes 4 (Scheme 3), with product isolation by simple fil-
tration.
DHA 1a–h were prepared according to our general pro-
cedure15 and were then subjected to bromination reactions.
The product yields of the bromination reaction in different
solvents are listed in Table 1. Gratifyingly, in AcOH, DHAs
1g–d were converted into the corresponding 1-bromo-3-
cyano-azulenes in high yields, like in the case of the me-
thoxy-substituted DHA 1h. All products precipitated from
AcOH and were hence conveniently isolated simply by suc-
tion filtration (some further product may even remain in
the mother liquor) and washing with heptane, which
Br
NC
Br
NC
CN
CN
X
X
Br2
CH2Cl2
1a–h
2a–g
Br2
CH2Cl2
Bu4NBr
X = OMe
CN
LiHMDS
X = H
Br
NC
CN
X
X
Br
4f, h
3a–g
X = p-NO2 (a), p-CN (b), m-I (c), p-Br (d), p-I (e), H (f), p-Me (g), p-OMe (h)
Scheme 2 2-Aryl-1,8a-dihydroazulene-1,1-dicarbonitriles (DHA) as
precursors for 1-bromo-3-cyano-substituted azulenes or 7-bromo-sub-
stituted DHA
A protocol for the bromination at position C3 of DHA
was also developed,16 employing an AlCl3-induced ring-
opening of DHA and a radical bromination of the corre-
sponding VHF with N-bromosuccinimide. The procedure is
for now limited to only two examples (X = H, Me). For more
detailed discussion of the synthesis and functionalization
of DHA, we refer to a recently published review.17 In regard
to halogenation of azulenes, electrophilic aromatic substi-
Br
CN
NC
Br
NC
CN
CN
X
X
X
Br2
Br2
unpolar
solvent
polar
solvent
Br
2a–h
X = p-NO2 (a), p-CN (b), m-I (c), p-Br (d), p-I (e), H (f), p-Me (g), p-OMe (h)
Scheme 3 Bromination of DHA in polar and unpolar solvents
1a–h
4d–h
Table 1 Outcomes of Bromination of DHA in Different Solventsa
22
Reactant
X
σp
Product in CS2
(0.065b)
Yield (%)
Product in CH2Cl2 Yield (%)
(0.309b)
Product in AcOH Yield (%)
(0.648b)
1a
1b
1c
1d
1e
1f
4-O2N
4-CN
3-I
0.78
0.66
0.35c
0.23
0.18
0
2a
2b
>99
>99
2a
2b
>9915
>9915
2a
2b
2c
4d
4e
4f
77
67
67
82
95
81
83
5315
4-Br
4-I
2d
2e
2f
>99
>99
>99
>99
>99
2d
2e
2f
>9915
>9915
>9914
>9915
4-H
1g
1h
4-Me
4-MeO
–0.17
–0.27
2g
2h
2g
4g
4h
a All listed yields are of pure isolated materials.
b Normalized Dimroth–Reichardt ETN solvent-polarity parameter.23
c σm
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 450–454

452
M. D. Kilde et al.
Letter
Synlett
makes the overall synthetic procedure very efficient as the
DHA precursors also can be obtained in large scale without
the need of chromatographic purification.15 As a represen-
tative example, we prepared the product 4g on a two-gram
scale (in 83% yield).20 The structure of 4e was determined
by X-ray crystallography, confirming the position of the
bromo substituent and the completely planar and conjugat-
ed azulene system (Figure 1).
NC
NC
NC
CN
CN
OMe
OMe
5
1h
p-CN-C6H4-B(OH)2
Pd(OAc)2 (5 mol%)
RuPhos (10 mol%)
K3PO4 (2 equiv)
Br2 r.t.
>99%
PhMe/H2O (9:1)
75 °C, overnight
32% (2 steps)
CS2
Br
NC
Br
Br
NC
CN
CN
OMe
OMe
2h
3h
LiHMDS (1 equiv)
THF, 0–25 °C, 1h
Scheme 4 Synthesis of donor-acceptor-functionalized DHA 5
Figure 1 Molecular structure of 4e (crystals grown from CH2Cl2–hep-
tanes, CCDC no. 1421530)21 with displacement ellipsoids at 50% proba-
bility for non-H atoms
For DHA 1a–c, the bromination in AcOH did not lead to
the formation of azulene, but instead the DHA were selec-
tively brominated at the C7–C8 double bond, as with our
well-established procedure in CH2Cl2 at –78 °C. All products
precipitated from AcOH and were hence isolated, for char-
acterization, by filtration.
The various outcomes, product 2 vs. 4, indicate that
there is a correlation between the donating and withdraw-
ing strength of the substituents on the 2-position of DHA
and the polarity of the solvent in the bromination reaction.
To illustrate this, Table 1 includes Hammett substituent
constants (σp)22 for the various substituents and normal-
ized Dimroth–Reichardt solvent parameters (ETN).23
In order to expand the scope of DHA functionalization
Figure 2 Molecular structure of 5 (crystals grown from EtOAc–hep-
tanes, CCDC no. 1421531)21 with displacement ellipsoids at 50% proba-
bility for non-H atoms
It seems that formation of a 1-bromo-3-cyano-substi-
tuted azulene has reached its limit with the bromo-substi-
tuted DHA 1d, i.e. that the substituent should not have a σp
larger than 0.23. Even increasing the solvent polarity from
to also include donating groups such as a methoxy (σp, OMe
=
N
N
–0.27) on the phenyl on the 2-position we turned to the
very unpolar solvent CS2 (ETN = 0.065). Now, the dibromide
2h was successfully isolated as a powder in quantitative
yield.24 It was, however, very unstable and could only be
kept long enough to allow characterization by 1H NMR
spectroscopy. Nevertheless, we managed to convert the di-
bromide into 7-Br DHA 3h using our previously reported
elimination procedure (Scheme 4).14 Subsequently, this 7-Br
DHA was subjected to a palladium-catalyzed Suzuki cross-
coupling25 with 4-cyanophenylboronic acid to give the do-
nor-acceptor-substituted DHA 5 in 32% yield over two
steps. This product was ultimately characterized by X-ray
crystallography (Figure 2), showing the characteristic boat-
shaped conformation of the seven-membered ring with the
C7–C8 double bond out of plane. In addition, the DHA with
neutral and electron-withdrawing substituents on the 2-
position also underwent a clean conversion into the corre-
sponding 7,8-dibromo-DHA when using CS2 as solvent (Ta-
ble 1).
AcOH (ET = 0.648) to MeOH (ET = 0.762) in the bromina-
tion of 1c (X = 3-I, σm = 0.35) did not change the outcome as
the dibromide 2c was the only product formed.
With the novel donor-acceptor DHA 5 in hand, we de-
cided to study its photophysical properties in solution. In-
deed, this 7-substituted DHA underwent a light-induced
(365 nm) ring-opening reaction to form the metastable
VHF in MeCN solution. Both the DHA and VHF showed
characteristic absorptions with λmax at 369 and 478 nm, re-
spectively (Figure 3, top). The VHF in turn underwent a
thermally induced ring-closure to form a mixture of 7- and
6-substituted DHA 5 and 6 (Figure 4) as expected, due to a
known E/Z isomerization around the exocyclic double bond
of the VHF.14,26 This mixture has a redshifted absorption
maximum. By plotting the VHF absorption against time
(first-order kinetics), the rate constant (VHF → DHA) was
determined to be 2.04 ± 0.002·10–5 s–1 (see Supporting In-
formation). This value is in accordance with our recently
published13 Hammett correlation for the ring-closure of
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 450–454

453
M. D. Kilde et al.
Letter
Synlett
VHF to DHA with substituents on both the 2- and 7-posi-
tions where the difference in substituent constants is used
for evaluating the net electronic effect exerted by the sub-
stituents. Using this correlation, we estimate a rate constant
for the ring-closure of 1.81 ± 0.2·10–5 s–1 as shown in Figure
3 (bottom), close to the value actually determined.
products of which the former acts as precursors for bromo-
substituted DHA photoswitches. With the right choice of
solvent, the method ultimately allowed us to prepare a do-
nor-acceptor-functionalized DHA with a 4-MeOC6H4 sub-
stituent at C2 and a 4-NCC6H4 substituent at C7.
Acknowledgment
The Danish Council for Independent Research | Technology and Pro-
duction Sciences (#12-126668) and University of Copenhagen are ac-
knowledged for financial support.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560823.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
(1) Hafner, K. Angew. Chem., Int. Ed. Engl. 1964, 3, 165.
(2) Michl, J.; Thulstrup, E. W. Tetrahedron 1976, 32, 205.
(3) Liu, R. S. H.; Muthyala, R. S.; Wang, X.; Asato, A. E. Org. Lett.
2000, 2, 269.
(4) (a) Wheland, G. W.; Mann, D. E. J. Chem. Phys. 1949, 17, 264.
(b) Anderson, A. G. Jr.; Steckler, B. M. J. Am. Chem. Soc. 1959, 81,
4941.
(5) Möllerstedt, H.; Piqueras, M. C.; Crespo, R.; Ottoson, H. J. Am.
Chem. Soc. 2004, 126, 13938.
(6) Tang, T.; Lin, T.; Wang, F.; He, C. Polym. Chem. 2014, 5, 2980.
(7) Lacroix, P. G.; Malfant, I.; Iftime, G.; Razus, A. C.; Nakatani, K.;
Delaire, J. A. Chem. Eur. J. 2000, 6, 2599.
(8) Schmitt, S.; Baumgarten, M.; Simon, J.; Hafner, K. Angew. Chem.
Int. Ed. 1998, 37, 1077.
(9) Zhang, X.-H.; Li, C.; Wang, W.-B.; Cheng, X.-X.; Wang, X.-S.;
Zhang, B.-W. J. Mater. Chem. 2007, 17, 642.
(10) Petersen, M. Å.; Kilså, K.; Kadziola, A.; Nielsen, M. B. Eur. J. Org.
Chem. 2007, 1415.
(11) (a) Daub, J.; Knöchel, T.; Mannschreck, A. Angew. Chem., Int. Ed.
Engl. 1984, 23, 960. (b) Broman, S. L.; Nielsen, M. B. Phys. Chem.
Chem. Phys. 2014, 16, 21172.
(12) (a) Görner, H.; Fischer, C.; Gierisch, S.; Daub, J. J. Phys. Chem.
1993, 97, 4110. (b) Broman, S. L.; Brand, S. L.; Parker, C. R.;
Petersen, M. Å.; Tortzen, C. G.; Kadziola, A.; Kilså, K.; Nielsen, M.
B. ARKIVOC 2011, (ix), 51.
Figure 3 Top: UV-Vis absorption spectra recorded in MeCN at 25 °C of
pure 7-DHA 5 (solid), its corresponding VHF (dotted), and a mixture of
7- and 6-substituted DHA 5 and 6 (dashed) resulting after a light/heat
cycle. Bottom: Previously published13 Hammett correlation for the ring-
closure of VHF with substituents on both 2- and 7-position (referring to
DHA numbering) used for predicting the rate constant for the ring-clo-
sure reaction forming a mixture of DHA 5 and 6. Through-conjugation
Hammett substituent constants, σp+, were used for the Y substituents.
NC
CN
(13) Broman, S. L.; Jevric, M.; Nielsen, M. B. Chem. Eur. J. 2013, 19,
9542.
NC
OMe
(14) Petersen, M. Å.; Broman, S. L.; Kadziola, A.; Kilså, K.; Nielsen, M.
B. Eur. J. Org. Chem. 2009, 2733.
6
(15) Broman, S. L.; Jevric, M.; Bond, A. D.; Nielsen, M. B. J. Org. Chem.
2014, 79, 41.
Figure 4 6-Substituted DHA isomer 6
(16) Mazzanti, V.; Cacciarini, M.; Broman, S. L.; Parker, C. R.; Schau-
Magnussen, M.; Bond, A. D.; Nielsen, M. B. Beilstein J. Org. Chem.
2012, 8, 958.
(17) Cacciarini, M.; Broman, S. L.; Nielsen, M. B. ARKIVOC 2014, (i),
249.
(18) Anderson, A. G. Jr.; Nelson, J. A.; Tazuma, J. J. J. Am. Chem. Soc.
1953, 75, 4980.
(19) (a) Shoji, T.; Higashi, J.; Ito, S.; Okujima, T.; Yasunami, M.;
Morita, N. Chem. Eur. J. 2011, 17, 5116. (b) Shoji, T.; Ito, S.;
Okujima, T.; Morita, N. Chem. Eur. J. 2013, 19, 5721.
In conclusion, we have shown that bromination of 1,8a-
dihydroazulenes can give either the addition product in the
seven-membered ring or the azulene product with a bromo
substituent in the five-membered ring, depending on the
electronic character of a substituent group at C2 of the
starting material and the polarity of the solvent medium.
The conditions were optimized to promote either of these
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 450–454

454
M. D. Kilde et al.
Letter
Synlett
(20) 3-Bromo-2-(4-methylphenyl)azulene-1-carbonitrile (4g)
A stirred suspension of methyl DHA 1g (2.045 g, 7.564 mmol) in
AcOH (90 mL) under an argon atmosphere, excluded from light,
was warmed to allow dissolution. This solution was allowed to
cool to r.t., whereby a solution of Br2 (9.76 mL, 0.78 M in AcOH,
7.564 mmol) was added dropwise to the dark yellow solution,
which after 10 min resulted in a thick blue precipitate. Next day,
this precipitation was collected by suction filtration and
washed with heptane (300 mL) to afford the title compound as
a blue solid (2.023 g, 6.278 mmol, 83%); mp 214.0–215.5 °C. TLC
(25% heptanes–CH2Cl2): Rf = 0.64. 1H NMR (500 MHz, C6D6): δ =
8.24 (d, J = 9.6 Hz, 1 H), 8.15 (d, J = 9.8 Hz, 1 H), 7.84 (d, J = 7.9
Hz, 2 H), 7.09 (d, J = 7.9 Hz, 2 H), 6.92 (app. t, J = 9.8 Hz, 1 H),
6.71 (app. t, J = 9.8 Hz, 1 H), 6.63 (app. t, J = 9.8 Hz, 1 H), 2.09 (s,
3 H). 13C NMR (126 MHz, C6D6): δ = 151.2, 143.6, 139.7, 139.4,
139.2, 137.5, 136.2, 130.7, 130.6, 129.7, 127.81, 127.79, 116.5,
104.5, 97.7, 21.3 ppm. Anal. Calcd (%) for C18H12BrN (322.20): C,
67.10; H, 3.75; N, 4.35. Found: C, 67.07; H, 3.41; N, 4.24. HRMS
(MALDI+): m/z (%) calcd for [C18H12BrN•+ 79/81Br] 321.0148 (100),
323.0127 (97.3); found: 321.0146 (100), 323.0125 (94.6).
(22) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
(23) Reichardt, C. Solvents and Solvent Effects in Organic Chemistry,
3rd ed.; Wiley-VCH: Weinheim, 2003.
(24) 2-(4′-Methoxy)-7,8-dibromo-7,8,1,8a-tetrahydroazulene-
1,1-dicarbonitrile (2h)
To a stirred solution of methoxy DHA 1h (262 mg, 0.915 mmol)
in CS2 (18 mL) under an argon atmosphere, excluded from light,
a solution of Br2 in CS2 (1.18 mL, 0.915 mmol, 0.78 M) was
added dropwise. After 10 min, the solution took upon a dark
purple color. The solution was stirred for 80 min after which the
solvent was removed with nitrogen gas flow, and the residue
was concentrated under reduced pressure, which gave 2h (408
mg, 0.915 mmol, >99%) as a dark purple solid. 1H NMR (300
MHz, CDCl3): δ = 7.69 (d, J = 8.8 Hz, 2 H), 6.98 (d, J = 8.8 Hz, 2 H),
6.82 (s, 1 H), 6.20 (dd, J = 7.6, 2.1 Hz, 1 H), 6.08 (dd, J = 12.0, 7.6
Hz, 1 H), 5.88 (dd, J = 12.0, 5.7 Hz, 1 H), 5.35–5.29 (m, 1 H),
5.05–5.00 (m, 1 H), 4.63 (br s, 1 H), 3.88 (s, 3 H).
(25) Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866.
(26) (a) Broman, S. L.; Petersen, M. Å.; Tortzen, C. G.; Kadziola, A.;
Kilså, K.; Nielsen, M. B. J. Am. Chem. Soc. 2010, 132, 9165.
(b) Petersen, M. Å.; Broman, S. L.; Kilså, K.; Kadziola, A.; Nielsen,
M. B. Eur. J. Org. Chem. 2011, 1033.
(21) CCDC 1421530 (4e) and CCDC 1421531 (5) contain the supple-
mentary crystallographic data for this paper. The data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/getstructures.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 450–454