Synthesis of cyclic azobenzene analogues

Article abstract of DOI:10.1016/j.tet.2012.06.007

Reaction of 2,20-dinitrodibenzyl with lead metal powder in the presence of a basic triethylammonium formate buffer gave a cyclic azoxybenzene, 11,12 dihydrodibenzo[c,g][1,2]diazocine-5-oxide. The latter compound was converted into cyclic azobenzene and analogues (chloro-, bromo-, and cyano-) through subsequent transformations. Hydrolysis of the cyano cyclic azobenzene gave the corresponding carboxylic acid. This carboxylic acid was finally reacted with D-threoninol to give the corresponding amide, which readily undergoes photoisomerization upon illumination with light.

Full text of DOI:10.1016/j.tet.2012.06.007

Tetrahedron 68 (2012) 8670e8676
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Tetrahedron
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Synthesis of cyclic azobenzene analogues
,
Dhruval K. Joshi a, Matthew J. Mitchell a, Doug Bruce b, Alan J. Lough c, Hongbin Yan a
*
a Department of Chemistry, Brock University, 500 Glenridge Ave., St. Catharines, ON L2S 3A1, Canada
b Department of Biological Sciences, Brock University, 500 Glenridge Ave., St. Catharines, ON L2S 3A1, Canada
c Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada
a r t i c l e i n f o
a b s t r a c t
Reaction of 2,20-dinitrodibenzyl with lead metal powder in the presence of a basic triethylammonium
formate buffer gave a cyclic azoxybenzene, 11,12-dihydrodibenzo[c,g][1,2]diazocine-5-oxide. The latter
compound was converted into cyclic azobenzene and analogues (chloro-, bromo-, and cyano-) through
subsequent transformations. Hydrolysis of the cyano cyclic azobenzene gave the corresponding
Article history:
Received 25 April 2012
Received in revised form 1 June 2012
Accepted 4 June 2012
Available online 12 June 2012
carboxylic acid. This carboxylic acid was finally reacted with
amide, which readily undergoes photoisomerization upon illumination with light.
Ó 2012 Elsevier Ltd. All rights reserved.
D-threoninol to give the corresponding
Keywords:
Azo compounds
Azoxybenzene
Cyclic azobenzene
Isomerization
Photoswitch
1. Introduction
As can be seen from Fig. 2a, the (E)-azobenzene isomer displays
a strong absorption band at 318 nm and another weak absorption
band at 432 nm. The (Z)-isomer has two absorption bands, a strong
absorption at 260 nm and a weak absorption at 440 nm. There is an
obvious overlap in the absorption of the two isomers, and as such,
isomerization of this system is not very efficient. Furthermore, al-
though it is possible to derivatize azobenzene to achieve bi-
directional switching without UV light,11 the isomerization of the
unmodified azobenzene generally necessitates irradiation by light
in the UV region, which readily causes damages to biomolecules,
particularly nucleic acids through photodamage. In addition, azo-
benzene has relatively low quantum yields for direct photo-
isomerization (trans/cis and cis/trans).12
Among the many azobenzene analogues known in the literature,
the cyclic (or ‘bridged’) azobenezene 5,6-dihydrodibenzo[c,g][1,2]
diazocine 2 where the benzene rings are constrained with an eth-
ylenic bridge is of particular interest. In this system, the (Z)-isomer
is the more stable isomer, instead of the (E)-isomer in azobenzene,
and it can be transformed into the (E)-isomer with an efficiency
greater than 90% by irradiation with blue light (370e400 nm). The
(E)-isomer can be switched back to the (Z)-isomer with virtually
quantitative efficiency by illumination with green light
(480e550 nm) (Figs. 2b and 3).14 In addition, this system is likely to
be better tolerated in biological systems as irradiation wavelengths
are shifted away from the UV region.
Aromatic azo compounds possess a conjugate system that can
be readily ‘tuned’ through structural modifications to adjust their
chemical and photochemical properties, and have thus found wide
applications as dyes and pigments, food additives, radical initiators,
therapeutic agents, as well as functional materials.1e4 In addition,
some aromatic azo compounds, such as azobenzene 1, have been
shown to undergo photo- and thermoisomerization, where the E-
and Z-isomers oscillate back and forth when excited by light of
selected wavelength or heat (Fig. 1). This latter phenomenon has
been exploited as a useful photoswitch where a signal can be in-
duced by light and harnessed.5,6 One such application involves the
incorporation of azobenzene into biomolecules, such as proteins
and nucleic acids to trigger conformational changes to the bio-
molecules that impact their functions.7e10
Fig. 1. EeZ isomerization of azobenzene.
Considerable interest has been invested towards understanding
this new photoswitch, particularly from the theoretical point of
view.15e20 What has been challenging with this system is the
* Corresponding author. Tel.: þ1 905 688 5550x3545; fax: þ1 905 682 9020;
e-mail address: tyan@brocku.ca (H. Yan).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.007

D.K. Joshi et al. / Tetrahedron 68 (2012) 8670e8676
8671
When 2,20-dinitrodibenzyl 3 was treated with zinc powder under
neutral pH, cyclic hydrazine 4 (5,6,11,12-tetrahydro-dibenzo[c,g]
[1,2]diazocine) was formed in moderate yields (up to 70%); how-
ever, this transformation was found to be highly dependent on the
surface properties and/or impurity of zinc powder, as use of newer
batches of zinc powder only gave 4 in very low yields (<5%). Work
is currently underway to investigate the causes of this discrepancy.
On the other hand treatment of 2,20-dinitrodibenzyl 3 with lead
metal at pH 9.5 in methanol gave cyclic azoxybenzene 5 (11,12-
dihydrodibenzo[c,g][1,2]diazocine-5-oxide) in moderate yields
(61%) (Scheme 1). It was noted that a rather efficient method to
prepare this cyclic azoxybenzene 5 from the N-nitrosohydroxyl-
amine ammonium salt of 2,20-dinitrodibenzyl was previously
documented.28 This literature procedure was not used in the
present study as it necessitates an extra step from a commercially
available compound.
The azoxybenzene 5 was subsequently transformed into the
corresponding bridged azobenzene 2 in 59% yield through catalytic
deoxygenation using triphenylphosphine as oxygen acceptor in the
presence of a molybdenum catalyst.29,30 Structure of the cyclic
azobenzene 2 was confirmed by X-ray crystallography, where the
ethylene bridge is disordered over two sets of sites with refined
occupancies of 0.552 (14) and 0.448 (14) (Fig. 4a). The azox-
ybenzene 5 also undergoes concomitant deoxygenation and halo-
genation when treated with aluminium halide (chloride or
bromide) in carbon disulfide31 to give the corresponding chloro (6)
or bromo (7) analogues in poor yields (8 and 9% for the 6 and 7,
respectively). It was found, however, that azoxybenzene 5 can be
brominated with bromine32 to give the corresponding bromoa-
zoxybenzene
8 (2-bromo-11,12-dihydrodibenzo[c,g][1,2] diazo-
cine-6-oxide) in 70% yield. The identity of bromoazoxybenzene 8
was established by X-ray crystal structure (Fig. 4b), where two in-
dependent molecules with slightly different conformations were
found in the asymmetric unit. Interestingly, treatment of bromoa-
zoxybenzene 8 with triphenylphosphine and the molybdenum
catalyst failed to give cyclic bromoazobenzene 7.
Fig. 2. UV/vis absorption spectra of (a). azobenzene 1 (solid line: (Z)-isomer; dash line:
(E)-isomer) (reprinted with permission from Zimmerman, G.; Chow, L.-Y.; Paik, U.-J. J.
Am. Chem. Soc. 1958, 80, 3528e3531.13 Copyright 1958 American Chemical Society); (b).
cyclic azobenzene 2 (solid line: (Z)-isomer; dash line: (E)-isomer) (reprinted with
When bromoazoxybenzene 8 was treated with copper (I) cya-
nide,34 the corresponding cyanoazoxybenzene 9 was obtained in
69% yield. Treatment of the latter compound 9 with aluminium and
hydrazine hydrate35 gave a mixture of cyclic cyanoazobenzene 11
and the over-reduced hydrazine 10, with the latter being a major
product. The hydrazine 10 can be transformed into corresponding
cyclic cyanoazobenzene 11 by treating with titanium (III) chloride,
hydrobromic acid and hydrogen peroxide.36 Finally, cyclic cyanoa-
zobenzene 11 was hydrolyzed under basic conditions to give the
corresponding carboxylic acid 12 in 78% yield. This carboxylic
€
permission from Siewertsen, R.; Neumann, H.; Buchheim-Stehn, B.; Herges, R.; Nather,
C.; Renth, F.; Temps, F. J. Am. Chem. Soc. 2009, 131, 15594.14 Copyright 2009 American
Chemical Society).
compound was readily condensed with D-threoninol using dicy-
clohexylcarbodiimide as activator in the presence of N-hydrox-
ysuccinimide. Work is currently underway in our laboratory to
incorporate cyclic azobenzene into biomolecules using analogue
13. When the amide 13 was subjected to LED irradiation at either
380 or 400 nm (the LED light source spansꢀ5 nm), a clear colour
change from yellow (the (Z)-isomer) to red (the (E)-isomer) was
observed (Fig. 5).
Extents of photoisomerization can be qualitatively determined
by HPLC (Fig. 6). As can be seen in Fig. 6a and b, when the un-
modified cyclic azobenzene 2 was subjected to irradiation with LED
light at 380ꢀ5 nm for 2 h, 90% of the (Z)-isomer was converted to
the (E)-isomer (Fig. 6b). The extent of the isomerization of 2 is
consistent with yield reported in the literature.14 Under the same
conditions, approximately 70% of (Z)-isomer of amide 13 was
converted to the corresponding (E)-isomer (Fig. 6c and d).
The UV/vis spectra of (Z)-13 and the isomerization product
(with an approximate Z/E ratio of 30:70) are shown in Fig. 7a.
Compared with the UV/vis spectra of (Z)-2 and the corresponding
isomerization product (with an approximate Z/E ratio of 10:90)
Fig. 3. Isomerization of the cyclic azobenzene.
extremely poor efficiency of its synthesis (4%) from 2,20-dini-
trodibenzyl14,21,22 and thereafter the lack of effective methods for
further modification, which would be of particular concern if
this system were to be incorporated into biomolecules as
a photoswitch. We report herein the transformation of 2,20-
dinitrodibenzyl into cyclic azobenzene and analogues, which
would allow for further incorporation of this cyclic azobenzene into
other molecules.
2. Results/discussion
Although a number of approaches were reported for the syn-
thesis of azo- from arylnitro-compounds with high efficiency,23e27
treatment of 2,20-dinitrodibenzyl 3 under these conditions has in-
variably failed to give the cyclic azobenzene 2 in sufficient yields.

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D.K. Joshi et al. / Tetrahedron 68 (2012) 8670e8676
Scheme 1. Reagents and conditions: (i). Pb, pH 9.5, MeOH; (ii). Zn, pH 7.0, EtOH; (iii). TiCl3, aq. HBr, H2O2; (iv). Ph3P, MoCl2O2 (dmf) 2, THF; (v). AlCl3, CS2; (vi). AlBr3, CS2; (vii). Br2,
CH3COOH; (viii). CuCN, DMF; (ix). Al, NH2NH2; (x). (a). KOH, EtOH, H2O, reflux; (b). aq. HCl; (xi). D-threoninol, DCC, N-hydroxysuccinimide, DMF.
(Fig. 7b), the maximal absorption wavelengths for (Z)-2 and (Z)-13
are the same (at 400 nm), whereas that of (E)-13 shifted from 483
nm for (E)-2 to 487 nm.
light. Incorporation of this building block into oligonucleotides
through the phosphoramidite chemistry8 is currently underway in
this laboratory.
The time course of (Z)/(E)-13 isomerization was followed by
measuring the percentage transmission at 480 nm of the methanol
solution exposed to 380 nm LED light over time. After the trans-
mission reached the minimum, the solution is illuminated at
480 nm and the transmission at 480 nm was measured again over
time. As can be seen from Fig. 8, under this condition, the (Z)/(E)
isomerization reached the maximum steady state after approxi-
mately 40 min, whereas the (E)/(Z) isomerization was slower with
a full recovery of transmission after approximately 2 h.
4. Experimental
4.1. General
1H NMR spectra were measured at 600 MHz with a Bruker
AV600 spectrometer; tetramethylsilane was used as an internal
standard; J values are given in Hertz. 13C NMR spectra were mea-
sured at 150.9 MHz with the same spectrometer. Chemical shifts
are given in parts per million. Low and high resolution mass spectra
were obtained with Kratos Concept 1S high resolution mass spec-
trometer using electron impact sources interfaced with DART 32 bit
acquisition system through a Sun Sparcstation 10 and Mach 3
software. Desican 230e400 mesh silica gel 60 was used for flash
column chromatography, respectively. Thin layer chromatography
was performed on Silicycle SiliaPlate F-254 TLC plates using
dichloromethaneehexane (90:10, v/v) unless stated otherwise.
3. Conclusion
In conclusion, bromo-, chloro-, cyano-, carboxyl and unsub-
stituted cyclic azobenzene were prepared from 2,20-dini-
trodibenzyl. Condensation of the carboxylic analogue with
D-
threoninol gave a building block with both a primary and second-
ary alcohols that can be readily isomerized by illumination with
Fig. 4. The molecular structure of (a) 2 (the dashed lines indicate the bonds of a minor component of disorder) and (b) 8 (two independent molecules with slightly different
conformations were found in the asymmetric unit) with 30% probability displacement ellipsoids (prepared with PLATON).33
.

D.K. Joshi et al. / Tetrahedron 68 (2012) 8670e8676
8673
Fig. 5. Colour change of 13 as a result of photoisomerization.
Fig. 7. UV/vis spectra. (a). (Z)- and (Z)/(E)-2 in methanol (0.60 mM); (b). (Z)- and (Z)/
(E)-13 in methanol (1.1 mM).
Fig. 6. HPLC profiles of cyclic azobenzene 2 and 13. (a). (Z)-2; (b). (E)-2; (c). (Z)-13; (d).
(E)-13. (Profiles a and b: linear gradient of watereacetonitrile (55:45 to 15:85, v/v) over
15 min; profiles c and d: linear gradient of watereacetonitrile (90:10 to 55:45, v/v)
over 15 min).
Reverse phase high-performance liquid chromatography (HPLC)
was carried out on a 4.6ꢁ150 mm Acclaim PA C18 3
m column: the
column was eluted with watereacetonitrile mixtures at a flow rate
of 0.80 ml/min. UV/vis spectra were recorded with a Biochrom
Ultrospec 2100pro UV/visible spectrophotometer. Chemicals were
purchased from Aldrich or TCI America and used without further
purification unless stated otherwise. Dichloromethane, toluene and
dimethylformamide were purified by Pure-Solv Solvent Purifica-
ꢀ
Fig. 8. Isomerization time course of 13 in methanol (0.94 mM) as determined by the
percent transmission at 480 nm. A: (Z)/(E) isomerization illuminated at 380 nm; O:
(E)/(Z) isomerization illuminated at 480 nm.
tion Systems (Innovative Technology), and stored over activated 4 A
molecular sieves.
4.2. 11,12-Dihydrodibenzo[c,g][1,2]diazocine-5-oxide (5)
(14 mL). The final pH of the solution was adjusted to 9.5 with
triethylamine (ca. 20 mL). To this solution were added 2,20-dini-
trodibenzyl (1.00 g, 3.67 mmol) and lead metal powder (3.50 g,
16.9 mol, w200 mesh, 99% metal basis). After the reaction mixture
Triethylamine (22 mL, 0.16 mol) was added to methanol (50 mL)
followed by addition of formic acid (1 mL, 0.026 mol) and water

8674
D.K. Joshi et al. / Tetrahedron 68 (2012) 8670e8676
was stirred vigorously at room temperature for 24 h, another por-
tion of lead metal powder (3.50 g, 14.5 mmol) was added, and
stirring was continued for another 24 h. The products were filtered
and the filtrate was concentrated under reduced pressure. The
residue was re-dissolved in dichloromethane (30 mL) and extracted
with saturated aqueous sodium hydrogen carbonate (3ꢁ10 mL).
The organic layer was dried (MgSO4) and concentrated under re-
duced pressure. The residue was purified by column chromatog-
raphy on silica gel. The appropriate fractions, which were eluted
with dichloromethaneehexane (40:60 v/v), were pooled and con-
centrated under reduced pressure to give the title compound as
a pale yellow solid (500 mg, 61%). Mp 167e169 ꢂC (ethanol). Rf:
0.49. HRMS (EI) found 224.09420, C14H12N2O required 224.09496.
dH(CDCl3): 2.88 (1H, ddd, J¼5.9, 9.6, and 14.4), 2.98 (1H, ddd, J¼5.2,
10.0, and 14.9), 3.22 (1H, ddd, J¼5.1, 10.1, and 14.6), 3.37 (1H, ddd,
J¼5.9, 10.1, and 15.0), 6.94 (1H, d, J¼7.8), 7.02 (2H, d, J¼4.0), 7.04
(1H, d, J¼7.6), 7.10e7.20 (4H, m). dC(CDCl3): 30.1, 31.2, 121.6, 121.7,
127.2, 127.3, 127.8, 129.6, 130.3, 130.4, 131.5, 131.8, 146.0, 148.7.
4.5. 11,12-Dihydrodibenzo[c,g][1,2]diazocine (2)
To solution of 11,12-dihydrodibenzo[c,g][1,2]diazocine-5-
a
oxide 5 (100 mg, 0.446 mmol) in dry tetrahydrofuran (5 mL)
were added triphenylphosphine (585 mg, 2.23 mmol) and molyb-
denum dioxo dichloride (dmf)229,30 (20 mg, 5.6 mmol). The reaction
mixture was heated under reflux for 3 h and then concentrated
under reduced pressure. The residue was purified by column
chromatography on silica gel. The appropriate fractions, which
were eluted with dichloromethaneehexane (30:70 v/v), were
combined and concentrated under reduced pressure to give 5,6-
dihydrodibenzo[c,g][1,2]diazocine
2 as a light yellow solid
(55 mg, 59%). Mp111e113 ꢂC (ethanol), lit.21 112e113 ꢂC. Rf: 0.72.
HRMS (EI) found: 208.10023, C14H12N2 required 208.10005.
dH(CDCl3): 2,75e2.83 (2H, m), 2.97e3.05 (2H, m), 6.85 (2H, d,
J¼7.8), 7.00 (2H, t, J¼7.5), 7.03 (2H, t, J¼7.3), 7.15 (2H, J¼7.3).
dC(CDCl3): 31.7, 118.7, 126.7, 127.1, 128.1, 129.6, 155.5.
4.6. 2-Bromo-11,12-dihydrodibenzo[c,g][1,2]diazocine-6-
oxide (8)
4.3. 2-Chloro-11,12-dihydrodibenzo[c,g][1,2]diazocine (6)
To a suspension of aluminium chloride (208 mg, 1.56 mmol) in
carbon disulfide (3.0 mL), a solution of 11,12-dihydrodibenzo[c,g]
[1,2]diazocine-5-oxide 5 (350 mg, 1.56 mmol) in carbon disulfide
(2.0 mL) was added drop-wise under nitrogen. The reaction mix-
ture was heated under reflux for 5 h and then cooled and con-
centrated under reduced pressure. To the dark residue was added
hydrochloric acid (0.1 M, 6 mL), and the mixture was extracted with
diethyl ether (3ꢁ5 mL). The organic layers were washed first with
water (2ꢁ20 mL) and then with saturated aqueous sodium bi-
carbonate (2ꢁ20 mL), dried (MgSO4), and concentrated under re-
duced pressure. The residue was purified by column
chromatography on silica gel. The appropriate fractions, which
were eluted with dichloromethaneehexane (30:70 v/v), were
combined and concentrated under reduced pressure to give the title
compound as a light yellow solid (30 mg, 8%). Mp 80e82 ꢂC (etha-
nol). Rf: 0.78. HRMS (EI) found 242.06156, C14H11ClN2 required
242.06108. dH(CDCl3): 2.76 (2H, m), 2.98 (2H, br, m), 6.79 (1H, d,
J¼8.4), 6.85 (1H, d, J¼7.8), 6.99 ( 1H, d, J¼1.5), 7.01 (1H, d, J¼7.5),
7.06 (1H, t, J¼7.5), 7.11 (1H, dd, J¼1.9 and 8.4), 7.17 (1H, t, J¼7.7).
dC(CDCl3): 31.4, 31.7, 118.7, 120.4, 126.8, 126.9, 127.4, 127.6, 129.5,
129.7, 130.2, 132.2, 153.7, 155.3.
To a solution of azoxybenzene 5 (100 mg, 0.446 mmol) in acetic
acid (1.0 mL), bromine (100 mL, 1.95 mmol) was added drop-wise.
After the reaction mixture was heated at 50 ꢂC for 4 h, stirring
was allowed to continue overnight at room temperature. The
products were then diluted with cold water (50 mL). Sodium hy-
drogen sulfite (40% aqueous solution) was added drop-wise until
the colour changed from brown to pale yellow. The mixture was
extracted with dichloromethane (3ꢁ30 mL). The organic layers
were combined and washed with water (2ꢁ25 mL) and saturated
bicarbonate solution (2ꢁ25 mL). The organic layer was dried
(MgSO4) and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel. The desired
product was obtained upon evaporation of appropriate fractions,
which were eluted with dichloromethaneehexane (40:60 v/v), as
a light brown solid (94.5 mg, 70%). Mp 143e146 ꢂC (ethanol). Rf:
0.54. HRMS (EI) found 302.00508, C14H11BrN2O required
302.00547. dH(CDCl3): 2.84 (1H, ddd, J¼5.9, 9.6, and 14.8), 2.98 (1H,
ddd, J¼5.1, 9.9 and 14.8), 3.21 (1H, ddd, J¼5.1, 10.1, and 14.8), 3.36
(1H, ddd, J¼5.9, 9.9, and 15.0), 6.82 (1H, d, J¼8.4), 7.07 (1H, d, J¼7.5),
7.16e7.22 (3H, m), 7.24e7.26 (2H, m). dC(CDCl3): 30.1, 30.9, 120.5,
121.7, 123.5, 128.1, 129.6, 130.3, 130.6, 131.1, 133.2, 134.1, 145.0, 148.7.
4.4. 2-Bromo-11,12-dihydrodibenzo[c,g][1,2]diazocine (7)
4.7. 2-Cyano-11,12-dihydrodibenzo[c,g][1,2]diazocine-6-
To a suspension of aluminium bromide (145 mg, 0.544 mmol) in
carbon disulfide (3.0 mL) a solution of 11,12-dihydrodibenzo[c,g]
[1,2]diazocine-5-oxide 5 (100 mg, 0.446 mmol) in carbon disulfide
(2.0 mL) was added drop-wise under nitrogen. The reaction mix-
ture was heated under reflux for 5 h, and then cooled and con-
centrated under reduced pressure. The dark residue was then
treated carefully with hydrochloric acid (0.1 M, 6 mL), and extracted
with diethyl ether (3ꢁ5 mL). The ether layers were combined and
washed successively with water (2ꢁ20 mL) and saturated aqueous
sodium bicarbonate (2ꢁ20 ml). The organic layer was separated,
dried (MgSO4) and evaporated to dryness under reduced pressure.
The residue was purified by column chromatography on silica gel.
The appropriate fractions, which were eluted with dichlor-
omethaneehexane (30:70 v/v), were combined and concentrated
under reduced pressure to give the title compound as a light yellow
solid (12 mg, 9%). Rf: 0.78. HRMS (EI) found 286.01081, C14H11BrN2
required 286.01056. dH(CDCl3): 2.76 (2H, m), 2.99 (2H, br, m), 6.73
(1H, d, J¼8.4), 6.85 (1H, d, J¼7.8), 7.02 (1H, d, J¼7.5), 7.07 (1H, t,
J¼7.4), 7.15 (1H, d, J¼1.6), 7.18 (1H, t, J¼7.5), 7.26 (1H, dd, J¼1.7 and
8.4). dC(CDCl3): 31.4, 31.6, 118.7, 120.3, 120.6, 127.0, 127.4, 127.5,
129.7, 129.8, 130.4, 132.4, 154.2, 155.3.
oxide (9)
To a solution of 2-bromo-11,12-dihydrodibenzo[c,g][1,2]diazo-
cine-6-oxide 8 (1.08 g, 3.56 mmol) in dry N,N-dimethyl formamide
(8.5 mL), copper (I) cyanide (480 mg, 5.36 mmol) was added. After
the reaction mixture was heated under reflux overnight, the
products were cooled to room temperature, followed by addition of
ethylenediamine (10% aqueous solution, 100 mL) and the mixture
was extracted with dichloromethane (3ꢁ30 mL). The organic layer
was separated and successively washed with sodium cyanide (10%
aqueous solution, 50 mL) and water (3ꢁ30 mL). The organic layer
was dried (MgSO4) and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel. The
desired product was obtained upon evaporation of appropriate
fractions, which were eluted with dichloromethaneehexane
(60:40 v/v) as a pale yellow solid (615 mg, 69%). Mp 178e181 ꢂC
(ethanol). Rf: 0.32. HRMS (EI) found 249.08949, C15H11N3O required
249.09021. dH(CDCl3): 2.94 (1H, ddd, J¼5.3,10.0, and 14.8), 3.02 (1H,
ddd, J¼4.8, 10.1, and 14.8), 3.26 (1H, ddd, J¼4.6, 10.3, and 14.7), 3.40
(1H, ddd, J¼5.2, 10.0, 14.8), 7.05 (1H, d, J¼8.2), 7.07 (1H, d, J¼7.5),
7.17 (1H, d, J¼7.6), 7.22 (1H, t, J¼7.4), 7.25 (1H, d, J¼7.4), 7.35 (1H, s),

D.K. Joshi et al. / Tetrahedron 68 (2012) 8670e8676
8675
7.43 (1H, d, J¼8.1). dC(CDCl3): 29.9, 30.7, 111.0, 118.1, 121.6, 122.8,
required 252.08988. dH(CDCl3): 2.83 (1H, m), 2.89 (1H, m), 3.04 (2H,
m), 6.87 (1H, d, J¼7.8), 6.92 (1H, d, J¼8.1), 7.00 (1H, d, J¼7.6), 7.05
(1H, t, J¼7.7), 7.17 (1H, t, J¼7.5), 7.76 (1H, d, J¼1.2), 7.87 (1H, dd,
J¼1.3 and 8.1). dC(CDCl3): 31.4, 31.5, 118.6, 118.8, 127.0, 127.4, 127.5,
127.6, 128.9, 129.9, 131.8, 155.4, 159.8, 169.9.
128.3, 129.8, 130.7, 131.0, 131.3, 133.8, 134.2, 148.6, 149.5.
4.8. 5,6,11,12-Tetrahydrodibenzo[c,g][1,2]diazocine-2-
carbonitrile (10)
To a solution of 2-cyano-11,12-dihydrodibenzo[c,g][1,2]diazo-
cine-6-oxide 9 (1.00 g, 4.02 mmol) in methanol (30 mL), hydrazine
monohydrate (5.0 mL, 0.10 mol) and aluminium powder (1.40 g,
51.9 mmol) were added. After the reaction mixture was heated
under reflux for 24 h, the products were filtered through a thin
layer of Celite and washed with dichloromethane (50 mL). The fil-
trate and washing were combined and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel. The desired product was obtained upon evaporation of
appropriate fractions, which were eluted with ethyl aceta-
teehexane (20:80 v/v), as a pale yellow solid (620 mg, 66%). Rf: 0.43.
HRMS (EI) found 235.11045, C15H13N3 required 235.11095.
dH(DMSO-d6): 2.97e2.99 (2H, m, br), 2.31e2.34 (2H, m, br), 6.84
(1H, dt, J¼1.0 and 7.3), 6.86 (1H, d, J¼8.2), 6.87 (1H, d, J¼7.3), 7.03
(1H, dt, J¼1.2 and 7.4), 7.08 (1H, d, J¼7.2), 7.26 (1H, d, J¼4.3), 7.43
(1H, dd, J¼1.9 and 8.3), 7.48 (1H, d, J¼1.5), 7.93 (1H, d, J¼4.3).
dC(DMSO-d6): 30.2, 31.3, 101.0, 116.3, 118.4, 120.5, 121.9, 126.7, 130.7,
131.2, 132.5, 132.8, 134.6, 147.8, 153.3.
4.11. (Z)-N-((2S,3S)-1,3-Dihydroxybutan-2-yl)-11,12-dihydro-
dibenzo[c,g][1,2]diazocine-2-carboxamide (13)
To a solution of 11,12-dihydrodibenzo[c,g][1,2]diazocine-2-car-
boxylic acid 12 (100 mg, 0.397 mmol) in dry N,N-dimethyl form-
amide (2.0 ml),
D
-threoninol (35 mg, 0.33 mmol), N,N0-
dicyclohexylcarbodiimide (82 mg, 0.40 mmol) and N-hydrox-
ysuccinamide (46 mg, 0.40 mmol) were added. After the reaction
mixture was stirred for 5 h at room temperature under a nitrogen
atmosphere, the precipitate was removed by filtration and the fil-
trate was evaporated under reduced pressure. The oily residue was
purified by column chromatography on silica gel. Evaporation of
appropriate fractions, which were eluted by dicholor-
omethaneemethanol (95:5 v/v), gave the title compound as a pale
yellow solid (105 mg, 93% based on
(dichloromethaneemethanol, 90:10 v/v). ½ ꢃD ꢄ12.8 (c¼0.10,
D
-threoninol). Rf: 0.74
a 20
¼
methanol). HRMS (EI) found 339.1569, C19H21N3O3 required
339.15829. dH(DMSO-d6): 1.01 (3H, t, J¼6.1), 2.83e2.86 (2H, m),
2.88e2.91 (2H, m), 3.40e3.45 (1H, m), 3.51e3.55 (1H, m),
0.3.81e3.84 (1H, m), 3.85e3.88 (1H, m), 4.56e4.61 (2H, m, br, OH,
ex), 6.88 (1H, d, J¼7.8), 6.92 (1H, d, J¼8.1), 7.07 (1H, t, J¼7.3), 7.10
(1H, d, J¼7.2), 7.19 (1H, dt, J¼7.19) (1H, t, J¼7.2), 7.60 (1H, d, J¼2.9),
7.66 (1H, d, J¼8.1), 7.71 (1H, d, J¼8.3, NH, ex). dC(DMSO-d6): 20.6
and 20.7, 31.2 and 31.4, 57.2, 60.7 and 60.9, 65.3, 118.6 and 118.7,
118.8, 126.5 and 126.6, 127.4, 127.8, 128.1, 128.5 and 128.6, 129.5 and
129.6, 130.4, 133.8, 155.6, 157.5, 166.1.
4.9. 11,12-Dihydrodibenzo[c,g][1,2]diazocine-2-carbonitrile (11)
To a solution of 5,6,11,12-tetrahydrodibenzo[c,g][1,2]diazocine-
2-carbonitrile 10 (500 mg, 2.13 mmol) in methanol (9 mL), tita-
nium (III) chloride (25
solution of TiCl3 in 20e30 wt.% hydrochloric acid with 10 mL of
methanol) and hydrobromic acid solution (25 L, prepared by di-
luting 1 mL of 33% hydrobromic acid in acetic acid with 10 mL of
methanol) were added using a 50 L Hamilton syringe at room
temperature under nitrogen. After a solution of hydrogen peroxide
(450 L, 20% in water, 2.37 mmol) was added drop-wise at room
mL, prepared by diluting 1 mL of w10 wt.%
m
m
4.12. Crystal growth
m
Single crystals of 2 and 8 were obtained by slow evaporation of
temperature, the reaction mixture was stirred at room temperature
for 15 min. The volatiles were removed under reduced pressure
and the solid residue was purified by column chromatography on
silica gel. The appropriate fractions, which were eluted with
dichloromethaneehexane (55:45 v/v), were combined and con-
centrated under reduced pressure to give the title compound as
a light yellow solid (390 mg, 79%). Rf: 0.60. HRMS (EI) found
233.09554, C15H11N3 required 233.09530. dH(CDCl3): 2.78e2.87
(2H, m), 3.00e3.07 (2H, m), 6.87 (1H, d, J¼7.7), 6.92 (1H, d, J¼8.1),
7.01 (1H, d, J¼7.5), 7.08 (1H, dt, J¼1.2 and 7.5), 7.19 (1H, t, J¼7.5),
7.32 (1H, d, J¼1.2), 7.44 (1H, dd, J¼1.4 and 8.0). dC(CDCl3): 31.9,
110.8, 118.2, 118.6, 119.5, 127.0, 127.2, 127.8, 129.9, 130.1, 130.7, 133.5,
155.3, 158.7.
corresponding solutions in absolute ethanol.
4.13. X-ray diffraction experiment
Data were collected on a Nonius Kappa-CCD diffractometer us-
ing monochromated Mo-K
a
radiation and were measured using
scans with offsets, to fill the Ewald
a combination of scans and
f
u
k
sphere. The data were processed using the Denzo-SMN package.37
Absorption corrections were carried out using SORTAV.38 The
structure was solved and refined using SHELXTL V6.139 for full-
matrix least-squares refinement that was based on F2. All H
atoms were included in calculated positions and allowed to refine
in riding-motion approximation with Uiso tied to the carrier atom.
CCDC 859314 and 859315 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
4.10. 11,12-Dihydrodibenzo[c,g][1,2]diazocine-2-carboxylic
acid (12)
The carbonitrile 11 (350 mg, 1.50 mmol) was placed in a solution
of potassium hydroxide (9.3 g) in ethanol (65 mL) and water
(20 mL) and heated under reflux for 4 h. Ethanol was removed
under reduced pressure and the residue was treated with aqueous
hydrochloric acid (6 N) until the mixture turned acidic (pH 4). The
mixture was extracted with ethyl acetate (3ꢁ30 mL). The combined
organic layers were washed with brine (2ꢁ15 mL), dried (MgSO4),
and concentrated under reduced pressure to give the crude car-
boxylic acid, which is purified by column chromatography on silica
gel. The appropriate fractions, which were eluted with dichlor-
omethaneemethanol (95:5 v/v), were combined and concentrated
under reduced pressure to give the title compound as a light yellow
solid (293 mg, 78%). HRMS (EI) found 252.08979, C15H12N2O2
4.14. Photoisomerization experiments
A home-built LED light source was used for the isomerization
experiments. Photoisomerization of 2 and 13 was carried out by
illuminating methanol solutions of (Z)-2 and (Z)-13 at 380 (ꢀ5) nm
with an energy density of 0.45 mW/cm2 or (Z)/(E)-mixture of 13 at
480 (ꢀ5) nm with an energy density of 32.3 mW/cm2.
Acknowledgements
The authors wish to thank the Natural Science and Engineering
Research Council of Canada for funding this work. The authors

8676
D.K. Joshi et al. / Tetrahedron 68 (2012) 8670e8676
16. Jiang, C.-W.; Xie, R.-H.; Li, F.-L.; Allen, R. E. J. Phys. Chem. A 2011, 115, 244e249.
17. Carstensen, N. O.; Dieterich, J. M.; Hartke, B. Phys. Chem. Chem. Phys. 2011, 13,
2903e2910.
would like to thank Allen Derks for providing the LED light source
for the isomerization experiments.
18. Siewertsen, R.; Schoenborn, J. B.; Hartke, B.; Renth, F.; Temps, F. Phys. Chem.
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19. Carstensen, O.; Sielk, J.; Schoenborn, J. B.; Granucci, G.; Hartke, B. J. Chem. Phys.
Supplementary data
2010, 133, 124305.
NMR spectra of the compounds reported in this paper are
available online as Supplementary data. Supplementary data
related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2012.06.007.
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