Synthesis of a BF2 complex of indol-2-yl-isoindol-1-ylidene-amine: a fully conjugated azadipyrromethene

Article abstract of DOI:10.1016/j.tetlet.2009.12.003

Starting from commercially available 3-methylindole and 1,3-diiminoisoindoline, the BF₂ complex of indol-2-yl-isoindol-1-ylidene-amine (7) has been prepared in three steps; its wavelength of maximum visible absorption is similar to that of a tetra-phenyl-conjugated azadipyrromethene (4).

Full text of DOI:10.1016/j.tetlet.2009.12.003

Tetrahedron Letters 51 (2010) 811–814
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Tetrahedron Letters
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Synthesis of a BF2 complex of indol-2-yl-isoindol-1-ylidene-amine: a fully
conjugated azadipyrromethene
*
Yan Li, David Dolphin , Brian O. Patrick
Department of Chemistry, The University of British Columbia, 2036 Main Mall, Vancouver, B.C., Canada V6T 1Z1
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 June 2009
Revised 21 November 2009
Accepted 1 December 2009
Available online 4 December 2009
Starting from commercially available 3-methylindole and 1,3-diiminoisoindoline, the BF2 complex of
indol-2-yl-isoindol-1-ylidene-amine (7) has been prepared in three steps; its wavelength of maximum
visible absorption is similar to that of a tetra-phenyl-conjugated azadipyrromethene (4).
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Indole
1,3-Diiminoisoindoline
Nucleophilic substitution
Azadipyrromethene
BF2 complex
Azadipyrromethenes are the bridged nitrogen analogues of dip-
yrromethenes and have longer wavelengths of maximum visible
absorption. Although azadipyrromethene itself is unknown, vari-
their typical structures were shown in Figure 1. 5,50-Diph-
enylazadipyrromethene (1) has a maximum visible absorption at
595 nm in ethanol.1c While the additional phenyl groups at 3 and
30 positions in 3,30,5,50-tetraphenylazadipyrromethene (2a) slightly
blue-shift the maximum visible absorption to 587 nm,3 the elec-
tron-donating substituents on 5,50-diphenyl groups in the BF2
complexes of 2 give rise to a red-shift of the maximum visible
absorption from 650 (R = H),1d 688 (R = OMe)1d to 799 (R = NMe2)1h
nm in chloroform. Differences were also seen in the X-ray
ous azadipyrromethenes with extended or expanded
p-conjuga-
tion have been synthesized,1,2 and some of their BF2 complexes
have shown potential applications in photodynamic therapy and
as biological probes.1d,f,h
The known
p-conjugation-extended azadipyrromethenes are
diarylazadipyrromethenes and tetraarylazadipyrromethenes and
N
N
N
NH
N
NH
N
NH
N
H3CO
R
OCH3
R
2a R = H
2b R = OCH3
1
3
2c R = N(CH3)2
Figure 1. Typical structures of p-conjugation-extended azadipyrromethenes.
* Corresponding author. Tel.: +1 604 8224571; fax: +1 604 8229678.
E-mail address: david.dolphin@ubc.ca (D. Dolphin).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.003

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Y. Li et al. / Tetrahedron Letters 51 (2010) 811–814
crystallographic structures. As shown in Figure 2,4 the four phenyl
groups in the BF2 complex of 2a are not effectively conjugated with
the core plane, the dihedral angles between the phenyl planes C3–
C8, C12–C17, C18–C23, and C27–C32 and the core plane
B1N1C9C10C11C1N2C2C26C25C24 N3 are 45.32°, 3.79°, 53.22°,
and 39.93°, respectively. With dimethylamino substituents, the
5,50-diaryl groups in the BF2 complex of 2c become fully coplanar
with the core plane.1h When the 5,50-diaryl groups have restricted
conformations, the maximum visible absorption of the BF2 com-
plex of 3 can reach to 740 nm.1f
at the 2-position using NCS and then nucleophilically substituted,
in situ, with the amino form of 1,3-diiminoisoindoline to give (3-
amino-isoindol-1-ylidene)-(3-methyl-indol-2-yl)-amine 10.10 This
method was developed from the reaction of 2-chloroindole with
aniline leading to 2-arylaminoindole.11 Tautomers 10a–c are the
most likely structures for compound 10. While 10a and 10c should
exhibit three N–H signals in the 1H NMR, only two such signals,
with a ratio of 1:2, were observed at 11.23 and 8.68 ppm, suggest-
ing that the amino form (10b) is the predominant tautomer.
According to the literature,12 1,3-diimineisoindoline can undergo
replacement of the exocylic imino group by amines along with
the evolution of ammonia. In our case, when indolisoindolaza-
methene 10 was dissolved in dipropylamine under argon and re-
fluxed for 10 hours, 10 was converted into (3-dipropylamino-
isoindol-1-ylidene)-(3-methyl-indol-2-yl)-amine (11) in moderate
yield. The 1H NMR of 11 contains only one N–H signal at
11.75 ppm; the proton signals of dipropylamino group appear at
3.79, 2.58, and 1.93 ppm, with integrations for four, four, and six
protons, respectively.13 The desired product 12 was readily ob-
tained by refluxing indolisoindolazamethene 11 with boron tri-
fluoride etherate for 1 h in the presence of diisopropylethylamine
under argon.14 Complex 12 has been characterized by 1H and 13B
NMR and HR-MS. The N–H proton signal disappears; the 13B signal
is a triplet due to coupling with the neighboring fluorines and ap-
pears at 1.74 ppm (referenced to BF3ꢀOEt2), whereas the 13B signal
of the BF2 complex of 2a appears at 0.94 ppm.3
Relatively, the
p-conjugation-expanded azadipyrromethenes
have received less attention. Among their possible structures
(Fig. 3), the BF2 complex of di(benz[c,d]indol) azamethene (4) has
been reported.2b Diisoindolazamethene (5) and pyrrolisoindolaza-
methene (6) are subunits of phthalocyanines, which have been
suggested as photosensitizers for clinical photodynamic therapy.5
But the known complexes of diisoindolazamethenes (5)2a,d and
pyrrolisoindolazamethenes (6)2c also have extended conjugation
through two phenyl substituents. Our attempts to prepare diindo-
lazamethene (8) failed when 1-Boc-2-nitrosoindole was condensed
with indole6 or when 2-bromoindole7 was reacted with sodium
azide.8 1-Boc-2-nitrosoindole was prepared in situ by lithiation9
of 1-Boc-indole followed by the reaction with isoamylnitrite, but
its condensation product with indole, identified by mass spectros-
copy, was di(indol-2-yl)amine, which could not be oxidized to the
desired diindolazamethene. We describe here the design and syn-
thesis of the BF2 complex of (3-dipropylamino-isoindol-1-ylidene)-
(3-methyl-indol-2-yl)-amine (12), which is an analogue of indol-
isoindolazamethene (7) (Scheme 1).
As shown in Figure 4, indolisoindolazamethenes 10 and 11 ex-
hibit maximum visible absorptions at 465 nm and 484 nm, respec-
tively. The minor absorption peaks appearing as shoulders on the
blue and red sides belong to tautomers. The BF2 complex 12 has
its maximum visible absorption at 528 nm with a half band width
The starting materials were commercially available 3-methylin-
dole and 1,3-diiminoisoindoline. 3-Methylindole was chlorinated
Figure 2. ORTEP view and side view of the BF2 complex of 2a and selected bond distances (Å) and angles (°): B1–N1: 1.561(2). B1–N3: 1.553(2). N2–C1: 1.320(2). N2–C2:
1.328(2). N1–B1–N3: 105.3(1). C1–N2–C2: 119.7(1).
N
N
N
NH
N
N
NH
N
NH
N
N
4
5
6
N
N
N
NH
NH
N
NH
7
8
9
Figure 3. Some possible structures of p-conjugation-expanded azadipyrromethenes.

Y. Li et al. / Tetrahedron Letters 51 (2010) 811–814
813
+
N
H2N
NH
H
N
NCS
DIEA
H
N
N
N
NH
N
NH
NH
HN
N
NH2
NH
NH
10a
10b
10c
HN(C3H7)2
N
N
B
BF3
NH
N
F
N
N
DIEA
F
N(C3H7)2
N(C3H7)2
11
12
Scheme 1. Synthesis of indolisoindolazamethene–BF2 complex.
We thank the NMR and Mass spectroscopy labs of the Chemistry
Department at the University of British Columbia.
1.0
0.8
References and notes
1. For
p-conjugation-extended azadipyrromethenes: (a) Rogers, M. A. T. J. Chem.
Soc. 1943, 590; (b) Knott, E. B. J. Chem. Soc. 1947, 1196; (c) Bird, C. W.; Jiang, L.
Tetrahedron Lett. 1992, 33, 7253; (d) Killoran, J.; Allen, L.; Gallagher, J. F.;
Gallagher, W. M.; O’Shea, D. F. Chem. Commun. 2002, 17, 1862; (e) McDonnell, S.
O.; Hall, M. J.; Allen, L. T.; Byrne, A.; Gallagher, W. M.; O’Shea, D. F. J. Am. Chem.
Soc. 2005, 127, 16360; (f) Zhao, W.; Carreira, E. M. Angew. Chem., Int. Ed. 2005,
44, 1677; (g) Zhao, W.; Carreira, E. M. Chem. Eur. J. 2006, 12, 7254; (h)
McDonnell, S. O.; O’Shea, D. F. Org. Lett. 2006, 8, 3493; (i) Gawley, R. E.; Mao, H.;
Haque, M. M.; Thorne, J. B.; Pharr, J. S. J. Org. Chem. 2007, 72, 2187; (j) Coskun,
A.; Yilmaz, M. D.; Akkaya, E. U. Org. Lett. 2007, 9, 607.
0.6
0.4
0.2
10
11
12
2. For p-conjugation-expanded azadipyrromethenes: (a) Bredereck, H.; Vollmann,
H. W. Chem. Ber. 1972, 7, 2271; (b) Vasilenko, N. P.; Mikhailenko, F. A. Ukr. Khim.
Zh. 1986, 52, 308; (c) Misawa, T.; Sugimoto, K.; Nishimoto, T.; Tsukahara, H.;
Takuma, K. JP 11092479, 1999; CAN, 130, 304098.; (d) Donyagina, V. F.;
Shimizu, S.; Kobayashi, N.; Lukyanets, E. A. Tetrahedron Lett. 2008, 49, 6152.
3. 3,30,5,50-Tetraphenylazadipyrromethene (2a) and its BF2 complex were prepared
according to the literature.1a Diffraction-quality crystal of the BF2 complex of
2a was grown by the slow evaporation of solutions in dichloromethane and
hexane at 5 °C.
0.0
300
400
500
600
700
Wavelength (nm)
4. Crystal data for the BF2 complex of 2a (C32H22BF2N3): M = 497.34, monoclinic,
Figure 4. The UV–vis absorption spectra of 10 ( ), 11 ( ) and 12 ( ).
P21/c,
a = 14.0667(9),
b = 7.6528(4),
c = 23.049(1) Å,
b = 94.272(2)°,
V = 2474.3(2) Å3, T = ꢁ100.0 0.1 °C, Z = 4, Dcalcd = 1.335 g/cm3, 53028
reflections collected, 5896 unique (Rint = 0.032); wR2 = 0.097, CCDC 727264.
5. The recent reviews: (a) Garcia, F. S.; Tedesco, A. C.; Bentley, M. V. L. B. Trends
Photochem. Photobiol. 2003, 10, 77; (b) Gorman, S. A.; Brown, S. B.; Griffiths, J. J.
Environ. Pathol. Toxicol.Oncol. 2006, 25, 79; (c) Taquet, J.-P.; Frochot, C.;
Manneville, V.; Barberi-Heyob, M. Curr. Med. Chem. 2007, 14, 1673.
6. Hall, M. J.; McDonnell, S. O.; Killoran, J.; O’Shea, D. F. J. Org. Chem. 2005, 70,
5571.
of 132 nm, which is in the same wavelength range as that of tetra-
phenyl-conjugated azadipyrromethene (4), whereas the BF2 com-
plex of 4 has two distinct absorptions at 502 and 537 nm.2b
In conclusion, we report the facile synthesis and spectral char-
acteristic of a novel BF2 complex of indol-2-yl-isoindol-1-ylidene-
7. Mistry, A. G.; Smith, K.; Bye, M. R. Tetrahedron Lett. 1986, 27, 1051.
8. Singh, J. P.; Xie, L. Y.; Dolphin, D. Tetrahedron Lett. 1995, 36, 1567.
9. Jiang, J.; Gribble, G. W. Tetrahedron Lett. 2002, 43, 4115.
amine as a new p-conjugation-expanded azadipyrromethene. Fur-
ther investigation into the variation of the indole ring substituents
and their effect on maximum absorption as well as their photo-
physical properties are in progress.
10. (3-Amino-isoindol-1-ylidene)-(3-methyl-indol-2-yl)-amine (10b): To a solution
of 3-methylindole (2.04 mmol, 0.268 g) in dichloromethane (40 mL) were
added diisopropylethylamine (2.25 mmol, 0.39 mL) and NCS (2.25 mmol,
0.300 g) under argon. The mixture was stirred at 0 °C for 2 h and then a
solution of trifluoroacetic acid (0.5 mmol, 0.04 mL) and 1,3-diiminoisoindoline
(3.06 mmol, 0.445 g) in dichloromethane (100 mL) was added. After stirring at
room temperature overnight, the resulting mixture was evaporated under
vacuum to dryness. The residue was purified by column chromatography
(silica gel) eluting with a mixture of ethyl acetate and hexane (1:1) to provide
Acknowledgments
This work is supported by QLT Inc., Vancouver, BC, and the Nat-
ural Sciences and Engineering Research Council (NSERC) of Canada.

814
Y. Li et al. / Tetrahedron Letters 51 (2010) 811–814
the orange product 10. Yield: 77%. mp: 223–224 °C. Anal. Calcd for C17H14N4ꢀ1/
1H, J = 7.40), 7.17 (d, 1H, J = 7.44), 7.16 (t, 1H, J = 7.44), 7.06 (t, 1H, J = 7.44),
3.79 (t, 4H, J = 7.94), 2.58 (s, 3H), 1.97–1.88 (m, 4H), 1.15–1.07 (m, 6H). 13C
NMR: (CDCl3): 167.2, 143.2, 141.9, 136.6, 134.7, 132.4, 130.3, 129.3, 129.0,
128.7, 123.1, 122.9, 122.6, 119.2, 118.8, 110.6, 52.4, 29.9, 21.8, 8.8. UV–vis
10CH2Cl2ꢀ1/10C6H14 (solvent of crystallization determined by NMR): C, 72.95;
H, 5.40; N, 19.22. Found: C, 72.53; H, 5.01; N, 18.82. 1H NMR (CDCl3): d 11.23 (s,
1H), 8.68 (b, 2H), 7.92 (d, 1H, J = 7.00), 7.83 (d, 1H, J = 7.07), 7.58–7.48 (m, 2H),
7.41 (d, 1H, J = 7.77), 7.24 (d, 1H, J = 7.99), 7.07–7.01 (dt, 1H, J = 7.16, 1.06),
6.96–6.90 (dt, 1H, J = 7.84, 0.79), 2.38 (s, 3H). 13C NMR (CDCl3): 168.0, 141.2,
140.6, 135.4, 132.5, 131.2, 129.8, 129.3, 128.5, 125.8, 123.5, 122.7, 119.5, 119.2,
(0.94 ꢂ 10ꢁ5 M, CH2Cl2): kmax (log
e) 458 (4.34), 483 (4.38), 515 (sh, 4.18). EI
MS: m/z (%) = 358 (100) [M]+, 315 (16), 258 (14). HR-EI MS: m/z calcd for
C23H26N4: 358.2158; found: 358.2161.
119.0, 111.0, 8.8. UV–vis (2.50 ꢂ 10ꢁ5 M, CH2Cl2): kmax (log
e) 440 (sh. 4.38),
14. BF2 complex of (3-dipropylamino-isoindol-1-ylidene)-(3-methyl-indol-2-yl)-amine
(12): To a solution of indolisoindolazamethene 11 (0.05 mmol, 0.018 g) in
464 (4.40), 494 (sh. 4.22). EI MS: m/z (%) = 273 (100) [M]+, 249 (5). HR-EI MS:
m/z calcd for C17H14N4: 274.1222; found: 274.1218.
benzene (10 mL) were added diisopropylethylamine (0.20 mmol, 34
lL) and
11. Bergman, J.; Engqvist, R.; Stålhandske, C.; Wallberg, H. Tetrahedron 2003, 59,
1033.
boron trifluoride diethyletherate (0.06 mmol, 6.8 L) under argon. The
l
resulting mixture was refluxed for 1 h and then evaporated under vacuum to
dryness. The residue was purified by column chromatography eluting with a
mixture of dichloromethane and hexane (1:1) to provide the desired product
12. Yield: 59%. Mp: 204–205 °C. 1H NMR (CDCl3): d 8.19 (d, 1H, J = 7.59), 7.73
(d, 1H, J = 8.17), 7.69–7.43 (m, 4H), 7.19 (dt, 1H, J = 8.15, 1.09), 7.02 (dt, 1H,
J = 7.02, 0.80), 4.15 (t, 4H, J = 7.61), 2.52 (s, 3H), 1.95–1.85 (m, 4H), 1.05 (t, 6H,
12. Spiessens, L. I.; Anteunis, M. J. O. Bull. Soc. Chim. Belg. 1988, 97, 431.
13. (3-Dipropylamino-isoindol-1-ylidene)-(3-methyl-indol-2-yl)-amine (11): To the
dipropylamine (20 mL) was added indolisoindolazamethene 10 (0.30 mmol,
0.083 g). The mixture was refluxed under argon for 10 h and then evaporated
under vacuum to recycle unreacted dipropylamine. The residue was purified
by column chromatography eluting with a mixture of ethyl acetate and hexane
(1:10) to give product 11. Yield: 23%. mp: 187–188 °C. 1H NMR (CDCl3): d 11.75
(s, 1H), 8.10 (d, 1H, J = 7.42), 7.55 (t, 2H, J = 7.40), 7.50 (d, 1H, J = 7.40), 7.42 (t,
J = 7.22). 13B NMR: d 1.74 (t). UV–vis (4.05 ꢂ 10ꢁ5 M, CH2Cl2): kmax (log
e) 528
(4.40). EI MS: m/z (%) = 406 (48) [M]+, 358 (100), 315 (30), 258 (40). HR-EI MS:
m/z calcd for C23H25N4BF2: 406.2140; found: 406.2153.