Tetrahedron Letters 51 (2010) 811–814

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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

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: Starting from commercially available 3-methylindole and 1,3-diiminoisoindoline, the BF2 complex of
Received 30 June 2009 indol-2-yl-isoindol-1-ylidene-amine (7) has been prepared in three steps; its wavelength of maximum
Revised 21 November 2009 visible absorption is similar to that of a tetra-phenyl-conjugated azadipyrromethene (4).
Accepted 1 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Available online 4 December 2009

Keywords:
Indole
1,3-Diiminoisoindoline
Nucleophilic substitution
Azadipyrromethene
BF2 complex

Azadipyrromethenes are the bridged nitrogen analogues of dip- their typical structures were shown in Figure 1. 5,50 -Diph-
yrromethenes and have longer wavelengths of maximum visible enylazadipyrromethene (1) has a maximum visible absorption at
absorption. Although azadipyrromethene itself is unknown, vari- 595 nm in ethanol.1c While the additional phenyl groups at 3 and
ous azadipyrromethenes with extended or expanded p-conjuga- 30 positions in 3,30 ,5,50 -tetraphenylazadipyrromethene (2a) slightly
tion have been synthesized,1,2 and some of their BF2 complexes blue-shift the maximum visible absorption to 587 nm,3 the elec-
have shown potential applications in photodynamic therapy and tron-donating substituents on 5,50 -diphenyl groups in the BF2
as biological probes.1d,f,h complexes of 2 give rise to a red-shift of the maximum visible
The known p-conjugation-extended azadipyrromethenes are absorption from 650 (R = H),1d 688 (R = OMe)1d to 799 (R = NMe2)1h
diarylazadipyrromethenes and tetraarylazadipyrromethenes and nm in chloroform. Differences were also seen in the X-ray

N
N N
NH N
NH N NH N

R H3CO
R OCH3
2a R = H
1 2b R = OCH 3 3
2c R = N(CH 3)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
812 Y. Li et al. / Tetrahedron Letters 51 (2010) 811–814

crystallographic structures. As shown in Figure 2,4 the four phenyl at the 2-position using NCS and then nucleophilically substituted,
groups in the BF2 complex of 2a are not effectively conjugated with in situ, with the amino form of 1,3-diiminoisoindoline to give (3-
the core plane, the dihedral angles between the phenyl planes C3– amino-isoindol-1-ylidene)-(3-methyl-indol-2-yl)-amine 10.10 This
C8, C12–C17, C18–C23, and C27–C32 and the core plane method was developed from the reaction of 2-chloroindole with
B1N1C9C10C11C1N2C2C26C25C24 N3 are 45.32°, 3.79°, 53.22°, aniline leading to 2-arylaminoindole.11 Tautomers 10a–c are the
and 39.93°, respectively. With dimethylamino substituents, the most likely structures for compound 10. While 10a and 10c should
5,50 -diaryl groups in the BF2 complex of 2c become fully coplanar exhibit three N–H signals in the 1H NMR, only two such signals,
with the core plane.1h When the 5,50 -diaryl groups have restricted with a ratio of 1:2, were observed at 11.23 and 8.68 ppm, suggest-
conformations, the maximum visible absorption of the BF2 com- ing that the amino form (10b) is the predominant tautomer.
plex of 3 can reach to 740 nm.1f According to the literature,12 1,3-diimineisoindoline can undergo
Relatively, the p-conjugation-expanded azadipyrromethenes replacement of the exocylic imino group by amines along with
have received less attention. Among their possible structures the evolution of ammonia. In our case, when indolisoindolaza-
(Fig. 3), the BF2 complex of di(benz[c,d]indol) azamethene (4) has methene 10 was dissolved in dipropylamine under argon and re-
been reported.2b Diisoindolazamethene (5) and pyrrolisoindolaza- fluxed for 10 hours, 10 was converted into (3-dipropylamino-
methene (6) are subunits of phthalocyanines, which have been isoindol-1-ylidene)-(3-methyl-indol-2-yl)-amine (11) in moderate
suggested as photosensitizers for clinical photodynamic therapy.5 yield. The 1H NMR of 11 contains only one N–H signal at
But the known complexes of diisoindolazamethenes (5)2a,d and 11.75 ppm; the proton signals of dipropylamino group appear at
pyrrolisoindolazamethenes (6)2c also have extended conjugation 3.79, 2.58, and 1.93 ppm, with integrations for four, four, and six
through two phenyl substituents. Our attempts to prepare diindo- protons, respectively.13 The desired product 12 was readily ob-
lazamethene (8) failed when 1-Boc-2-nitrosoindole was condensed tained by refluxing indolisoindolazamethene 11 with boron tri-
with indole6 or when 2-bromoindole7 was reacted with sodium fluoride etherate for 1 h in the presence of diisopropylethylamine
azide.8 1-Boc-2-nitrosoindole was prepared in situ by lithiation9 under argon.14 Complex 12 has been characterized by 1H and 13B
of 1-Boc-indole followed by the reaction with isoamylnitrite, but NMR and HR-MS. The N–H proton signal disappears; the 13B signal
its condensation product with indole, identified by mass spectros- is a triplet due to coupling with the neighboring fluorines and ap-
copy, was di(indol-2-yl)amine, which could not be oxidized to the pears at 1.74 ppm (referenced to BF3OEt2), whereas the 13B signal
desired diindolazamethene. We describe here the design and syn- of the BF2 complex of 2a appears at 0.94 ppm.3
thesis of the BF2 complex of (3-dipropylamino-isoindol-1-ylidene)- As shown in Figure 4, indolisoindolazamethenes 10 and 11 ex-
(3-methyl-indol-2-yl)-amine (12), which is an analogue of indol- hibit maximum visible absorptions at 465 nm and 484 nm, respec-
isoindolazamethene (7) (Scheme 1). tively. The minor absorption peaks appearing as shoulders on the
The starting materials were commercially available 3-methylin- blue and red sides belong to tautomers. The BF2 complex 12 has
dole and 1,3-diiminoisoindoline. 3-Methylindole was chlorinated its maximum visible absorption at 528 nm with a half band width

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
NH N NH N

4 5 6

N N
N
NH N NH N
NH N

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
H N NH

NCS
DIEA

H
N N N

NH N NH N NH HN
NH NH2 NH
10a 10b 10c

HN(C3H7)2

N N
BF3
NH N N N
DIEA B
N(C3H7)2 F F N(C3H7)2

11 12

Scheme 1. Synthesis of indolisoindolazamethene–BF2 complex.

We thank the NMR and Mass spectroscopy labs of the Chemistry

1.0 Department at the University of British Columbia.

References and notes

0.8
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.;
Absorption

0.6 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)
0.4 10 11 12 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.
2. For p-conjugation-expanded azadipyrromethenes: (a) Bredereck, H.; Vollmann,
0.2 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.
0.0 3. 3,30 ,5,50 -Tetraphenylazadipyrromethene (2a) and its BF2 complex were prepared
300 400 500 600 700 according to the literature.1a Diffraction-quality crystal of the BF2 complex of
Wavelength (nm) 2a was grown by the slow evaporation of solutions in dichloromethane and
hexane at 5 °C.
Figure 4. The UV–vis absorption spectra of 10 ( ), 11 ( ) and 12 ( ). 4. Crystal data for the BF2 complex of 2a (C32H22BF2N3): M = 497.34, monoclinic,
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.
of 132 nm, which is in the same wavelength range as that of tetra- 5. The recent reviews: (a) Garcia, F. S.; Tedesco, A. C.; Bentley, M. V. L. B. Trends
phenyl-conjugated azadipyrromethene (4), whereas the BF2 com- 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.;
plex of 4 has two distinct absorptions at 502 and 537 nm.2b Manneville, V.; Barberi-Heyob, M. Curr. Med. Chem. 2007, 14, 1673.
In conclusion, we report the facile synthesis and spectral char- 6. Hall, M. J.; McDonnell, S. O.; Killoran, J.; O’Shea, D. F. J. Org. Chem. 2005, 70,
acteristic of a novel BF2 complex of indol-2-yl-isoindol-1-ylidene- 5571.
7. Mistry, A. G.; Smith, K.; Bye, M. R. Tetrahedron Lett. 1986, 27, 1051.
amine as a new p-conjugation-expanded azadipyrromethene. Fur- 8. Singh, J. P.; Xie, L. Y.; Dolphin, D. Tetrahedron Lett. 1995, 36, 1567.
ther investigation into the variation of the indole ring substituents 9. Jiang, J.; Gribble, G. W. Tetrahedron Lett. 2002, 43, 4115.
and their effect on maximum absorption as well as their photo- 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
physical properties are in progress.
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
Acknowledgments 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
This work is supported by QLT Inc., Vancouver, BC, and the Nat- vacuum to dryness. The residue was purified by column chromatography
ural Sciences and Engineering Research Council (NSERC) of Canada. (silica gel) eluting with a mixture of ethyl acetate and hexane (1:1) to provide
814 Y. Li et al. / Tetrahedron Letters 51 (2010) 811–814

the orange product 10. Yield: 77%. mp: 223–224 °C. Anal. Calcd for C17H14N41/ 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),
10CH2Cl21/10C6H14 (solvent of crystallization determined by NMR): C, 72.95; 3.79 (t, 4H, J = 7.94), 2.58 (s, 3H), 1.97–1.88 (m, 4H), 1.15–1.07 (m, 6H). 13C
H, 5.40; N, 19.22. Found: C, 72.53; H, 5.01; N, 18.82. 1H NMR (CDCl3): d 11.23 (s, NMR: (CDCl3): 167.2, 143.2, 141.9, 136.6, 134.7, 132.4, 130.3, 129.3, 129.0,
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), 128.7, 123.1, 122.9, 122.6, 119.2, 118.8, 110.6, 52.4, 29.9, 21.8, 8.8. UV–vis
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), (0.94  105 M, CH2Cl2): kmax (log e) 458 (4.34), 483 (4.38), 515 (sh, 4.18). EI
6.96–6.90 (dt, 1H, J = 7.84, 0.79), 2.38 (s, 3H). 13C NMR (CDCl3): 168.0, 141.2, MS: m/z (%) = 358 (100) [M]+, 315 (16), 258 (14). HR-EI MS: m/z calcd for
140.6, 135.4, 132.5, 131.2, 129.8, 129.3, 128.5, 125.8, 123.5, 122.7, 119.5, 119.2, C23H26N4: 358.2158; found: 358.2161.
119.0, 111.0, 8.8. UV–vis (2.50  105 M, CH2Cl2): kmax (log e) 440 (sh. 4.38), 14. BF2 complex of (3-dipropylamino-isoindol-1-ylidene)-(3-methyl-indol-2-yl)-amine
464 (4.40), 494 (sh. 4.22). EI MS: m/z (%) = 273 (100) [M]+, 249 (5). HR-EI MS: (12): To a solution of indolisoindolazamethene 11 (0.05 mmol, 0.018 g) in
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, boron trifluoride diethyletherate (0.06 mmol, 6.8 lL) under argon. The
1033. resulting mixture was refluxed for 1 h and then evaporated under vacuum to
12. Spiessens, L. I.; Anteunis, M. J. O. Bull. Soc. Chim. Belg. 1988, 97, 431. dryness. The residue was purified by column chromatography eluting with a
13. (3-Dipropylamino-isoindol-1-ylidene)-(3-methyl-indol-2-yl)-amine (11): To the mixture of dichloromethane and hexane (1:1) to provide the desired product
dipropylamine (20 mL) was added indolisoindolazamethene 10 (0.30 mmol, 12. Yield: 59%. Mp: 204–205 °C. 1H NMR (CDCl3): d 8.19 (d, 1H, J = 7.59), 7.73
0.083 g). The mixture was refluxed under argon for 10 h and then evaporated (d, 1H, J = 8.17), 7.69–7.43 (m, 4H), 7.19 (dt, 1H, J = 8.15, 1.09), 7.02 (dt, 1H,
under vacuum to recycle unreacted dipropylamine. The residue was purified 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,
by column chromatography eluting with a mixture of ethyl acetate and hexane J = 7.22). 13B NMR: d 1.74 (t). UV–vis (4.05  105 M, CH2Cl2): kmax (log e) 528
(1:10) to give product 11. Yield: 23%. mp: 187–188 °C. 1H NMR (CDCl3): d 11.75 (4.40). EI MS: m/z (%) = 406 (48) [M]+, 358 (100), 315 (30), 258 (40). HR-EI MS:
(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, m/z calcd for C23H25N4BF2: 406.2140; found: 406.2153.