Preparation of polyfunctional aryl azides from aryl triazenes. A new synthesis of ellipticine, 9-methoxyellipticine, isoellipticine, and 7-carbethoxyisoellipticine

Article abstract of DOI:10.1021/jo070774z

(Chemical Equation Presented) The preparation of polyfunctional aryl azides by the reaction of aryl triazenes with NaN₃ in the presence of KHSO₄ or BF₃·OEt₂/TFA (trifluoroacetic acid) has been described. A variety of functional groups (halides, esters, ketones, nitriles, aldehydes, and boronic esters) are tolerated under the Lewis acidic conditions. By using this methodology, the potent antitumor agents, ellipticine and 9-methoxyellipticine, have been synthesized. In addition, isoellipticine and a related derivative, 7-carbethoxyisoellipticine, were also prepared.

Full text of DOI:10.1021/jo070774z

Preparation of Polyfunctional Aryl Azides from Aryl Triazenes. A
New Synthesis of Ellipticine, 9-Methoxyellipticine, Isoellipticine, and
7-Carbethoxyisoellipticine
Ching-Yuan Liu and Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t Mu¨nchen, Butenandtstrasse 5-13,
Haus F, 81377 Munich, Germany
paul.knochel@cup.uni-muenchen.de
ReceiVed April 13, 2007
The preparation of polyfunctional aryl azides by the reaction of aryl triazenes with NaN3 in the presence
of KHSO4 or BF3‚OEt2/TFA (trifluoroacetic acid) has been described. A variety of functional groups
(halides, esters, ketones, nitriles, aldehydes, and boronic esters) are tolerated under the Lewis acidic
conditions. By using this methodology, the potent antitumor agents, ellipticine and 9-methoxyellipticine,
have been synthesized. In addition, isoellipticine and a related derivative, 7-carbethoxyisoellipticine, were
also prepared.
SCHEME 1. Conversion of Triazenes of Type 1 to Azides
of Type 2
1. Introduction
The use of aryl azides as synthetic intermediates has attracted
much attention due to their potential applications in organic
synthesis.1 They have been used for the synthesis of anilines,2
in cycloaddition reactions,3 and for the generation of nitrenes.4
Recently, Bra¨se has prepared aryl azides starting from polymer-
bound triazenes.5 A variety of triazene resins have proved to
be useful intermediates for the solid-phase synthesis of aryl
azides. We also reported a halogen-magnesium exchange
reaction of halogenated aryl triazenes (X ) Br or I) by using
the mixed Mg/Li-reagent i-PrMgCl‚LiCl.6 This method allowed
us to prepare polyfunctional aryl triazenes of type 1 (Scheme
1).6h The triazene functionality (ArNdNsNR2) can be consid-
ered as being a synthetic equivalent of a protected diazonium
salt. This allows the reactive diazonium salt to carry through
several synthetic steps. More noteworthy is the conversion of a
triazene moiety to an azide group under mild reaction conditions,
* Address correspondence to this author. Fax: (+49) 89-2180-77680.
(1) (a) Bra¨se, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem.
2005, 117, 5320; Angew. Chem., Int. Ed. 2005, 44, 5188;. (b) Patai, S. The
Chemistry of Diazonium and Diazo Groups. In The Chemistry of Functional
Groups; Patai, S., Ed.; John Wiley: Chichester, UK, 1978.
(2) Kumar, H. M. S.; Reddy, B. V. S.; Anjaneyulu, S.; Jadav, J. S.
Tetrahedron Lett. 1999, 40, 8305.
(3) (a) Huisgen, R. Angew. Chem. 1963, 75, 604; Angew. Chem., Int.
Ed. 1963, 2, 565. (b) Huisgen, R.; Knorr, R.; Mo¨bius, L.; Szeimies, G.
Chem. Ber. 1965, 98, 4014.
(6) (a) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43,
3333. (b) Kopp, F.; Krasovskiy, A.; Knochel, P. Chem. Commun. 2004,
2288. (c) Ren, H.; Krasovskiy, A.; Knochel, P. Org. Lett. 2004, 6, 4215.
(d) Ren, H.; Krasovskiy, A.; Knochel, P. Chem. Commun. 2005, 543. (e)
Kopp, F.; Sklute, G.; Polborn, K.; Marek, J.; Knochel, P. Org. Lett. 2005,
7, 3789. (f) Liu, C. Y.; Ren, H.; Knochel, P. Org. Lett. 2006, 8, 617. See
also: (g) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp,
F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42,
4302. (h) Liu, C. Y.; Knochel, P. Org. Lett. 2005, 7, 2543.
(4) (a) Tiemann, F. Ber. Dtsch. Chem. Ges. 1891, 24, 4162. (b) Gritsan,
N. P.; Pritchina, E. A. Russ. Chem. ReV. 1992, 61, 500. (c) Budyka, M. F.;
Kantor, M. M.; Alfimov, M. V. Russ. Chem. ReV. 1992, 61, 25. Bucher, G.
In CRC Handbook of Organic Photochemistry and Photobiology; CRC:
Boca Raton, FL, 2004; S. 44/1-44/31.
(5) Bra¨se, S.; Gil, C.; knepper, K.; Zimmermann, V. Synlett 2004, 1163.
10.1021/jo070774z CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/18/2007
7106
J. Org. Chem. 2007, 72, 7106-7115

Polyfunctional Aryl Azides from Aryl Triazenes
SCHEME 2. Retrosynthetic Analysis of Compounds 3a, 3b, 4a, and 4b: (a) Thermal Decomposition of Azides and (b)
Conversion of the Triazene Group to an Azide
SCHEME 3. Synthesis of the Triazenes 1a-f
SCHEME 4. Synthesis of the Polyfunctional Triazene 1g
reaction as shown in Schemes 4-8. Thus, 1-(2-iodophenylazo)-
pyrrolidine (1a) was obtained from 2-iodoaniline 5a in 92%
yield via a diazotation and trapping with pyrrolidine.6h Triazenes
1b-f were also readily prepared from the corresponding anilines
5b-f under similar reaction conditions (Scheme 3).6h,7,8 1-(4-
Cyano-2-iodophenylazo)pyrrolidine (6g)6h reacted with iPrMgCl‚
LiCl affording the expected arylmagnesium derivative, which
was transmetalated with CuCN‚2LiCl to the corresponding
organocopper species.9 This copper reagent readily underwent
an addition-elimination reaction with 3-iodo-2-cyclohexen-1-
one10 giving the triazene 1g in 81% yield (Scheme 4). The
iodoaryltriazenes 6h-j reacted with iPrMgCl‚LiCl (-40 °C,
0.7-1 h) giving the magnesiated triazenes, which underwent a
copper-catalyzed acylation with furoyl chloride leading to the
polyfunctional ketones 1h-j in 85-88% (Scheme 5). Reaction
of the arylmagnesium derivative of 1-(2-carbethoxy-4-iodophe-
nylazo)pyrrolidine (6k) with N,N-dimethylformamide furnished
the expected triazene 1k in 85% yield (Scheme 6). Iron(III)-
catalyzed oxidative homocoupling11 of 1-(4-carbethoxy-2-io-
dophenylazo)pyrrolidine (6l) afforded the bis-triazene 1l in 52%
yield with use of Fe(acac)3 (0.5 equiv, -40 °C to rt, 1 h, Scheme
6). The arylmagnesium species of 6m-n were transmetalated
a transformation that would further extend the scope of this
important functionality. Thus, in spite of the importance and
usefulness of azides, a practical synthesis of natural products
involving a triazene to azide conversion as a key step has not
been reported yet. Herein, we wish to develop an efficient
method for the conversion of triazenes of type 1 to the
polyfunctional aryl azides of type 2 (Scheme 1).
By using this approach, we have envisioned that the biologi-
cally active compounds ellipticine (3a) and 9-methoxyellipticine
(3b) could be readily prepared in two steps starting from the
corresponding aryl triazenes of type 1 via aryl azides of type 2.
Similarly, the synthesis of isoellipticine (4a) and 7-carbethoxyi-
soellipticine (4b) might also be envisaged by using the same
strategy (Scheme 2).
(7) (a) Wallach, O. Liebigs Ann. Chem. 1886, 235, 233. (b) Wallach,
O.; Heusler, F. Liebigs Ann. Chem. 1888, 243, 219. (c) Merkushev, E. B.
Synthesis 1988, 923. (d) Gross, M. L.; Blank, D. H.; Welch, W. M. J. Org.
Chem. 1993, 58, 2104. (e) Satamurthy, N.; Barrio, J. B.; Bida, G. T.; Phelps,
M. E. Tetrahedron Lett. 1990, 31, 4409. (f) Cohen, T.; Dietz, A. G., Jr.;
Miser, J. R. J. Org. Chem. 1977, 42, 2053.
(8) (a) Nicolaou, K. C.; Boddy, C. N. C.; Natarajan, S.; Yue, T. Y.; Li,
H.; Bra¨se, S.; Ramanjulu, J. M. J. Am. Chem. Soc. 1997, 119, 3421. (b)
Nicolaou, K. C.; Li, H.; Boddy, C. N. C.; Ramanjulu, J. M.; Yue, T. Y.;
Natarajan, S.; Chu, X. J.; Bra¨se, S.; Ru¨bsam, F. Chem. Eur. J. 1999, 5,
2584.
(9) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
2. Results and Discussion
Preparation of Polyfunctional Aryl Triazenes of Type 1.
Triazenes 1a-f were easily prepared from the corresponding
anilines 5a-f (Scheme 3), and the polyfunctional triazenes 1g-o
were prepared from the halo-substituted triazenes 6g-o, which
were further functionalized by using a I/Mg- or Br/Mg-exchange
(10) Barnier, J. P.; Blanco, L. Synth. Commun. 2003, 33, 2487.
(11) Nagono, T.; Hayashi, T. Org. Lett. 2005, 7, 491.
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Liu and Knochel
SCHEME 5. Synthesis of the Polyfunctional Triazenes 1h-j
SCHEME 6. Synthesis of the Polyfunctional Triazenes 1k,l
SCHEME 9. Synthesis of the Polyfunctional Aryl Azides
2a-m (Method A) and 2n,o (Method B)
SCHEME 7. Synthesis of the Polyfunctional Triazenes 1m,n
Preparation of Polyfunctional Aryl Azides of Type 2. The
aryl triazenes of type 1 can be readily converted to the
corresponding azides of type 2 in moderate to excellent yields.
The azidation reactions were performed either by using BF3‚
OEt2/TFA (trifluoroacetic acid) in CH2Cl2 (Method A)5 or by
using KHSO4 in CH2Cl2/H2O (Method B) at room temperature
in the presence of sodium azide (Scheme 9).
Thus, the azidation of 1-(2-iodophenylazo)pyrrolidine (1a)
was accomplished by using a mixture of BF3‚OEt2 and TFA
(1/1, 2 equiv to the triazene) and sodium azide (2 equiv to the
triazene) in CH2Cl2 at room temperature (Method A) affording
the expected 1-azido-2-iodobenzene (2a) in 80% yield (entry 1
of Table 1).
SCHEME 8. Synthesis of the Polyfunctional Triazene 1o
The azidation of aryl triazenes 1b-m with the same reaction
conditions as described above furnished the aryl azides 2b-m
in 72-94% yield (entries 2-13). It is worth noting that the
combination of BF3‚OEt2 and TFA is a more efficient reagent
than either reagent alone, BF3‚OEt2 or TFA. For instance, the
reaction of aryl triazenes 1b-m with either BF3‚OEt2 (2.0 equiv)
or TFA (2.0 equiv) in the presence of sodium azide (2.0 equiv)
did not proceed to completion and 30-40% of the starting
material was recovered when the reaction mixture was stirred
at room temperature for 1 h. The mixture of BF3‚OEt2 and TFA
with ZnBr2 to the corresponding arylzinc reagents, then the
Negishi cross-coupling reactions12 were performed respectively
with 1,2-diiodobenzene or 3-iodopyridine providing the biphenyl
triazenes 1m (88%) and 1n (76%) as shown in Scheme 7.
Treatment of the arylmagnesium derivative of 1-(4-iodopheny-
lazo)pyrrolidine (6j) with triisopropyl borate followed by the
addition of neopentyl glycol produced the expected triazene-
substituted boronic ester 1o in 86% yield (Scheme 8).
(12) (a) Green, L.; Chauder, B.; Snieckus, V. J. Heterocycl. Chem. 1999,
36, 1453. (b) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc.
1980, 102, 3298. (c) Kobayashi, M.; Negishi, E. J. Org. Chem. 1980, 45,
5223. (d) Negishi, E. Acc. Chem. Res. 1982, 15, 340. (e) Tamaru, Y.; Ochiai,
H.; Nakamura, T.; Yoshida, Z. Tetrahedron Lett. 1986, 27, 955. (f) Klement,
I.; Rottla¨nder, M.; Tucker, C. E.; Majid, T. N.; Knochel, P.; Venegas, P.;
Cahiez, G. Tetrahedron 1996, 52, 7201.
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Polyfunctional Aryl Azides from Aryl Triazenes
TABLE 1. Preparation of Polyfunctional Aryl Azides of Type 2
a Isolated yield of analytically pure product. b Prepared according to Method A: BF3‚OEt2/TFA, NaN3, CH2Cl2, rt, 10-25 min. c Prepared according to
Method B: KHSO4, NaN3, CH2Cl2/H2O, rt, 12-16 h. TFA ) trifluoroacetic acid.
J. Org. Chem, Vol. 72, No. 19, 2007 7109

Liu and Knochel
SCHEME 10. Retrosynthetic Analysis of 3a and 3b
can be regarded as a super-Brønsted acid,13 a more powerful
and convenient reagent for the conversion of triazenes to azides.
A range of functional groups are also tolerated under these mild
reaction conditions giving a practical access to a variety of new
functionalized aryl azides. The triazenes 1n and 1o were readily
converted to the corresponding aryl azides 2n (78%, entry 14)
and 2o (96%, entry 15) by using KHSO4 (10 equiv) in CH2Cl2
at room temperature in the presence of sodium azide (5 equiv).
It is interesting to note that heterocycles or reactive functional
groups, such as a pyridine ring (compound 2n) or a boronic
ester (compound 2o), are tolerated. Thus, with KHSO4 as the
reagent, a smooth conversion of an aryl triazene to an aryl azide
is achieved. However, the reaction time is usually longer (12-
16 h; Method B).
Synthesis of Ellipticine and 9-Methoxyellipticine by the
Thermal Decomposition of Azides. The Ochrosia and Aspi-
dosperma plant alkaloid ellipticine (3a)14 and its 9-oxygenated
derivatives have been shown to exhibit potential anticancer
activities.15 Particularly, 9-methoxyellipticine (3b) was used to
treat patients with acute myeloblastic leukemia.16 Therefore, the
preparation of 3a or 3b has attracted the interest of synthetic
organic chemists for the past half century and numerous total
or partial syntheses have been reported.17-24 We have envisioned
a synthesis starting from polyfunctional aryl azides (7a, 7b),
which would undergo a thermal decomposition giving the
ellipticine derivatives such as ellipticine (3a) and 9-methox-
yellipticine (3b) (Scheme 10).25
Herein, we describe a short and practical synthesis of these
potent anticancer agents using three key synthetic transforma-
tions, namely, a Negishi cross-coupling, azidation, and cycliza-
tion. The precursors were prepared by using a Negishi cross-
coupling reaction12 of the zinc species of 1-(2-iodophenylazo)-
pyrrolidine (1a) or 1-(4-methoxy-2-iodophenylazo)pyrrolidine
(6n) with 7-bromo-5,8-dimethylisoquinoline (9) to give the aryl
triazene 8a or 8b, which was then converted to the aryl azide
7a or 7b followed by a thermal cyclization (Scheme 10).
The preparation of 7-bromo-5,8-dimethylisoquinoline (9) was
achieved starting from the 1,4-dibromo-2,5-dimethylbenzene
(10). First, we have performed a Br/Li-exchange with n-BuLi
followed by the addition of DMF affording the aldehyde 11 in
99% yield.26 The reaction of 11 with NaBH4 provided the benzyl
alcohol 12 (99%), which was then converted to the benzyl
chloride 13 (93%) by the addition of SOCl2. The malonate 14
was prepared by the reaction of 13 with diethyl malonate in
88% yield.27 Hydrolysis and decarboxylation gave the corre-
sponding carboxylic acid 15 in 83% overall yield. Polyphos-
phoric acid (PPA) catalyzed ring closure28 furnished the
indanone 16 (88%), which was then reduced to the correspond-
ing indanol, followed by a dehydration with a catalytic amount
of p-TsOH in refluxing benzene affording the indene 17 in 78%
overall yield. Ozonolysis of 17 in a mixture of MeOH/CH2Cl2,
followed by a reductive workup with Me2S and treatment with
concd NH4OH provided 7-bromo-5,8-dimethylisoquinoline (9)
in 95% yield (Scheme 11).29
(13) (a) Ishihara, K.; Hasegawa, A.; Yamamoto, H. Synlett 2002, 1296.
(b) Ishihara, K.; Hasegawa, A.; Yamamoto, H. Synlett 2002, 1299.
(14) (a) Goodwin, S.; Smith, A. F.; Horning, E. C. J. Am. Chem. Soc.
1959, 81, 1903. (b) Woodward, R. B.; Iacobucci, G. A.; Hochstein, F. A.
J. Am. Chem. Soc. 1959, 81, 4434.
(15) Van-Bac, N.; Moisand, C.; Gouyette, A.; Muzard, G.; Dat-Xuong,
N.; Le Pecq, J. B.; Paoletti, C. Cancer Treat. Rep. 1980, 64, 879 and
references cited therein.
(16) Mathe´, G.; Hayat, M.; De Vassal, F.; Schwarzenberg, L.; Schneider,
M.; Schlumberger, J. R.; Jasmin, C.; Rosenfeld, C. ReV. Eur. Etud. Clin.
Biol. 1970, 15, 541.
(17) Sainsbury, M. Ellipticines. In Chemistry of Antitumour Agents;
Wilman, D. E. V., Ed.; Blackie: Glasgow and London, UK, 1990.
(18) Gribble, G. W. Synthesis and Antitumour Activity of Ellipticine
Alkaloids and Related Compounds. In The Alkaloids; Brossi, A., Ed.;
Academic Press: San Diego, CA, 1990; Vol. 39, p 239.
(19) Gribble, G. W.; Saulnier, M. G. Heterocycles 1985, 23, 1277.
(20) Gribble, G. W. Synthetic Approaches to the Ellipticine Alkaloids
via Metalation and Cycloaddition Chemistry. In: AdVances in Heterocyclic
Natural Product Synthesis; W. H. Pearson, W. H., Ed.; Jai Press:
Greenwich, CT, 1990; Vol. 1.
(23) May, C.; Moody, C. J. J. Chem. Soc., Chem. Commun. 1984, 926.
(24) May, C.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1988, 1, 247.
(25) (a) Smith, P. A. S.; Brown, B. B. J. Am. Chem. Soc. 1951, 73, 2435.
(b) Jian, H.; Tour, J. M. J. Org. Chem. 2003, 68, 5091.
(26) Jørgensen, M.; Krebs, F. C. J. Org. Chem. 2004, 69, 6688.
(27) Musso, D. L.; Cochran, F. R.; Kelley, J. L.; McLean, E. W.; Selph,
J. L.; Rigdon, G. C.; Orr, G. F.; Davis, R. G.; Cooper, B. R.; Styles, V. L.;
Thompson, J. B.; Hall, W. R. J. Med. Chem. 2003, 46, 399.
(28) Lewis, M. L.; de Meijere, A. Synlett 1997, 261.
(21) Gribble, G. W. Synlett 1991, 289.
(22) Gribble, G. W.; Saulnier, M. G.; Sibi, M. P.; Obaza-Nutaitis, J. A.
J. Org. Chem. 1984, 49, 4518.
(29) Miller, R. B.; Stowell, J. G.; Dugar, S.; Moock, T. E.; Jenks, C.
W.; Farmer, S. C.; Phan, B.; Wujcik, C. E.; Olmstead, M. M. Tetrahedron
2002, 58, 6061.
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Polyfunctional Aryl Azides from Aryl Triazenes
SCHEME 11. Synthesis of the Isoquinoline 9
SCHEME 12. Synthesis of Ellipticine (3a)
A new ellipticine synthesis30 was accomplished by starting
with the triazene 1a. After I/Mg exchange with iPrMgCl‚LiCl
(-40 °C, 1 h) and transmetalation with ZnBr2, the resulting
zinc intermediate was submitted to a Negishi cross-coupling12
with 7-bromo-5,8-dimethylisoquinoline (9) leading to the poly-
functional aryl triazene 8a (75%). This compound was readily
converted to the corresponding aryl azide 7a (78%) by the
addition of BF3‚OEt2/TFA in CH2Cl2 in the presence of NaN3
(Method A). Thermal decomposition of azide 7a in refluxing
mesitylene (6 h) gave ellipticine (3a) in 57% yield (Scheme
12).
the presence of NaN3 (Method B). A solution of 7b in
mesitylene was heated at reflux for 5 h to give 9-methoxyell-
ipticine (3b) in 68% yield (Scheme 13).
Synthesis of Isoellipticine and 7-Carbethoxyisoellipticine
by a Thermal Decomposition of Azides. Interestingly, we
found that this method was also successfully applied to the
preparation of isoellipticine (4a) and a related derivative,
7-carbethoxyisoellipticine (4b). Thus, the arylmagnesium species
generated from 1a and 18 (iPrMgCl‚LiCl, -40 °C, 0.7-1 h)
were transmetalated with ZnBr2. These arylzinc reagents
underwent Negishi cross-coupling reactions12 with 6-bromo-
5,8-dimethylisoquinoline (19)29,31 affording the derived poly-
functional aryl triazenes 20a (78%) and 20b (81%). These
triazenes 20a,b were readily converted to the aryl azides 21a
(95%) and 21b (81%) by using Method B and Method A,
respectively. Thermal decomposition of the aryl azides 21a,b
in refluxing mesitylene (4-6 h) furnished the isoellipticines 4a
(63%) and 4b (64%) (Scheme 14).
The same approach was used for preparing 9-methoxyellip-
ticine (3b). Indeed, starting with the Grignard reagent derived
from 1-(4-methoxy-2-iodophenylazo)pyrrolidine (6n) (iPrMgCl‚
LiCl, -20 to -10 °C, 1.2 h), we performed after transmetalation
with ZnBr2 a Negishi cross-coupling12 with the isoquinoline 9
leading to the triazene 8b (63%), which was readily converted
to the aryl azide 7b (94%) by using KHSO4 in CH2Cl2/H2O in
(30) Kno¨lker, H. S.; Reddy, K. R. Chem. ReV. 2002, 102, 4303.
(31) Miller, R. B.; Moock, T. Tetrahedron Lett. 1980, 21, 3319.
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Liu and Knochel
SCHEME 13. Synthesis of 9-Methoxyellipticine (3b)
SCHEME 14. Synthesis of Isoellipticine (4a) and 7-Carbethoxyisoellipticine (4b)
literature procedures: ethyl 4-amino-3-bromobenzoate (5b);32 meth-
yl 4-amino-3,5-dibromobenzoate (5e);8b 2,4,6-tribromoaniline (5f);8b
aryl triazenes 6g-m, 1d, 1h-j, 1m, 186h and 1e-f;8b and 6-bromo-
5,8-dimethyl-isoquinoline (19).29,31 Procedures for the synthesis of
compounds 1a-o and 2a-o are given in the Supporting Informa-
tion.
3. Conclusion
In summary, we have developed an efficient synthetic method
for the preparation of polyfunctional aryl azides from the
corresponding polyfunctional aryl triazenes, which are readily
obtained from the anilines or the iodo- or bromo-substituted
aryl triazenes by using a novel exchange protocol.6 Furthermore,
as an application of the versatility of these polyfunctional aryl
azides, we have used them for a new synthesis of ellipticine,
9-methoxyellipticine, isoellipticine, and 7-carbethoxyisoellip-
ticine. Extensions of this methodology are currently being
investigated in our laboratories.
4-Bromo-2,5-dimethylbenzaldehyde (11). To a solution of 1,4-
dibromo-2,5-dimethylbenzene (10) (2.64 g, 10 mmol) in THF (5
mL) was slowly added n-BuLi (4.4 mL, 10.5 mmol, 2.4 M in
hexane) at -78 °C. The reaction mixture was continuously stirred
at -78 °C for 10 min. After 10 min, a complete conversion to the
corresponding lithium reagent was observed as indicated by GC
analysis of hydrolyzed reaction aliquots. N,N-Dimethylformamide
(1.6 mL, 20 mmol) was added and the reaction mixture was warmed
to rt and stirred again for 1 h before the addition of aq NH4Cl (20
mL). The aqueous phase was extracted with ether (2 × 50 mL).
The organic layers were washed with brine (100 mL), dried
(MgSO4), and concentrated in vacuo to give the pure product 11
(2.1 g, 99%) as a white powder. Mp 58.2-59.8 °C; 1H NMR
(CDCl3, 300 MHz) δ 10.15 (s, 1H), 7.58 (s, 1H), 7.41 (s, 1H),
2.56 (s, 3H), 2.38 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 191.7,
139.2, 136.1, 135.4, 133.5, 133.0, 131.2; IR (KBr) 2956 (w), 2923
4. Experimental Section
Caution! Aryl triazenes are known carcinogens, and ellipticine
derivatives are potent cytostatics. Proper precautions during the
work with these compounds are strongly recommended. Any skin
contact or risk of inhalation of dust of these compounds should be
avoided.
Starting Materials. 2-Iodoaniline (5a), 1-amino-4-bromonaph-
thaline (5c), and 2,6-dibromoaniline (5d) are commercially avail-
able. The following compounds were prepared according to
(32) Tobe, Y.; Utsumi, N.; Kawabata, K.; Nagono, A.; Adachi, K.; Araki,
S.; Sonoda, M.; Hirose, K.; Naemura, K. J. Am. Chem. Soc. 2002, 124,
5350.
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Polyfunctional Aryl Azides from Aryl Triazenes
(w), 2862 (w), 2836 (w), 2760 (w), 2724 (w), 1682 (s), 1595 (m),
solid was filtered and washed with water to give the pure product
15 (555 mg, 83%) as a white powder. Mp 93.2-94.5 °C; 1H NMR
(CDCl3, 400 MHz) δ 12.0 (br s, 1H), 7.29 (s, 1H), 7.06 (s, 1H),
2.68 (t, J ) 7.8 Hz, 2H), 2.41 (t, J ) 7.8 Hz, 2H), 2.21 (s, 3H),
2.16 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 174.4, 139.3, 136.4,
134.9, 133.7, 131.8, 121.9, 34.5, 27.8, 22.5, 18.7; IR (KBr) 2900-
3400 (broad), 2571 (w), 1692 (s), 1487 (m), 1453 (m), 1416 (m),
1304 (m), 1213 (w), 1166 (w), 1024 (m), 962 (m) cm-1; MS (EI,
70 eV) 256 (M+, 50), 240 (3), 225 (2), 210 (8), 197 (100), 135
(23), 117 (32), 103 (9), 91 (21); HRMS (EI) calcd for C11H13BrO2
256.0099, found 256.0087.
6-Bromo-4,7-dimethylindan-1-one (16). The mixture of 15 (475
mg, 1.86 mmol) and polyphosphoric acid (2.2 mL) was heated at
100 °C for 2.5 h. After the mixture was cooled, ice water (7.5 mL)
was added and the reaction mixture was stirred for 0.5 h, and then
the aqueous phase was extracted with ether (2 × 15 mL). The
organic layers were washed with 10% aqueous NaHCO3 (30 mL)
and water (2 × 20 mL), dried (Na2SO4), and concentrated in vacuo
to give the pure product 16 (391 mg, 88%) as a pale yellow solid.
Mp 127.8-128.6 °C; 1H NMR (CDCl3, 300 MHz) δ 7.51 (s, 1H),
2.80-2.90 (m, 2H), 2.60-2.72 (m, 5H), 2.27 (s, 3H); 13C NMR
(CDCl3, 75 MHz) δ 207.1, 154.1, 137.8, 135.6, 135.3, 134.4, 124.9,
36.8, 23.6, 17.1, 16.5; IR (KBr) 3076 (w), 3030 (w), 2920 (w),
2857 (w), 1697 (s), 1568 (w), 1469 (m), 1435 (m), 1367 (w), 1252
(m), 1220 (m), 1102 (w), 989 (w) cm-1; MS (EI, 70 eV) 238 (M+,
100), 223 (6), 210 (12), 196 (6), 159 (41), 131 (35), 115 (32), 103
(6), 91 (16); HRMS (EI) calcd for C11H11BrO 237.9993, found
237.9984.
1546 (m), 1443 (m), 1382 (m), 1235 (m), 1182 (m), 959 (m) cm-1
;
MS (EI, 70 eV) 213 (M+, 100), 183 (32), 104 (35), 77 (31); HRMS
(EI) calcd for C9H9BrO:211.9837, found 211.9836.
4-Bromo-2,5-dimethylbenzyl Alcohol (12). A solution of 11
(1.02 g, 4.77 mmol) in EtOH (20 mL) was cooled in an ice bath
and NaBH4 (181 mg, 4.77 mmol) was added over 5 min with
stirring. Then the reaction mixture was gradually warmed to rt.
After 0.5 h the solvent was evaporated and H2O (20 mL) was added.
The aqueous mixture was extracted with ether (2 × 20 mL) and
the combined organic layers were washed with brine, dried (Na2-
SO4), and concentrated in vacuo to give the pure product 12
1
(1.01 g, 99%) as a white powder. Mp 92.0-92.7 °C; H NMR
(CDCl3, 600 MHz) δ 7.32 (s, 1H), 7.19 (s, 1H), 4.58 (s, 2H), 2.34
(s, 3H), 2.25 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 137.8, 135.20,
135.18, 133.7, 129.9, 123.7, 62.8, 22.3, 17.8; IR (KBr) 3100-3400
(broad), 2981 (m), 2918 (m), 2858 (m), 1754 (w), 1557 (w), 1484
(s), 1452 (s), 1387 (m), 1282 (w), 1185 (w), 1134 (w), 1040 (s),
957 (m) cm-1; MS (EI, 70 eV) 214 (M+, 60), 196 (100), 185 (13),
171 (8), 135 (19), 117 (38), 107 (54), 91 (75), 77 (25); HRMS
(EI) calcd for C9H11BrO 213.9993, found 213.9991.
4-Bromo-2,5-dimethylbenzyl Chloride (13). To a solution of
12 (930 mg, 4.35 mmol) in CHCl3 (3 mL) in an ice bath was added
slowly a solution of SOCl2 (0.4 mL) in CHCl3 (0.6 mL). After 10
min, the reaction mixture was warmed to rt and stirred for 0.5 h
before the addition of H2O (5.0 mL). The aqueous phase was
extracted with ether (2 × 5 mL). The organic layers were washed
with brine (10 mL), dried (Na2SO4), and concentrated in vacuo to
give the pure product 13 (945 mg, 93%) as a pale yellow liquid.
1H NMR (CDCl3, 600 MHz) δ 7.36 (s, 1H), 7.15 (s, 1H), 4.50 (s,
2H), 2.34 (s, 3H), 2.33 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ
136.3, 135.7, 134.7, 134.2, 132.0, 125.1, 44.1, 22.2, 18.0; IR (neat)
2948 (m), 2921 (m), 2876 (w), 1488 (s), 1449 (s), 1263 (s), 962
(s) cm-1; MS (EI, 70 eV) 234 (M+, 33), 197 (100), 115 (30), 103
(8), 91 (18), 77 (8); HRMS (EI) calcd for C9H10BrCl 231.9654,
found 231.9644.
6-Bromo-4,7-dimethylindan-1-ol. A solution of 16 (180 mg,
0.76 mmol) in EtOH (3.2 mL) was cooled in an ice bath and NaBH4
(29 mg, 0.76 mmol) was added over 5 min with stirring. Then the
reaction mixture was gradually warmed to rt. After 0.5 h the solvent
was evaporated and H2O (5 mL) was added. The aqueous mixture
was extracted with ether (2 × 5 mL) and the combined organic
layers were washed with brine, dried (Na2SO4), and concentrated
in vacuo to give the pure product (179 mg, 98%) as a pale yellow
1
solid. Mp 124.0-125.5 °C; H NMR (CDCl3, 400 MHz) δ 7.27
2-(4-Bromo-2,5-dimethylbenzyl)malonic Acid Diethyl Ester
(14). To a mixture of sodium hydride (720 mg, 18 mmol, 60%
dispersion in mineral oil) in 1,2-dimethoxyethane (4.5 mL) under
a nitrogen atmosphere was added dropwise a solution of diethyl
malonate (3.04 g, 19 mmol) in 1,2-dimethoxyethane (9 mL). After
the reaction mixture was stirred at rt for 2 h, a solution of 13 (840
mg, 3.6 mmol) in 1,2-dimethoxyethane (1.8 mL) was added
dropwise. The reaction mixture was refluxed for 12 h and then
concentrated in vacuo, and the residue was treated with a mixture
of water (6 mL) and CH2Cl2 (6 mL). The aqueous phase was
extracted with CH2Cl2 (2 × 10 mL). The organic layers were
washed with brine (30 mL), dried (Na2SO4), and concentrated in
vacuo to give the crude product. Purification by flash chromatog-
raphy (pentane:ether ) 9:1) yielded the pure product 14 (1.13 g,
88%) as a white powder. Mp 47.8-48.7 °C; 1H NMR (CDCl3, 300
MHz) δ 7.28 (s, 1H), 6.97 (s, 1H), 4.14 (q, J ) 7.2 Hz, 4H), 3.56
(t, J ) 7.8 Hz, 1H), 3.12 (d, J ) 7.8 Hz, 2H), 2.28 (s, 3H), 2.25
(s, 3H), 1.20 (t, J ) 7.2 Hz, 6H); 13C NMR (CDCl3, 75 MHz) δ
168.8, 135.6, 135.4, 135.3, 135.0, 133.8, 131.6, 61.5, 52.2, 31.3,
22.2, 18.5, 14.0; IR (KBr) 2983 (m), 2936 (w), 2874 (w), 1738
(s), 1724 (s), 1489 (w), 1368 (m), 1327 (m), 1288 (m), 1222 (m),
1170 (m), 1149 (m), 1026 (m), 958 (m) cm-1; MS (EI, 70 eV) 356
(M+, 30), 338 (30), 312 (19), 284 (48), 265 (50), 239 (100), 210
(29), 197 (81), 185 (48), 158 (59), 145 (10), 129 (60), 115 (66),
103 (14), 91 (30), 77 (14); HRMS (EI) calcd for C16H21BrO4
356.0623, found 356.0619.
(s, 1H), 5.27 (d, J ) 6.0 Hz, 1H), 2.88-3.02 (m, 1H), 2.68 (ddd,
J ) 17.0, 9.5, 2.6 Hz, 1H), 2.41 (s, 3H), 2.30-2.37 (m, 1H), 2.18
(s, 3H), 1.96-2.12 (m, 1H), 1.64 (br s, 1H); 13C NMR (CDCl3,
100 MHz) δ 144.2, 142.1, 133.2, 133.1, 132.0, 123.2, 76.0, 34.8,
28.7, 18.4, 15.2; IR (KBr) 3000-3400 (broad), 2922 (m), 1467
(s), 1378 (m), 1308 (w), 1254 (w), 1180 (m), 1154 (m), 1044 (s),
958 (s) cm-1; MS (EI, 70 eV) 240 (M+, 72), 222 (100), 209 (4),
197 (8), 183 (10), 161 (30), 143 (86), 128 (48), 115 (40), 103 (8),
91 (16); HRMS (EI) calcd for C11H13BrO 240.0150, found
240.0143.
5-Bromo-4,7-dimethyl-1H-indene (17). A solution of 6-bromo-
4,7-dimethylindan-1-ol (164 mg, 0.68 mmol) and p-TsOH (1.7 mg,
7 µmol) in benzene (17 mL) was heated at reflux. After 2 h, the
reaction mixture was allowed to cool and the solvent was evaporated
in vacuo (30 °C, 30 mmHg) to give the crude product. Purification
by flash chromatography (pentane) yielded the pure product 17 (130
1
mg, 86%) as a pale yellow liquid. H NMR (CDCl3, 400 MHz) δ
7.53 (s, 1H), 7.27 (dt, J ) 5.7, 2.0 Hz, 1H), 6.89 (dt, J ) 5.7, 2.0
Hz, 1H), 3.56 (t, J ) 2.0 Hz, 2H), 2.78 (s, 3H), 2.61 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ 144.8, 141.3, 134.5, 131.7, 130.9, 129.3,
127.5, 123.0, 38.3, 18.6, 18.1; IR (neat) 3061 (w), 2974 (w), 2919
(w), 2857 (w), 1666(w), 1583 (w), 1549 (w), 1461 (m), 1372 (m),
1247 (w), 1170 (w), 950 (m) cm-1; MS (EI, 70 eV) 222 (M+, 34),
207 (4), 143 (100), 128 (52), 115 (20), 102 (8), 89 (8), 77 (8);
HRMS (EI) calcd for C11H11Br 222.0044, found 222.0038.
7-Bromo-5,8-dimethylisoquinoline (9). A solution of 17 (100
mg, 0.45 mmol) in MeOH (2.5 mL) and CH2Cl2 (2.5 mL) was
cooled to -78 °C and treated with ozone until the solution turned
blue. Then the solution was purged with nitrogen until the blue
color disappeared. Me2S (0.3 mL) and NaHCO3 (52 mg) were
added, and the reaction mixture was stirred for 4 h at rt.
Concentrated NH4OH (2.5 mL) was added and reaction mixture
3-(4-Bromo-2,5-dimethylphenyl)propionic Acid (15). A mix-
ture of malonic ester 14 (927 mg, 2.6 mmol) and potassium
hydroxide (296 mg, 5.2 mmol) in water (4.5 mL) was refluxed for
5 h. The reaction mixture was concentrated in vacuo to remove
the ethanol, and then a solution of concd sulfuric acid (0.5 mL)
and water (1.5 mL) was added. The mixture was refluxed for 20 h.
The reaction mixture was chilled in an ice bath and the resulting
J. Org. Chem, Vol. 72, No. 19, 2007 7113

Liu and Knochel
was stirred overnight. The solvent was mostly evaporated and the
remaining aqueous suspension was extracted with CHCl3 and the
combined organic layers were washed with brine, dried (Na2SO4),
and evaporated to afford the crude product. Recrystallization
(EtOAc) gave 9 (101 mg, 95%) as bright yellow crystals. Mp
102.5-103.5 °C; 1H NMR (CDCl3, 400 MHz) δ 9.39 (s, 1H), 8.54
(d, J ) 5.3, 1H), 7.63 (d, J ) 5.3 Hz, 1H), 7.56 (s, 1H), 2.75 (s,
3H), 2.53 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 149.4, 142.8,
134.6, 134.5, 133.0, 132.0, 128.2, 123.2, 117.2, 18.0, 17.6; IR (KBr)
3050 (w), 2945 (w), 2920 (w), 2855 (w), 1588 (m), 1564 (m), 1491
(m), 1433 (m), 1378 (m), 1274 (m), 1212 (w), 1072 (w) cm-1; MS
(EI, 70 eV) 235 (M+, 100), 220 (3), 156 (86), 141 (11), 128 (23),
116 (6), 102 (6), 77 (11); HRMS (EI) calcd for C11H10BrN
234.9997, found 235.0007.
Triazene (8a) was prepared from 1-(2-iodophenylazo)pyrrolidine
(1a) (903 mg, 3 mmol) and 7-bromo-5,8-dimethylisoquinoline (9)
(705 mg, 3 mmol) according to the procedures for the preparation
of 1n and yielding the pure product 8a (743 mg, 75%) as a pale
yellow solid. Mp 121.3-123.6 °C; 1H NMR (CDCl3, 600 MHz) δ
9.53 (s, 1H), 8.57 (d, J ) 5.7 Hz, 1H), 7.49 (d, J ) 7.6 Hz, 1H),
7.44 (s, 1H), 7.32-7.37 (m, 1H), 7.17-7.23 (m, 2H), 2.80-4.10
(br s, 4H), 2.62 (s, 3H), 2.49 (s, 3H), 1.83 (br s, 4H); 13C NMR
(CDCl3, 150 MHz) δ 150.1, 148.9, 142.0, 138.8, 135.9, 134.7,
134.2, 130.8, 130.7, 129.7, 128.3, 127.9, 124.9, 117.3, 117.0, 23.6,
18.3, 15.5; IR (KBr) 2990 (w), 2868 (w), 1597 (w), 1406 (s), 1315
(m), 1268 (m), 1200 (w), 1095 (w) cm-1; MS (EI, 70 eV) 330
(M+, 6), 260 (6), 245 (46), 232 (98), 217 (100), 202 (11), 189 (15),
108 (9); HRMS (EI) calcd for C21H22N4 330.1844, found 330.1844.
Aryl azide (7a) was prepared from the corresponding triazene
(8a) (165 mg, 0.5 mmol) according to the general procedure B and
yielding the pure product 7a (107 mg, 78%) as a yellow liquid. 1H
NMR (CDCl3, 300 MHz) δ 9.55 (s, 1H), 8.61 (d, J ) 5.7 Hz, 1H),
7.79 (d, J ) 5.7 Hz, 1H), 7.42-7.51 (m, 1H), 7.21-7.35 (m, 4H),
2.67 (s, 3H), 2.55 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 150.0,
142.7, 138.1, 136.0, 135.2, 133.1, 132.8, 131.4, 131.0, 130.9, 129.0,
127.7, 124.7, 118.4, 117.3, 18.3, 15.1; IR (neat) 2923 (w), 2120
(s), 1599 (w), 1570 (w), 1487 (w), 1443 (w), 1386 (w), 1284 (m),
1095 (w), 961 (w) cm-1; MS (EI, 70 eV) 274 (M+, 10), 246 (100),
231 (80), 203 (10), 152 (5), 109 (6), 88 (4); HRMS (EI) calcd for
C17H14N4 274.1218, found 274.1232.
H); 13C NMR (CDCl3, 150 MHz) δ 157.3, 150.3, 143.1, 142.4,
138.8, 137.2, 135.0, 134.1, 131.1, 130.0, 128.1, 118.2, 117.5, 115.5,
114.4, 55.8, 23.9, 18.5, 15.8; IR (KBr) 2962 (w), 2850 (w), 1596
(m), 1495 (m), 1407 (m), 1319 (m), 1269 (m), 1209 (m), 1109
(w), 1035 (m), 817 (m) cm-1; MS (EI, 70 eV) 360 (M+, 28), 290
(22), 275 (15), 262 (100), 247 (56), 231 (22), 219 (18), 204 (15);
HRMS (EI) calcd for C22H24N4O 360.1950, found 360.1933.
Aryl azide (7b) was prepared from the corresponding triazene
(8b) (281 mg, 0.78 mmol) according to the general procedure C,
yielding the pure product 7b (223 mg, 94%) as a brown liquid. 1H
NMR (CDCl3, 300 MHz) δ 9.53 (s, 1H), 8.60 (d, J ) 5.8 Hz, 1H),
7.76 (d, J ) 5.8 Hz, 1H), 7.30 (s, 1H), 7.18 (d, J ) 8.8 Hz, 1H),
6.98 (dd, J ) 8.8, 3.1 Hz, 1H), 6.76 (d, J ) 3.1 Hz, 1H), 3.81 (s,
3H), 2.64 (s, 3H), 2.53 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ
156.6, 150.2, 150.1, 143.0, 135.9, 134.3, 133.4, 132.5, 131.0, 130.6,
127.7, 119.5, 117.2, 116.7, 114.6, 55.6, 18.4, 15.1; IR (neat) 2938
(w), 2110 (s), 1596 (m), 1488 (m), 1462 (m), 1420 (m), 1384 (m),
1285 (m), 1225 (m), 1177 (m), 1032 (m) cm-1; MS (EI, 70 eV)
304 (M+, 6), 276 (100), 261 (96), 246 (23), 233 (30), 218 (28),
204 (7), 117 (5), 102 (3); HRMS (EI) calcd for C18H16N4O
304.1324, found 304.1340.
9-Methoxyellipticine (3b). A solution of the aryl azide 7b (100
mg, 0.33 mmol) in mesitylene (3.3 mL) was heated at reflux. After
5 h, the solvent was evaporated in vacuo to give the crude product.
Purification by flash chromatography (methanol:ether ) 1:9) yielded
the pure product 3b (62 mg, 68%) as an amber solid. Mp 276.3-
1
278.5 °C dec (lit.37 mp 275-278 °C dec); H NMR (CDCl3, 300
MHz) δ 9.14 (s, 1H), 8.69 (d, J ) 5.2 Hz, 1H), 7.59 (d, J ) 8.4
Hz, 1H), 7.19 (d, J ) 5.2 Hz, 1H), 6.98 (d, J ) 2.6 Hz, 1H), 6.87
(dd, J ) 8.4, 2.6 Hz, 1H), 6.49 (s, 1H), 3.85 (s, 3H), 2.07 (s, 3H);
13C NMR (CDCl3, 75 MHz) δ 158.6, 152.4, 148.2, 146.1, 144.1,
143.4, 135.0, 124.2, 122.2, 118.5, 116.5, 115.5, 114.6, 112.7, 108.6,
55.7, 27.6, 18.9; IR (KBr) 3310 (s), 2921 (m), 1722 (w), 1588 (s),
1468 (s), 1367 (w), 1348 (w), 1285 (s), 1207 (m), 1027 (s) cm-1
;
MS (EI, 70 eV) 276 (M+, 100), 261 (60), 246 (27), 233 (27), 218
(33), 204 (5), 190 (10), 177 (5), 164 (7), 138 (7), 116 (7), 109 (7),
95 (5), 88 (5); HRMS (EI) calcd for C18H16N2O 276.1263, found
276.1268.
Triazene (20a) was prepared from 1-(2-iodophenylazo)pyrroli-
dine (1a) (160 mg, 0.53 mmol) and 6-bromo-5,8-dimethylisoquino-
line (19) (150 mg, 0.53 mmol) according to the procedure for the
preparation of 1n, yielding the pure product 20a (136 mg, 78%) as
a pale yellow solid. Mp 55.5-56.5 °C; 1H NMR (CDCl3, 300 MHz)
δ 9.42 (s, 1H), 8.56 (d, J ) 6.2 Hz, 1H), 7.80 (d, J ) 6.2 Hz, 1H),
7.49 (d, J ) 8.0 Hz, 1H), 7.31-7.38 (m, 1H), 7.30 (s, 1H), 7.18-
7.22 (m, 2H), 3.00-4.00 (br s, 4H), 2.73 (s, 3H), 2.36 (s, 3H),
1.77-1.87 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ 149.6, 148.7,
142.9, 141.8, 136.1, 135.7, 131.3, 130.4, 129.1, 128.3, 126.9, 124.9,
117.6, 117.1, 65.8, 23.7, 18.2, 15.6; IR (KBr) 2970 (w), 2867 (w),
1612 (w), 1443 (w), 1408 (m), 1314 (m), 1268 (w), 1209 (w), 1157
(w), 1102 (w) cm-1; MS (EI, 70 eV) 330 (M+, 5), 260 (5), 245
(40), 232 (100), 217 (66), 202 (11), 189 (16), 108 (9); HRMS (EI)
calcd for C21H22N4 330.1844, found 330.1837.
Aryl azide (21a) was prepared from the corresponding triazene
(20a) (122 mg, 0.37 mmol) according to the general procedure C,
yielding the pure product 21a (96 mg, 95%) as a pale yellow liquid.
1H NMR (CDCl3, 300 MHz) δ 9.46 (s, 1H), 8.60 (d, J ) 5.8 Hz,
1H), 7.83 (d, J ) 5.8 Hz, 1H), 7.40-7.50 (m, 1H), 7.15-7.30 (m,
4H), 2.77 (s, 3H), 2.39 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ
149.7, 143.4, 138.9, 138.0, 135.7, 133.3, 132.6, 131.2, 130.1, 129.5,
129.1, 124.8, 118.4, 117.9, 117.7, 18.3, 15.3; IR (neat) 3057 (w),
2961 (w), 2923 (w), 2855 (w), 2123 (s), 2098 (s), 1612 (m), 1482
(m), 1382 (w), 1301 (m), 1277 (m), 1034 (w) cm-1; MS (EI, 70
eV) 274 (M+, 8), 246 (100), 231 (74), 217 (10), 204 (12), 189 (8),
176 (8), 152 (6), 122 (8), 108 (14); HRMS (EI) calcd for C17H14N4
274.1218, found 274.1221.
Ellipticine (3a). A solution of the aryl azide 7a (101 mg, 0.37
mmol) in mesitylene (5 mL) was heated at reflux. After 6 h, the
solvent was evaporated in vacuo to give the crude product.
Purification by flash chromatography (methanol:ether ) 1:9) yielded
the pure product 3a (52 mg, 57%) as a yellow solid. Mp 247.3-
1
249.1 °C (lit.36 mp 243-250 °C); H NMR (CDCl3, 600 MHz) δ
9.71 (s, 1H), 8.49 (d, J ) 5.8 Hz, 1H), 8.37 (d, J ) 7.8 Hz, 1H),
7.85 (d, J ) 5.8 Hz, 1H), 7.46-7.54 (m, 2H), 7.28-7.34 (m, 2H),
3.30 (s, 3H), 2.77 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 150.2,
144.6, 141.8, 141.2, 130.3, 129.5, 129.0, 127.4, 126.1, 124.3, 124.2,
120.2, 116.1, 115.1, 110.6, 14.9, 12.2; IR (KBr) 3480 (s), 1630
(m), 1605 (m), 1440 (w), 1400 (w), 1377 (w), 1303 (m), 1230 (m),
1010 (m) cm-1; MS (EI, 70 eV) 246 (M+, 100), 231 (97), 216 (6),
204 (12), 176 (6), 122 (6), 109 (5), 96 (6), 51 (3); HRMS (EI)
calcd for C17H14N2 246.1157, found 246.1145.
Triazene (8b) was prepared from 1-(4-methoxy-2-iodopheny-
lazo)pyrrolidine (6n) (993 mg, 3.0 mmol) and 7-bromo-5,8-
dimethylisoquinoline (9) (705 mg, 3 mmol) according to the
procedures for the preparation of 1n, yielding the pure product 8b
1
(680 mg, 63%) as a brown solid. Mp 62.1-64.5 °C; H NMR
(CDCl3, 600 MHz) δ 9.52 (s, 1H), 8.57 (d, J ) 6.0 Hz, 1H), 7.76
(d, J ) 6.0 Hz, 1H), 7.45 (d, J ) 9.0 Hz, 1H), 7.43 (s, 1H), 6.91
(dd, J ) 9.0, 2.8 Hz, 1H), 6.76 (d, J ) 2.8 Hz, 1H), 3.82 (s, 3H),
2.90-3.75 (br s, 4H), 2.62 (s, 3H), 2.51 (s, 3H), 1.77-1.84 (m, 4
(33) Harris, N. V.; Smith, C.; Bowden, K. Synlett 1990, 577.
(34) Kondo, Y.; Kojima, S.; Sakamoto, T. J. Org. Chem. 1997, 62, 6507.
(35) Lizos, D.; Tripoli, R.; Murphy, J. A. Chem. Commum. 2001, 2732.
(36) Sha, C. K.; Yang, J. F. Tetrahedron 1992, 48, 10645.
(37) Gribble, G. W.; Saulnier, M. G.; Obaza-Nutaitis, J. A.; Ketcha, D.
M. J. Org. Chem. 1992, 57, 5891.
7114 J. Org. Chem., Vol. 72, No. 19, 2007

Polyfunctional Aryl Azides from Aryl Triazenes
Isoellipticine (4a). A solution of the aryl azide 21a (22 mg, 0.08
mmol) in mesitylene (1 mL) was heated at reflux. After 5 h, the
solvent was evaporated in vacuo to give the crude product.
Purification by flash chromatography (methanol:ether ) 1:9) yielded
the pure product 4a (12 mg, 63%) as a yellow solid. Mp 309.0-
310.0 °C (lit.36 mp 312-314 °C); 1H NMR (DMSO-d6, 400 MHz)
δ 11.4 (br s, 1H), 9.54 (s, 1H), 8.08 (d, J ) 6.0 Hz, 1H), 7.44-
7.58 (m, 2H), 7.20 (t, J ) 8.0 Hz, 1H), 3.10 (s, 3H), 2.92 (s, 3H);
13C NMR (DMSO-d6, 100 MHz) δ 149.5, 143.8, 139.2, 139.1,
128.9, 128.3, 126.4, 125.9, 125.5, 124.9, 123.3, 119.6, 117.5, 111.4,
111.3, 15.2, 12.6; IR (KBr) 3420 (s), 3143 (m), 3076 (m), 2977
(w), 2921 (w), 2869 (w), 1613 (m), 1596 (m), 1497 (w), 1461 (w),
1406 (m), 1319 (m), 1273 (m), 1230 (m), 1012 (m) cm-1; MS (EI,
70 eV) 246 (M+, 100), 231 (29), 217 (9), 123 (12), 108 (9), 95
(6); HRMS (EI) calcd for C17H14N2 246.1157, found 246.1140.
Triazene (20b) was prepared from 1-(4-carbethoxy-2-iodophe-
nylazo)pyrrolidine (18) (746 mg, 2 mmol) and 6-bromo-5,8-
dimethylisoquinoline (19) (472 mg, 2 mmol) according to the
procedure for the preparation of 1n, yielding the pure product 20b
(651 mg, 81%) as a white solid. Mp 71.6-72.0 °C; 1H NMR
(CDCl3, 600 MHz) δ 9.47 (s, 1H), 8.58 (d, J ) 5.9 Hz, 1H), 8.02
(d, J ) 8.8 Hz, 1H), 7.91 (s, 1H), 7.82 (d, J ) 5.9 Hz, 1H), 7.56
(d, J ) 8.8 Hz, 1H), 7.29 (s, 1H), 4.35 (q, J ) 7.3 Hz, 2H), 3.84
(br s, 2H), 3.14 (br s, 2H), 2.75 (s, 3H), 2.35 (s, 3H), 1.86 (br s,
4H), 1.36 (t, J ) 7.3 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ
166.8, 152.4, 149.8, 142.9, 136.1, 136.0, 132.3, 132.0, 131.3, 130.0,
129.5, 127.2, 126.7, 118.0, 117.0, 116.8, 61.0, 51.2, 46.7, 24.1,
23.5, 18.4, 15.9, 14.6; IR (KBr) 2975 (w), 2870 (w), 1707 (s), 1600
(m), 1401 (m), 1362 (m), 1310 (m), 1283 (m), 1263 (m), 1240 (s),
1100 (s), 1026 (m) cm-1; MS (EI, 70 eV) 402 (M+, 7), 357 (8),
317 (56), 260 (25), 232 (100), 216 (41), 202 (15), 189 (7), 115 (5),
86 (14); HRMS (EI) calcd for C24H26N4O2 402.2056, found
402.2042.
7.0 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ 165.6, 149.7, 143.4,
142.5, 138.0, 135.7, 133.2, 132.9, 132.5, 130.5, 129.8, 129.6, 127.2,
127.0, 118.2, 117.6, 61.2, 18.3, 15.3, 14.3; IR (KBr) 2970 (w),
2124 (s), 1712 (s), 1604 (m), 1586 (m), 1494 (w), 1466 (w), 1444
(w), 1385 (w), 1364 (w), 1285 (s), 1228 (s), 1126 (m), 1098 (m),
1026 (m) cm-1; MS (EI, 70 eV) 346 (M+, 18), 318 (100), 303
(43), 289 (77), 275 (54), 245 (70), 230 (20), 216 (12), 189 (8), 145
(7), 108 (11); HRMS (EI) calcd for C20H18N4O2 346.1430, found
346.1442.
7-Carbethoxyisoellipticine (4b). A solution of the aryl azide
21b (464 mg, 1.34 mmol) in a mixture of mesitylene (14 mL) and
DMF (1 mL) was heated at reflux. After 6 h, the solvent was
evaporated in vacuo to give the crude product. Purification by flash
chromatography (methanol:ether ) 1:9) yielded the pure product
1
4b (273 mg, 64%) as a bright yellow solid. Mp 250 °C dec; H
NMR (DMSO-d6, 300 MHz) δ 11.73 (s, 1H), 9.55 (s, 1H), 8.88 (s,
1H), 8.40 (d, J ) 5.9 Hz, 1H), 8.05-8.15 (m, 2H), 7.56 (d, J )
8.6 Hz, 1H), 4.33 (q, J ) 7.0 Hz, 2H), 3.09 (s, 3H), 2.90 (s, 3H),
1.34 (t, J ) 7.0 Hz, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 166.9,
149.6, 146.8, 139.7, 139.3, 129.5, 129.4, 126.3, 126.2, 125.8, 123.1,
120.9, 117.5, 117.4, 112.3, 111.1, 61.1, 15.2, 15.0, 12.5; IR (KBr)
3200 (s), 2925 (w), 1710 (s), 1612 (m), 1465 (w), 1364 (w), 1277
(m), 1244 (s), 1167 (m), 1098 (m), 1017 (m) cm-1; MS (EI, 70
eV) 318 (M+, 100), 304 (33), 289 (40), 273 (21), 245 (33), 229
(19), 207 (35), 191 (6), 175 (6), 115 (10), 73 (10); HRMS (EI)
calcd for C20H18N2O2 318.1368, found 318.1349.
Acknowledgment. We thank the Fonds der Chemischen
Industrie for financial support. We thank BASF (Ludwigshafen,
Germany), Boehringer-Ingelheim (Vienna, Austria), and Che-
metall GmbH (Frankfurt, Germany) for the generous gift of
chemicals. We thank Dr. Andrei Gavryushin for helpful
discussions.
Aryl azide (21b) was prepared from the corresponding triazene
(20b) (200 mg, 0.5 mmol) according to the general procedure B,
yielding the pure product 21b (131 mg, 76%) as a pale yellow solid.
Mp 122.5-123.9 °C; 1H NMR (CDCl3, 600 MHz) δ 9.46 (s, 1H),
8.62 (d, J ) 5.8 Hz, 1H), 8.12 (d, J ) 8.4 Hz, 1H), 7.91 (s, 1H),
7.83 (d, J ) 5.8 Hz, 1H), 7.30 (d, J ) 8.4 Hz, 1H), 7.16 (s, 1H),
4.36 (q, J ) 7.0 Hz, 2H), 2.77 (s, 3H), 2.38 (s, 3H), 1.37 (t, J )
Supporting Information Available: General procedures A-C,
synthetic procedures for compounds 1a-o and 2a-o, and 1H and
13C NMR spectra of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO070774Z
J. Org. Chem, Vol. 72, No. 19, 2007 7115