Synthesis of fused indazole ring systems and application to nigeglanine hydrobromide

Article abstract of DOI:10.1021/ol300303s

The single-step synthesis of fused tricyclic pyridazino[1,2-a]indazolium ring systems is described. Structural details revealed by crystallography explain the unexpected reactivity. The method is applied to the gram scale synthesis of nigeglanine hydrobro

Full text of DOI:10.1021/ol300303s

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1600–1603
Synthesis of Fused Indazole Ring Systems
and Application to Nigeglanine
Hydrobromide
Aaron C. Sather, Orion B. Berryman, and Julius Rebek Jr.*
The Scripps Research Institute Mail MB-26, 10550 North Torrey Pines Road, La Jolla,
California 92037, United States
jrebek@scripps.edu
Received February 13, 2012
ABSTRACT
The single-step synthesis of fused tricyclic pyridazino[1,2-a]indazolium ring systems is described. Structural details revealed by crystallography
explain the unexpected reactivity. The method is applied to the gram scale synthesis of nigeglanine hydrobromide.
Indazole derivatives are a versatile class of compounds
that have found use in biology, catalysis, and medicinal
chemistry.1 Although rare in nature,2 indazoles exhibit a
variety of biological activities such as HIV protease
inhibition,3 antiarrhythmic and analgesic activities,4 anti-
tumor activity,5 and antihypertensive properties.6 Indazo-
lium ions have found additional uses as precursors to
N-heterocyclic carbenes (NHCs) with organo-catalytic
(1) Schmidt, A.; Beutler, A.; Snovydovych, B. Eur. J. Org. Chem.
2008, 4073–4095.
(2) (a) Atta-ur-Rahman, M. S.; He, C. H.; Clardy, J. Tetrahedron
Lett. 1985, 26, 2759–2762. (b) Atta-ur-Rahman, M. S.; Malik, S.; Hasan,
S.; Choudhary, M. I.; Ni, C.; Clardy, J. Tetrahedron Lett. 1995, 36, 1993–
1996. (c) Liu, Y.; Yang, J.; Liu, Q. Chem. Pharm. Bull. 2004, 52, 454–455.
(d) Ali, Z.; Ferreira, D.; Carvalho, P.; Avery, M. A.; Khan, I. A. J. Nat.
Prod. 2008, 71, 1111–1112.
(3) (a) Han, W.; Pelletier, J. C.; Hodge, C. N. Bioorg. Med. Chem.
Lett. 1998, 8, 3615–3620. (b) Patel, M.; Rodgers, J. D.; McHugh, R. J.,
Jr.; Johnson, B. L.; Cordova, B. C.; Klaba, R. M.; Bacheler, L. T.;
Erickson-Viitanen, S.; Ko, S. S. Bioorg. Med. Chem. Lett. 1999, 9, 3217–
3220. (c) Sun, J.-H.; Teleha, C. A.; Yan, J.-S.; Rodgers, J. D.; Nugiel,
D. A. J. Org. Chem. 1997, 62, 5627–5629.
(4) Mosti, L.; Menozzi, G.; Fossa, P.; Filippelli, W.; Gessi, S.;
Rinaldi, B.; Falcone, G. Arzneim.-Forsch./Drug Res. 2000, 50, 963–972.
(5) (a) Jakupec, M. A.; Reisner, E.; Eichinger, A.; Pongratz, M.;
Arion, V. B.; Galanski, M; Hartinger, C. G; Keppler, B. K. J. Med.
Chem. 2005, 48, 2831–2837. (b) Showalter, H. D. H.; Angelo, M. M.;
Berman, E. M.; Kanter, G. D.; Ortwine, D. F.; Ross-Kesten, S. G.;
Sercel, A. D.; Turner, W. R.; Werbel, L. M.; Worth, D. F.; Elslager,
E. F.; Leopald, W. R.; Shillis, J. L. J. Med. Chem. 1988, 31, 1527–1539.
(6) Goodman, K. B.; Cui, H.; Dowdell, S. E.; Gaitanopoulos, D. E.;
Ivy, R. L.; Sehon, C. A.; Stavenger, R. A.; Wang, G. Z.; Viet, A. Q.; Xu,
W.; Ye, G.; Semus, S. F.; Evans, C.; Fries, H. E.; Jolivette, L. J.;
Kirkpatrick, R. B.; Dul, E.; Khandekar, S. S.; Yi, T.; Jung, D. K.;
Wright, L. L.; Smith, G. K. J. Med. Chem. 2007, 50, 6–9.
(7) (a) Schmidt, A.; Snovydovych, B.; Habeck, T.; Drottboom, P;
Gjikaj, M.; Adam, A. Eur. J. Org. Chem. 2007, 4909–4916. (b) Schmidt,
A.; Snovydovych, B.; Gjikaj, M. Synthesis 2008, 17, 2798–2804.
(8) Jothibasu, R.; Huynh, H. V. Chem. Commun. 2010, 46, 2986–
2988.
(9) (a) Wheeler, R. C.; Baxter, E.; Campbell, I. B.; Macdonald.,
S. J. F. Org. Process Res. Dev. 2011, 15, 565–569. (b) Spiteri, C.; Keeling,
S.; Moses, J. E. Org. Lett. 2010, 12, 3368–3371. (c) Counceller, C. M.;
Eichman, C. C.; Wray, B. C.; Stambuli, J. P. Org. Lett. 2008, 10, 1021–
1023. (d) Wray, B. C.; Stambuli, J. P. Org. Lett. 2010, 12, 4576–4579. (e)
Inamoto, K.; Katsuno, M.; Yoshino, T.; Arai, Y.; Hiroya, K.; Sakamoto, T.
Tetrahedron 2007, 63, 2695–2711. (f) Lukin, K.; Hsu, M. C.; Fernando, D.;
Leanna, M. R. J. Org. Chem. 2006, 71, 8166–8172. (g) Jin, T.; Yamamoto,
Y. Angew. Chem., Int. Ed. 2007, 46, 3323–3325. (h) Stadlbauer, W. Sci.
Synth. 2002, 12, 227–324.
r
10.1021/ol300303s
Published on Web 03/02/2012
2012 American Chemical Society

activity,7 and they are strong donor ligands for transition
metal complexes.8 While a variety of capable synthetic
methods exist for indazole synthesis,9 we report a new
precursor for indazole formation, 2-formyl dialkylanilines.
With hydroxylamine, this precursor allows for easy entry
to the fused tricyclic pyridazino[1,2-a]indazolium ring
system seen in the indazole natural products. This reaction
invloves anexchangeof the NÀO bond of the oxime for the
NÀN bond of the heterocycle and was applied to the gram
scale synthesis of nigeglanine hydrobromide (1).
During our investigation of ortho-hydroxyaryloxime anti-
dotes for organophosphorous nerve agent sensing we found
that treatment of aldehyde 2 with hydroxylamine hydro-
chloride in ethanol at 65 °C gave the expected oxime (3) only
as the minor product (1:4, Figure 1). The major product was
identified by single crystal X-ray diffraction as the substi-
tuted N-methyl indazole 4 (Figure 1, bottom right).
We used 2-pyrrolidinyl benzaldehyde (5) to determine
the nature of the nucleophile involved in the dealkylation
step. Increased temperatures were required for the reaction
to proceed, and after 4 h at 150 °C the three expected
products were obtained: the oxime (6), the N-alkyl inda-
zole product (8), and the tricyclic indazolium (9). NMR
and MS analysis (see Supporting Information (SI)) con-
firms that chloride dealkylates the quaternary nitrogen of
the former pyrrolidine, giving rise to 8. The proposed
mechanism for this transformation is shown in Scheme 1.
In specific cases, spirocyclic quaternary nitrogen atoms of
the type shown in the scheme (7) have been isolated as
betaines (1,1-disubstituted indazol-3-ylio oxides) and are
known to dealkylate in a similar manner.12 By extending
the reaction time it is possible to obtain the tricyclic
indazolium product exclusively and in high yield.
The oxime product (3) can be obtained in better yield at
room temperature, and its crystal structure (Figure 1,
bottom left) reveals the reason for the unexpected forma-
tion of 4. The dimethylamino group is twisted out of the
aromatic ring plane to avoid steric clashes with the adja-
cent bulky bromine atom. Although phenols react with
activated oximes to form isoxazoles,10 the nitrogen of the
twisted aniline is more basic and its lone pair electrons are
predisposed to attack the oxime. This reaction results in
NÀN bond formation as water is lost. Demethylation,
presumably by the halide, completes the sequence.
Scheme 1. Proposed Mechanism for the Synthesis of Fused
Indazolium Ring Systems
In general indazoles, or heterocycles, are synthesized by
NÀC bond forming reactions, but examples of indazoles
formed from creating NÀN bonds have also been re-
ported. Electrophilic amination of this type has been
exploited previously by Hassner11 and more recently by
Stambuli.9c,d In both examples an activating agent, DCC
in the former and MsCl in the later, was used to promote
attack of the oxime nitrogen to form the NÀN bond. In
our approach, no such activating agent is required.
We optimized reaction conditions (1.2 equiv,
NH2OH HCl, EtOH, 150 °C, 18 h, sealed tube) and
3
explored the scope of this cyclization cascade with a series
of substituted 2-pyrrolidinyl benzaldehydes. These were
obtained from commercially available 2-fluorobenzalde-
hydes and pyrrolidine (see SI). As shown in Scheme 2, both
electron-donating and -withdrawing groups are tolerated.
The strongly donating pyrrolidinyl group (16) gave the
highest yield. Halogens Br (11), Cl (14), and F (10) were
also well tolerated. The use of methoxy derivatives in place
of the free phenols is recommended due to decomposition
of the latter during the cyclization reaction. Mild electron-
withdrawing groups such as trifluoromethyl (18) and
carboxylate (17) also form products but in lower yields.
Substitution with a nitro group (19) on the other hand
gives a different product: dehydration of the oxime is
favored, and the nitrile 19 is formed (see SI for X-ray
structure of 19).
Besides altering the substitutents on the aromatic ring,
we variedthe aniline ring sizetofurther testthe scope of the
reaction (see SI, Table S-1). Increasing the ring size of the
Figure 1. Initial reaction discovery (top). Crystal structure of oxime
3 (bottom left). Crystal structure of indazole 4 (bottom right).
ꢀ
(12) (a) Ruiz, J. R.; Aran, V. J.; Stud, M. Tetrahedron Lett. 1988, 29,
ꢀ
697–700. (b) Aran, V. J.; Asensio, J. L.; Ruiz., J.; Stud, M. J. Chem. Soc.,
Perkin Trans. 1 1993, 1119–1127. (c) Waldron, N. M.; Montevalli, M.;
Azam, S.; Dasopoulos, P. C. J. Chem. Soc., Chem. Commun. 1995, 81–
82. (d) Waldron, N. M.; Raza, M. J. Chem. Soc., Perkin Trans. 1 1996,
271–276.
(10) Dale, T. J.; Sather, A. C.; Rebek, J., Jr. Tetrahedron Lett. 2009,
50, 6173–6175.
(11) Hassner, A.; Michelson, M. J. J. Org. Chem. 1962, 27, 298–301.
Org. Lett., Vol. 14, No. 6, 2012
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1,4,-dibromobutane and subsequent decarboxylation and
deprotection to give nigeglanine as the HBr salt (1) in 12
steps and 13% overall yield.
Scheme 2. Scope of the Reaction with Substituted 2-Pyrrolidinyl
Benzaldehydesa
Our synthesis began from commercially available
3-fluoro-5-methylphenol (20) (Scheme 3). The phenol
was alkylated with cesium carbonate and methyl iodide
in DMF to give 21. We expected the methoxy and fluorine
functions to direct ortho lithiation,14 which occurred at the
desired position and led to formylation with DMF to
afford 22 as a single regioisomer. We synthesized the
aniline using pyrrolidine under SNAr conditions (DSMO,
potassium carbonate, 100 °C) to give 23 in good yield. The
cyclization cascade of this compound went smoothly on
the gram scale to yield methylated nigeglanine 24. Depro-
tection of the methoxy group was carried out with Kelly’s
reported method, using BBr3 in DCM to give 1.6 g of the
natural product nigeglanine as the HBr salt (1), in 5 steps
and ∼47% overall yield. Pentane diffusion into a metha-
nol/chloroform solution of 1 provided single crystals
suitable for X-ray diffraction. The pale yellow bars crystal-
lized asanonmerohedral twin,15 and refinementconfirmed
the structure of 1.
Scheme 3. Gram Scale Synthesis and Crystal Structure of Ni-
geglanine Hydrobromide (1)a
a Isolated yields are reported.
aniline from five (pyrrolidine) to six (piperidine) gave the
chloroalkyl indazole in moderate yield, showing that for-
mation of the seven-membered ring is unfavored even at
high temperatures. We were unable to synthesize aniline
starting materials with smaller ring sizes, having observed
rapid decomposition in the SNAr reaction with azetidine
and aziridine, which prevented these anilines from being
investigated. We also explored the synthesis of C3 sub-
stituted indazole products from acetophenone or benzo-
phenone substrates. These substrates provided the N-
alkylchloride indazole along with the usual ketoxime. Ring
closure to the tricyclic indazolium products was observed
only in trace amounts (<2%).
a Counteranion is omitted for clarity.
To highlight our method we set out to synthesize a
member of the indazole natural product family, nigegla-
nine. Isolated from Nigella glandulifera,2c nigeglanine is
one member of a small family of four indazole natural
products, all of which contain the tricyclic pyridazino[1,2-a]-
indazolium ring system. Located largely in southwest
and western China, the whole herb has been used as a folk
remedy for a variety of aliments such as cold, cough,
insomnia, and bronchial asthma. Nigeglanine and related
nigellicine have been synthesized previously by Kelly and
co-workers.13 Their synthesis of nigeglanine proceeds by
transformation of an isatin to give an advanced indazole
intermediate, followed by alkylation of the indazole with
In summary we report the serendipitous discovery of a
new precursor for the one-step preparation of indazoles,
and crystal structures of oxime 2 and the corresponding
indazole 3 that provide clues to the reaction mechanism.
The reaction conditions were generalized to afford several
examples of the tricyclic pyridazino[1,2-a]indazolium ring
system (9À18) and extended to the gram scale synthesis of
nigeglanine hydrobromide1. Wenote inpassing thatmany
of these indazolium ions are fluorescent with colors of blue
(9), blue/green (1), and purple (15). As this method quickly
(14) Marzi, E.; Mongin, F.; Spitaleri, A.; Schlosser, M. Eur. J. Org.
Chem. 2001, 2911–2915.
(15) TWINABS - Bruker AXS scaling for twinned crystals - Version
(13) Elliott, E. L.; Bushell, S. M.; Cavero, M.; Tolan, B.; Kelly, T. R.
Org. Lett. 2005, 7, 2449–2451.
2012/1.
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Org. Lett., Vol. 14, No. 6, 2012

affords indazollium analogs of the natural product, their
fluorescence may provide an opportunity for cellular
imaging studies in the future.
like to thank Dr. Curtis E. Moore (UCSD) for assistance
with solution of the X-ray structures.
Supporting Information Available. General information
and full experimental details for all compounds discussed.
Cif files for all crystal structures along with tables of
relevant structure data are included. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We are grateful to the Skaggs Insti-
tute and the NIGMS (GM 27953) for financial support. A.
C.S. is a Skaggs Predoctoral Fellow and an ARCS scholar.
A Ruth L. Kirschstein Postdoctoral fellowship for O.B.B.
was provided by the NIH (F32GM087068). Wewould also
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
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