Fischer indole synthesis with organozinc reagents

Article abstract of DOI:10.1002/anie.201005319

Updated classic: Primary and secondary alkylzinc reagents add to various aryldiazonium salts leading regioselectively to polyfunctional indoles by means of a [3,3]-sigmatropic shift and subsequent aromatization. This organometallic variation of the Fischer indole synthesis tolerates a wide range of functional groups and displays absolute regioselectivity. Copyright

Full text of DOI:10.1002/anie.201005319

Angewandte
Chemie
DOI: 10.1002/anie.201005319
Indole Synthesis
Fischer Indole Synthesis with Organozinc Reagents**
Benjamin A. Haag, Zhi-Guang Zhang, Jin-Shan Li, and Paul Knochel*
Indoles (1) are an important class of N-heterocycles present in
many natural products and pharmaceuticals.[1] Their synthesis
presents a great challenge, and a range of new synthetic
approaches to indoles have been reported in recent years.[2]
Metal-catalyzed or -mediated methods have proved to be
especially useful.[3] The classical Fischer indole synthesis[4]
starting from aryl hydrazines[5,6] 2 and ketones 3 is still
extensively used, although this method suffers from several
drawbacks.[7,8] The highly acidic reaction conditions combined
with moderate functional-group tolerance and the poor
availability of aryl hydrazines 2 strongly limit this method.
Furthermore, unsymmetrical ketones result in regioisomeric
mixtures of indoles.[7] Since organozinc reagents are readily
available, inexpensive, and compatible with numerous func-
tional groups,[9] we envisioned a new retrosynthetic pathway
for the Fischer indole synthesis, in which the key intermedi-
ates 4A and 4B would not be obtained from 2 and 3, but
rather from the reaction of readily available aryldiazonium
salts of type 5 and functionalized alkylzinc reagents of type 6
(Scheme 1).[10,11]
This approach proved to be very fruitful, since many
functional groups such as ester, cyano, nitro, and keto groups
are tolerated, and unexpectedly the issue of regioselectivity
mentioned above is resolved. Thus, the reaction of ethyl 4-
bromobutanoate (7a, 1.1 equiv) with zinc dust (2 equiv),
ZnBr2 (2 equiv),[12] and LiCl (1.1 equiv) in THF produces the
expected alkylzinc halide 6a in 90% yield (508C, 1 h).[13] The
addition of a solution of 6a (1 equiv) in THF to the
Scheme 1. Alternative retrosynthetic analysis of the Fischer indole
synthesis. FG=functional group.
indole 1a in 90% yield.[14] Similarly, a secondary alkylzinc
halide such as 6b (90% yield) was prepared from the
corresponding secondary alkyl bromide 7b (1.1 equiv; Zn,
LiCl, ZnBr2, 508C, 12 h). Its addition to ester-substituted
diazonium salt 5b[10a,12] at À608C to 258C followed by
addition of Me3SiCl and microwave irradiation (1258C,
90 min) furnished regioselectively the trisubstituted indole
1b in 75% yield (Scheme 2).
functionalized
aryldiazonium
tetrafluoroborate
5a
(1.25 equiv, À608C to 258C) is thought to produce an azo
compound of type 4B, which isomerizes to the unsaturated
hydrazine 4A. Me3SiCl (1 equiv) is added and the reaction
mixture is heated using microwave irradiation (1258C,
90 min) to furnish after standard workup the polyfunctional
[*] B. A. Haag, Prof. Dr. P. Knochel
Department Chemie, Ludwig Maximilians-Universitꢀt
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
Fax: (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
Homepage: http://www.knochel.cup.uni-muenchen.de/
Scheme 2. Preparation of polyfunctional indoles 1a and 1b. a) Zn
(2 equiv), LiCl (1.1 equiv), ZnBr2 (2 equiv), THF, 508C, 1 h; b) À608C
to 258C; then Me3SiCl (1 equiv), 1258C, 90 min, microwave irradiation;
c) Zn (2 equiv), LiCl (1.1 equiv), ZnBr2 (2 equiv), THF, 508C, 12 h.
Z.-G. Zhang, Prof. Dr. J.-S. Li
State Key Laboratory of Elemento-Organic Chemistry
Nankai University, Tianjin 300071 (China)
[**] We thank the European Research Council (ERC) in the context of the
European Community’s Seventh Framework Programme (FP7/
2007-2013, ERC grant no. 227763) for financial support. Z.-G.Z.
thanks the Chinese Scholarship Program for financial support. We
also thank BASF AG (Ludwigshafen), W. C. Heraeus GmbH
(Hanau), and Chemetall GmbH (Frankfurt) for generous gifts of
chemicals.
The alkylzinc reagent 6b also reacted with substituted
aryldiazonium salts 5a,c,d providing the functionalized indole
derivatives 1c–e) in 65–73% yield (Table 1, entries 1–3). By
applying the same procedure to sBuZnBr[12] (6c) and to the
functionalized aryldiazonium tetrafluoroborates 5a–g[10a,12,15]
we obtained the polyfunctional 2,3-dimethylindoles 1 f–l
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005319.
Angew. Chem. Int. Ed. 2010, 49, 9513 –9516
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9513

Communications
Table 1: Preparation of polyfunctional indoles 1 by the addition of
alkylzinc reagents 6 to aryldiazonium tetrafluoroborates 5.
electron-rich substrates conventional heating rather than
microwave irradiation was also successful, but under these
conditions the cyclization to give the indole derivatives
required longer reaction times.
Entry
Zinc reagent
Aryldiazonium salt
Product[a]
We applied this organometallic variation of the Fischer
indole synthesis to prepare indomethacin (8), an anti-
inflammatory drug,[3q,17] and iprindole (9),[18] an antidepres-
sant. Thus, the reaction of the zinc reagent 6b with the
aryldiazonium salt 5e under standard conditions produced
the indole 10, which was converted in two steps to indome-
thacin (8; Scheme 3). Similarly, cyclooctylzinc bromide (6h)
adds to PhN2BF4 (5h) and provides after microwave irradi-
ation the indole 11, which was N-alkylated leading to
iprindole (9; Scheme 3).
1
2
3
6b
6b
6b
5a: R1 =OMe, R2 =NO2
5c: R1 =Ac, R2 =H
1c: 69%
1d: 73%
1e: 65%
5d: R1 =OPiv, R2 =H
4
5
6
7
8
9
10
6c
6c
6c
6c
6c
6c
6c
5a: R1 =OMe, R2 =NO2
5b: R1 =CO2Et, R2 =H
5d: R1 =OPiv, R2 =H
5e: R1 =OMe, R2 =H
5c: R1 =Ac, R2 =H
5 f: R1 =I, R2 =H
1 f: 81%[b]
1g: 75%
1h: 78%[b]
1i: 84%[b]
1j: 81%
1k: 85%
1l: 78%
5g: R1 =CN, R2 =H
11
6d
5e
1m: 46%
12
13
6e
6e
5a: R1 =OMe, R2 =NO2
5b: R1 =CO2Et, R2 =H
1n: 68%
1o: 78%
Scheme 3. Preparation of indomethacin (8) and iprindole (9).
a) À608C to 258C; then Me3SiCl (1 equiv), 1258C, 30 min, microwave
irradiation; b) KOtBu (1.2 equiv), 08C, 20 min; then p-ClC6H4COCl
(1.2 equiv), 258C, 10 h; c) LiOH (10 equiv), H2O, THF, 258C, 6 h;
d) KOtBu (1.2 equiv), 08C, 20 min; then Cl(CH2)3NMe2 (1.2 equiv),
1258C, 3 h, microwave irradiation.
14
15
16
17
6 f
6 f
6 f
6 f
5a: R1 =OMe, R2 =NO2
5b: R1 =CO2Et, R2 =H
5g: R1 =CN, R2 =H
5c: R1 =Ac, R2 =H
1p: 89%[b]
1q: 81%
1r: 81%
1s: 88%
In the course of our studies, we have found that the key
hydrazine intermediate of type 4A can also be obtained by
the addition of an alkenylmagnesium reagent such as cyclo-
hexenylmagnesium iodide (12)[19] to a methoxy-substituted
azobenzene like 13 leading to the magnesiated hydrazine 14,
which after addition of Me3SiCl and microwave irradiation
produces the carbazole 15 (Scheme 4).
18
19
20
6g
6g
6g
5a: R1 =OMe, R2 =NO2
5b: R1 =CO2Et, R2 =H
5g: R1 =CN, R2 =H
1t: 86%[b]
1u: 89%
1v: 92%
In summary, we have described a new organometallic
variation of the Fischer indole synthesis for the preparation of
various polyfunctional indoles from readily available aryldia-
[a] Yield of isolated product estimated to be analytically pure product by
1H NMR spectroscopy. [b] No Me3SiCl was added. Piv=pivaloyl.
regioselectively in 78–85% yield (Table 1, entries 4–10). None
of the regioisomeric 3-ethylindoles were observed. The
benzylic zinc reagent 6d[16] reacted with 4-methoxybenzene-
diazonium tetrafluoroborate (5e) providing, after microwave
irradiation (1258C, 90 min), the expected 2-phenylindole
derivative 1m in 46% yield (Table 1, entry 11). Secondary
cycloalkylzinc halides such as 6e–g[13,12] add to functionalized
aryldiazonium salts (5a–g) furnishing after microwave irra-
diation (1258C, 0.5–2 h) the polysubstituted indole deriva-
tives 1n–v in 68–92% yield (Table 1, entries 12–20). For
Scheme 4. Preparation of the substituted tetrahydrocarbazole 15 by
the addition of alkenylmagnesium reagent 12 to azobenzene 13.
a) THF, À788C to 258C; b) Me3SiCl (1 equiv), NMP (20 vol%), 1258C,
30 min, microwave irradiation. NMP=N-methylpyrrolidinone.
9514
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 9513 –9516

Angewandte
Chemie
Tokuyama, Y. Kaburagi, X. Chen, T. Fukuyama, J. Am. Chem.
zonium tetrafluoroborates and functionalized alkylzinc hal-
ides. High regioselectivity is observed in the formation the
indole ring. This variation enhances the scope of the original
Fischer indole synthesis as a broad range of functionalities are
tolerated and remarkable regioselectivity is achieved. Further
extensions of the method for the preparation of indole-
containing natural products are underway.
Soc. 1999, 121, 3791 – 3792; c) S. Wagaw, B. H. Yang, S. L.
Buchwald, J. Am. Chem. Soc. 1998, 120, 6621 – 6622; d) L. S.
Hegedus, G. F. Allen, E. L. Waterman, J. Am. Chem. Soc. 1976,
98, 2674 – 2676; e) G. Bartoli, R. Leardini, A. Medici, D. Rosini,
J. Chem. Soc. Perkin Trans. 1 1978, 692 – 696; f) R. C. Larock,
E. K. Yum, J. Am. Chem. Soc. 1991, 113, 6689 – 6690; g) C. E.
Castro, E. J. Gaughan, D. C. Owsley, J. Org. Chem. 1966, 31,
4071 – 4078; h) M. Mori, K. Chiba, Y. Ban, Tetrahedron Lett.
1977, 18, 1037 – 1040; i) P. G. Gassman, T. J. van Bergen, D. P.
Gilbert, B. W. Cue, J. Am. Chem. Soc. 1974, 96, 5495 – 5508;
j) A. D. Batcho, W. Leimgruber, US Patent, 1973, No. 3732245;
k) D. Zhang, L. Liebeskind, J. Org. Chem. 1996, 61, 2594 – 2595;
l) H. Hemetsberger, D. Knittel, Monatsh. Chem. 1972, 103, 194 –
204; m) D. Taber, W. Tian, J. Am. Chem. Soc. 2006, 128, 1058 –
1059; n) A. Reissert, Ber. Dtsch. Chem. Ges. 1897, 30, 1030; o) T.
Sugasawa, M. Adachi, K. Sasakura, A. Kitagawa, J. Org. Chem.
1979, 44, 578 – 586; p) J. Dunetz, R. Danheiser, J. Am. Chem.
Soc. 2005, 127, 5776 – 5777; q) K. Campos, J. Woo, S. Lee, R.
Tillyer, Org. Lett. 2004, 6, 79 – 82.
Experimental Section
Typical procedure: 1a: In a flame-dried and argon-flushed Schlenk
flask, a solution of 6a (2.0 mmol, 2.7 mL, 0.74m in THF) was added
dropwise to a solution of ZnBr2 (4.0 mmol, 4 mL, 1m in THF). After
the reaction mixture had been stirred at 258C for 10 min, the
organozinc reagent was transferred slowly to a solution of 5a
(2.5 mmol, 667 mg) in THF (6 mL) at À608C. The reaction mixture
was allowed to slowly warm to 258C. Subsequently, the solvent
volume was reduced to half, Me3SiCl (2.0 mmol, 217 mg) was added,
and the reaction mixture was heated by microwave irradiation at
1258C for 30 min. After cooling to 258C, the mixture was diluted with
Et2O (5 mL) and quenched with brine (10 mL). The aqueous layer
was extracted with EtOAc (3 ꢀ 15 mL). The combined organic phases
were dried over Na2SO4 and concentrated in vacuo. Purification by
flash column chromatography (aluminum oxide, activity II–III;
pentane/EtOAc/MeOH = 95:5:1) afforded the indole 1a as a red
solid (526 mg, 90%).
[4] a) E. Fischer, F. Jourdan, Ber. Dtsch. Chem. Ges. 1883, 16, 2241 –
2245; b) B. Robinson, in The Fischer Indole Synthesis, Wiley-
Interscience, New York, 1982.
[5] For the preparation of functionalized aryl hydrazines, see: R. J.
Lundgren, M. Stradiotto, Angew. Chem. 2010, DOI:
ange.201003764; Angew. Chem. Int. Ed. 2010, DOI:
anie.201003764.
[6] R. J. Lundgren, B. D. Peters, P. G. Alsabeh, M. Stradiotto,
Angew. Chem. 2010, 122, 4165 – 4168; Angew. Chem. Int. Ed.
2010, 49, 4071 – 4074.
Received: August 25, 2010
Published online: October 26, 2010
[7] For recent reviews, see: a) M. Bandini, A. Eichholzer, Angew.
Chem. 2009, 121, 9786 – 9824; Angew. Chem. Int. Ed. 2009, 48,
9608 – 9644; b) G. R. Humphrey, J. T. Kuethe, Chem. Rev. 2006,
106, 2875 – 2911; c) G. Zeni, R. C. Larock, Chem. Rev. 2004, 104,
2285 – 2309; d) S. Cacchi, G. Fabrizi, Chem. Rev. 2005, 105, 2873 –
2920; e) T. L. Gilchrist, J. Chem. Soc. Perkin Trans. 1 2001, 2491 –
2515; f) G. Gribble, J. Chem. Soc. Perkin Trans. 1 2000, 1045 –
1075.
Keywords: annulation · diazo compounds · indoles ·
nitrogen heterocycles · zinc
.
[1] a) R. J. Sundberg in Comprehensive Heterocyclic Chemistry II,
Vol. 2 (Eds.: A. R. Katritzky, C. W. Ress, E. F. V. Scriven, C. W.
Bird), Pergamon Press, Oxford, 1996, p. 119; b) A. Joule,
“Indole and its Derivatives” in Science of Synthesis: Methods
of Molecular Transformations (Houben-Weyl), Cat. 2, Vol. 10
(Eds.: E. J. Thomas), Thieme, Stuttgart, 2000, chap. 10.13; c) T.
Eicher, S. Hauptmann, in The Chemistry of Heterocycles:
Structure, Reactions, Syntheses, and Applications, Wiley-VCH,
Weinheim, 2nd ed., 2003.
[2] a) N. Okamoto, Y. Miwa, H. Minami, K. Takeda, R. Yanada,
Angew. Chem. 2009, 121, 9873 – 9876; Angew. Chem. Int. Ed.
2009, 48, 9693 – 9696; b) D. Solꢁ, O. Serrano, J. Org. Chem. 2008,
73, 2476 – 2479; c) P. S. Baran, C. A. Guerrero, N. B. Ambhaikar,
B. D. Hafensteiner, Angew. Chem. 2005, 117, 612 – 615; Angew.
Chem. Int. Ed. 2005, 44, 606 – 609; d) M. P. Kumar, R.-S. Liu, J.
Org. Chem. 2006, 71, 4951 – 4955; e) K. Alex, A. Tillack, N.
Schwarz, M. Beller, Angew. Chem. 2008, 120, 2337 – 2340;
Angew. Chem. Int. Ed. 2008, 47, 2304 – 2307; f) T. Pei, C.-y.
Chen, P. G. Dormer, I. W. Davies, Angew. Chem. 2008, 120,
4299 – 4301; Angew. Chem. Int. Ed. 2008, 47, 4231 – 4233; g) Z.
Shi, C. Zhang, S. Li, D. Pan, S. Ding, Y. Cui, N. Jiao, Angew.
Chem. 2009, 121, 4642 – 4646; Angew. Chem. Int. Ed. 2009, 48,
4572 – 4576; h) J. Barluenga, A. Jimꢁnez-Aquino, F. Aznar, C.
Valdꢁs, J. Am. Chem. Soc. 2009, 131, 4031 – 4041; i) S. Rakshit,
F. W. Patureau, F. Glorius, J. Am. Chem. Soc. 2010, 132, 9585 –
9587; j) M. Nazarꢁ, C. Schneider, A. Lindenschmidt, D. W. Will,
Angew. Chem. 2004, 116, 4626 – 4629; Angew. Chem. Int. Ed.
2004, 43, 4526 – 4528; k) P. Kothandaraman, W. Rao, S. J. Foo,
P. W. H. Chan, Angew. Chem. Int. Ed. 2010, 49, 4619 – 4623.
[3] a) S. Kirchberg, R. Frꢂhlich, A. Studer, Angew. Chem. 2009, 121,
4299 – 4302; Angew. Chem. Int. Ed. 2009, 48, 4235 – 4238; b) H.
[8] For a review of the Japp–Klingemann reaction, see: R. R.
Phillips, Org. React. 1959, 10, 143 – 178.
[9] a) P. Knochel in Handbook of Functionalized Organometallics,
Wiley-VCH, Weinheim, 2005; b) A. LeprÞtre, A. Turck, N. Plꢁ,
P. Knochel, G. Quꢁguiner, Tetrahedron 2000, 56, 265 – 273.
[10] For the reaction of arylzinc reagents with diazonium salts, see:
a) B. A. Haag, Z. Peng, P. Knochel, Org. Lett. 2009, 11, 4270 –
4273; b) D. Curtin, J. Tveteen, J. Org. Chem. 1961, 26, 1764 –
1768.
[11] E. Yasui, M. Wada, N. Takamura, Tetrahedron 2009, 65, 461 –
468.
[12] The addition of ZnBr2 (2.0 equiv) proved to be essential to
ensure a selective reaction with the diazonium salt in the next
reaction step. In the absence of ZnBr2, double-addition products
to diazonium salts have been detected.
[13] a) A. Krasovskiy, V. Malakhov, A. Gavryushin, P. Knochel,
Angew. Chem. 2006, 118, 6186 – 6190; Angew. Chem. Int. Ed.
2006, 45, 6040 – 6044; b) F. M. Piller, P. Appukkuttan, A.
Gavryushin, M. Helm, P. Knochel, Angew. Chem. 2008, 120,
6907 – 6911; Angew. Chem. Int. Ed. 2008, 47, 6802 – 6806; c) F. M.
Piller, A. Metzger, M. A. Schade, B. A. Haag, A. Gavryushin, P.
Knochel, Chem. Eur. J. 2009, 15, 7192 – 7202.
[14] The addition of Me3SiCl (1 equiv) was found to accelerate the
cyclization reaction.
[15] I. Sapountzis, P. Knochel, Angew. Chem. 2004, 116, 915 – 918;
Angew. Chem. Int. Ed. 2004, 43, 897 – 900.
[16] A. Metzger, C. Argyo, P. Knochel, Synthesis 2010, 882 – 891.
[17] a) K.-J. Hwang, S.-J. Lee, B.-T. Kim, S. Raucher, Bull. Korean
Chem. Soc. 2006, 27, 933 – 935; b) T. Y. Shen, T. B. Windholz, A.
Angew. Chem. Int. Ed. 2010, 49, 9513 –9516
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
9515

Communications
Rosegay, B. E. Witzel, A. N. Wilson, J. D. Willett, W. J. Holtz,
[18] a) L. M. Rice, E. Hertz, M. E. Freed, J. Med. Chem. 1964, 7, 313 –
319; b) B. L. Baxter, M. I. Gluckman, Nature 1969, 223, 750 –
752.
[19] H. E. Ramsden, J. R. Leebrick, S. D. Rosenberg, E. H. Miller,
J. J. Walburn, A. E. Balint, R. Cserr, J. Org. Chem. 1957, 22,
1602 – 1605.
R. L. Ellis, A. R. Matzuk, S. Lucas, C. H. Stammer, F. W. Holly,
L. H. Sarett, E. A. Risley, G. W. Nuss, C. A. Winter, J. Am.
Chem. Soc. 1963, 85, 488 – 489; c) C. Mukai, Y. Takahashi, Org.
Lett. 2005, 7, 5793 – 5796; d) I. V. Magedov, S. A. Maklakov,
Yu. I. Smushkevich, Chem. Heterocycl. Compd. 2005, 41, 449 –
451.
9516
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 9513 –9516