Directed ortho metalation approach to C-7-substituted indoles. Suzuki-Miyaura cross coupling and the synthesis of pyrrolophenanthridone alkaloids

Article abstract of DOI:10.1021/ol0344772

(Matrix presented) Although the indole N-phosphinoyl derivative 4 undergoes n-BuLi deprotonation/electrophile quench to afford C-7-substituted products, its deprotection requires harsh conditions. On the other hand, the N-amide 12, upon sequential or one-pot C-2 metalation, silylation, C-7 metalation, and electrophile treatment, furnishes indoles 7 in good overall yields. In combination with the Suzuki-Miyaura protocol, C-7 aryl (heteroaryl)-substituted indoles 14 and 16 are obtained, including hippadine and pratosine, members of the pyrrolophenanthridone alkaloid family.

Full text of DOI:10.1021/ol0344772

ORGANIC
LETTERS
2003
Vol. 5, No. 11
1899-1902
Directed ortho Metalation Approach to
C-7-Substituted Indoles. Suzuki−Miyaura
Cross Coupling and the Synthesis of
Pyrrolophenanthridone Alkaloids
Christian G. Hartung, Anja Fecher, Brian Chapell,† and Victor Snieckus*
Department of Chemistry, Queen’s UniVersity, Kingston, ON, K7L 3N6, Canada
snieckus@chem.queensu.ca
Received March 19, 2003
ABSTRACT
Although the indole N-phosphinoyl derivative 4 undergoes n-BuLi deprotonation/electrophile quench to afford C-7-substituted products, its
deprotection requires harsh conditions. On the other hand, the N-amide 12, upon sequential or one-pot C-2 metalation, silylation, C-7 metalation,
and electrophile treatment, furnishes indoles 7 in good overall yields. In combination with the Suzuki−Miyaura protocol, C-7 aryl (heteroaryl)-
substituted indoles 14 and 16 are obtained, including hippadine and pratosine, members of the pyrrolophenanthridone alkaloid family.
We wish to report a new, general, and efficient method for
the preparation of C-7 functionalized indoles, 5, 7, 13, 14,
and 16, by directed ortho metalation (DoM) and combined
DoM/Suzuki-Miyaura cross-coupling strategies.1 These
findings provide an entry into a difficult indole substitution
and bear general consequences on the synthesis of alkaloids2
and bioactive molecules, which incorporate the key indole
moiety.
In addition to traditional methodologies that rely on
incorporation of functionality prior to indole ring construc-
tion,2b,3 recent routes to substituted indoles have been
dominated by DoM protocols. Although C-2 and C-3
functional group introduction may be thereby readily achieved
(A, Scheme 1),4,5 relatively minor effort has been dedicated
to benzenoid ring functionalization via metalation tactics.6
(3) For a selection of de novo methods of indole ring construction, see:
(a) Batcho, A. D.; Leimgruber, W. Org. Synth. 1985, 63, 214. (b) Bartoli,
G.; Bosco, M.; Dalpozzo, R.; Palmieri, G.; Marcantoni, E. J. Chem. Soc.,
Perkin Trans. 1 1991, 2757. (c) Soederberg, B. C.; Shriver, J. A. J. Org.
Chem. 1997, 62, 5838, and refs cited therein. (d) Gribble, G. W. J. Chem.
Soc., Perkin Trans. 1 2000, 1045 and refs cited therein. (e) Beller, M.;
Breindl, C.; Riermeier, T. H.; Tillack, A. J. Org. Chem. 2001, 66, 1403. (f)
Lindsay, D. M.; Dohle, W.; Jensen, A. E.; Kopp, F.; Knochel, P. Org. Lett.
2002, 4, 1819.
(4) (a) Gribble, G. W. In AdVances in Heterocyclic Natural Product
Synthesis; Pearson, W. H., Ed.; Jai Press: Greenwich, CT, 1990; Vol. 1, p
43. (b) Snieckus, V. Chem. ReV. 1990, 90, 879. (c) Turck, A.; Ple, N.;
Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4489. For relevant selected
indole metalation chemistry, see: (d) Comins, D. L. Synlett 1992, 615. (e)
Matsuzono, M.; Fukuda, T.; Iwao, M. Tetrahedron Lett. 2001, 42, 7621.
(f) Vasquez, E.; Davies, I. W.; Payack, J. F. J. Org. Chem. 2002, 67, 7551.
(5) (a) Rewcastle, G. W.; Katritzky, A. R. AdV. Heterocycl. Chem. 1993,
56, 172. (b) Ishikura, M.; Matsuzaki, Y.; Agata, I. Heterocycles 1997, 45,
2309.
† Current address: Mohawk College, Department of Chemical and
Environmental Technology, P.O. Box 2034, Hamilton, ON, L8N 3T2,
Canada.
(1) For recent reviews, see: (a) Anctil, E. J.-G.; Snieckus, V. J.
Organomet. Chem. 2002, 653, 150. (b) Hartung, C. G.; Snieckus, V. In
Modern Arene Chemistry; Astruc, D., Ed.; Wiley-VCH: Weinheim,
Germany, 2002; p 330.
(6) (a) Greenhill, J. V. In ComprehensiVe Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol.
4, p 497. (b) Chauder, B.; Larkin, A.; Snieckus, V. Org. Lett. 2002, 4, 815.
For C-4/C-6 DoM chemistry on C-5 O-carbamates, see: (c) Griffen, E. J.;
Roe, D. G.; Snieckus, V. J. Org. Chem. 1995, 60, 1484.
(2) (a) Lounasmaa, M.; Hanhihen, P. The Alkaloids 2001, 55, 1-89. (b)
Sundberg, R. J. Indoles, 2nd ed.; Academic Press: San Diego, CA, 1996.
10.1021/ol0344772 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/01/2003

Thus, using 2 equiv of LDA at 0 °C for 15 min provided,
after TMSCl quench, N-di-tert-butylphosphinoyl-2-trimeth-
ylsilylindole in 82% yield. In complete regioselective
contrast, use of 2.2 equiv of n-BuLi at -40 °C for 2 h and
TMSCl quench afforded 5a exclusively (Table 1). Other
Scheme 1. Indole Functionalization by DoM
Table 1. Metalation and Electrophile Quench of
N-(Di-tert-butylphosphinoyl)indole 4
Iwao has provided two DoM approaches for C-7-substituted
indoles: via N-Boc indolines followed by oxidation7 and,
recently, via N-(diethylbutanoyl)(DEB)indoles.8,9 In the
excellent latter study, while good yields of C-7 products were
achieved, the value of the method was compromised by C-7/
C-2 regioselectivity (B, Scheme 1).10
The method described herein uses the silicon protection
tactic11 at C-2 for clean C-7 deprotonation leading to indoles
7, which may be readily N-deprotected and, by cross
coupling, converted into compounds 14 and 16, including
pyrrolophenanthridone alkaloids 2a,b. The significance of
the new methodology relates to the existence of natural
products (e.g., 7-prenylindole 1 as a prototype12 and
pyrrolophenanthridone alkaloids 2a-c,13 Scheme 2) and to
the demand, in today’s drug discovery programs, for interest-
ing indole scaffolds (e.g., Etodolac 314).
E+
Me3SiCl
product (E)
5a (SiMe3)
yield (%)
72
93
87
53
44
78
MeI
5b (Me)
BrCH2CHdCMe2
5c (CH2CHdCMe2)
5d (CHO)
5e (PPh2)
5f (I)
DMF
ClPPh2
I2
representative electrophiles gave the identical regioselectivity
result providing indoles 5b-f in modest to very good
yields.16 In consonance with the proposal by Iwao for the
corresponding DEB-indole (B, DMG ) COCEt3, Scheme
1),8 the high steric demand of the tert-butyl groups may lead
to a complex in which the PdO bond orientation favors C-7
hydrogen abstraction rather than the normal higher thermo-
dynamically acidic C-2 site.17 The proposed phosphinoyl
group orientation is evident in the single-crystal X-ray
analysis of 5c (Supporting Information, CCDC 207794).
Deprotection of 5c and other C-7-substituted indoles in this
series was unsuccessful using basic or acidic conditions but
was achieved by reduction (LiAlH4/toluene/reflux). For
example, the natural product 1 (Scheme 2) was thereby
obtained in 44% yield from 5c.16
Scheme 2. 7-Substituted Indole Alkaloids and Drugs
The harsh conditions for cleavage of 5 prompted a search
for alternative N-DMGs that would promote this direct C-7
deprotonation and yet be cleaved under mild conditions.
Considerable experimentation of numerous conditions using
N-DMG ) Boc, SO2Ph, CONR2 (R ) Et, i-Pr, Ph, pyrro-
lidinyl) showed that only C-2 deprotonation was achievable.
Furthermore, adapting the silicon protection mode to the
above substrates11 afforded clean results of C-7 lithiation with
only the N-CONEt2 derivative 6 (preparation from indole:
(1) NaH/ClCONEt2/THF/0 °C to room temperature, >98%
yield (Kugelrohr distillation); (2) TMSCl/t-BuLi/THF/-78
°C, 97%).
In an early test, the powerful P(O)(t-Bu)2 Directed
Metalation Group (DMG)15 was appended to indole ((1)
n-BuLi/THF/0 °C and then ClP(t-Bu)2; (2) H2O2/MeOH) to
give 4 in 78% overall yield. Highly regioselective C-2 or
C-7 deprotonation of 4 was achieved by choice of conditions.
(7) Iwao, M.; Kuraishi, T. Heterocycles 1992, 34, 1031.
(8) Fukuda, T.; Maeda, R.; Iwao, M. Tetrahedron 1999, 55, 9151.
(9) For C-7 functionalization via Cr(CO)3 derivatives, see: (a) Masters,
N. F.; Mathews, N.; Nechvatal, G.; Widdowson, D. A. Tetrahedron 1989,
45, 5955. Via C-H activation, see: (b) Chatani, N.; Yorimitsu, S.; Asaumi,
T.; Kakiuchi, F.; Murai, S. J. Org. Chem. 2002, 67, 7557.
(10) For use of DEB-indole for C-2 and C-3 functionalization by
metalation reactions, see: Fukuda, T.; Mine, Y.; Iwao, M. Tetrahedron
2001, 57, 975.
Using the optimized metalation conditions (1.5-2.5 equiv
of s-BuLi/TMEDA/THF/-78 °C/2-3 h)18 on 6 followed by
electrophile quench gave products 7a-k and 8 in moderate
(11) Mills, R. J.; Taylor, N. J.; Snieckus, V. J. Org. Chem. 1989, 54,
4372.
(12) Achenbach, H.; Renner, C. Heterocycles 1985, 23, 2075.
(13) Grundon, M. F. Nat. Prod. Rep. 1989, 6, 79.
(14) Jones, R. A. Inflammopharmacology 2001, 9, 63.
(15) Gray, M.; Chapell, B. J.; Felding, J.; Taylor, N. J.; Snieckus, V.
Synlett 1998, 422.
(16) For the complete study, see: Chapell, B. J., Ph.D. Thesis, University
of Waterloo, Waterloo, ON, Canada, 2001.
(17) This may be reasonably rationalized by a complex induced proximity
effect (CIPE): Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356.
(18) Success of this reaction is highly dependent on the quality and
quantity of the s-BuLi; see also footnote 23 in ref 8.
1900
Org. Lett., Vol. 5, No. 11, 2003

to high yields (Table 2). Although deuteration is not
quantitative (entry 1), a variety of carbon (entries 2-6),
Scheme 3. One-Pot Conversion of 12 into 2,7-Substituted
Indole Derivatives 7 and Further C-6 Functionalization to 13
Table 2. Metalation and Electrophile Quench of
1-(N,N-Diethylcarbamoyl)-2-trimethylsilylindole 6a
entry
E+
product (E)
7a (D)
yield (%)
1
2
MeOD
MeI
>99b
81
7b (Me)
3
EtI
7c (Et)
7d (CH2CHdCMe2)
8d (CHO)
70
66
40
4c
BrCH2CHdCMe2
DMF
5
6c
7
8
9c
10c
11c
ClCONEt2
Me3SiCl
Bu3SnCl
BrCH2CH2Br
I2
7ee (CONEt2)
7f e (SiMe3)
7g (SnBu3)
7h (Br)
72
82
33
69
75
60
h). Corresponding C-7-substituted indoles were thus ob-
tained: indole from 6 (i, 85%; ii, 94%; iii, 92%), 7-methyl
indole from 7b (i, 75%), 7-TMS indole from 7f (i, 94%),
7-bromo indole from 7h (ii, 88%), 7-diethylcarboxamide
indole from 7e (ii, 82%), and 7-phenylindole from 14f (ii
but reflux, 15 h, 71%).
7ie (I)
(1) B(OiPr)3, (2) pinacol 7j
12c
(1) B(OiPr)3, (2) H2O2
7k e (OH)
58
a Typical procedure: (1) 2.5 equiv of s-BuLi/TMEDA/THF/-78 °C/
2-3 h/0.5 M; (2) E+/-78 °C to room temperature/8-12 h. b D:H ) 5:1.
c s-BuLi (1.5 equiv)/TMEDA. d Product: 7-formyl-indole-1-carboxylic acid
diethylamide. e 7e, 7f, 7i, and 7k can be obtained without chromatography
by direct recrystallization of the crude product.
Table 3. Suzuki-Miyaura Cross-Coupling Reactions of the
7-Iodo, 7-Bromo, and 7-Pinacolboronate Indole Derivativesa
silicon (entry 7), tin (entry 8), halogen (entries 9 and 10),
boron (entry 11), and oxygen (entry 12) electrophiles are
introduced.19 To improve operational efficacy, on the basis
of the observation that C-2 TMS introduction proceeds in
quantitative yield (GC analysis), a one-pot procedure was
developed (Scheme 3) that provided the 7-functionalized
indole derivatives in yields within experimental error to those
obtained by stepwise reactions. Further walk-around-the-ring
metalation was demonstrated by the conversion of 7e into
the 6-TMS derivative 13 in high yield. N-CONEt2 (and
simultaneous 2-TMS) cleavage was effected using (i) 25%
KOH or 25% aqueous NaOH (EtOH/reflux/1-16 h),20 (ii)
5 equiv of KOtBu (THF/rt/1.5-12 h), or (iii) 1 equiv of
TBAF (THF, 1 h) and then 2.2 equiv of KOtBu (THF/rt/2
(19) For entries 6 and 11, products 9 (10%) and 10 (16%) were isolated;
for entries 9 and 10, 11 (10-20%) was obtained. Product 11, presumably
the result of benzyne formation of the normal product (7h, 7i) followed by
carbamoyl R-deprotonation-cyclization, is formed in 50% yield under the
following conditions: (1) 3 equiv of s-BuLi/TMEDA/THF/-78 °C/2 h;
(2) 3 equiv of Br2 or I2/-78 °C f rt (Supporting Information).
a Typical procedure: 1.2 equiv of ArX/5 mol % Pd(PPh3)4/DMF/3 equiv
of K3PO4/80 °C/15-20 h. b Pd(PPh3)4(2 mol %)/DME/H2O/1.5 equiv of
Na2CO3/80 °C/16 h. c After 20 h: addition of 1.1 equiv TBAF in THF/2
h/rt.
(20) Comins, D. L.; Stroud, E. D. Tetrahedron Lett. 1986, 27, 1869. (b)
Castells, J.; Troin, Y.; Diez, A.; Rubiralta, M.; Grierson, D. S.; Husson, H.
P. Tetrahedron 1991, 47, 7911.
Org. Lett., Vol. 5, No. 11, 2003
1901

To explore combined DoM/Suzuki-Miyaura cross-
coupling methodology, a general theme pursued in our
laboratories,1a the haloindoles 7h and 7i along with indole
boronate 7j were tested with representative aryl boronic acids
and halides (Table 3), respectively.21 Thus, coupling of iodide
7i and bromide 7h with phenyl boronic acid (entry 1) and
substituted phenylboronic acids (entries 2-6) afforded
products 14a-e in generally high yields even in ortho-
substituted cases. Inversion of the coupling partners (entries
7 and 8) also efficiently furnished products 14f and 14g. In
some cases of the Suzuki-Miyaura processes, concurrent
C-2 desilylation was observed (entries 2 and 5-8).
As an application of the overall method, the synthesis of
representative members of the pyrrolophenanthridone alka-
loids (Amaryllidaceae), exhibiting antitumor and other
biological activities,13 was targeted.22 Thus, Suzuki-Miyaura
reaction of the boron pinacolate 7j with aryl bromides 15a-c
provided products 16a-c (Scheme 4) accompanied by 2a
and 17 in good yields (up to 80% for the hydrolysis of 16a-c
with LiOH or NaOH).
In summary, while the indole N-P(O)(t-Bu)2 is a powerful
DMG for selective C-2 or C-7 indole deprotonation (Table
1), its synthetic value is compromised by severe cleavage
conditions. On the other hand, the N-CONEt2 derivative 12
with prior C-2 TMS protection is very effective for the
synthesis of C-7-substituted indoles (7a-k) and, via subse-
quent Suzuki-Miyaura cross-coupling reactions, for 7-aryl
indoles (14a-g and 16a-c), including pyrrolophenanthri-
done alkaloids (2a, 2b, and 17). The dependence on indole
as a starting point (rather than de novo construction3 from
intermediate anilines or nitrobenzenes), the formulation of
a one-pot procedure by metalation of 12, and the demonstra-
tion of further DoM chemistry (13) allow anticipation of
further application of this methodology for the construction
of natural products and bioactive molecules.
Acknowledgment. We are grateful to NSERC Canada
for support of our synthetic programs. We thank Sheldon
Lyn and Yen Dang for their diligent work on this project
and Nicholas J. Taylor for measuring and solving the X-ray
structure. C.G.H. and A.F. thank the Alexander von Hum-
boldt Foundation and the DAAD for postdoctoral fellow-
ships, respectively.
Scheme 4. Synthesis of Pyrrolophenanthridone Alkaloidsa
Supporting Information Available: Experimental pro-
cedures and characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0344772
(21) Considering the explosion of cross-coupling chemistry, it is fair to
say that indole C-7 derivatives have been infrequently described: see, e.g.:
(a) Siddiqui, M. A.; Snieckus, V. Tetrahedron Lett. 1990, 31, 1523. (b)
Sakamoto, T.; Yasukura, A.; Kondo, Y.; Yakamaka, H. Heterocycles 1993,
36, 2597. (c) Black, D. S. C.; Keller, P. A.; Kumar, N. Tetrahedron 1993,
49, 151. (d) Banwell, M. G.; Bissett, B. D.; Busato, S.; Cowden, C. J.;
Hockeless, D. C. R.; Holman, J. W.; Read, R. W.; Wu, A. W. J. Chem.
Soc., Chem. Commun. 1995, 2551. (e) Hutchings, R. H.; Meyers, A. I. J.
Org. Chem. 1996, 61, 1004. (f) Carbonnelle, A.-C.; Zamora, E. G.;
Beugelmans, R.; Rossi, G. Tetrahedron Lett. 1998, 39, 4467 and refs cited
therein. (g) Tsuge, O.; Hatta, T.; Tsuchiyama, H. Chem. Lett. 1998, 155.
(22) For previous syntheses, see: (a) ref 21 and refs cited therein. (b)
Miki, Y.; Shirokoshi, H.; Matsushita, K.-i. Tetrahedron Lett. 1999, 40, 4347
and refs cited therein. (c) Boger, D. L.; Wolkenberg, S. E. J. Org. Chem.
2000, 65, 9120 and refs cited therein. (d) Pouysegu, L.; Avellan, A.-V.;
Quideau, S. J. Org. Chem. 2002, 67, 3425 and refs cited therein.
a Key: (a) 1.2 equiv of ArX 15/ 5-7.5 mol % Pd(PPh3)4/DMF/3
equiv of K3PO4/80 °C/20-24 h. a: R ) OMe, Y ) NEt2, 16a
40%, 2a 18% (Pratosine). b: R ) -OCH2O-, Y ) OEt, 16b 90%,
2b 7% (Hippadine). c: R ) H, Y ) OEt, 16c 76%, 17 13%. (b)
LiOH (2.5 M) in MeOH/THF or 25% aqueous NaOH in EtOH/
reflux/6-60 h/66-88%.
(pratosine) (18%), 2b (hippadine) (7%), and 17 (13%) as
side products. Prolonged cross-coupling reaction times or
hydrolysis of the isolated compounds 16a-c (LiOH/MeOH/
THF/reflux or aqueous NaOH/EtOH/reflux) afforded 2a, 2b,
1902
Org. Lett., Vol. 5, No. 11, 2003