Iridium-catalyzed, silyl-directed borylation of nitrogen-containing heterocycles

Article abstract of DOI:10.1021/ja1006405

Chemical Figure Presented Selective methods for the functionalization of indoles and other nitrogen heterocycles would provide access to the core structures of many natural products and pharmaceuticals. Although there are many methods and strategies for the synthesis of substituted indoles or functionalization of the azole ring, strategies for the selective functionalization of the benzo-fused portion of the indole skeleton, particularly the 7-position, are less common. We report a one-pot, iridium-catalyzed, silyl-directed C-H borylation of indoles at the 7-position. This process occurs in high yield with a variety of substituted indoles, and conversions of the 7-borylindole products to 7-aryl-, 7-cinnamyl-, and 7-haloindoles are demonstrated. The lr-catalyzed, silyl-directed C-H borylation also occurs with several other nitrogen heterocycles, including carbazole, phenothiazines, and tetrahydroquinoline. The utility of this methodology is highlighted by the one-pot synthesis of a member of the pyrrolophenanthrldone class of alkaloid natural products. Copyright

Full text of DOI:10.1021/ja1006405

Published on Web 03/03/2010
Iridium-Catalyzed, Silyl-Directed Borylation of Nitrogen-Containing
Heterocycles
Daniel W. Robbins, Timothy A. Boebel, and John F. Hartwig*
Department of Chemistry, UniVersity of Illinois at Urbana-Champaign, Urbana, Illinois 61801
Received January 24, 2010; E-mail: jhartwig@illinois.edu
Selective methods for the direct functionalization of nitrogen
heterocycles could lead to rapid access to materials that are cumber-
some to prepare by classical methods. Although progress has been
made,1-3 few systems selectively functionalize the benzo-fused
aromatic ring of indoles and related heterocycles because of the greater
reactivity of the azole ring,4 and the selective functionalization of other
biologically important nitrogen-containing heterocycles, such as car-
bazoles and tetrahydroquinolines,5-7 has been less studied. Some
chloroperoxidases form 7-chloroindoles, but these reactions have not
been reported on a synthetic scale or with a scope beyond tryptophan8,9
or the parent indole.10
With this result in hand, we sought to develop a one-pot protocol
for indole borylations by installation of the silyl group, directed
borylation, and desilylation. To do so, we first sought conditions for
the generation of N-hydrosilylindoles from indole and dihydrosilanes
by dehydrogenative coupling under neutral conditions. Studies of
several potential catalysts for this reaction showed that [Ru(p-
cymene)Cl2]2 formed the N-hydrosilylindole from diethylsilane and
indole at room temperature. Indole derivatives that could not be
silylated in this fashion were silylated with dimethylchlorosilane and
triethylamine as the base.
After evaporation of the solvent, the combination of [Ir(cod)Cl]2
and dtbpy catalyzed the subsequent borylation of the resulting
hydrosilylindole at the 7-position without interference from the
residual ruthenium. Full conversion of the silyl indole occurred after
4 h at 80 °C in the presence of just 0.25% [Ir(cod)Cl]2.16 Workup
with 3 M aqueous NaOAc released the silyl group to give the free
7-borylindole.
Studies of the scope of the silyl-directed borylation of substituted
indoles are summarized in Figure 1. The directed borylation reaction
tolerates a variety of substituents at the 3-, 4-, and 5-positions of the
indole framework. Reactions of indoles containing halogens, cyano
groups, and alkoxy and benzyloxy groups all occurred to exclusively
form the corresponding 7-borylindoles, as determined by GC-MS
analysis. The isolated yields shown correspond to those for the full
reaction sequence starting from the N-H indole.
Scheme 1. Previous Functionalization of the 7-Position of Indoles
Selective functionalization of the 7-position of an indole by chemical
methods typically requires a substituent at the 2-position to block
reactivity at this site (Scheme 1). The borylation of indoles at the
7-position would create a method for preparing a variety of 7-indole
derivatives by exploiting the reactivity of the heteroarylboronate
products. Because the 2-position of indole is inherently the most
reactive site for metalation,11 the existing direct borylations of indoles
at the 7-position12 or indirect borylations by initial 7-lithiation of
N-carbamoyl indoles have been conducted with 2-substituted deriva-
tives.13 Here we report the application of our recently disclosed
hydrosilyl directing group for C-H borylation14 to alter the inherent
selectivity for the reactions of nitrogen heterocycles. This change in
selectivity leads to the 7-borylation of indoles lacking any substituent
at the 2-position, as well as the borylation of the analogous sites of
benzo-fused nitrogen heterocycles containing an N-H bond.
To assess the ability of a hydrosilyl group to affect the selectivity
of the borylation of nitrogen heterocycles, we evaluated the borylation
of 1-diethylsilylindole with bis(pinacolato)diboron (B2pin2) in the
presence of the combination of [Ir(cod)Cl]2 and 4,4′-di-tert-butylbi-
pyridine (dtbpy).15 The borylation of this indole derivative occurred
in good yield with complete selectivity for borylation at the 7-position
(eq 1). In contrast, the undirected borylation of indole gives 2- or 2,7-
functionalized products, depending on the amount of boron reagent
(eq 2). Thus, the hydrosilyl group completely overrides the inherent
site selectivity for the borylation of indole at the 2-position. We
envision that this directing effect results from temporary docking of
the catalyst on the silyl group (eq 1, right) by reversible reaction of
[Ir(dtbpy)(Bpin)3] with the Si-H bond to release HBpin and form an
intermediate silyl complex. The selectivity for borylation at the
7-position would then result from formation of a five-membered
metallacycle through C-H bond cleavage at the 7-position, as shown
in eq 1, versus formation of a four-membered metalacycle through
C-H bond cleavage at the 2-position.
Figure 1. Scope of Ir-catalyzed, silyl-directed indole borylation. Conditions:
[Ir(cod)Cl]2 (0.25%), dtbpy (0.5%), B2pin2 (1 equiv), HBpin (5%), THF, 80 °C.
For the case marked with a superscript “a”, the yield of the two-step process
run without a drybox was 56%.
9
4068 J. AM. CHEM. SOC. 2010, 132, 4068–4069
10.1021/ja1006405  2010 American Chemical Society

C O M M U N I C A T I O N S
products that have shown promising antitumor and other biological
activity. Previous syntheses of this class of natural products have utilized
prefunctionalized starting materials,20 such as 7-bromoindole,21 and
relied on blocking groups at the C2 position,13 and typically required
several steps or harsh reaction conditions. In contrast, the Ir-catalyzed,
silyl-directed 7-borylation of indole, followed by Suzuki-Miyaura
coupling of the desired o-bromobenzoate and lactamization in situ,
gave the pyrrolophenanthridone alkaloid core and the natural product
Hippadine in a single, one-pot sequence in good yield (eq 3). Because
this approach begins with an indole and a benzoate, this method should
allow the modular introduction of groups on both the indole and arene
units.
Figure 2. Ir-catalyzed, silyl-directed borylation of other N-heterocycles.
Scheme 2. Functionalization of 7-Borylindoles
The borylation of 3-methylindole reveals the striking effect of the
N-silyl group. Most iridium-catalyzed borylations of arenes with B2pin2
are strongly disfavored at positions ortho to substituents, but borylations
of 3-substituted indoles give 2-borylindoles in the absence of a directing
group. For example, the borylation of 3-methylindole with B2pin2
catalyzed by [Ir(cod)Cl]2 and dtbpy gave a ∼2:1 mixture of 2-boryl-
and 2,7-diboryl-3-methylindole, whereas the borylation of 3-methyl-
N-diethylhydrosilylindole occurred exclusively at the 7-position in good
yield.
The silyl group also directs borylation exclusively to the indole
7-position in the presence of other aryl C-H bonds. The borylation
of 3-phenylindole forms a mixture of at least three products, whereas
the borylation of 3-phenyl-N-diethylsilylindole formed 7-boryl-3-
phenylindole without borylation of the phenyl substituent. Moreover,
the borylation of N-silylindole in a THF solution containing 6 equiv
of added benzene led to exclusive borylation of the indole, as assayed
by GC-MS. Conversely, the borylation of indole in the presence of
6 equiv of benzene gave a mixture of 2-borylindole, 2,7-diborylindole
and Ph-Bpin.
In conclusion, a highly selective method for the Ir-catalyzed, silyl-
directed C-H borylation of nitrogen heterocycles, including a general
borylation of indole at the 7-position, has been developed. This
transformation occurs with a low catalyst loading in short reaction
times under mild conditions. Furthermore, this reaction possess good
functional group tolerance, can be extended to the directed borylation
of other nitrogen-containing heterocycles, and creates a versatile
intermediate for further functionalization. Studies of the origin of the
regioselectivity and application of this approach to additional directed
functionalizations are in progress.
Acknowledgment. We thank the NSF (CHE-0910641) for sup-
port, Johnson-Matthey for iridium, and Eastman Chemicals for a
summer fellowship to D.W.R.
Supporting Information Available: Experimental procedures and
characterization of reaction products. This material is available free of
charge via the Internet at http://pubs.acs.org.
The hydrosilyl group accelerated not only the rates of the borylation
of indoles lacking a 2-substituent but also the rates and yields of the
borylations of 2-substituted indoles. The silyl-directed borylation of
1,2,3,4-tetrahydrocyclopentindole occurred at the 7-position in 64%
yield for the two-step silylation-borylation process after 8 h, whereas
this reaction of indole lacking the silyl group occurred in only 45%
yield after a longer time of 36 h.12
References
(1) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41,
1013.
(2) Campos, K. R. Chem. Soc. ReV. 2007, 36, 1069.
(3) Fairlamb, I. J. S. Chem. Soc. ReV. 2007, 36, 1036.
(4) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608.
(5) Ito, C.; Itoigawa, M.; Aizawa, K.; Yoshida, K.; Ruangrungsi, N.; Furukawa,
H. J. Nat. Prod. 2009, 72, 1202.
The results of silyl-directed, Ir-catalyzed borylations of other
nitrogen heterocycles containing N-H bonds are shown in Figure 2.
The borylation of carbazole, phenothiazines, and tetrahydroquinoline
occurred to full conversion and in moderate to good yield in the
presence of 1 mol % [Ir(cod)OMe]2 and 2 mol % dtbpy. The lower
yields observed in some cases were due to protodeborylation during
cleavage of the silyl group. 2-Chlorophenothiazine underwent selective
borylation at the less hindered ortho C-H bond. Phenothiazine is the
core of a number of neuroleptic antipsychotic drugs, including
chlorpromazine, fluphenazine, and prochlorperazine, and is contained
within components of organic solar cells and photovoltaics.17
The conversion of 7-borylindole to further-functionalized materials is
shown in Scheme 2. Suzuki-Miyaura coupling with bromobenzene in
the presence of catalytic Pd(dba)2 and PPh3 with K3PO4 as the base in
DMF at 80 °C gave 7-phenylindole. Palladium-catalyzed allylation with
PdCl2, tri-2-furylphosphine, cinnamyl acetate, and KF in MeOH gave
7-cinnamylindole.18 Halogenation using the protocol developed for the
conversion of arylboronates gave 7-bromo- and 7-chloroindole.19
To further illustrate the potential of the silyl-directed, Ir-catalyzed
borylation of indoles to facilitate the synthesis of biologically active
compounds, we prepared the core of the pyrrolophenanthridone natural
(6) Ito, C.; Itoigawa, M.; Sato, A.; Hasan, C. M.; Rashid, M. A.; Tokuda, H.;
Mukainaka, T.; Nishino, H.; Furukawa, H. J. Nat. Prod. 2004, 67, 1488.
(7) Ito, C.; Katsuno, S.; Itoigawa, M.; Ruangrungsi, N.; Mukainaka, T.; Okuda,
M.; Kitagawa, Y.; Tokuda, H.; Nishino, H.; Furukawa, H. J. Nat. Prod.
2000, 63, 125.
(8) Heemstra, J. R.; Walsh, C. T. J. Am. Chem. Soc. 2008, 130, 14024.
(9) Dong, C.; Flecks, S.; Unversucht, S.; Haupt, C.; van Pee, K.-H.; Naismith,
J. H. Science 2005, 309, 2216.
(10) Wiesner, W.; van Pee, K.-H.; Lingens, F. FEBS Lett. 1986, 209, 321.
(11) Takagi, J.; Sato, K.; Hartwig, J. F.; Ishiyama, T.; Miyaura, N. Tetrahedron
Lett. 2002, 43, 5649.
(12) Paul, S.; Chotana, G. A.; Holmes, D.; Reichle, R. C.; Maleczka, R. E.;
Smith, M. R. J. Am. Chem. Soc. 2006, 128, 15552.
(13) Hartung, C. G.; Fecher, A.; Chapell, B.; Snieckus, V. Org. Lett. 2003, 5,
1899.
(14) Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 7534.
(15) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig,
J. F. J. Am. Chem. Soc. 2002, 124, 390.
(16) Reactions with a catalyst loading of 0.1% [Ir(cod)Cl]2 also occurred in
high yield; however, a longer reaction time was needed, and a second
portion of catalyst was often required to achieve full conversion of the
silyl indole.
(17) Wong, W.-Y.; Chow, W.-C.; Cheung, K.-Y.; Fung, M.-K.; Djurisic, A. B.;
Chan, W.-K. J. Organomet. Chem. 2009, 694, 2717.
(18) Ortar, G. Tetrahedron Lett. 2003, 44, 4311.
(19) Murphy, J. M.; Liao, X.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 15434.
(20) Ganton, M. D.; Kerr, M. A. Org. Lett. 2005, 7, 4777.
(21) Mentzel, U. V.; Tanner, D.; Tonder, J. E. J. Org. Chem. 2006, 71, 5807.
JA1006405
9
J. AM. CHEM. SOC. VOL. 132, NO. 12, 2010 4069