Bismuth Acetate as a Catalyst for the Sequential Protodeboronation of Di- and Triborylated Indoles

Article abstract of DOI:10.1021/acs.orglett.6b00356

Bismuth(III) acetate is a safe, inexpensive, and selective facilitator of sequential protodeboronations, which when used in conjunction with Ir-catalyzed borylations allows access to a diversity of borylated indoles. The versatility of combining Ir-catalyzed borylations with Bi(III)-catalyzed protodeboronation is demonstrated by selectively converting 6-fluoroindole into products with Bpin groups at the 4-, 5-, 7-, 2,7-, 4,7-, 3,5-, and 2,4,7-positions and the late-stage functionalization of sumatriptan.

Full text of DOI:10.1021/acs.orglett.6b00356

Letter
pubs.acs.org/OrgLett
Bismuth Acetate as a Catalyst for the Sequential Protodeboronation
of Di- and Triborylated Indoles
Fangyi Shen,† Sriram Tyagarajan,‡ Damith Perera,† Shane W. Krska,‡ Peter E. Maligres,*,‡
Milton R. Smith, III,*,† and Robert E. Maleczka, Jr.*,†
†Department of Chemistry, Michigan State University, 578 South Shaw Lane, East Lansing, Michigan 48824, United States
‡Department of Process Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: Bismuth(III) acetate is a safe, inexpensive, and
selective facilitator of sequential protodeboronations, which
when used in conjunction with Ir-catalyzed borylations allows
access to a diversity of borylated indoles. The versatility of
combining Ir-catalyzed borylations with Bi(III)-catalyzed
protodeboronation is demonstrated by selectively converting 6-fluoroindole into products with Bpin groups at the 4-, 5-, 7-,
2,7-, 4,7-, 3,5-, and 2,4,7-positions and the late-stage functionalization of sumatriptan.
rylboronates are versatile synthetic building blocks.1,2
Iridium catalyzed C−H activation/borylation reactions are
phenes the first Bpin group to be installed during the Ir-
catalyzed borylation was also the first Bpin to be removed in
the Ir-catalyzed protodeboronation.
During a total synthesis project, we prepared 7-borylated 2 as
shown in Scheme 1. The next step in the synthesis called for
BiCl3-promoted removal of the Boc group9 (Scheme 2). Close
A
a powerful way of making such compounds as they can obviate
the need for prior functionalization (e.g., halogenation),
pyrophoric reagents, cryogenic conditions, etc.3 While the
regioselectivity of aromatic C−H borylations is mainly driven
by steric effects, C−H acidity is a secondary driver.4 For
example, Ir-catalyzed borylation of unprotected indoles first
installs a Bpin group at C2 and then upon further reaction at
C7.5
Scheme 2. Discovery of Bicatalyzed Protodeboronations
Recently, Movassaghi and co-workers6 showed that the 2,7-
diborylation of tryptophans, tryptamines, and 3-alkylindoles
could be followed by in situ palladium-catalyzed C2-
protodeboronation to selectively afford the C7 products
(Scheme 1). While this tactic may not seem atom economical,
examination of this deprotection revealed that 3 formed along
with trace amounts of byproduct 4 where the C7-BPin was
missing. This small amount of deborylated byproduct led us to
consider whether bismuth salts could facilitate selective
protodeboronation in a way similar to the previously described
Ir- and Pd-catalyzed protodeboronations. Such a method would
be quite attractive because bismuth salts are earth abundant,
harmless, and orders of magnitude less expensive than the
corresponding precious metal salts.10
Scheme 1. Prior Art
After screening BiCl3, Bi(OTf)3 and numerous other metal
salts and other additives,11 Bi(OAc)3 emerged as the catalyst of
choice. Subjecting purified 1 to 20 mol % Bi(OAc)3 in MeOH
(127 equiv) and THF at 80 °C (sealed tube) for 7 h afforded 7-
borylated 2 in 90% yield (Scheme 3).
Given this favorable result, a series of indoles were subjected
to multiple borylations (Table 1). Several of these Ir-catalyzed
borylations are worthy of comment. Following C7 borylation,
the next site for C−H borylation proved to be C4. In this way,
from a strategic perspective such a borylation/protodeborona-
tion sequence enables a streamlined approach to 7-borylated
indoles that are otherwise difficult to access without additional
steps and/or prefunctionalization7 We too had observed
selective deborylations of a number of diborylated heterocycles,
including several 2,7-diborylated indoles (Scheme 1).8 Our
protodeboronations were Ir-catalyzed and for some systems
could be exposing a crude Ir-catalyzed borylation mixture to
protic material. Perhaps most usefully, we noted that for
diborylated indoles, azaindoles, thiophenes, and benzthio-
Received: February 3, 2016
© XXXX American Chemical Society
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Scheme 3. Bi(OAc)3 Catalyzed Protodeboronation of 1
Table 2. Bi(OAc)3 Catalyzed Protodeboronations
Table 1. Ir-Catalyzed Borylation of Indoles
a
b
Isolated yields. Borylations ran with 2.0 equiv B2pin2, 2.8 mol %
HBpin, 0.5 mol % [Ir(OMe)COD]2, 1 mol % dtbpy, at 80 °C.
c
Borylations ran as described above, but with 1.0 equiv B2pin2.
a
b
d
Isolated yields. Ratio determined by 1H NMR of the crude reaction
Substrate stirred in neat HBpin (4 equiv) at rt for 1 h before being
c
d
e
mixture. See Supporting Information for details. 3 mol %
[Ir(OMe)COD]2, 40 equiv MeOH, THF at rt.
subjected to the borylation conditions. Borylation ran with 2.0 equiv
B2pin2, 3 mol % [Ir(OMe)COD]2, 6 mol % dtbpy, at 80 °C.
2,4,7-triborylated indoles 7 and 10 (entries 2 and 4)12,13 and
4,7-diborylated 12 and 14 (entries 5 and 6) were generated. We
previously showed that placing a Boc14 or Bpin15 on the indole
nitrogen directs borylation to the C3-position. Herein we
report for the first time that, provided the C6 position is
blocked, borylation of in situ N-borylated (entry 7) or N-Boc
protected (entry 8) indoles occurs at the C3 and then the C5-
positions, affording 15 and 17 respectively.16−18
compound with 20 mol % Bi(OAc)3 and 125 equiv of ACS
grade MeOH in THF afforded the 7-borylated indole (17) in
82% yield after 17 h (entry 1). Curiously, when we looked to
deuterate 6, the reaction was complete (83% isolated yield, 87%
deuterium incorporation19,20) after stirring with 60 equiv of
99.8% CD3OD for 12 h at room temperature (entry 2). A
closer look into these differences revealed that, as we had
observed with some of the Ir-catalyzed deboronations,8 the
grade of MeOH could significantly impact the reaction rate. For
example, protodeboronation of 6 was complete in less than 3 h
when anhydrous MeOH that came in sealed bottles was
With the borylated indoles in hand, we explored their
Bi(OAc)3 mediated protodeboronations (Table 2). Examining
first 2,7-diborylated indole (6), we found that heating this
B
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employed. Notably, reactions with either grade of methanol
were reproducible. To highlight the method’s relative robust-
ness and economy, we chose to continue our study with the
lower grade methanol.21
Scheme 4. Changing the Sequence of Protodeboronation
Within these parameters, 2,4,7-triborylated indole (7) was
monoprotodeboronated to afford 4,7-diborylated indole (19)
in 75% yield under similar conditions (entry 3). Attempts at the
selective C2/C7 diprotodeboronation of 7 were disappointing.
While 4-borylated indole (20) was formed as the major
product, NMR analysis of the crude reaction mixture revealed a
50/45/5 mixture of 20/19/indole.22 In contrast, 2,4,7-
triborylated-6-fluoroindole (10) underwent clean diprotode-
boronation to afford 20 in 80% yield (entry 4) when the
amount of MeOH was increased. A qualitative feature of
deborylating 10 is that upon completion the reaction mixture
takes on a slight pink color. Monoprotodeboronation of 10
(entry 5) provided further indication that these reactions are in
part substrate dependent, as relative to 7, trisboylated 10
required less time and equivalents of methanol to achieve the
selective deborylation of the Bpin at C2 in similar yields.
The protodeboronation of 4,7-diborylated-2-carboethoxy-
indole 12 (entry 6) was instructive for comparing the synthetic
efficiency of Bi vs Ir-catalyzed deboronations. After 24 h at 80
°C, indole 12 and 40 mol % Bi(OAc)3 in MeOH/THF gave
monoprotodeboronated 22 as the major product along with
fully protodeboronated 11 and unreacted 12 in a 54/9/41 ratio
per NMR analysis of the crude reaction product. Our recently
published Ir-mediated conditions of 2 h at 1.5 mol %
[Ir(OMe)COD]2 in 2:1 MeOH/CH2Cl2 at 60 °C8 performed
worse, giving the fully protodeboronated 11 and 22 in a ratio of
67:33. However, Ir catalysis in MeOH/THF (∼1:6) at rt
reacted best, affording 22 in 54% isolated yield along with 13%
11. 4,7-Diborylated-2-methyindole 14 under the Bi(OAc)3
conditions also afforded a 52/5/43 mixture of monoprotode-
boronated 23 to 13 to 14, respectively. Indole 14 was another
substrate where Ir-mediated protodeboronation proved supe-
rior, giving a 91/9 mixture of 23 and starting material 14 with
23 being isolated in 74% yield (entry 7).
The 3,5-diborylated indoles (15 and 17) were informative
substrates in their own right. 15 was exclusively monoproto-
deboronated at C3 by 20 mol % Bi(OAc)3 in MeOH/THF
after 3 h at 80 °C, affording 24 in 88% yield (entry 8).
Deboronation of 15 under our published Ir-catalyzed
protodeboronation conditions proved less selective. With Ir,
the crude reaction product contained 13% of fully deboronated
6-fluoroindole (8) and 24 was isolated in 66% yield. Attempts
to optimize Ir-catalyzed deboronation of 15 never met with the
selectivity observed with Bi(OAc)3 unless the reaction was
stopped prior to complete consumption of starting material.22
In contrast to 15, Boc-protected 17 failed to undergo any
deboronation by the action of Bi(OAc)3 (entry 9). Indole 17
was susceptible to Ir-catalyzed deboronation, but again those
conditions proved too harsh, giving the N-Boc protected 6-
fluoroindole as the major product (21/79 25/16 in the crude
reaction mixture). The ratio of 25/16 improved to 60/40 (47%
isolated yield of 25) when the protodeboronation was run with
3 mol % Ir in MeOH/THF at room temperature for 10 h.
The reactivity difference between unprotected and N-Boc-
indoles was probed further. 4,7-Diborylated-6-fluoroindole 21
was converted to its Boc derivative (26) and then subjected to
both the Bi and Ir deboronation conditions (Scheme 4). Again,
there was no reaction by Bi(OAc)3. However, under the Ir-
catalyzed protodeboronation conditions, using CD3OD as the
protic material, afforded the C4 deuterated product 27 in 78%
yield. This result demonstrates that the general order of the first
boron “on” being the first boron “off” in Ir-catalyzed
deboronations can be altered subsequent to borylation by
introducing nearby functionality that is sterically demanding.
To demonstrate this chemistry in late-stage functionalization,
we applied the one-pot diborylation/deboronation sequence to
5-HT receptor agonist sumatriptan (28) (Scheme 5). Thus,
Scheme 5. Functionalization of Sumatriptan
indole 28 was thus converted to the 2,7-diborylated product.
Selective Bi(OAc)3 catalyzed deboronation of the crude
product was then achieved in 85% yield by quantitative
HPLC. However, the highly polar nature of 29 coupled with
the hydrolytic instability of the Bpin ester made purification a
challenge and the isolated yield of 29 was only 28%.
Questions on the mechanism of these deboronations remain.
Analysis of the crude reaction material showed a mixture of
boronates but no evidence of MeOBpin. The above examples
do point to an interaction with the indole nitrogen as being
important to achieving selectivity and gaining reactivity. Given
Movassaghi and co-workers’ Pd-catalyzed C2 protodeborona-
tion of indoles with HOAc as the proton source,6 we
questioned if HOAc, either residual in the Bi(OAc)3 or in
situ generated, was playing a part in our bismuth-catalyzed
protodeboronations. Toward this end, we examined the
reactivity of diborylated 10 with 0.6 equiv of HOAc, which
would correspond to the theoretical amount of acetic acid
available from 20 mol % of Bi(OAc)3 (Scheme 6). Under these
conditions no protodebornation was observed. Increasing the
amount of HOAc to 40 equiv had no affect as again only
starting 10 was observed after 5 h at 80 °C. The next set of
experiments was performed with Bi(OAc)3 that had been
washed with CCl4 until the washings showed no HOAc by
Scheme 6. Exploring the Potential Role of HOAc
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(2) Reck, F.; Zhou, F.; Eyermann, C. J.; Kern, G.; Carcanague, D.;
Ioannidis, G.; Illingworth, R.; Poon, G.; Gravestock, M. B. J. Med.
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M. R., III J. Am. Chem. Soc. 2013, 135, 7572−7582.
NMR. Somewhat surprisingly, HOAc free Bi(OAc)3 exhibited
enhanced reactivity, as washed Bi(OAc)3 afforded a 3:1 mixture
of 21 and 20 while the same reaction with unwashed Bi(OAc)3
gave no 20. While not quantified, it appears that adventitious
HOAc lowers the relative reactivity of the unwashed Bi(OAc)3,
perhaps by interfering with a putative Bi/indole nitrogen
interaction.
(4) (a) Vanchura, B. A., II; Preshlock, S. M.; Roosen, P. C.; Kallepalli,
V. A.; Staples, R. J.; Maleczka, R. E., Jr.; Singleton, D. A.; Smith, M. R.,
III Chem. Commun. 2010, 46, 7724−7726. (b) Tajuddin, H.;
Harrisson, P.; Bitterlich, B.; Collings, J. C.; Sim, N.; Batsanov, A. S.;
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Lin, Z.; Marder, T. B.; Steel, P. G. Chem. Sci. 2012, 3, 3505−3514.
(5) For representative examples, see: (a) Takagi, J.; Sato, K.; Hartwig,
J. F.; Ishiyama, T.; Miyaura, N. Tetrahedron Lett. 2002, 43, 5649−5651.
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5798−5800.
In conclusion, bismuth(III) acetate is a safe, shelf stable,
inexpensive, and operationally simple alternative to Ir and Pd
for the catalytic protodeboronations of indoles. Where as the
conditions for deboronations with Ir8 and Pd6 call for an inert
atmosphere, Bi(III)-catalyzed deboronations can be run under
air. Furthermore, while reaction times are dependent on the
grade of methanol employed, solvents need not be distilled or
degassed. In general, sequential deboronations with Bi(OAc)3
occur in the same order in which the Bpin groups are installed
via Ir-catalyzed borylation. Relative to related methods,
Bi(OAc)3 tends to offer greater selectivity in protodeborona-
tions of di- and triborylated indoles. Thus, by tuning the C−H
borylation and deboronation conditions, one can access a
variety of boron substitution patterns from a single starting
indole.
(6) Loach, R. P.; Fenton, O. S.; Amaike, K.; Siegel, D. S.; Ozkal, E.;
Movassaghi, M. J. Org. Chem. 2014, 79, 11254−11263.
(7) For a recent selective synthesis of a monoborylated indazole by
selective deborylation of a diborylated indazole using KOH, see:
Sadler, S. A.; Hones, A. C.; Roberts, B.; Blakemore, D.; Marder, T. B.;
Steel, P. G. J. Org. Chem. 2015, 80, 5308−5314.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00356.
■
S
(8) Kallepalli, V. A.; Gore, K. A.; Shi, F.; Sanchez, L.; Chotana, G. A.;
Miller, S. L.; Maleczka, R. E., Jr.; Smith, M. R., III J. Org. Chem. 2015,
80, 8341−8353.
Experimental details and product characterization data
(PDF)
(9) Procedure adapted from Navath, R. S.; Pabbisetty, K. B.; Hu, L.
Tetrahedron Lett. 2006, 47, 389−393.
(10) Mohan, R. Nat. Chem. 2010, 2, 336.
(11) Details of the screening studies will be presented elsewhere.
(12) Indole and 6-fluoroindole can be triborylated directly, but the
overall yields and combined catalyst loads are better if 6 and 9 are
isolated and then converted to 7 and 10.22
AUTHOR INFORMATION
Corresponding Authors
■
*P.E.M.: tel, 732-594-7856; E-mail, peter_maligres@merck.
com.
*M.R.S.: tel, 517-353-1071; E-mail, smithmil@msu.edu.
*R.E.M.: tel, 517-353-0834; E-mail, maleczka@chemistry.msu.
edu.
(13) For a report of other Ir-catalyzed trisborylations, see:
Eastabrook, A. S.; Sperry, J. Aust. J. Chem. 2015, 68, 1810−1814.
(14) Kallepalli, V. A.; Shi, F.; Paul, S.; Onyeozili, E. N.; Maleczka, R.
E., Jr.; Smith, M. R., III J. Org. Chem. 2009, 74, 9199−9201.
(15) Preshlock, S. M.; Plattner, D. L.; Maligres, P. E.; Krska, S. W.;
Maleczka, R. E., Jr.; Smith, M. R., III Angew. Chem., Int. Ed. 2013, 52,
12915−12919.
Author Contributions
The manuscript was written through contributions of all
authors. All authors approved the final version of this
manuscript.
(16) For the 3,5-diborylation of 7-azaindole, see ref 8.
(17) Ir-catalyzed borylation of 3-borylated-N-Boc-indole afforded an
∼1:1 mixture of 3,5- and 3,6-bisborylated-N-Boc-indole.
(18) For a selective Ir-catalyzed C−H borylation of a fully protected
tryptophan and N-TIPS protected indoles, see: Feng, Y.; Holte, D.;
Zoller, J.; Umemiya, S.; Simke, L. R.; Baran, P. S. J. Am. Chem. Soc.
2015, 137, 10160−10163.
Notes
The authors declare the following competing financial
interest(s): MRS and REM acknowledge financial interest in
BoroPharm, Inc..
(19) 10% Deuterium incorporation was initially observed at C3.
Washing with H2O reprotonated this carbon.
ACKNOWLEDGMENTS
(20) The percent deuterium incorporation was determined by
integration of the H NMR spectrum.
■
1
We thank the NIH (GM63188), NSF (GOALI-1012883),
Merck, and the ACS/GCI Pharmaceutical Roundtable for
financial support, BoroPharm, Inc., for supplying B2pin2, and
Judy Morris (Merck) for assistance with preparative separations
of Sumatriptan derivatives. A Thomas J. Pinnavaia Fellowship
supported F.S. LRMS data were obtained from MSU’s
Molecular Metabolism and Disease Collaborative Mass
Spectrometry Core facility.
(21) We suspect the protodeboronations are slowed by materials
leaching from the plastic bottle and/or common MeOH impurities
such as formaldehyde, DMAc, and dimethyl acetals of simple
alkanones and/or alkanals: Guella, G.; Ascenzi, D.; Franceschi, P.;
Tosi, P. Rapid Commun. Mass Spectrom. 2007, 21, 3337−3344.
(22) See Supporting Information for details.
REFERENCES
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