Palladium-Catalyzed Regioselective Hydrodebromination of Dibromoindoles: Application to the Enantioselective Synthesis of Indolodioxane U86192A

Article abstract of DOI:10.1021/jo035819k

A novel approach to the selective preparation of 4-bromoindoles was developed via Pd(OAc)₂/rac-BINAP catalytic reactions. A variety of 4,6-dibromoindoles were transformed to 4-bromoindoles with high regioselectivity. This methodology, along wit

Full text of DOI:10.1021/jo035819k

P a lla d iu m -Ca ta lyzed Regioselective Hyd r od ebr om in a tion of
Dibr om oin d oles: Ap p lica tion to th e En a n tioselective Syn th esis of
In d olod ioxa n e U86192A
J unghyun Chae and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139
sbuchwal@mit.edu
Received December 15, 2003
A novel approach to the selective preparation of 4-bromoindoles was developed via Pd(OAc)2/rac-
BINAP catalytic reactions. A variety of 4,6-dibromoindoles were transformed to 4-bromoindoles
with high regioselectivity. This methodology, along with C-N and C-O bond-forming reactions
developed in our laboratory, was applied to the enantioselective synthesis of indolodioxane U86192A,
an antihypertensive agent.
SCHEME 1
The Fischer indole synthesis has been one of the most
versatile methods for the preparation of indoles for over
100 years, and its variations have continually improved
on its drawbacks.1 However, preparation of 4- or 6-sub-
stituted or 4,5-disubstituted indoles, which appear in an
important class of alkaloids,2 via the Fischer synthesis
is still a significant challenge due to the regiochemical
ambiguity occurring during the [3,3]-sigmatropic rear-
rangement, an integral step in this process.1a,b A variety
of traditional3-6 and palladium-catalyzed methods7-10
have been developed to construct the pyrrole ring using
an annelative method from properly substituted aromatic
precursors. These methods have the disadvantage in that
they require specifically polyfunctionalized benzenes,
which are often difficult or expensive to make.
SCHEME 2. Retr osyn th etic An a lysis for th e
Syn th esis of In d olod ioxa n e U86192A
The conceptual outline for our approach is outlined in
Scheme 1. It involves the synthesis of intermediate A,
(1) (a) Robinson, B. The Fischer Indole Synthesis; J ohn Wiley and
Sons: Chichester, 1982. (b) Hughes, D. L. Org. Prep. Proced. Int. 1993,
25, 609. (c) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J . Am. Chem.
Soc. 1999, 121, 10251.
(2) (a) Raffauf, R. F.A Handbook of Alkaloids and Alkaloid-contain-
ing Plants; Wiley-Interscience: New York, 1970. (b) Rahman, A. Indole
Alkaloids; Harwood Academic Publisher: Amsterdam, 1998. (c) Man-
ske, R. H. F.; Holmes, H. L. The Alkaloids: The Ergot Alkaloids;
Academic Press: New York, 1965; Vol. 8, p 725.
(3) For reviews on indole syntheses, see: (a) Gribble, G. W. J . Chem.
Soc., Perkin Trans. 1 2000, 1045. (b) Sundberg, R. J . Indoles; Academic
Press: San Diego, 1996.
(4) (a) Madelung, W. Chem. Ber. 1912, 45, 1128. (b) Houlihan, W.
J .; Parrino, V. A.; Uike, Y. J . Org. Chem. 1981, 46, 4511. (c) Wacker,
D. A.; Kasireddy, P. Tetrahedron Lett. 2002, 43, 5189.
(5) (a) Reissert, A. Chem. Ber. 1897, 30, 1030. (b) Izumi, T.; Soutome,
M.; Miura, T. J . Heterocycl. Chem. 1992, 29, 1625. (c) Butin, A. V.;
Stroganova, T. A.; Lodina, I. V.; Krapivin, G. D. Tetrahedron Lett. 2001,
42, 2031.
(6) (a) Leimgruber, W.; Batcho, A. D. Org. Synth. 1985, 63, 214 (c)
Clark, R. D.; Repke, D. B. Heterocycles 1984, 22, 195.
(7) For reviews on metal-catalyzed indole synthesis, see: (a) Hege-
dus, L. S. Angew. Chem., Int. Ed. 1988. 27, 1113. (b) Larock, R. C. J .
Organomet. Chem. 1999, 576. 111. (c) ref. (3).
in which the substituents at C-4 and C-6 are identical.
To access, in a selective manner, B and/or C, regioselec-
tive transformations that proceed with high selectivity
must be developed. Herein, we describe our first realiza-
tion of this approach that is a highly selective route to
4-bromo-5-substituted indoles.12 In addition, we use the
method, in combination with other processes recently
developed in our laboratory, as the keystones of an
asymmetric synthesis of indolodioxane U86192A (Scheme
2, 1), a compound with interesting antihypertensive
activity.20
Resu lts a n d Discu ssion
(8) (a) Hegedus, L. S.; Allen, G. F.; Waterman, E. L. J . Am. Chem.
Soc. 1976, 98, 2674. (b) Hegedus, L. S.; Allen, G. F.; Bozell, J . J .;
Waterman, E. L. J . Am. Chem. Soc. 1978, 100, 5800. (c) Hegedus, L.
S.; Allen, G. F.; Olsen, D. J . J . Am. Chem. Soc. 1980, 102, 3583.
(9) (a) Larock, R. C.; Yum, E. K. J . Am. Chem. Soc. 1991, 113, 6689.
(b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J . Org. Chem. 1998, 63,
7652.
P a lla d iu m -Ca t a lyzed R egioselect ive H yd r od e-
br om in a tion of Dibr om oin d oles. As a prototypical
example of A, we prepared a series of 4,6-dibromoindoles
in a one-pot process via the chemoselective (I vs Br) Cu-
catalyzed coupling of symmetric dibromoaryliodides and
(10) Soderberg, B. C.; Schriver, J . A. J . Org. Chem. 1997, 62, 5838.
10.1021/jo035819k CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/20/2004
3336
J . Org. Chem. 2004, 69, 3336-3339

Pd-Catalyzed Debromination and Synthesis of Indolodioxane U86192A
TABLE 1. On e-P ot P r ep a r a tion of 4,6-Dibr om oin d olesa
TABLE 2. Regioselective Hyd r od ebr om in a tion of
4,6-Dibr om oin d oles
a
Reaction conditions: Cu-catalyzed couplings; 1.0 equiv of
dibromoaryl iodide, 1.2 equiv of tert-butylcarbazate, 5 mol % of
CuI, 1.4 equiv of Cs2CO3, and DMF (4 mL/mmol of dibromoaryl
iodide). Fischer indole cyclization: (A) 1.0 equiv of ketone, 1.6 equiv
of p-TsOH‚H2O, EtOH, 90 °C or (B) 1.5 equiv of ketone, 2 mL of
a
Reaction conditions: 1.0 equiv of 4,6-dibromoindole, 5 mol %
b
Eaton’s reagent, CH2Cl2,16 45 °C. Isolated yields for two steps
of Pd(OAc)2, 5.5 mol % of rac-BINAP, 1.5 equiv of TMEDA, 1.0-
1.05 equiv of NaBH4 (1.0 M solution in diglyme), THF. Isolated
b
(average of two runs) of compounds estimated to be >95% pure
as determined by 1H NMR and combustion analysis. c For the
cyclization to the indole, method B was used.
yields (average of two runs) of compounds estimated to be >95%
pure as determined by 1H NMR and combustion analysis.
tert-butylcarbazate,13 followed by Fischer indolization
(Table 1). As can be seen from the results presented in
Table 1, a variety of polysubstituted 4,6-dibromo-5-
substituted indoles can be produced. The method em-
ployed, which utilizes a variation of that described in our
prior report,14 provides easy access to aryl hydrazines
generated in situ without the need for the preparation
and isolation in a separate step.15
of doubly debrominated products, which were easily
separable by chromatography, were formed. The selectiv-
ity of the reduction process appears to be largely con-
trolled by steric factors. Electronic effects, however, also
seem to play a role in the observed regioselectivity. For
example, while the lack of a substituent at C-3 renders
the bromide at C-4 less sterically differentiated from that
at C-6, an electron-withdrawing group at C-2 (entries 5
and 8) compensates and a high level regioselectivity is
seen.
Ap p lica tion to th e En a n tioselective Syn th esis of
In d olod ioxa n e U86192A. As an application of this
methodology, a concise route to indolodioxane U86192A
(1) has been developed. U86192A is a potent antihyper-
tensive agent among the derivatives of the nonnatural
hybrid of three 5-HT1A receptor binding molecules: 5-hy-
droxytryptamine, spiroxatrine, and pindolol.20 We envi-
sioned forming the dioxolane ring of 1 using Pd-catalyzed
C-O bond-forming methodology developed in our group
(Scheme 2).21 Using this process, a key intermediate (2),
With 4,6-dibromoindoles in hand, we decided to exam-
ine their regioselective hydrodebromination.17 Our pre-
liminary attempts, utilizing ammonium formate and Pd/
C, a widely used dehalogenation protocol,18 revealed that
initial hydrodebromination was occurring at C-6. How-
ever, the first formed 4-bromoindoles (B) reacted faster
than A. To find a means to overcome this problem, we
screened various catalytic systems to discover one that
would effect selective debromination. This included many
Pd-catalyzed reduction systems with phosphine ligands
including PPh3, DPPE, DPPF, Xantphos, and BINAP,
along with several stoichiometric reductants. After some
experimentation, we found that selective debromination
could be effected using catalytic Pd(OAc)2/rac-BINAP and
NaBH4 as the stoichiometric reductant in the presence
of TMEDA as a base.19 These reaction conditions were
then applied to the dibromoindoles (Table 2) that we had
prepared. Dibromoindoles with no substituent at C-5
(entries 1 and 2) were reduced with no regioselectivity.
A mixture of the two regioisomeric bromides (∼1:1) with
25-35% of the doubly debrominated indoles was ob-
served. On the other hand, substrates with C-5 substit-
uents (entries 3-10) were transformed with high regi-
oselectivity to 4-bromoindoles B. In these cases, 3-10%
(11) Another approach to prepare 4-substituted indoles involves the
direct introduction of a substituent at 4-position via thallation/
palladation or lithiation. Both are limited to indoles with specific
directing functional groups at the 3-position, however, and use of toxic
metals such as thallium detracts from the synthetic utility. Thallation/
palladation: (a) Somei, M.; Amari, H.; Makita, Y. Chem. Pharm. Bull.
J pn. 1986, 34, 3971. (b) Somei, M.; Ewasa, E.; Yamada, F. Heterocycles
1986, 24, 3065. Lithiation: (a) Iwao, M. Heterocycles 1993, 36, 29. (b)
Chauder, B.; Larkin, A.; Snieckus, V. Org. Lett. 2002, 4, 815.
(12) After the methodological portion of this work was complete, two
papers that describe the preparation of 4,7- or 5,7-disubstituted indoles
from 4,7- or 5,7-dibromoindoles via
exchange reaction appeared. (a) Li, L.; Martins, A. Tetrahedron Lett.
2003, 44, 689. (b) Li, L.; Martins, A. Tetrahedron Lett. 2003, 44, 5987.
a selective lithium-bromine
J . Org. Chem, Vol. 69, No. 10, 2004 3337

Chae and Buchwald
SCHEME 3. Syn th esis of In d olod ioxa n e U86192A
(I)
SCHEME 4. Syn th esis of In d olod ioxa n e U86192A
(II)
which has previously been converted to (()-1, should be
accessible from 3. Compound 3, in turn, would derive
from 4 (R ) H) via alkylation of the phenol with an (S)-
glycidol equivalent. The bromide 4 would arise from
selective reduction of dibromide 5. Intermediate 5, in
turn, would derive from the components shown via the
Fischer indolization method described earlier.
Our initial approach to 1 is shown in Scheme 3.
Beginning with 2,6-dibromophenol, allyl ether 7 was
prepared via conventional chemistry. The Cu-catalyzed
formation of the N-aryl N-Boc hydrazide proceeded to
give 8 in 70% yield. This was then used in the Fischer
protocol; in this instance, condensation of 8 with methyl
pyruvate was carried out under acidic conditions. The
crude hydrazone intermediate, after drying under vacuum,
was treated with Eaton’s reagent (P2O5 in methane-
sulfonic acid) to give indole (9) in 71% yield (two steps).
This was then subjected to Sharpless asymmetric dihy-
droxylation,22 and the results are as shown. The best
compromise between isolated yield and enantioselectivity
was found using 10 mol % (DHQD)2PYR and 1 mol %
(13) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3,
3803.
(14) (a) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J . Am. Chem. Soc.
1998, 120, 6621. (b) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J . Am.
Chem. Soc. 1999, 121, 10251.
(15) Aryl hydrazines are toxic, corrosive, and prone to redox
chemistry as well as radical decomposition, complicating the prepara-
tion, storage, and use of these compounds; see: Smith, P. A. S.
Derivatives of Hydrazine and the Hydronitrogens Having N-N Bonds,
2nd ed.; The Benjamin/Cummings Publishing Co.: Reading, MA, 1983.
(16) Zhao, D.; Hughes, D. L.; Bender D. R.; DeMarco, A. M.; Reider,
P. J . J . Org. Chem. 1991, 56, 3001.
t
K2OsO2(OH)4 in BuOH/H2O for 3 days at 4 °C. In this
way, an 88% yield of diol 10 (78% ee) was isolated.
Conversion of the diol 10 to the acetonide followed by
regioselective reduction produced 12 in 85% overall yield.
Deprotection of 12 produced an intermediate diol that
(17) For regioselective catalytic monodehalogenation of dihaloarenes,
see: (a) Page, P. C. B.; Hussain, F.; Bonham, N. M.; Morgan P.; Maggs,
J . L.; Park, B. K. Tetrahedron, 1991, 47, 2871. (b) Xie, Y.; Ng, S.; Hor,
T. S.; Chan, H. S. O. J . Chem. Res., Synop. 1996, 150.
(18) Cortese, N. A.; Heck, R. F. J . Org. Chem. 1977, 42, 3491.
(19) Wei, B.; Hor, T. S. J . Mol. Catal. A 1998, 132, 223.
(20) Ennis, M. D.; Baze, M. E.; Smith, M. W.; Lawson, C. F.; McCall,
R. B.; Lahti, R. A.; Piercey, M. F. J . Med. Chem. 1992, 35, 3058.
(21) Kuwabe, S.; Torraca, K. E.; Buchwald, S. L. J . Am. Chem. Soc.
2001, 123, 12202.
(22) (a) Crispino, G. A.; J eong, K,; Kolb, H. C.; Wang, Z.; Xu, D.;
Sharpless, K. B. J . Org. Chem. 1993, 58, 3785. (b) Becker, H.;
Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 448.
3338 J . Org. Chem., Vol. 69, No. 10, 2004

Pd-Catalyzed Debromination and Synthesis of Indolodioxane U86192A
commercial sources and used without further purification. A
could be converted to (2) using our previously reported
method for intramolecular C-O bond formation.21
detailed description is given in the Supporting Information.
Gen er a l P r oced u r e for On e-P ot P r ep a r a tion of 4,6-
Dibr om oin d oles (Ta ble 1). An oven-dried resealable Schlenk
tube was charged with dibromoaryl iodide (1.00 mmol), tert-
butylcarbazate (158 mg, 1.20 mmol), CuI (14.3 mg, 9.50 mmol),
and Cs2CO3 (455 mg, 1.40 mmol). The Schlenk tube was
evacuated and backfilled with Ar. Anhydrous DMF (4 mL) was
added, and the reaction mixture was stirred at room temper-
ature for 10 min and heated at 80 °C (preheated oil bath) until
the dibromoaryl iodide was consumed as determined by GC
analysis. The reaction mixture was allowed to cool to room
temperature and diluted with ether (∼20 mL) and water (∼40
mL). The aqueous phase was extracted with ether (∼20 mL ×
2), and the combined ethereal layers were washed with water
and brine and dried over Na2SO4. The solvent was removed
in vacuo, and the crude aryl hydrazide was used directly for
the Fischer indole cyclization without purification. The crude
aryl hydrazide, ketone (1.00 mmol), and p-TsOH‚H2O (304 mg,
1.60 mmol)27 were dissolved in EtOH (8 mL), and the solution
was stirred at 100 °C (preheated oil bath) until the aryl
hydrazide was consumed as determined by TLC analysis. After
the reaction mixture was allowed to cool to room temperature,
EtOH was removed under vacuum. The reaction mixture was
diluted with EtOAc (∼ 30 mL) and neutralized with saturated
NaHCO3 solution. The aqueous phase was extracted with
EtOAc (∼25 mL × 2), and the combined organic layers were
washed with water and brine, dried over Na2SO4, and con-
centrated under vacuum. Purification of the crude product by
column chromatography afforded the analytically pure indole
product.
Gen er a l P r oced u r e for Regioselective Hyd r od ebr o-
m in a tion of 4,6-Dibr om oin d oles (Ta ble 2). An oven-dried
Schlenk tube was charged with 4,6-dibromoindole (0.500
mmol), Pd(OAc)2 (5.60 mg, 0.0250 mmol), and rac-BINAP (17.0
mg, 0.028 mmol). The Schlenk tube was evacuated and
backfilled with Ar, and anhydrous THF (1 mL) was added. The
reaction mixture was stirred for 20 min at room temperature.
TMEDA (113 µL, 0.750 mmol) and additional THF (1 mL) were
added, and the reaction mixture was stirred for 20 min at room
temperature. NaBH4 (0.5 M solution in diglyme, 1.05 mL,
0.525 mmol) was slowly added, and the reaction mixture was
stirred at room temperature or 50 °C (preheated oil bath) for
24 h. After the reaction mixture was allowed to cool to room
temperature, it was diluted with EtOAc (∼2 mL). The resulting
heterogeneous mixture was then filtered through a pad of silica
gel eluting with EtOAc. The filtrate was concentrated, and
purification of the concentrated filtrate by column chromatog-
raphy afforded the desired product.
While we were pleased at having demonstrated that a
route that combined both C-N and C-O bond-forming
processes with our preparation of 4,5-disubstituted in-
doles could be used to access 1, we were disappointed
with the level of enantioselectivity that was realized in
the Sharpless asymmetric dihydroxylation step. Thus, we
embarked on a second, related route, to 1. As shown in
Scheme 4, the initial steps of this second synthetic path
were similar to that of the first one, save that a methoxy
group at 5-position was used instead of an allyloxy. In
this way, 15, the analogue of 9 was prepared. Its selective
debromination followed by demethylation produced bro-
mophenol 17. This set the stage for the key stereochem-
ical process in the synthesis. J acobsen’s phenolic kinetic
resolution (PKR) was utilized with 17 and racemic
glycidol TBS ether. Previous incarnations of PKR could
not handle bromophenol substrates.23a Fortunately, a
second generation oligomeric cobalt salen catalyst (20)
was recently developed by J acobsen’s group.23c Applica-
tion of 20 provided a 73% yield of the differentially
protected diol 18 that had an ee of >99%.24 Application
of our C-O bond-forming procedure21 followed by removal
of the TBS group produced (S)-2 in 73% yield. While (()-2
had previously been converted to (()-1, the transforma-
tion occurred in modest yield.20 We chose to utilize a
Mitsunobu reaction which, after removal of the protecting
group on nitrogen using Fukuyama conditions,25 gave
(S)-1 in 88% yield. The overall yield for our synthesis of
(S)-1 was 12.5%,26 which compares favorably to the
previous synthesis that gave (()-1 in 10.7% overall yield.
Con clu sion
In summary, we have developed a novel approach to
the selective preparation of 4-substituted indoles. The
method, a variation of the Fischer indole synthesis,
allows for the preparation of a variety of 2,3,4,5-
substituted indoles from aryl halides. The method should
be applicable with a number of different functional
groups X (Scheme 1) and for a number of different
transformations. We have applied this process along with
C-N and C-O bond-forming reactions developed in our
laboratory for an enantioselective synthesis of (S)-
U86192A.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM58160) for funding as well as Pfizer,
Merck, and Bristol-Myers Squibb for additional support.
We thank Professor Eric J acobsen and Mr. David White
(Harvard University) for kindly providing 19 as well as
for helpful discussions. We are grateful to Professor Rick
Danheiser for suggesting the Mitsunobu/Fukuyama
deprotection strategy and Dr. Alex Muci for help with
the manuscript.
Exp er im en ta l Section
All nonaqueous reactions were run in oven-dried glassware
under an argon atmosphere unless otherwise stated. Yields
reported in Table 1 and 2 are isolated and an average of two
independent runs. The Co-Salen oligomer (19) was obtained
from Professor Eric N. J acobsen and Mr. David White (Har-
vard University). All other reagents were purchased from
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedures and characterization of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(23) (a) Ready, J . M.; J acobsen, E. N. J . Am. Chem. Soc. 1999, 121,
6086. (b) Ready, J . M.; J acobsen, E. N. J . Am. Chem. Soc. 2001, 121,
2687. (c) White, D.; J acobsen, E. N. Tetrahedron: Asymmetry, in press.
(24) The absolute chemistry of 18 was assigned by the analogy to
those in ref 22.
J O035819K
(25) Fukuyama, T.; Cheung, M.; J ow, C.; Hidai, Y.; Kan, T.
Tetrahedron Lett. 1997, 38, 5831.
(26) Spectroscopic data for 1 were consistent with that previously
reported in ref 19.
(27) When ethyl pyruvate was used as a ketone component (Table
1, entry 5 and 7), Eaton’s reagent was used in place of p-TsOH‚H2O.
See the Supporting Information for details.
J . Org. Chem, Vol. 69, No. 10, 2004 3339