Arylboronic acids and arylpinacolboronate esters in suzuki coupling reactions involving indoles. Partner role swapping and heterocycle protection

Article abstract of DOI:10.1021/jo0491612

Yields of Suzuki couplings involving indoles depended upon (i) whether arylboronic acids or arylpinacolboronate esters were used, (ii) whether the heterocycle was the aryl halide or the arylboron coupling partner, and (iii) whether the heterocycle was protected or not. Highest yields, which were unaffected by incorporating Boc or Tos protection at the heterocyclic nitrogen, were obtained when indole bromides were reacted with phenylboronic acids. When indolylboronic acids were reacted with phenyl bromides, yields were somewhat lower and depended on the nitrogen substituent, being highest in the absence of protection, lower in the presence of the Boc group, and lowest of all with the Tos group. Arylpinacolboronate esters were less reactive than arylboronic acids. They required considerably longer reaction times and furnished generally lower yields of biaryl. Furthermore, irrespective of whether the heterocycle was the aryl bromide or the arylpinacolboronate ester, these yields were highest when it was protected with the Tos group. Yields were lower with the Boc group, and unprotected heterocycles gave only traces of biaryl. Careful selection of arylboron reagent, of coupling partner roles, and of protecting groups are essential to ensuring optimum results in these Suzuki couplings. These results may also be relevant to couplings involving other substrates.

Full text of DOI:10.1021/jo0491612

Ar ylbor on ic Acid s a n d Ar ylp in a colbor on a te Ester s in Su zu k i
Cou p lin g Rea ction s In volvin g In d oles. P a r tn er Role Sw a p p in g a n d
Heter ocycle P r otection
Mo`nica Prieto,† Esther Zurita,† Esmeralda Rosa,† Lourdes Mun˜oz,†
Paul Lloyd-Williams,*,† and Ernest Giralt*,†,‡
Department of Organic Chemistry, Universitat de Barcelona, Mart´ı i Franque`s, 1-11,
Barcelona E-08028, Spain, and IRBBsParc Cientı´fic de Barcelona, J osep Samitier 1,
E-08028 Barcelona, Spain
lloydwilliams@ub.edu
Received May 18, 2004
Yields of Suzuki couplings involving indoles depended upon (i) whether arylboronic acids or
arylpinacolboronate esters were used, (ii) whether the heterocycle was the aryl halide or the
arylboron coupling partner, and (iii) whether the heterocycle was protected or not. Highest yields,
which were unaffected by incorporating Boc or Tos protection at the heterocyclic nitrogen, were
obtained when indole bromides were reacted with phenylboronic acids. When indolylboronic acids
were reacted with phenyl bromides, yields were somewhat lower and depended on the nitrogen
substituent, being highest in the absence of protection, lower in the presence of the Boc group, and
lowest of all with the Tos group. Arylpinacolboronate esters were less reactive than arylboronic
acids. They required considerably longer reaction times and furnished generally lower yields of
biaryl. Furthermore, irrespective of whether the heterocycle was the aryl bromide or the
arylpinacolboronate ester, these yields were highest when it was protected with the Tos group.
Yields were lower with the Boc group, and unprotected heterocycles gave only traces of biaryl.
Careful selection of arylboron reagent, of coupling partner roles, and of protecting groups are
essential to ensuring optimum results in these Suzuki couplings. These results may also be relevant
to couplings involving other substrates.
In tr od u ction
steps have all been reported to be rate-determining in
certain cases. Nonetheless, there is broad consensus that
the main stages involved are those shown in Scheme 1.
Extensive investigation has allowed the performance
of different palladium salts, ligands, bases and solvent
systems to be evaluated and optimized.3-6,15 Neverthe-
less, the reaction is still not fully understood and much
remains to be clarified. Although both arylboronic acids
and arylboronate esters can be used as reagents, no
systematic comparative study of their performance has,
to our knowledge, been reported. This is surprising since
we have found that the choice of arylboron reagent may
profoundly affect the outcome of a given coupling reac-
tion, particularly since it usually determines the selection
of other key reaction parameters such as solvent, base,
and palladium(0) source. In contemporary practice, Su-
zuki couplings often employ widely differing reaction
chemistries depending upon whether arylboronic acids
or arylboronate esters are used as reagents. The decision
of which to adopt may be crucial to success.
The Suzuki coupling reaction1-6 has, over the past
decade or so, established itself as a powerful method for
the formation of carbon-carbon bonds, especially those
involving sp2-hybridized centers. It has, consequently,
been widely applied in the formation of biaryl compounds
where it usually involves the Pd(0)-mediated linking of
an aryl halide with an arylboronic acid or arylboronate
ester. The mechanism by which it proceeds is known to
be complex in its details,7-10 and the oxidative addi-
tion,2,6,11 transmetalation,12,13 and reductive elimination14
* Corresponding authors.
† Universitat de Barcelona.
‡ IRBBsParc Cient´ıfic de Barcelona.
(1) Lloyd-Williams, P.; Giralt, E. Chem. Soc. Rev. 2001, 30, 145.
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Chem. Rev. 2002, 102, 1359.
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61, 2346.
All other factors being equal, best results are usually
obtained when the aryl halide coupling partner is electron-
deficient and the arylboron partner electron-rich, a
situation that favors oxidative addition and transmeta-
(11) Fitton, P.; Rick, E. A. J . Organomet. Chem. 1971, 28, 287.
(12) Badone, D.; Baroni, M.; Cardamone, R.; Ielmini, A.; Guzzi, U.
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10.1021/jo0491612 CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/31/2004
6812
J . Org. Chem. 2004, 69, 6812-6820

Arylboronic Acids and Arylpinacolboronate Esters
SCHEME 1
in comparing the performances of arylboronic acids and
pinacol-derived arylboronate esters.
(2) Swapping the partner roles, such that couplings in
which the heterocycle functioned as the aryl halide might
be compared with those in which it functioned as the
arylboron derivative.
(3) Protection at the heterocyclic nitrogen atom, which
also provides a means whereby the consequences of
modulation of the electronic character of the heterocycle
may be explored. In particular, we wished to compare
the behavior of substrates lacking protection at this atom
with those in which it was afforded by the Boc or the
Tos group,31-33 both commonly used in peptide synthesis
involving tryptophan.34
To investigate these issues we carried out four series
of Suzuki couplings using the following combinations of
partners: (i) indole bromides and phenylboronic acids,
(ii) indolylboronic acids and phenyl bromides, (iii) indole
bromides and phenylpinacolboronate esters, and (iv)
indolylpinacolboronate esters and phenyl bromides (see
Scheme 2). Here we report the results of this study, which
supplement and extend earlier work in this area and
which may have a wider relevance to couplings involving
other substrates.
lation, respectively.6 However, with complex, polyfunc-
tionalized substrates it may not always be easy to judge
which ring should be which component. Alternatively,
tactical considerations may require that a particular
coupling reaction be carried out with the coupling partner
roles inverted or swapped with respect to those that are
a priori desirable. The outcome of a given coupling may
be significantly affected by the assignment of partner
roles.
The indole ring is a key substructure in both organic
and medicinal chemistry,16,17 and a number of studies
document its arylation as a starting-point for further
elaboration.18-26 We were interested in carrying out
Suzuki couplings between 5-, 6- and 7-substituted
indole27-30 derivatives 1 and simple phenyl compounds
2 (see Scheme 2) with a view toward optimizing reaction
conditions and yields. Although isolated examples of
similar Suzuki couplings have been reported,24-26 we
wished to carry out a more extensive and systematic
study that would allow us to evaluate the effect on biaryl
coupling yields of:
Resu lts a n d Discu ssion
All Suzuki chemistry was carried out using aryl
bromides since they are inexpensive and easily prepared.
They are somewhat less reactive than the more expensive
aryl iodides but considerably more reactive than the
corresponding aryl chlorides. A given series of couplings
was carried out under similar reaction conditions with
regard to stoichiometry, catalyst batch, solvent composi-
tion, concentration, reaction time, and temperature. For
the series employing arylboronic acids, Pd(Ph3P)4 was
used as the catalyst, Na2CO3 as the base, and a mixture
of toluene-EtOH-H2O as the solvent. For the series
employing arylboronate esters, PdCl2(dppf) was used as
the Pd(0) source, K3PO4 as the base, and 1,4-dioxane as
the solvent. These conditions reflect typical current
practice for these chemistries. Each reaction was per-
formed at least twice and repeated as necessary to
establish yield reproducibility.
(1) The use of arylboronate esters as an alternative to
arylboronic acids. More specifically, we were interested
1. Su zu k i Cou p lin gs Usin g Ar ylbor on ic Acid s: (a )
Rea ction s of In d ole Br om id es w ith P h en ylbor on ic
Acid s. Couplings between indole bromides (1a -g, X1 )
5-, 6-, or 7-Br, R1 ) H, Boc, or Tos) and commercially
available substituted phenylboronic acids [2a -d , X2 )
B(OH)2, R2 ) 4-Me, 4-OMe, 2-Me, or 2-OMe] all occurred
in good to excellent yield (66-99%) (Table 1, entries
1-20). Although this range is perhaps wider than
anticipated, and possibly indicates a certain degree of
irreproducibility in the chemistry, certain general trends
can, nevertheless, still be discerned. First, as might be
expected, the position of the bromine atom in the indoles
(16) Brase, S.; Gil, C.; Knepper, K. Bioorg. Med. Chem. 2003, 10,
2415.
(17) Gribble, G. W. Pure Appl. Chem. 2003, 75, 1417.
(18) Zhang, H. C.; Ye, H.; White, K. B.; Maryanoff, B. E. Tetrahedron
Lett. 2001, 42, 4751.
(19) Tois, J .; Franzen, R.; Aitio, O.; Laakso, I.; Huuskonen, J .;
Taskinen, J . Comb. Chem. High Throughput Screen. 2001, 4, 521.
(20) Liu, Y. B.; Gribble, G. W. Tetrahedron Lett. 2000, 41, 8717.
(21) Roussi, G.; Zamora, E. G.; Carbonnelle, A.-C.; Beugelmans, R.
Heterocycles 1999, 51, 2041.
(22) J ohnson, C. R. Synlett 1998, 1025.
(23) Malapel-Andrieu, B.; Me´rour, J .-Y. Tetrahedron 1998, 54,
11079.
(24) Carbonelle, A.-C.; Zamora, E. G.; Beugelmans, R.; Roussi, G.
Tetrahedron Lett. 1998, 39, 4467.
(25) Carrera, G. M.; Sheppard, G. S. Synlett 1994, 93.
(26) Yang, Y.; Martin, A. R. Heterocycles 1992, 34, 1395.
(27) Moyer, M. P.; Shiurba, J . F.; Rapoport, H. J . Org. Chem. 1986,
51, 5106.
(28) Ayer, W. A.; Craw, P. A.; Ma, Y.-T.; Miao, S. Tetrahedron 1992,
48, 2919.
(29) Rinehart, K. L.; Kobayashi, J .; Harbour, G. C.; Gilmore, J .;
Mascal, M.; Holt, T. G.; Shield, L. S.; Lafargue, F. J . Am. Chem. Soc.
1987, 109, 3378.
(31) Grehn, L.; Ragnarsson, U. Angew. Chem., Int. Ed. Engl. 1984,
23, 296.
(32) Gribble, G. W.; Saulnier, M. G.; Obaza-Nutaitis, J . A.; Ketcha,
D. M. J . Org. Chem. 1992, 57, 5891.
(33) Busacca, C. A.; J ohnson, R. E.; Swestock, J . J . Org. Chem. 1993,
58, 3299.
(34) Lloyd-Williams, P.; Albericio, F.; Giralt, E. Chemical Approaches
to the Synthesis of Peptides and Proteins; CRC Press: Boca Raton, FL,
1997.
(30) Anderson, J . A.; Kohler, R. D. Synthesis 1974, 277.
J . Org. Chem, Vol. 69, No. 20, 2004 6813

Prieto et al.
SCHEME 2
TABLE 1. Su zu k i Cou p lin gs betw een In d oles a n d P h en yl Der iva tives Usin g Ar ylbor on ic Acid s
entry
aryl bromide
arylboronic acid
biaryl yielda (%)
1
2
3
4
5
6
7
8
9
1a , X1 ) 5-Br, R1 ) H
1a , X1 ) 5-Br, R1 ) H
1a , X1 ) 5-Br, R1 ) H
1a , X1 ) 5-Br, R1 ) H
1b, X1 ) 6-Br, R1 ) H
1b, X1 ) 6-Br, R1 ) H
1c, X1 ) 7-Br, R1 ) H
1c, X1 ) 7-Br, R1 ) H
1d , X1 ) 5-Br, R1 ) Boc
1d , X1 ) 5-Br, R1 ) Boc
1d , X1 ) 5-Br, R1 ) Boc
1d , X1 ) 5-Br, R1 ) Boc
1e, X1 ) 6-Br, R1 ) Boc
1e, X1 ) 6-Br, R1 ) Boc
1f, X1 ) 5-Br, R1 ) Tos
1f, X1 ) 5-Br, R1 ) Tos
1f, X1 ) 5-Br, R1 ) Tos
1f, X1 ) 5-Br, R1 ) Tos
1g, X1 ) 6-Br, R1 ) Tos
1g, X1 ) 6-Br, R1 ) Tos
2e, X2 ) Br, R2 ) 4-Me
2f, X2 ) Br, R2 ) 4-OMe
2g, X2 ) Br, R2 ) 2-Me
2h , X2 ) Br, R2 ) 2-OMe
2f, X2 ) Br, R2 ) 4-OMe
2h , X2 ) Br, R2 ) 2-OMe
2f, X2 ) Br, R2 ) 4-OMe
2h , X2 ) Br-, R2 ) 2-OMe
2e, X2 ) Br, R2 ) 4-Me
2f, X2 ) Br, R2 ) 4-OMe
2g, X2 ) Br, R2 ) 2-Me
2h , X2 ) Br, R2 ) 2-OMe
2f, X2 ) Br, R2 ) 4-OMe
2h , X2 ) Br, R2 ) 2-OMe
2a , X2 ) B(OH)2, R2 ) 4-Me
2b, X2 ) B(OH)2, R2 ) 4-OMe
2c, X2 ) B(OH)2, R2 ) 2-Me
2d , X2 ) B(OH)2, R2 ) 2-OMe
2b, X2 ) B(OH)2, R2 ) 4-OMe
2d , X2 ) B(OH)2, R2 ) 2-OMe
2b, X2 ) B(OH)2, R2 ) 4-OMe
2d X2 ) B(OH)2, R2 ) 2-OMe
2a , X2 ) B(OH)2, R2 ) 4-Me
2b, X2 ) B(OH)2, R2 ) 4-OMe
2c, X2 ) B(OH)2, R2 ) 2-Me
2d , X2 ) B(OH)2, R2 ) 2-OMe
2b, X2 ) B(OH)2, R2 ) 4-OMe
2d , X2 ) B(OH)2, R2 ) 2-OMe
2a , X2 ) B(OH)2, R2 ) 4-Me
2b, X2 ) B(OH)2, R2 ) 4-OMe
2c, X2 ) B(OH)2, R2 ) 2-Me
2d , X2 ) B(OH)2, R2 ) 2-OMe
2b, X2 ) B(OH)2, R2 ) 4-OMe
2d , X2 ) B(OH)2, R2 ) 2-OMe
1h , X1 ) 5-B(OH)2, R1 ) H
1h , X1 ) 5-B(OH)2, R1 ) H
1h , X1 ) 5-B(OH)2, R1 ) H
1h , X1 ) 5-B(OH)2, R1 ) H
1i, X1 ) 6-B(OH)2, R1 ) H
1i, X1 ) 6-B(OH)2, R1 ) H
1j X1 ) 7-B(OH)2, R1 ) H
3a , 97
3b, 85
3c, 99
3d , 91
3e, 76
3f, 80
3g, 67
3h , 66
3i, 79
3j, 70
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
3k , 99
3l, 94
3m , 67
3n , 84
3o, 70
3p , 93
3q, 74
3r , 97
3s, 80
3t, 89
3a , 65
3b, 80
3c, 60
3d , 94
3e, 75
3f, 65
3g, 52
3h , 87
3i, 34
3j, 50
1j, X1 ) 7-B(OH)2, R1 ) H
1k , X1 ) 5-B(OH)2, R1 ) Boc
1k , X1 ) 5-B(OH)2, R1 ) Boc
1k , X1 ) 5-B(OH)2, R1 ) Boc
1k , X1 ) 5-B(OH)2, R1 ) Boc
1l, X1 ) 5-B(OH)2, R1 ) Tos
1l, X1 ) 5-B(OH)2, R1 ) Tos
3k , 18
3l, 8
3p , 10
3r , tracesb
a
b
All yields refer to isolated products after column chromatography on silica gel. Product only detected by mass spectrometry of the
reaction crudes.
studied has little influence on the yield. Second, the effect
of increased steric hindrance in the phenylboronic acid,
occasioned by the presence of an ortho substituent, is
negligible. Third, yields were not significantly affected
by whether the heterocyclic nitrogen was protected or not.
These results are in line with expectations and indicative
of optimal choices both in the partner roles and in the
reaction conditions used.
(b) Rea ction s of In d olylbor on ic Acid s w ith P h en -
yl Br om id es. Swapping the chemical roles of the cou-
pling partners required the synthesis of indolylboronic
acids35 [1h -l, X1 ) 5-, 6-, or 7-B(OH)2, R1 ) H, Boc, or
Tos] from the corresponding indole bromides (1a -d ,f, X1
) 5-, 6-, or 7-Br, R1 ) H, Boc, or Tos). This was done
using previously reported methods.6,24,27 However, since
we found that satisfactory purification and characteriza-
tion of the required indolylboronic acids was not easy to
accomplish, and since others2 have commented on the
difficulties of preparating and isolating of boronic acids
in a pure state, we used the crude products directly. The
possibility that impurities might affect the yields for this
series of couplings cannot be discounted, but we have no
evidence that this is the case.
In Suzuki couplings with substituted phenyl bromides
(2e-h , X2 ) Br, R2 ) 2-Me, 4-Me, 2-OMe, or 4-OMe),
yields showed effectively no dependence on the posi-
tion of the boronic acid group within the indole. Neither
was the effect of increased steric hindrance in ortho-
substituted phenyl bromides appreciable in those cou-
(35) Tyrrell, E.; Brookes, P. Synthesis 2003, 469.
6814 J . Org. Chem., Vol. 69, No. 20, 2004

Arylboronic Acids and Arylpinacolboronate Esters
SCHEME 3
plings involving unprotected heterocycles (Table 1, en-
tries 21-28). It did, however, become noticeable in
couplings involving Boc-protected indolylboronic acids
(Table 1, entries 29-32). Yields for couplings involving
the Tos-protected counterparts were too low to allow any
such relationship to be reliably established.
among the most widely used.36-41 They can be formed
under mild conditions by Pd(0)-catalyzed reaction36 be-
tween aryl halides and bis(pinacolato)diboron via a
mechanism similar to that shown in Scheme 3. This
method may be advantageously applied to substrates
incorporating easily epimerizable stereogenic carbon
atoms or sensitive functional groups, since the use of
organolithiums or other strong bases is avoided.
The arylpinacolboronate esters we describe in this
study are among the first reported in Suzuki arylations
of indoles. To expedite the coupling reactions, the crude
products were not purified prior to use; instead, they
were employed directly. Nevertheless, unlike the indolyl-
boronic acids described above in Section 1b, arylpinacol-
boronate esters were much more amenable to chromato-
graphic purification and spectroscopic characterization
(see Experimental Section and Supplementary Informa-
tion).
The conspicuous dependence of yield on the substituent
present at the heterocyclic nitrogen atom (Table 1, entries
21-34) is the most noteworthy feature of this series of
reactions. With indolylboronic acids in which this atom
was unprotected, they ranged between 52 and 94% (Table
1, entries 21-28). Protection with the Boc group caused
them to drop to the range 8-50% (Table 1, entries 29-
32), and with the Tos group they fell further to 10% at
best (Table 1, entry 33).
These results show that swapping the partner roles
caused Suzuki coupling yields to become more sensitive
to steric and electronic factors. The lower overall values
in comparison to the first series of reactions [see Section
1a above], the incipient sensitivity to steric impediment
in ortho-substituted phenyl bromides, and the clear
variation observed with regard to the substituent at the
heterocyclic nitrogen atom are all indicative of this.
(a ) Rea ction s betw een In d ole Br om id es a n d P h e-
n ylp in a colbor on a te Ester s. Suzuki couplings between
indole bromides (1a ,b,d -g, X1 ) 5- or 6-Br, R1 ) H, Boc,
or Tos) and phenylpinacolboronate esters (2i-j, X2
)
Bpin, R2 ) 2-OMe or 4-OMe) occurred in yields that were,
even at best, considerably lower than those obtained with
the corresponding phenylboronic acids (cf. Table 2,
entries 1-11, and Table 1, entries 1-20). Furthermore,
a clear dependence on the substituent at the heterocyclic
nitrogen was observed. Yields were highest (40-62%)
when the heterocycle was protected with the Tos group
The diminished yields may be a consequence of the
reduced effectiveness with which the more electron-rich
phenyl bromides participate in the oxidative addition to
Pd(0) catalyst.11 The variation with respect to the sub-
stituent at the heterocyclic nitrogen atom is in agreement
with the supposition that more electron-deficient indolyl-
boronic acids undergo transmetalation more reluctantly.6
However, it should be borne in mind that the results of
this second series of reactions may also reflect, to a
greater or lesser extent, the yields in which the different
indolylboronic acids themselves were formed.
(36) Ishiyama, T.; Murata, M.; Miyaura, N. J . Org. Chem. 1995, 60,
7508.
(37) Giroux, A.; Han, Y.; Prasit, P. Tetrahedron Lett. 1997, 38, 3841.
(38) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett.
1997, 38, 3447.
(39) Murata, M.; Watanabe, S.; Masuda, Y. J . Org. Chem. 1997, 62,
6458.
(40) Zhu, L.; Duquette, J .; Zhang, M. B. J . Org. Chem. 2003, 68,
3729.
(41) Baudoin, O.; Cesario, M.; Guenard, D.; Gueritte, F. J . Org.
Chem. 2002, 67, 1199.
2. Su zu k i Cou p lin gs Usin g Ar ylp in a colbor on a tes.
Arylboronate esters provide an attractive alternative to
arylboronic acids, and the pinacol derivatives have been
J . Org. Chem, Vol. 69, No. 20, 2004 6815

Prieto et al.
SCHEME 4
(Table 2, entries 8-11). With the less electron-withdraw-
ing Boc group, yields dropped to the range of 8-34%
(Table 2, entries 4-7), and when the indole was unpro-
tected only traces of the desired biaryls could be detected
in the reaction crudes (Table 2, entries 1-3). The effect
of steric hindrance in the phenylboronate partner, oc-
casioned by ortho substitution, was also evident. Ortho-
substituted phenylpinacolboronates almost always gave
lower yields than their para-substituted counterparts, in
contrast to the series using phenylboronic acid partners,
where this was not the case. All couplings with these
boronate esters also required significantly longer reaction
times than those necessary for arylboronic acids.
These data indicate that phenylpinacolboronate esters
are less reactive than phenylboronic acids. The generally
lower coupling yields obtained, the longer reaction times
required, and the sensitivity to steric hindrance observed
all corroborate this. This lower reactivity may have its
origin in steric factors. The bulkiness occasioned by the
presence of two pairs of geminal methyl groups in
arylpinacolboronate esters may hamper their participa-
tion in the transmetalation stage of Suzuki coupling (see
Scheme 1). This would disfavor completion of the catalytic
cycle and lead to decreased formation of biaryl. It is also
possible that the steric requirements of arylpinacolbor-
onate esters impede the interaction of base with the boron
atom, inhibiting its quaternization to give an “ate”
complex. This step is known to be crucial for efficient
transmetalation in the Suzuki coupling,6,42,43 and its
obstruction would be expected to have an adverse effect
on yield. Some support for these hypotheses is to be found
in the generally lower coupling yields observed for ortho-
substituted arylpinacolboronate esters compared to their
para-substituted counterparts. Steric congestion would
be expected to be greater in the former cases, and the
adverse effect on yield would be expected to be cor-
respondingly more pronounced, in line with the experi-
mental results obtained for this series.
The correlation between coupling yields and the sub-
stituent at heterocyclic nitrogen may be explained by the
greater facility with which more electron-deficient indole
bromides participate in the oxidative addition to Pd(0).
Indoles substituted with the more electron-withdrawing
Tos group should undergo this step most readily, followed
by those substituted with the Boc group. Unprotected
indoles, on the other hand, would undergo oxidative
addiion more reluctantly. The experimental results for
this series of couplings support this view. As seen in
Section 1a above, when phenylboronic acids were em-
ployed as coupling partners, the impact of any differences
in the rates of oxidative addition on the coupling yields
was not appreciable. However, in this series of couplings,
under the different reaction conditions employed and
with the less reactive phenylboronate esters its influence
becomes discernible.
SCHEME 5
Nevertheless, the conspicuous difference in perfor-
mance between phenylboronic acids and phenylpinacol-
boronate esters, when reacted with the same unprotected
indole bromide partners, is striking. In the former case
high yields of biaryl were obtained, whereas in the latter
only traces were produced (cf. Table 1, entries 1-8, and
Table 2, entries 1-3). This discrepancy would seem to
be symptomatic of some other cause. Competing side
reactions of the unprotected indoles with the Pd(II) or
(42) Wallow, T. I.; Novak, B. M. J . Org. Chem. 1994, 59, 5034.
(43) Norrild, J . C.; Hanne, E. J . Am. Chem. Soc. 1995, 117, 1479.
6816 J . Org. Chem., Vol. 69, No. 20, 2004

Arylboronic Acids and Arylpinacolboronate Esters
SCHEME 6
SCHEME 7
Pd(0) species present suggest themselves as possibilities,
among others.
heterocycles in comparison to the series of reactions
employing indolylboronic acids. As seen in Section 1b
above, when the latter were coupling partners, highest
yields were obtained in the absence of indole protection
and lowest ones in the presence of the Tos group, with
Boc-protected heterocycles presenting intermediate val-
ues. In the present series of couplings, this trend was
inverted. Only traces of biaryls were produced in cou-
plings involving indolylpinacolboronates having an un-
protected heterocyclic nitrogen (Table 2, entries 12-14).
The presence of Boc and Tos protection led to improved
yields, which were higher (24-62%) for the more electron-
withdrawing Tos group (Table 2, entries 19-22) than for
the Boc group (16-39%) (Table 2, entries 15-18).
The results of this series confirm the previously
observed lower reactivity and greater sensitivity to steric
effects of arylpinacolboronate esters in comparison to
arylboronic acids. There is, however, an inversion in the
yield trend, and the difference in performance between
unprotected indolylboronic acids, which gave good yields
of biaryls, and unprotected indolylpinacolboronate esters,
which gave only traces, in couplings with the same
phenyl bromide partners is remarkable (cf. Table 1,
entries 21-28, and Table 2, entries 12-14). This result
parallels that seen in the previous series of reactions [see
(b) Rea ction s betw een In d olylp in a colbor on a tes
a n d P h en yl Br om id es. In a final series of couplings,
partner roles were swapped and indolylpinacolboronates
(1m -r , X2 ) 5- or 6-Bpin, R1 ) H, Boc, or Tos), derived
from the corresponding indole bromides (1a ,b,d -g, X1
) 5- or 6-Br, R1 ) H, Boc or Tos), were reacted with
substituted phenyl bromides (2, X2 ) Br, R2 ) 2-Me,
4-Me, 2-OMe, or 4-OMe). Reaction times similar to those
necessary for the reactions of the previous series
were required to achieve optimum yields. Even so, these
were consistently lower than those obtained with indolyl-
boronic acids (cf. Table 2, entries 12-22, and Table 1,
entries 21-34). The effect of increased steric hindrance,
occasioned by ortho-substitution in the phenyl bromide
was again clearly noticeable. Ortho-substituted phenyl
bromides always gave lower yields than their para-
substituted counterparts in couplings with indolylpina-
colboronate partners. This contrasts, to some extent, with
the series of reactions employing indolylboronic acids,
which displayed less sensitivity to this factor.
However, the most noteworthy characteristic of this
series of couplings is the inversion in the trend of the
yields for the Tos- and Boc-protected and unprotected
J . Org. Chem, Vol. 69, No. 20, 2004 6817

Prieto et al.
TABLE 2. Su zu k i Cou p lin gs betw een In d oles a n d P h en yl Der iva tives Usin g Ar ylp in a colbor on a te Ester s
entry
aryl bromide
arylboronate
biaryl yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
1a , X1 ) 5-Br, R1 ) H
1a , X1 ) 5-Br, R1 ) H
1b, X1 ) 6-Br, R1 ) H
1d , X1 ) 5-Br, R1 ) Boc
1d , X1 ) 5-Br, R1 ) Boc
1e, X1 ) 6-Br, R1 ) Boc
1e, X1 ) 6-Br, R1 ) Boc
1f, X1 ) 5-Br, R1 ) Tos
1f, X1 ) 5-Br, R1 ) Tos
1g, X1 ) 6-Br, R1 ) Tos
1g, X1 ) 6-Br, R1 ) Tos
2f, X2 ) Br, R2 ) 4-OMe
2h , X2 ) Br, R2 ) 2-OMe
2f, X2 ) Br, R2 ) 4-OMe
2f, X2 ) Br, R2 ) 4-OMe
2h , X2 ) Br, R2 ) 2-OMe
2f, X2 ) Br, R2 ) 4-OMe
2h , X2 ) Br, R2 ) 2-OMe
2f, X2 ) Br, R2 ) 4-OMe
2h , X2 ) Br, R2 ) 2-OMe
2f, X2 ) Br, R2 ) 4-OMe
2h , X2 ) Br, R2 ) 2-OMe
2i, X2 ) Bpin, R2 ) 4-OMe
2j, X2 ) Bpin, R2 ) 2-OMe
2i, X2 ) Bpin, R2 ) 4-OMe
2i, X2 ) Bpin, R2 ) 4-OMe
2j, X2 ) Bpin, R2 ) 2-OMe
2i, X2 ) Bpin, R2 ) 4-OMe
2j, X2 ) Bpin, R2 ) 2-OMe
2i, X2 ) Bpin, R2 ) 4-OMe
2j, X2 ) Bpin, R2 ) 2-OMe
2i, X2 ) Bpin, R2 ) 4-OMe
2j, X2 ) Bpin, R2 ) 2-OMe
1m , X1 ) 5-Bpin, R1 ) H
1m , X1 ) 5-Bpin, R1 ) H
1n , X1 ) 6-Bpin, R1 ) H
1o, X1 ) 5-Bpin, R1 ) Boc
1o, X1 ) 5-Bpin, R1 ) Boc
1p , X1 ) 6-Bpin, R1 ) Boc
1p , X1 ) 6-Bpin, R1 ) Boc
1q, X1 ) 5-Bpin, R1 ) Tos
1q, X1 ) 5-Bpin, R1 ) Tos
1r , X1 ) 6-Bpin, R1 ) Tos
1r , X1 ) 6-Bpin, R1 ) Tos
3b, tracesb
3d , tracesb
3e, tracesb
3j, 22
3l, 8
3m , 19
3n , 34
3p , 62
3r , 45
3s, 55
3t, 40
3b, tracesb
3d , tracesb
3e, tracesb
3j, 36
3l, 16
3m , 39
3n , 30
3p , 43
3r , 24
3s, 62
3t, 42
a
b
All yields refer to isolated products after column chromatography on silica gel. Product only detected by mass spectrometry of the
reaction crudes.
Section 2a above] between indole bromide and phenyl-
pinacolboronate ester partners. The trend in yield was
similar, with the unprotected indoles again giving rise
to only traces of biaryl. Also worth mentioning is the
difference in performance between Tos-protected indolyl-
boronic acids and Tos-protected indolylpinacolboronate
esters. In these cases, it was the former that gave rise to
poor yields of biaryl. Indolylpinacolboronates, on the
other hand, underwent Suzuki coupling most satisfacto-
rily and produced the corresponding biaryls in acceptable
yields (cf Table 1, entries 33-34, and Table 2, entries
19-22).
R1 ) Boc; 1p , X1 ) 6-Bpin, R1 ) Boc) were isolated after
workup of these reactions, demonstrating both the in-
stability of the Boc group and the reluctance to react of
the indolylpinacolboronate esters.
Third, the different results obtained when Tos-protect-
ed indolylboronic acids and Tos-protected indolylbor-
onates were reacted with the same phenyl bromide
partners (only very poor yields of biaryl in the former
case; good yields in the latter) may reflect the relative
ease with which the arylboron intermediates themselves
are formed, bearing in mind the quite different mecha-
nisms involved.
This inversion of the trend in yields probably does not
have one single cause but is, rather, the outcome of a
combination of different factors. We believe that the
following three points are relevant. First, although
Suzuki couplings involving unprotected indolylpinacol-
boronates gave only traces of biaryl, this was not because
the boronate esters themselves (1m -n , R1 ) H) did not
form. On the contrary, they were the main products
isolated after reaction workup and chromatography.
Their reluctance to participate in Suzuki couplings is
intriguing and parallels the similar reluctance displayed
by unprotected indole bromide partners in the previous
series of reactions [see Section 2a, above]. As in that
previous case, we can only speculate that this may have
its origin in competing side-reaction between the unpro-
tected indoles and the Pd(II) or Pd(0) species present
under the reaction conditions used.
We suggest that, in this series of reactions, the overall
result is to produce a yield trend that is inverted with
respect to that which would be predicted on the basis of
a consideration of the relative electron deficiencies of the
indoles themselves. As has been seen in Section 1b above,
this contrasts with the results obtained using indolylbo-
ronic acids, which could be rationalized in terms of the
relative electronic characters of the heterocycle.
Con clu sion s
In Suzuki couplings involving 5-, 6-, or 7-substituted
indoles, yields were found to depend on the following
interrelated factors:
(1) Whether arylboronic acids or arylpinacolboronate
esters were used as coupling partners. The former were
more reactive and almost always furnished biaryls in
higher yields, the exceptions being Tos-protected indolyl-
boronic acids, which performed poorly. Arylpinacolbor-
onate esters, on the other hand, were considerably less
reactive and generally gave lower yields of biaryl, espe-
cially in couplings involving unprotected indoles where
they gave only traces of the desired biaryls.
Second, the yields of those couplings involving Boc-
protected indolylboronates are diminished by a partial
instability of the protecting group to the reaction condi-
tions. This contributes to the lowering of the yields of
couplings involving Boc-protected indolylboronate part-
ners compared to their Tos-protected counterparts, in
contrast to the results observed with indolylboronic acids.
(Reduction of reaction times and/or temperatures led to
(2) The assignment of partner roles. Reactions employ-
ing arylboronic acids gave different results when partner
roles were swapped. Biaryl formation proceeded most
efficiently when the heterocycle was the bromoaryl
lower yields of biaryls). Both unprotected (1m , X1
)
5-Bpin, R1 ) H; 1n , X1 ) 6-Bpin, R1 ) H) and Boc-
protected indolylpinacolboronate esters (1o, X1 ) 5-Bpin,
6818 J . Org. Chem., Vol. 69, No. 20, 2004

Arylboronic Acids and Arylpinacolboronate Esters
under argon was continued for a further 4 h. After the mixture
was cooled, the solvent was removed and the resulting crude
was purified by chromatography [silica, hexanes-EtOAc, 9:1],
giving the product as a white solid (0.31 g, 85%).
partner. When indolylboronic acids were coupled with
phenyl bromides, yields were generally lower.
In contrast, partner role swapping had a very limited
impact in couplings employing arylpinacolboronates, with
similar results being obtained irrespective of whether the
heterocycle was the aryl bromide or the arylboronate
ester.
(3) Whether the indole was protected or not. The
influence of the substituent at nitrogen was unimportant
in couplings between indole bromides and phenylboronic
acids. It was, however, substantial in couplings between
phenyl bromides and indolylboronic acids where yields
diminished as the electron-withdrawing capacity of the
substituent increased.
On the other hand, couplings employing either phenyl-
or indole-derived arylpinacolboronate esters gave only
traces of biaryl with unprotected indoles: yields were
acceptable only when protection was afforded by the
strongly electron-withdrawing Tos group.
The different influences on yield discerned in this study
may also operate in couplings involving other substrates,
making it difficult to predict the best choices of reagents
and reaction conditions. Nevertheless, it seems clear that
careful selection both of protecting groups and of the
arylboron reagent, together with a judicious assignment
of the component roles, is crucial to ensure optimum
results in some Suzuki couplings.
(ii) F r om In d ol-5-ylbor on ic Acid 1h a n d 4-Br om oa n i-
sole 2f. KH (0.10 g, 2.60 mmol) was suspended in THF (4 mL)
under argon at 0 °C. 5-Bromoindole (0.50 g, 2.6 mmol) was
added, and the mixture was stirred for 15 min. The resulting
t
solution was cooled to -78 °C, and BuLi (3.4 mL of a 1.5 M
solution in pentane, 5.1 mmol) was added over 1 min. The
cooling bath was removed, and the mixture was stirred for 10
min. After the mixture was recooled to -78 °C, B(OMe)3 (0.60
mL, 5.10 mmol) was added and the mixture was allowed to
warm to rt and stirred for 3 h. H2O was added, and the mixture
was extracted with EtOAc. The aqueous phase was acidified
to pH 1 with 10% HCl and extracted with EtOAc. The
combined organic extracts were dried, and the solvent was
removed, furnishing the crude indolylboronic acid as a light-
brown oil.
The crude boronic acid (0.41 g, 2.60 mmol) in 1:1 toluene-
EtOH (4 mL) was added to 4-bromoanisole (0.12 mL, 0.64
mmol), 1 M aqueous Na2CO3 (1.8 mL, 1.8 mmol), and Pd-
(Ph3P)4 (0.037 g, 0.03 mmol) in 1:1 toluene-EtOH (1.5 mL),
and the mixture was heated at reflux under argon for 1 h. Pd-
(Ph3P)4 (0.037 g, 0.03 mmol) in 1:1 toluene-EtOH (1.5 mL)
was added, and heating at reflux under argon was continued
for a further 4 h. After the mixture was cooled, the solvent
was removed and the resulting crude was purified by chro-
matography [silica, hexanes-EtOAc, 9:1], giving the product
as a white solid (0.11 g, 80%): mp 102-106 °C (lit.26 118-200
°C); δH (200 MHz, CDCl3) 3.85 (s, 3H), 6.58 (m, 1H), 6.98 (d, J
8.8, 2H), 7.19 (m, 1H), 7.40 (d, J 1.4, 2H), 7.57 (d, J 8.8, 2H),
7.80, (s, 1H), 8.11 (bs, 1H); δC (50 MHz, CDCl3) 55.3 (CH3),
102.9 (CH), 111.1 (CH), 114.1 (CH), 118.7 (CH), 121.7 (CH),
124.7 (CH), 128.3 (CH), 128.4 (C), 133.0 (C), 135.0 (C), 135.2
(C), 158.0 (C); m/z (%) 224 [(M + 1), 100]; HRMS (EI) calcd
for C15H13NO 223.099714, found 223.100298. Anal. Calcd for
C15H13NO: C, 80.69; H, 5.87; N, 6.27. Found: C, 80.47; H, 5.59;
N, 5.99.
(b) P r ep a r a tion s of 1-ter t-Bu toxyca r bon yl-5-(4-m eth -
ylp h en yl)in d ole 3i: (i) F r om 1-Boc-5-br om oin d ole 1d a n d
4-Meth ylp h en ylbor on ic Acid 2a . Aqueous Na2CO3 (3 mL
of a 1 M solution, 3 mmol) and Pd(Ph3P)4 (0.06 g, 0.06 mmol)
in 1:1 toluene-EtOH (10 mL) were added to a solution of
1-Boc-5-bromoindole (0.34 g, 1.20 mmol) and 4-methylphenyl-
boronic acid (0.33 g, 2.20 mmol) in 1:1 toluene-EtOH (4 mL),
and the resulting mixture was heated at reflux under argon
for 1 h. Pd(Ph3P)4 (0.06 g, 0.06 mmol) in 1:1 toluene-EtOH (4
mL) was added, and heating at reflux under argon was
continued for a further 4 h. After the mixture was cooled, the
solvent was removed and the resulting crude was purified by
chromatography [silica, hexanes-EtOAc, 9:1], giving the
product as a white solid (0.38 g, 79%).
Exp er im en ta l Section
1. Gen er a l Meth od s. All chemicals and reagents used in
this study were purchased commercially and used as received.
THF and 1,4-dioxane were freshly distilled from sodium and
benzophenone. Dichloromethane was distilled from calcium
hydride. Toluene was used as received. H2O refers to deionized
water. Organic layers were dried over anhydrous magnesium
or sodium sulfate. Evaporation of solvents was carried out on
a rotary evaporator at reduced pressure.
Column chromatography was performed using silica gel 60
(70-230 mesh). Solvent ratios are given as v/v.
1H NMR spectra were recorded at 200, 300, or 400 MHz on
Varian spectrometers in CDCl3 with tetramethylsilane as an
internal reference. Signals are quoted in parts per million as
δ downfield from tetramethylsilane (δ 0.00) as an internal
standard. Coupling constants (J values) are given in hertz.
13C NMR spectra were recorded at 50, 75, or 100 MHz,
respectively. Chemical shifts were referenced to the deuterated
solvent signals.
Low-resolution electron impact (EI) and chemical ionization
(CI) mass spectra were obtained on a ThermoFinnigan TRACE
DSQ apparatus run by the Servei de Espectrometria de Masses
(SCT) of the University of Barcelona. High-resolution mass
spectrometry (HRMS) in both EI and CI modes were obtained
from the Unidad de Masses of the Univeristy of Santiago de
Compostela.
(ii) F r om 1-Boc-in d ol-5-ylbor on ic Acid 1k a n d 4-Br o-
m otolu en e 2e. KH (0.07 g, 1.72 mmol) was suspended in THF
(4 mL) under argon at 0 °C. 1-Boc-5-bromoindole (0.51 g, 1.73
mmol) was added, and the mixture was stirred for 15 min.
t
The resulting solution was cooled to -78 °C, and BuLi (2.0
mL of a 1.5 M solution in pentane, 3.0 mmol) was added over
1 min. The cooling bath was removed, and the mixture was
stirred for 10 min. After the mixture was recooled to -78 °C,
B(OMe)3 (0.40 mL, 3.40 mmol) was added and the mixture was
allowed to warm to rt and stirred for 3 h. H2O was added, and
the mixture was extracted with EtOAc. The aqueous phase
was acidified to pH 1 with 10% HCl and extracted with EtOAc
(3 × 25 mL). The combined organic extracts were dried, and
the solvent was removed, furnishing the crude indolylboronic
acid as a light-brown oil.
The crude boronic acid (0.45 g, 1.70 mmol) in 1:1 toluene-
EtOH (4 mL) was added to 4-bromotoluene (0.08 mL, 0.45
mmol), 1 M aqueous Na2CO3 (1.2 mL of a 1 M solution, 1.2
mmol), and Pd(Ph3P)4 (0.025 g, 0.02 mmol) in 1:1 toluene-
Elemental analyses were performed by the Laboratorio de
Analisis Elemental, Instituto de Qu´ımica Me´dica (CSIC),
Madrid.
Melting points are uncorrected.
2. Selected Exa m p les of Gen er a l Rea ction P r oced u r es.
(a ) P r ep a r a tion s of 5-(4-Meth oxyp h en yl)in d ole 3b: (i)
F r om 5-Br om oin d ole 1a a n d 4-Meth oxyp h en ylbor on ic
Acid 2b. Aqueous Na2CO3 (4 mL of a 1 M solution, 4 mmol)
and Pd(Ph3P)4 (0.04 g, 0.03 mmol) in 1:1 toluene-EtOH (4 mL)
were added to a solution of 5-bromoindole (0.32 g, 1.70 mmol)
and 4-methoxyphenylboronic acid (0.50 g, 3.40 mmol) in 1:1
toluene-EtOH (4 mL), and the resulting mixture was heated
at reflux under argon for 1 h. Pd(Ph3P)4 (0.04 g, 0.03 mmol)
in 1:1 toluene-EtOH (4 mL) was added, and heating at reflux
J . Org. Chem, Vol. 69, No. 20, 2004 6819

Prieto et al.
EtOH (1.5 mL), and the mixture was heated at reflux under
argon for 1 h. Pd(Ph3P)4 (0.025 g, 0.02 mmol) in 1:1 toluene-
EtOH (1.5 mL) was added, and heating at reflux under argon
was continued for a further 4 h. After the mixture was cooled,
the solvent was removed and the resulting crude was purified
by chromatography [silica, hexanes-EtOAc, 9:1], giving the
product as a white solid (0.15 g, 34%): mp 85-87 °C; δH (200
MHz, CDCl3) 1.68 (s, 9H), 2.39 (s, 3H), 6.59 (d, J 3.6, 1H), 7.25
(m, 2H), 7.55 (m, 4H), 7.75 (d, J 1.4, 1H), 8.16 (d, J 8.8, 1H);
δC (50 MHz, CDCl3) 21.1 (CH3), 28.2 (CH3), 83.5 (C), 107.5
(CH), 115.2 (CH), 119.1 (CH), 123.6 (CH), 126.3 (CH), 126.7
(CH), 129.4 (CH), 136.2 (C), 136.6 (C), 137.1 (C), 138.9 (C),
164.7 (C); m/z (%) 325 [(M + NH4)+, 100], 308 [(M + 1), 64];
HRMS (EI) calcd for C20H21NO2 307.157229, found 307.157840.
Anal. Calcd for C20H21NO2: C, 78.15; H, 6.89; N, 4.56. Found:
C, 77.94; H, 6.76; N, 4.45.
(c) P r ep a r a tion s of 1-(p-Tolu en esu lfon yl)-5-(4-m eth -
oxyp h en yl)in d ole 3p : (i) F r om 1-Tos-5-br om oin d ole 1f
a n d 4-Meth oxyp h en ylbor on ic Acid 2b. Aqueous Na2CO3
(2.2 mL of a 1 M solution, 2.2 mmol) and Pd(Ph3P)4 (0.05 g,
0.04 mmol) in 1:1 toluene-EtOH (10 mL) were added to a
solution of 1-Tos-5-bromoindole (0.31 g, 0.90 mmol) and
4-methoxyphenylboronic acid (0.20 g, 1.30 mmol) in 1:1
toluene-EtOH (4 mL), and the resulting mixture was heated
at reflux under argon for 1 h. Pd(Ph3P)4 (0.05 g, 0.04 mmol)
in 1:1 toluene-EtOH (4 mL) was added, and heating at reflux
under argon was continued for a further 4 h. After the mixture
was cooled, the solvent was removed and the resulting crude
was purified by chromatography [silica, hexanes-EtOAc, 9:1],
giving the product as a white solid (0.31 g, 93%).
dioxane (4 mL) were heated at 80 °C under argon for 14 h.
After the mixture was cooled, the solvent was removed, leaving
the crude boronate as a pale brown oil.
This boronate (0.071 g, 0.31 mmol), potassium phosphate
(0.28 g, 1.26 mmol), PdCl2(dppf) (0.008 g, 0.008 mmol), and
1-Tos-5-bromoindole (0.134 g, 0.38 mmol) in 1,4-dioxane (2 mL)
were heated at 100 °C under argon for 1 h. PdCl2(dppf) (0.004
g, 0.004 mmol) and boronate (0.036 g, 0.15 mmol) were added,
and the mixture was heated at 100 °C for a further 1 h. The
addition of catalyst and boronate were repeated twice more
at hourly intervals, and the mixture was then kept at 100 °C
under argon for a further 24 h. After the mixture was cooled
and filtered, the solvent was removed and the resulting crude
was purified by chromatography [silica, hexanes-EtOAc, 9:1]
giving the product as a white solid (0.09 g, 62%).
(iv) F r om P in a col 1-Tos-5-in d olylbor on a te 1q a n d
4-Br om oa n isole 2f. KOAc (0.23 g, 2.29 mmol), bis(pina-
colato)diboron (0.22 g, 1.1 mmol), 1-tos-5-bromoindole (0.267
g, 0.76 mmol), and PdCl2(dppf) (0.04 g, 0.05 mmol) in 1,4-
dioxane (4 mL) were heated at 100 °C under argon for 48 h.
After the mixture was cooled, the solvent was removed, leaving
the crude boronate as a pale brown oil.
This boronate (0.12 g, 0.31 mmol), potassium phosphate
(0.28 g, 1.26 mmol), PdCl2(dppf) (0.008 g, 0.008 mmol), and
4-bromoanisole (0.05 mL, 0.38 mmol) in 1,4-dioxane (2 mL)
were heated at 100 °C under argon for 1 h. PdCl2(dppf) (0.004
g, 0.004 mmol) and boronate (0.06 g, 0.15 mmol) were added,
and the mixture was heated at 100 °C under argon for a
further 1 h. The addition of catalyst and boronate were
repeated twice more at hourly intervals, and the mixture was
then kept at 100 °C under argon for a further 70 h. After the
mixture was cooled and filtered, the solvent was removed and
the resulting crude was purified by chromatography [silica,
hexanes-EtOAc, 9:1], giving the product as a white solid (0.09
g, 43%): mp 135-137 °C; δH (200 MHz, CDCl3) 2.33 (s, 3H),
3.84 (s, 3H), 6.67 (d, J 3.6, 1H), 6.96 (d, J 8.8 2H), 7.22 (d, J
8.0, 2H), 7.59 (m, 4H), 7.65 (s, 1H), 7.78 (d, J 8, 2H), 8.01 (d,
J 8.4, 1H); δC (50 MHz, CDCl3) 21.6 (CH3), 55.3 (CH3), 109.2
(CH), 113.6 (CH), 114.2 (CH), 119.2 (CH), 123.9 (CH), 126.8
(CH), 128.2 (CH), 129.8 (CH), 131.3 (C), 133.7 (CH), 135.2 (C),
136.4 (C), 144.9 (C), 158.9 (C); m/z (%) 378 [(M + H)+, 100];
HRMS (EI) calcd for C22H19NO3S 377.108565, found 377.108398.
Anal. Calcd for C22H19NO3S: C, 70.01; H, 5.07; N, 3.71.
Found: C, 69.92; H, 5.33; N, 3.77.
(ii) F r om 1-Tos-in d ol-5-ylbor on ic Acid 1l a n d 4-Br om o-
a n isole 2f. KH (0.07 g, 1.72 mmol) was suspended in THF (4
mL) under argon at 0 °C. 1-Tos-5-bromoindole (0.33 g, 1.72
mmol) was added, and the mixture was stirred for 15 min.
t
The resulting solution was cooled to -78 °C, and BuLi (2.3
mL of a 1.5 M solution in pentane, 3.5 mmol) was added over
1 min. The cooling bath was removed, and the mixture was
stirred for 10 min. After the mixture was recooled to -78 °C,
B(OMe)3 (0.40 mL, 3.40 mmol) was added and the mixture was
allowed to warm to rt and stirred for 3 h. H2O was added, and
the mixture was extracted with EtOAc. The aqueous phase
was acidified to pH 1 with 10% HCl and extracted with EtOAc.
The combined organic extracts were dried, and the solvent was
removed, furnishing the crude indolylboronic acid as a light-
brown oil.
Ack n ow led gm en t. We thank Dr. Fe`lix Urp´ı for
helpful discussions. This work was supported by funds
from Ministerio de Ciencia y Tecnolog´ıa (BIO 2002-
02301) and Generalitat de Catalunya [Grups Consoli-
dats (2001 SGR-47) and Centre de Refere`ncia en Bio-
tecnologia].
The crude boronic acid (0.30 g, 0.94 mmol) in 1:1 toluene-
EtOH (4 mL) was added to 4-bromoanisole (0.03 mL, 0.47
mmol), 1 M aqueous Na2CO3 (0.6 mL of a 1 M solution, 0.60
mmol), and Pd(Ph3P)4 (0.01 g, 0.01 mmol) in 1:1 toluene-EtOH
(1.5 mL), and the mixture was heated at reflux under argon
for 1 h. Pd(Ph3P)4 (0.01 g, 0.01 mmol) in 1:1 toluene-EtOH
(1.5 mL) was added, and heating at reflux under argon was
continued for a further 5 h. After the mixture was cooled, the
solvent was removed and the resulting crude was purified by
chromatography [silica, hexanes-EtOAc, 9:1], giving the
product as a white solid (0.009 g, 10%).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the synthesis of compounds 1b, 1d -g, 1m -o, 2i,
3a , 3c-h , 3j-o, and 3q-t, together with their characteriza-
tion data, and copies of the 1H and 13C NMR spectra for
compounds 1b, 1d -g, 1m -o, 2i and 3a -t. This material is
available free of charge via the Internet at http://pubs.acs.org.
(iii) F r om 1-Tos-5-br om oin d ole 1f a n d P in a col 4-Meth -
oxyp h en ylbor on a te 2i. KOAc (0.23 g, 2.29 mmol), bis-
(pinacolato)diboron (0.22 g, 1.1 mmol), 4-bromoanisole (0.097
mL, 0.76 mmol), and PdCl2(dppf) (0.04 g, 0.05 mmol) in 1,4-
J O0491612
6820 J . Org. Chem., Vol. 69, No. 20, 2004