5,6,7,12-Tetrahydrodibenz[c,f][1,5]azabismocines: Highly reactive and recoverable organo-bismuth reagents for cross-coupling reactions with Aryl Bromides

Article abstract of DOI:10.1002/anie.200250205

Hypervalent organobismuth compounds efficiently couple with aryl bromides in the presence of [Pd(PPh₃)₄] catalyst. Application of this protocol to a one-pot multi-coupling reaction with bromophenylboronic esters leads to the formation of up to nine bonds in good yields (see scheme).

Full text of DOI:10.1002/anie.200250205

Angewandte
Chemie
Transition-metal-catalyzed cross-coupling reactions of orga-
nometallic reagents, such as organotin, -boron, -silicon, -zinc,
and -magnesium compounds, with organic halides and
ꢀ
triflates is one of the most powerful methods to form C C
bonds.[1] Recently, tremendous effort has been devoted to the
improvement of efficiency and applicability of the cross-
coupling reaction by the development of highly active catalyst
systems as well as by the modification of the structure of the
organometallic reagents.[2] We believe that another important
direction of research should be to explore the applicability of
other organometallic reagents, which would broaden the
scope of the cross-coupling methodology. Recently, organo-
indium,[3] -manganese,[4] and -titanium[5] compounds have
been disclosed to be useful.
Bismuth is a nontoxic element[6] and its organic com-
pounds are potentially useful, low-toxicity reagents for
organic synthesis.[7] We have demonstrated that the organo-
bismuth compounds 2,6-Py(CR2O)2BiR1 (1: R1 = Ph or Me,
R = alkyl) and Ar3Bi (2) can be utilized for the cross-coupling
reaction with organic electrophiles such as bromides, iodides,
and triflates catalyzed by a palladium complex.[8] However,
compounds 1 and 2 suffer from a drawback in that their
applicability has considerable limitation. In particular, they
do not couple with electron-rich substrates efficiently, even in
the presence of stoichiometric amounts of activators. Herein
we report that the readily obtainable hypervalent organo-
bismuth compounds, 5,6,7,12-tetrahydrodibenz[c,f][1,5]aza-
bismocine derivatives 3a–3e, can couple with electron-
deficient, electron-neutral, and even electron-rich aryl bro-
mides efficiently in the absence of any additional activator by
Bi Reagents for C-C Cross-Coupling
5,6,7,12-Tetrahydrodibenz[c,f][1,5]azabismo-
cines: Highly Reactive and Recoverable Organo-
bismuth Reagents for Cross-Coupling Reactions
with Aryl Bromides**
using
a
simple commercially available Pd catalyst,
[Pd(PPh3)4]. There are additional advantages to reagents
3a–3e: 1) Selective one-pot multicoupling reactions by the
combination of compounds 3a–3e and bromophenylboronic
esters enabled the construction of up to nine bonds in good
yields in one pot. 2) Bismuth compounds, such as bromide 3 f
and chloride 3g, are recovered almost quantitatively after the
reaction and can be reused as the precursors to 3a–3e.
Shigeru Shimada,* Osamu Yamazaki,
Toshifumi Tanaka, Maddali L. N. Rao, Yohichi Suzuki,
and Masato Tanaka*
[*] Dr. S. Shimada, Prof. Dr. M. Tanaka, Dr. O. Yamazaki,
Dr. M. L. N. Rao
[Pd(PPh3)4]
+
+
Ar-Ph
+
(Ph-Ph)
3f
3a
Ar-Br
NMP, 80 °C, 3h
National Institute of Advanced Industrial Science
and Technology (AIST)
Tsukuba Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565 (Japan)
Fax: (+81)298-61-4511
E-mail: s-shimada@aist.go.jp
In the cross-coupling reactions with 1 and 2, yields were
highly dependent on the electronic nature of the organic
electrophiles. Additives such as K2CO3, Cs2CO3, and CsF
considerably improved the reactivities of 1 and 2. Never-
theless, the reactions of 1 and 2 with electron-rich substrates
were not satisfactory. We assumed that the reactivity
enhancement by the additives was derived from the formation
of the “ate complex”, electron-rich, higher-coordinated
reactive species by coordination of the anionic part of the
additives to the bismuth center. Accordingly electron-rich,
hypervalent organobismuth compounds are expected to be
more reactive than 1 and 2.
m.tanaka@res.titech.go.jp
T. Tanaka, Prof. Dr. Y. Suzuki
Department of Industrial Chemistry
College of Industrial Technology, Nihon University
1-2-1 Izumi-cho, Narashino, Chiba 275–8575 (Japan)
Prof. Dr. M. Tanaka
Chemical Resources Laboratory, Tokyo Institute of Technology
4259 Nagatsuta-cho, Midori-ku, Yokohama 226–8503 (Japan)
Fax: (+81)45-924-5244
[**] We are grateful to the Japan Science and Technology Corporation
(JST) for financial support through the CREST (Core Research for
Evolutional Science and Technology) program and for a postdoc-
toral fellowship to O.Y. and M.L.N.R.
The synthesis and structure of 6-methyl-5,6,7,12-tetrahy-
drodibenz[c,f][1,5]azabismocine derivatives 4 were reported
by Akiba and co-workers.[9] We introduced a tBu group in
place of the methyl group on the N atom to increase the
Supporting information for this articleis availableon theWWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2003, 42, 1845 – 1848
DOI: 10.1002/anie.200250205
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1845

Communications
Table 2: Cross-coupling reaction of 3b–3e with aryl bromides.[a]
electron-donating ability of the N atom and to protect the N
[Pd(PPh3)4]
atom from being involved in undesirable side reactions by the
steric bulk of the tBu group. Similarly to the synthesis of 4,[9]
compound 3g was prepared by the reaction of BiCl3 with (2-
LiC6H4CH2)2tBuN, which was generated in situ by the
lithiation of (2-BrC6H4CH2)2tBuN with nBuLi.[10] A third
organic group was introduced at the bismuth atom by the
reaction of 3g with organolithium or Grignard reagents.[9,11]
The cross-coupling reaction of 3a with 1-bromonaphtha-
lene 5a proceeded smoothly in the absence of any additives to
give 1-phenylnaphthalene quantitatively (NMP, 808C, 3 h,
[Pd(PPh3)4] (2mol%); Table 1, entry 1). The same reaction of
+
+
+
3f
3b – 3e
Ar-R
(R-R)
Ar-Br
NMP, 80 °C, 3h
Entry
3
ArBr
[Pd(PPh3)4]
[mol%]
Ar-R
[%][b]
R-R
[%][c]
1
2
3
4
5
6
7[e]
8[e]
9
3b
3c
5d
5a
5 f
5d
5a
5 f
5a
5 f
5d
5a
5 f
2
5
10
2
10
10
2
10
5
87
96
87
91
93
91
87
78
90
80
81
8
3
3
4
nd[d]
11
0
3d
3e
0
nd[d]
nd[d]
nd[d]
Table 1: Cross-coupling reaction of 3a with aryl bromides.[a]
10
11
5
5
[Pd(PPh3)4]
+
+
Ar-Ph
+
(Ph-Ph)
3f
3a
Ar-Br
NMP, 80 °C, 3h
[a] 3b–3e (0.30 mmol), ArBr (0.25 mmol), NMP (3 mL). [b] Yield of
isolated product based on ArBr. [c] Approximate values based on 3b–3e
calculated from relative peak intensities of Ar-R and R-R by GC analysis.
[d] Not determined. [e] Reaction time: 5 h.
Entry
ArBr[b]
[Pd(PPh3)4]
[mol%]
Ar-Ph
[%][c]
Ph-Ph
[%][d]
1
2
3
4
5
6
7
1-BrNpt (5a)
5a
2-BrAnt (5b)
4-AcC6H4Br (5c)
4-NCC6H4Br (5d)
4-MeC6H4Br (5e)
4-MeOC6H4Br (5 f)
4-Me2NC6H4Br (5g)
2-BrPy (5h)
2
0.5
2
2
2
10
10
10
2
97(100)
(98)
91
97
91
89
93
76
86(93)
3
4
nd[e]
3
9
6
5
nd[e]
2
which has two OMe groups ortho to the Bi substituent on R,
gave the products in good yields, although a slightly longer
reaction time was required (Table 2, entries 7–8). As observed
in the reaction of 3a with ArBr, small amounts of self-
coupling products of 3b and 3c, (3,5-(CF3)2C6H3-)2 and (3,4-
(CH2O2)C6H3-)2, respectively, were also formed, whereas that
of 3d was not observed probably because of the steric bulk of
the 2,4,6-(MeO)3C6H2- group.[12]
8
9[f]
10[g]
10
74
0
(5i)
After the reaction, the bismuth compound can be
recovered almost quantitatively as bromide 3 f or chloride
3g, which are the precursors for 3a–3e. During the cross-
coupling reaction, 3a–3e were converted into bromide 3 f.
Since 1.2equivalents of 3a–3e were used, small quantities of
the starting compounds remained unreacted after the reac-
tion. By the aqueous workup with dilute HCl solution, both 3 f
and unreacted 3a–3e are quantitatively converted into 3g. If
HBr solution is used instead of HCl solution, the bismuth
species can be recovered as bromide 3 f. Both 3 f and 3g are
stable to air and neutral or acidic aqueous conditions.[13]
Isolation of 3 f or 3g from the crude mixture can be performed
by solvent extraction of the cross-coupling product,[14] recrys-
tallization, chromatographic separation, or a combination of
these methods.
By invoking the difference in the protocols of the new
cross-coupling with the bismuth reagents and the well-
established Suzuki–Miyaura coupling with aryl boronic
acids and esters,[1,15] a one pot multicoupling reaction is
readily realized. Generally the latter palladium-catalyzed
cross-coupling reaction of aryl boronic compounds with
organic halides and triflates requires a base as an activator,
whereas the cross-coupling reaction of 3a–3e does not
require any additional activators. Accordingly 3a–3e can
selectively couple with bromophenylboronic esters without
self-condensation of the latter to leave the boronic ester
moiety intact. Subsequent addition of a second aryl halide and
a base activator affords multicoupling products in one pot as
shown in Table 3. All o-, m-, and p-bromophenylboronic
esters efficiently underwent cross-coupling in this one-pot
[a] 3a (0.30 mmol), ArBr (0.25 mmol), 1-methyl-2-pyrrolidinone (NMP;
3 mL). [b] Nap=naphthalene, Ant=anthracene, Py=pyridine. [c] Yield
of isolated product based on ArBr. Yields determined by GC with n-
hexadecane as an internal standard are shown in parentheses. [d] Yield
determined by GC based on 3a. [e] Not determined. [f] Reaction time:
6 h. [g] Reaction time: 10 h.
2,6-Py(CMe2O)2BiPh and Ph3Bi with 5a under similar
reaction conditions produced 1-phenylnaphthalene only in
15% and 2% yields, respectively, in the absence of additives
and in 88% and 76% yields in the presence of Cs2CO3
(2equiv) and CsF (8 equiv), respectively. [8b,c] The perform-
ance of compound 3a clearly seen in Table 1 can be
summarized as follows. All electron-deficient, electron-neu-
tral, and even electron-rich aryl bromides smoothly reacted in
the presence of [Pd(PPh3)4] as a catalyst without any
additives. Sterically hindered substrate 5i, which has a Me
group at the position adjacent to Br, also gave the cross-
coupled product in a good yield although a longer reaction
time was required (Table 1, entry 10). The amount of catalyst
can be decreased to 0.5 mol% as shown in the reaction of 5a
(Table 1, entry 2). In most cases, a small amount of biphenyl
was also formed as a by-product (Table 1).
The reactivity of azabismocines 3 with a substituted aryl
or alkenyl group toward aryl bromides is summarized in
Table 2. Electron-deficient and -rich aryl bismuth compounds
3b–3d as well as isopropenylbismuth compound 3e efficiently
reacted with electron-deficient, -neutral, and -rich aryl
bromides 5d, 5a and 5 f. Notably, sterically demanding 3d,
1846
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Angewandte
Chemie
Table 3: One-pot multicoupling reaction of 3a–3e with bromophenylboronic esters and aryl bromides.[a]
3a – 3e
with aryl bromides. Further studies
to clarify the scope and the mech-
anistic aspect of this reaction are
underway.
Ar2Br, K3PO4
O
+
[Pd(PPh3)4]
O
O
B
Ar2
NMP, 80 °C
Rn
80 °C, 16h
Rn
B
O
Brn
3h
BrArBpin[b]
Ar2Br
Product
Yield[%][c]
75
Received: September 20, 2002
Revised: December 13, 2002 [Z50205]
Entry
1[d,e]
3
Keywords: bismuth · boron · cross-
3e
.
coupling · hypervalent compounds ·
palladium
2[d]
3a
3b
5d
5h
84
76
[1] a) Metal-catalyzed Cross-coupling
Reactions (Eds.: F. Diederich, P. J.
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3[d]
4[d]
3c
89
[2] For
recent
examples,
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5[d,f]
3d
3e
3b
5d
5c
72
74
87
6[d]
7[g]
8[e,h]
3b
3e
74[i]
60[i]
7a: R=3,5-(CF3)2C6H3
9[h]
7b: R=CH2 C(Me)
¼
ꢀ
[a] See Supporting Information for details of the reaction procedures. [b] pin=-OCMe2CMe2O-. [c] Yield
of isolated product based on bromophenylboronic esters. [d] Bi/B/Pd/ArBr/K3PO4 =1.1:1.0:0.1:1.1:1.5.
[e] Reaction time for the first step: 8 h. [f] Reaction time for the first step: 5 h. [g] Bi/B/Pd/ArBr/
K3PO4 =1.1:1.0:0.1:1.5:1.5. Reaction time for the second step: 32 h. [h] Bi/B/Pd/ArBr/
K3PO4 =6.7:3.3:0.66:1.0:10. [i] Yield of isolated product based on 1,3,5-tribromobenzene.
[3] a) I. Perez, J. P. Sestelo, L. A. Sar-
andeses, Org. Lett. 1999, 1, 1267 –
1269; b) I. Perez, J. P. Sestelo, L. A.
synthesis and compounds 6a–6g were obtained in good
Sarandeses, J. Am. Chem. Soc. 2001, 123, 4155 – 4160.
yields.[16] By using 3,5-dibromophenylboronic ester and 1,3,5-
tribromobenzene, nine bonds were efficiently constructed in
one pot to give 7a and 7b in good yields.[17,18] In all cases
except Table 3, entry 5, the first step was nearly quantitative,
as judged by GC analysis. The second step, which was
performed under typical conditions for the Suzuki–Miyaura
reaction, remains to be optimized for further improvement of
the yields.
[4] a) E. Riguet, M. Alami, G. Cahiez, Tetrahedron Lett. 1997, 38,
4397 – 4400; b) E. Riguet, M. Alami, G. Cahiez, J. Organomet.
Chem. 2001, 624, 376 – 379.
[5] J. W. Han, N. Tokunaga, T. Hayashi, Synlett 2002, 871 – 874.
[6] a) S. Maeda in The Chemistryof Organic Arsenic, Antimonyand
Bismuth Compounds (Ed.: S. Patai), Wiley, New York, 1994,
chap. 19, pp. 725–759; b) J. Reglinski, in Chemistryof Arsenic,
Antimonyand Bismuth (Ed.: N. C. Norman), Blackie Academic
and Professional, London, 1998, chap. 8, pp. 403–440.
In summary, we have reported that 5,6,7,12-tetrahydrodi-
benz[c,f][1,5]azabismocine derivatives 3a–3e are highly effi-
cient and recoverable reagents for the cross-coupling reaction
[7] For reviews on the application of organobismuth compounds in
organic synthesis, see: a) H. Suzuki, T. Ikegami, Y. Matano,
Synthesis 1997, 249 – 267; b) G. I. Elliott, J. P. Konopelski,
Angew. Chem. Int. Ed. 2003, 42, 1845 – 1848
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Communications
Tetrahedron 2001, 57, 5683 – 5705; c) Organobismuth Chemistry
(Eds.: H. Suzuki, Y. Matano), Elsevier, Amsterdam, 2001.
[8] a) M. L. N. Rao, S. Shimada, M. Tanaka, Org. Lett. 1999, 1,
1271 – 1273; b) M. L. N. Rao, O. Yamazaki, S. Shimada, T.
Tanaka, Y. Suzuki, M. Tanaka, Org. Lett. 2001, 3, 4103 – 4105;
c) M. L. N. Rao, S. Shimada, O. Yamazaki, M. Tanaka, J.
Organomet. Chem. 2002, 659, 117 – 120.
[9] a) K. Ohkata, S. Takemoto, M. Ohnishi, K. Akiba, Tetrahedron
Lett. 1989, 30, 4841 – 4844; b) M. Minoura, Y. Kanamori, A.
Miyake, K. Akiba, Chem. Lett. 1999, 861 – 862.
[10] F. H. CarrØ, R. J. P. Corriu, G. F. Lanneau, P. Merle, F. Soulairol,
J. Yao, Organometallics 1997, 16, 3878 – 3888.
[11] Compounds 3a–3g were purified by recrystallization and are
thermally stable at least up to 1108C. Compounds 3a, 3b, 3 f, and
3g also can be purified by silica-gel column chromatography,
whereas 3d seems to decompose by column chromatography on
silica gel or alumina. Detail of the synthesis, structure, and some
properties of 3a–3g will be reported elsewhere.
[12] In the reaction of 3b and 3d with 4-bromoanisole, 3,5-
(CF3)2C6H3-Ph and 2,4,6-(MeO)3C6H2-Ph were also obtained
as a by-product in 4% and 21% yields, respectively. The phenyl
group of the by-products probably came from PPh3 as observed
in the related cross-coupling reaction; see: B. E. Segelstein, T. W.
Butler, B. L. Chenard, J. Org. Chem. 1995, 60, 12– 13.
[13] For example, 3g was quantitatively recovered when it was stirred
in a 1:1 mixture of CH2Cl2/1m aqueous HCl at room temperature
for 10 h. However, the recovery of 3g decreased to 70% when it
was stirred in a 1:1 mixture of CH2Cl2/4m aqueous HCl at room
temperature for 2days.
[14] For an experimental procedure, see Supporting Information.
[15] A. Suzuki, J. Organomet. Chem. 1999, 576, 147 – 168.
[16] Since a slight excess of 3a–3e and Ar2Br was used, small
amounts of direct coupling products between 3a–3e and Ar2Br
were also formed.
[17] Similar compounds have been prepared by multistep proce-
dures: T. M. Miller, T. X. Neenan, R. Zayas, H. E. Bair, J. Am.
Chem. Soc. 1992, 114, 1018 – 1025.
[18] The molecular structure of 7a was unambiguously confirmed by
X-ray analysis. See the Supporting Information for the crystal
data as well as a molecular drawing of 7a. CCDC-192709 (7a)
contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.cam.-
ac.uk/conts/retrieving.html (or from the Cambridge Crystallo-
graphic Data Centre, 12Union Road, Cambridge CB21EZ, UK;
fax: (+ 44)1223-336-033; or deposit@ccdc.cam.ac.uk).
1848
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Angew. Chem. Int. Ed. 2003, 42, 1845 – 1848