Suzuki-Miyaura cross-coupling of 2-nitroarenediazonium tetrafluoroborates: Synthesis of unsymmetrical 2-nitrobiphenyls and highly functionalized carbazoles

Article abstract of DOI:10.1002/adsc.200800162

The Suzuki-Miyaura cross-coupling of 2-nitrodiazonium tetrafluoroborate salts with substituted boronic acids is an effective and efficient means of preparing highly functionalized 2-nitrobiphenyls in modest to excellent yield under extremely mild reaction conditions. Cross-coupling of 2-nitrodiazonium tetrafluoroborate salts with ortho-methoxy- and benzyloxyphenylboronic acids was also demonstrated leading to the ortho-ortho-2-nitrobiphenyls. Reductive cyclization of the 2-nitrobiphenyl products allows for the overall three-step synthesis of uniquely substituted carbazoles from readily available 2-nitroanilines. The methodology was further highlighted by the short total synthesis of the carbazole alkaloids clausine V, N, C, and glycoborine.

Full text of DOI:10.1002/adsc.200800162

FULL PAPERS
DOI: 10.1002/adsc.200800162
Suzuki–Miyaura Cross-Coupling of2-Nitroarenediazonium
Tetrafluoroborates: Synthesis of Unsymmetrical 2-Nitrobiphenyls
and Highly Functionalized Carbazoles
Jeffrey T. Kuethea,* and Karla G. Childersa
a
Department of Process Chemistry, Merck & Co., Inc., P.OBox 2000, Rahway, New Jersey 07065, USA
Fax : (+1)-732-594-5170; e-mail: Jeffrey_Kuethe@merck.com
Received: March 17, 2008; Published online: June 13, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The Suzuki–Miyaura cross-coupling of 2- allows for the overall three-step synthesis of uniquely
nitrodiazonium tetrafluoroborate salts with substitut- substituted carbazoles from readily available 2-nitro-
ed boronic acids is an effective and efficient means anilines. The methodology was further highlighted by
of preparing highly functionalized 2-nitrobiphenyls the short total synthesis of the carbazole alkaloids
in modest to excellent yield under extremely mild re- clausine V, N, C, and glycoborine.
action conditions. Cross-coupling of 2-nitrodiazoni-
um tetrafluoroborate salts with ortho-methoxy- and
benzyloxyphenylboronic acids was also demonstrated Keywords: carbazoles; cross-coupling; natural prod-
leading to the ortho-ortho-2-nitrobiphenyls. Reduc- ucts; 2-nitrodiazonium tetrafluoroborates; 2-nitro-
tive cyclization of the 2-nitrobiphenyl products phenyls; Suzuki–Miyaura reaction
Introduction
diazonium tetrafluoroborate salts have successfully
been coupled with both aryl- and alkenylboronic
The palladium-catalyzed cross-coupling between aryl acids,[4,5,7] potassium trifluoroborates,[8] and vinylsi-
halides or sulfonates and arylboronic acids (the lanes[9] in the presence of catalytic amounts of palladi-
Suzuki–Miyaura coupling) is arguably the most versa- um in a number of solvent systems (MeOH, THF, and
tile and widely utilized transformation in modern syn- 1,4-dioxane being the most common). The reaction is
thetic chemistry. It is often the method of choice for typically carried out under extremely mild reaction
the preparation of both symmetrical and unsymmetri- conditions (0 to 508C) in the absence of added base,
cal biaryls, which constitute the core skeleton of a salt additives, or ligands, which allows for the prepara-
number of natural products, pharmaceuticals, agro- tion of substrates possessing sensitive functional
chemicals, optically active ligands, conducting poly- groups. While the use of phosphine ligands has been
mers, molecular wires, and liquid crystals.[1] Since the reported to be detrimental in these reactions due to
pioneering work of Suzuki and Miyaura,[2] numerous decomposition of the arenediazonium salts, several
studies have emerged aimed at the development of groups have successfully demonstrated that imidazoli-
new catalysts, ligands, and cross-coupling partners. um carbenes[10] and a C2-symmetrical thiourea[11] are
The reaction continues to attract the attention of both effective ligands for Suzuki–Miyaura cross-coupling
academic and industrial researchers as new applica- reactions. However, the full potential of this interest-
tions are uncovered.[3] The use of arenediazonium tet- ing reaction has remained academic since applications
rafluoroborate salts in Suzuki–Miyaura cross-coupling have been limited to the preparation of relatively
reactions, developed independently by GenÞt[4] and simple biaryl compounds.
Sengupta,[5] has recently surfaced as a highly efficient
Carbazoles are an important class of nitrogen het-
synthetic tool for carbon-carbon bond formation.[6] erocycles found in many biologically active natural
Arenediazonium tetrafluoroborate salts are easily products and medicinal agents.[12] Carbazole deriva-
prepared in high yield from inexpensive and readily tives often serve as organic materials due to their
available anilines, and are often more reactive than photoconducting[13] and semiconducting properties,[14]
aryl halides in palladium-catalyzed reactions when ox- as well as their high thermal and charge-transport
idative addition is the rate-determining step. Arene- properties.[15] Significant efforts have been devoted to
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Figure 1.
the preparation of carbazoles since funtionalization of
the parent carbazole nucleus is limited to certain posi-
tions of the ring at which electrophiles can be intro-
duced. When more highly functionalized carbazoles
are required, preparation of the carbazole ring bear-
ing the appropriate substituents is necessary. The
Scheme 1.
choice of method employed for the synthesis of carba- cal thiourea ligand 6 developed by Yang and co-work-
zoles is often dictated by functional groups present ers has been reported describing the preparation of o-
within the starting materials. Perhaps the most com- nitrobiphenyl 7 from 2-nitrobenzenediazonium tetra-
monly employed method for carbazole synthesis is fluoroborate salt 5 (Scheme 1).[1] Recently, Felpin and
the reductive cyclization of 2-nitrobiphenyl deriva- Fouquet have also reported the coupling of 5 with
tives due to functional group tolerance, increased sub- boronic acids in the presence of Pd(0)/barium carbon-
strate scope, and regiocontrol of the functional groups ate in MeOH.[16] While the use of commercially avail-
within the carbazole product. For the preparation of able 4-nitrobenzenediazonium salt 8 is well docu-
biologically active biaryls and carbazoles, the selectiv- mented providing the 4-nitrobiphenyls of type
ity and potency of these compounds depends on the 9,[4b,7a,e,8a–c,11] the failure of 2-nitrobenzenediazonium
nature of the substituents about each ring systems. In tetrafluoroborate salts 1 to participate in Suzuki–
order to fully define biological profiles, strategies Miyaura cross-coupling reactions has been attributed
which allow for the rapid assembly of both functional- to high redox-potentials and a preference for homo-
ized biaryls and carbazoles continue to offer signifi- lytic dediazotization pathways.[17] The o-nitro group
cant advantages. Reactions leading to increasing mo- can function as an electron-withdrawing group and
lecular complexity are important synthetic tools, and chelate the oxidative addition intermediate.[18] These
we reasoned that a combination of Suzuki–Miyaura factors would seem to favor the coupling of these re-
cross-coupling of 2-nitrobenzenediazonium salts 1 action partners since numerous couplings of 2-halo-
with arylboronic acids 2 to give 2-nitrobiphenyls 3 fol- gen-1-nitrobenzenes with boronic acids have been re-
lowed by reductive cyclization would allow for the ported.[19] It was with this background in mind that we
preparation of a unique set of carbazoles 4 possessing began our investigations.
a range of functionality and substitution patterns not
Our investigations began with the preparation of
accessible through current methodology (Figure 1). In the prerequisite 2-nitrobenzenediazonium tetrafluoro-
this paper, we document the realization of this strat- borate salts 1 which were prepared via the Doyle pro-
egy and present a complete account of our investiga- tocol (Scheme 2).[20] For example, treatment of 2-ni-
tions in this area.
troaniline 10 with BF3·OEt2 in CH2Cl2 at 08C fol-
lowed by the dropwise addition of tert-butyl nitrite
furnished 5 which crystallized from the reaction mix-
Results and Discussion
The coupling of 2-nitrobenzenediazonium tetrafluoro-
borate salts 1 with arylboronic acids 2 has remained
an unexplored landscape since the initial disclosure
by Sengupta who reported that the reaction failed in
the presence of 10 mol% Pd
ACHTRE(UNG OAc)2 in refluxing meth-
anol.[5] A single example employing the C2-symmetri- Scheme 2.
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Suzuki–Miyaura Cross-Coupling of 2-Nitroarenediazonium Tetrafluoroborates
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ture and was isolated in 95% yield. This general se- vents have been used in these types of couplings, a
quence allowed for the preparation of a number of simple solvent screen served as the starting point. For
structurally intriguing 2-nitrobenzenediazonium tetra- example, addition of 5 mol% PdCAHTRE(UGN OAc)2 to a mixture
fluoroborate salts in good to excellent yield as shown of 5 (1 equiv.) and 27 (1 equiv.) in MeOH at room
in Table 1. The salts depicted in Table 1 were stable at temperature resulted in an immediate reaction and
room temperature for at least 24 h, but decomposition rapid release of nitrogen, with palladium black being
was observed after several days. However, they can deposited within one minute. After allowing the reac-
be stored indefinitely in the freezer (À208C) without tion mixture to cool to room temperature, the crude
any degradation.
reaction mixture was filtered through Celite and con-
With an array of 2-nitrobenzenediazonium tetra- centrated. Examination of the residue by NMR re-
fluoroborate salts in hand, our attention turned to ex- vealed the formation of the desired product 28 in ap-
amination of appropriate conditions to affect Suzuki– proximately 50% yield. Also detected in the crude re-
Miyaura cross-coupling. Initial experiments were car- action mixture was 4,4’-dimethoxybiphenyl 29 (27%)
ried out between 5 and 4-methoxyphenylboronic acid resulting from homocoupling of 27 and nitrobenzene
27 (Scheme 3). As part of our initial experimental 30 (15%) arising from homolytic cleavage of 5. When
design, we elected to only examine ligand-free condi- the reaction was performed in anhydrous THF at
tions employing catalytic PdACHTRE(UNG OAc)2. As various sol- room temperature, little conversion to 28 was ob-
served even after stirring at room temperature for
24 h. The low solubility of 5 in THF may contribute
to the low conversion. On the other hand, treatment
Table 1.
of 5 and 27 with 5 mol% PdACHTRE(UNG OAc)2 in 1,4-dioxane
Entry 2-Nitroaniline 2-Nitrodiazonium tetrafluoro- Yield
borate salt
under the identical reaction conditions provided 28 in
just one hour in 75% isolated yield. Under these con-
ditions, only trace amounts of 29 (~5%) and 30
(<5%) were observed in the crude NMR. These
minor by-products were easily removed by silica gel
chromatography. While 5 appeared to have little solu-
bility in 1,4-dioxane, we speculate that a delicate bal-
ance between solubility and reactivity leads to the
high yield of the desired product. In addition, 1,4-di-
oxane is an aprotic solvent which appears to effective-
ly suppress the homolytic cleavage of 5 leading to 30.
When MeOH was used as the solvent, both 5 and 27
were soluble leading to multiple reaction pathways
and the rapid formation of 28, 29, and 30. The use of
1,4-dioxane as the optimal solvent for these reactions
has also been reported by GenÞt.[4] With 1,4-dioxane
as the solvent of choice, the reaction was optimized in
terms of catalyst and reagent charges. After extensive
experimentation it was discovered that the optimal
1
2
3
4
97%
94%
88%
97%
conditions employed 3 mol% PdACHTRE(UNG OAc)2, 1.1 equiv. of
5
6
7
99%
89%
97%
5, and 1.0 equiv. of 27 in 1,4-dioxane for 2 h at room
temperature which provided 28 in 85% isolated yield.
Although homocoupling of 27 could never be com-
pletely suppressed, the formation of 29 was minimized
to <5% and the formation of 30 was <5%. These re-
action conditions proved general, allowing for the
preparation of a diverse array of 2-nitrobiphenyls in
modest to excellent yield (Table 2). The results in
Table 2 demonstrate that both electron-poor and elec-
tron-rich boronic acids participate equally as well in
the coupling reaction. In addition, substitution about
the diazonium salts was well tolerated providing 2-ni-
trobiphenyls of increasing molecular complexity (en-
tries 5–11). We also examined the identical conditions
for the preparation of the isomeric 4-nitro analogues
(entries 12 and 13) which gave the expected products
8
99%
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Scheme 3.
in excellent yield. The excellent chemoselectivity of ortho substitutions on the diazonium component are
Suzuki–Miyaura cross-couplings that can be achieved generally well tolerated with both electron-donating
with halogen-containing boronic acids and arenedia- and electron-withdrawing groups readily participating
zonium salts, in conjunction with the mild reaction in cross-coupling reactions. However, it has also been
conditions, furnished 2-nitrobiphenyls having suitable reported that ortho substitution on the boronic acid
handles for further manipulation.
counterpart results in significant erosion in the isolat-
The effect of steric hindrance about both the 2-ni- ed yields (0–30%) of the biphenyl products regardless
trodiazonium tetrafluoroborate salts and boronic of the method employed.[4,5,7,8] Despite these reported
acids was next probed. It has been reported that limitations, we elected to investigate the coupling of
Table 2.
Entry
Diazonium salt
Boronic acid
2-Nitrobiphenyl
Yield
93%
1
5
2
5
85%
85%
77%
3
5
4
12
33
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Suzuki–Miyaura Cross-Coupling of 2-Nitroarenediazonium Tetrafluoroborates
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Table 2. (Continued)
Entry
Diazonium salt
Boronic acid
2-Nitrobiphenyl
Yield
5
12
81%
83%
6
12
7
8
9
16
22
26
91%
78%
77%
27
27
10
26
40
57%
11
12
24
65%
70%
88%
8
27
27
13
Fast Red B[a] 50
[a]
Fast Red B tetrafluoroborate salt 50 (2-methoxy-4-nitrobenzenediazonium tetrafluoroborate) is commercially available.
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Table 3.
Entry Diazonium Boronic acid
salt
Nitrobiaryl
Yield
85%
1
2
3
4
5
Scheme 4.
18
18
22
84%
89%
81%
2-nitrobenzenediazonium salts with ortho-substituted
boronic acids. We speculated that the electronic
nature of the ortho-substituent on the boronic acid
may actually override steric interactions leading to
successful cross-coupling. To this end, we explored
the cross-coupling of 5 with boronic acids 52 (elec-
tron-deficient), 53 (moderately electron-donating),
and 54 (strongly electron-donating) (Scheme 4).
Cross-coupling of 5 with 52 under our optimized con-
ditions resulted in no detectable amounts of 55 being
formed with the only identifiable reaction product
being 30 resulting from homolytic cleavage of 5.
Cross-coupling of 5 with 53 gave similar results and
the desired product 56 was only obtained in ~10%
yield. The mass balance of this reaction was 30 and
homocoupling of 52. On the other hand, cross-cou-
pling of 5 with 54 under the identical reaction condi-
tions provided 57 in 85% yield. From these results it
was apparent that boronic acids possessing strongly
electron-donating groups in the ortho-position were
particularly reactive. This extremely gratifying result
prompted us to further explore the coupling of vari-
ous diazonium tetrafluoroborate salts with boronic
acids bearing an alkoxy substituent in the ortho posi-
tion. The results are shown in Table 3 which illustrates
that ortho-methoxy- and benzyloxyphenylboronic
acids readily participate in Suzuki–Miyaura cross cou-
pling reactions with diazonium tetrafluoroborate salts
providing an interesting array of highly functionalized
2-nitrobiphenyls in good to excellent yield. Only in
the cases where either the diazonium salt (entry 7) or
the boronic acid (entry 8) presented significant steric
hurdles did the reaction perform poorly. Entry 9 illus-
trates that preparation of isomeric ortho-ortho’-4-
nitro derivatives (Fast Red B) was also possible and
4-nitrobiphenyl 71 was isolated in high yield.
5
6
20
20
58
72%
48%
64
60
7
8
24
5
23%
0%
We briefly examined the reverse coupling of 2-ni-
trophenylboronic acid 72 with 4-methoxybenzenedia-
zonium tetrafluoroborate salt 73 (Scheme 5). Reac-
tion of 72 with 73 under the optimized conditions de-
scribed above did not afford any detectable amounts
of 28 in the crude reaction mixture. The only identifi-
able product was nitrobenzene 30. Since it is an estab-
lished fact that the presence of an electron-withdraw-
9
50
62
90%
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Scheme 6.
Table 4.
Entry 2-Nitrobiphenyl Carbazole
Yield
1
59
63%
Scheme 5.
ing nitro group in the ortho-position of a carbon-
boron bond makes it susceptible to proto-deborona-
tion, this result was not completely surprising.[21]
With a wealth of 2-nitrobiaryl compounds in hand,
we next turned our attention to the formation of the
corresponding carbazoles. Although elegant palladi-
um-catalyzed cyclization strategies employing CO-in-
2
39
62%
59%
3
4
43
44
[22]
À
duced C H activation have been developed,
the
Cadogan–Sundberg cyclization[23] employing phos-
phite reagents, or the recently developed PPh3-medi-
ated reductive cyclization by Freeman and co-work-
ers,[24] remain the methods of choice for the rapid
preparation of carbazoles from 2-nitrobiphenyls. Due
to the relatively harsh reaction conditions utilized in
the PPh3-mediated protocol (refluxing dichloroben-
zene, 2.5 equiv. of PPh3) and the long reaction times
73%
81%
5
6
65
61
typically required when employing PACTHRE(UNG OEt)3 as solvent
and reductant, we became intrigued with the recently
reported microwave-enhanced Cadogan–Sundberg
cyclization reported by Dehaen and co-workers.[25]
Microwave irradiation has emerged as a valuable syn-
thetic tool since dramatic rate enhancements and su-
perior yields are often obtained under focused micro-
wave irradiation.[26] The microwave-enhanced Cado-
gan–Sundberg cyclization conditions reported by
Dehaen involved reaction of 2-nitrobiaryls in dilute P-
85%
7
8
9
63
41
45
86%
66%
ACHTREUNG(OEt)3 (0.08 molar) at 2108C for 10–20 min at a maxi-
mum irradiation power of 300 W. We briefly probed
the Dehaen conditions and settled on a slight modifi-
cation of the reaction conditions that involved run-
ning the reaction at 2008C for 10 min in PCAHTRE(UNG OEt)3
(0.5M) at a maximum irradiation power of 350 W.
For example, microwave irradiation of 37 under these
conditions furnished carbazole 74 which was isolated
in 71% yield (Scheme 6). These conditions were ex-
tended to selected 2-nitrobiaryls allowing for the
preparation of a range of structurally diverse carba-
zoles in modest to good yield as shown in Table 4.
Mono-, di-, tri-, tetra-, and pentasubstituted carba-
83%
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The facility with which 2-nitrobenzenediazonium
salts readily undergo Suzuki–Miyaura cross-coupling
to give 2-nitrobiphenyls followed by reductive cycliza-
tion to carbazoles was further highlighted by the short
total synthesis of the carbazole natural products clau-
sine V 88, clausine C 91, clausine N 93, and glycobor-
ine 95 (Scheme 7). The clausine alkaloids have been
isolated from the stem bark and roots of Clausena ex-
cavate,[27] a wild plant which has been claimed to be
useful in folk medicine as a detoxification agent and
for the treatment of snake bites.[28] Clausine V 88 has
been utilized in the preparation of a number of carba-
zole polymers having interesting electrochemical, con-
ductive, and magnetic properties.[29] The preparation
of clausine V 88, which closely parallels previous syn-
theses, involved the Suzuki–Miyaura cross coupling of
Table 4. (Continued)
Entry 2-Nitrobiphenyl Carbazole
Yield
85%
10
11
46
66
63%
41%
12
67
12 with boronic acid 27 in the presence of Pd
and provided 87 in 78% yield.[26] Reductive cycliza-
tion of 87 under microwave irradiation in P(OEt)3
ACHTREUNG(OAc)2
ACHTREUNG
gave clausine V 88 in 81% yield. For the preparation
of clausine C 91, coupling of 12 with boronic acid 89
zoles bearing functional handles for further manipula- under the optimized reaction conditions gave 90 in
tion were rapidly prepared in just three synthetic 73% yield. Reductive cyclization of 90 afforded a
steps from readily available starting materials.
1.4:1 mixture of clausine C 91 (41%) and the regioiso-
Scheme 7.
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Suzuki–Miyaura Cross-Coupling of 2-Nitroarenediazonium Tetrafluoroborates
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was added PdACTHRE(UNG OAc)2 ( 67 mg, 0.3 mmol, 0.03 equiv.). The re-
meric carbazole 92 (29%) which were easily separated
from one another by silica gel chromatography. Sapo-
nification of 91 in aqueous NaOH/MeOH gave clau-
sine N 93 in 92% yield and represents the first report-
ed total synthesis of clausine N 93. The three-step
total synthesis of glycoborine 95, isolated from Glyco-
smis arborea,[30] began with the cross-coupling of 14
with boronic acid 54 to give 2-nitrobiphenyl 94 in
sulting mixture was stirred at room temperature for 1–3 h
and concentrated under reduced pressure. The residue was
purified by silica gel chromatography to give the 2-nitrobiar-
yl product.
General Procedure for the Preparation of N-H
Carbazoles
81% yield. Reductive cyclization of 94 furnished gly- In a 10-mL glass vial was placed the appropriately substitut-
ed 2-nitrobiaryl (2.50 mmol) and 5 mL of triethyl phosphite.
The reaction was irradiated at a maximum power of 300 W
for 10 min at a temperature of 2008C and allowed to cool to
room temperature. The homogeneous solution was diluted
with 35 mL of EtOAc and added to a solution of 50 mL of 6
N HCl. The layers were well mixed for 20 min and separat-
ed. The aqueous layer was back-extracted with 20 mL of
EtOAc. The combined organic extracts were washed with
brine and dried over MgSO4. The solvent was concentrated
under reduced pressure and the residue was purified by
coborine 95 (82%) which was identical in all regards
to that reported for natural glycoborine.[29]
Conclusions
In conclusion, we have outlined an efficient protocol
for Suzuki–Miyaura cross-coupling of 2-nitrodiazoni-
um tetrafluoroborate salts with boronic acids under
extremely mild reaction conditions providing highly silica gel chromatography to afford the pure carbazole.
functionalized 2-nitrobiphenyls in modest to excellent
yield. Cross-coupling of 2-nitrodiazonium tetrafluoro-
borate salts with ortho-methoxy- and benzyloxyphe-
nylboronic acids was also demonstrated where strong-
Acknowledgements
ly electron-donating boronic acids provide increased
reactivity, despite steric interactions. Reductive cycli-
The authors wish to thank Dr. Michael Palucki, Dr. Greg
Beutner, and Dr. Nobuyoshi Yasuda for helpful discussions
zation of 2-nitrobiphenyls allows for the three-step
preparation of uniquely substituted carbazoles from
readily available 2-nitroanilines. This sequence was
further highlighted by the short synthesis of the car-
bazole natural products clausine V, clausine N, claus-
ing C, and glycoborine.
during the preparation of this manuscript.
References
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Experimental Section
Characterization data of all compounds is available in the
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[2] N. Miyaura, T. Yanagi, A. Suzuki, Synth. Commun.
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[3] For recent reviews, see: a) N. Miyaura, A. Suzuki
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General Procedure for the Preparation of 2-Nitroben-
zenediazonium Tetrafluoroborate Salts
To a solution of the appropriately substituted 2-nitroaniline
(10 mmol, 1.0 equiv.) in 100 mL of CH2Cl2 at 08C was added
BF3·OEt2 (12 mmol, 1.2 equiv.) followed by tert-butyl nitrite
(15 mmol, 1.5 equiv.). The resulting reaction mixture was al-
lowed to warm to room temperature and the slurry of the
product was stirred at this temperature for 30–60 min and
filtered. The crude product was washed with 25 mL of
CH2Cl2 and dried under vacuum/N2 sweep for 2 h to give
the 2-nitrobenzenediazonium tetrafluoroborate salt in
>95% yield.
General Procedure for Palladium-Catalyzed Cross-
Coupling ofNitrobenzenediazonium
Tetrafluoroborate Salts with Boronic Acids
[4] a) S. Darses, T. Jeffery, J.-P. GenÞt, Tetrahedron Lett.
1996, 37, 3857–3860; b) S. Darses, T. Jeffrey, J. L.
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1585

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