The gomberg-bachmann reaction for the arylation of anilines with aryl diazotates

Article abstract of DOI:10.1002/chem.201200430

Simply aqueous sodium hydroxide is sufficient to exclude ionic side reactions and to prepare 2-aminobiphenyls from aryl diazotates and anilines through a new variant of the Gomberg-Bachmann reaction (see scheme). The metal-free reaction under basic conditions allows to exploit the highly radical-stabilizing effect of the aniline's free amino function for the first time, which leads to a so far unreached regioselectivity. Copyright

Full text of DOI:10.1002/chem.201200430

COMMUNICATION
DOI: 10.1002/chem.201200430
The Gomberg–Bachmann Reaction for the Arylation of Anilines with Aryl
Diazotates
Gerald Pratsch, Tina Wallaschkowski, and Markus R. Heinrich*[a]
Regarding todayꢀs key research areas in organic chemis-
try, cross-coupling reactions to biaryls should ideally be car-
À
ried out as C H activations and not depend on the prepara-
tion of haloaromatics.[1] A well-known reaction fully in line
with such current requirements is the Gomberg–Bachmann
biaryl synthesis, which was first published in 1924.[2–4] How-
ever, all later developments and improvements for this reac-
tion type, among which many variants are exploiting phase-
transfer effects,[5] could not significantly increase its attrac-
tiveness. The main reason for this trend certainly is the su-
periority of modern organometallic cross-coupling reactions
with respect to regioselectivity.[6,7] Even though Gomberg–
À
Bachmann reactions can formally be regarded as C H acti-
vations,[8,9] which enables the use of simple and cheap start-
Scheme 1. Mechanism of the Gomberg–Bachmann reaction by
ing materials, the lack of selectivity narrows the scope of
suitable substrates to a few compounds, with simple benzene
being by far the most important.[10,11] Moreover, the aromat-
ic substrate needs to be employed in large excess and is
often even used as solvent.[12] Although conceptually new,
these limitations remain for recently developed organocata-
lytic biaryl syntheses with iodobenzenes.[13–15] Herein, we
present a novel variant of the Gomberg–Bachmann reaction
that allows the highly regioselective radical coupling of
phenyl diazotates with anilines.
When choosing diazonium salts as one of the most readily
available aryl radical sources,[16] reactions with free anilines
are basically complicated by the competing formation of tri-
azenes and azo compounds.[17] A known but not generally
effective or selective way out is to replace the anilines by
anilinium salts.[18] Nevertheless, to enable the use of free ani-
lines as reactants, we reasoned that the diazonium salt needs
to be protected from side reactions by a rapid ionic cou-
pling,[19] which, however, does not prevent the later forma-
tion of aryl radicals. Interestingly, this prospective reaction
course overlaps with the mechanism generally accepted for
Gomberg–Bachmann reactions.[20] Under basic conditions,
diazonium ions 1 are first converted to a mixture of diazo-
Rꢁchardt.[20]
(Scheme 1). The formation of biphenyl 9 proceeds via the
homolytic cleavage of 4 to give aryl radical 5 and azoxy rad-
ical 6, the addition of 5 to the aromatic substrate 7, and the
final rearomatization of 8.
Preliminary experiments with seven literature-known
Gomberg–Bachmann protocols,[21] however, revealed that
neither 4-chlorophenyldiazonium chloride nor its corre-
sponding tetrafluoroborate 1 (R1 =Cl) were able to give
more than trace amounts of the desired 2-aminobiphenyl 9
upon reaction with 4-fluoroaniline (7, R2 =NH2, R3 =F)
under any conditions.[22] To now ensure a reaction course via
an aryl diazotate 3 as a protected derivative of diazonium
ion 1, solutions of the specific diazotate 10 were prepared
from 4-chlorophenyldiazonium chloride and investigated
spectroscopically.[22–24] Selected results from the coupling of
10 with 4-fluoroaniline (11) under various conditions are
summarized in Table 1. Accordingly, the radical arylation re-
action proceeds well at temperatures between 50 and 1108C
(entries 2–5).[25] Slight decreases in yield were observed for a
slower or faster addition of diazotate 10 to the reaction mix-
ture (entries 8 and 9) and upon addition of a phase-transfer
catalyst or a reductant (entries 13 and 14). Minor improve-
ments compared to the standard conditions resulted from
changing to a nitrogen atmosphere (entry 6) or from the use
of a higher concentrated alkaline solution (entry 10). A re-
duction of the excess of 4-fluoroaniline 11 from 12.5 equiva-
lents (standard) to 5.0 equivalents did also only slighly
effect the formation of aminobiphenyl 12 (entries 11 and
12).
hydroxides 2, diazotates 3, and diazo anhydrides
4
[a] G. Pratsch, T. Wallaschkowski, Prof. Dr. M. R. Heinrich
Department fꢁr Chemie und Pharmazie, Pharmazeutische Chemie
Friedrich-Alexander-Universitꢂt Erlangen-Nꢁrnberg
Schuhstraße 19, 91052 Erlangen (Germany)
Fax : (+49)9131-85-22585
E-mail: Markus.Heinrich@medchem.uni-erlangen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200430.
Chem. Eur. J. 2012, 00, 0 – 0
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Table 1. Arylation of 4-fluoroaniline (11) with diazotate 10.
Table 2. Radical arylation of anilines with diazotates.[a]
Entry
Variation vs. standard conditions[a]
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
–
74
36
70
78
74
78
73
58
68
78
78
63
65
65
80[c]
room temperature
508C
908C
1108C
nitrogen atmosphere
argon atmosphere
addition of 10 to 11 over 6 min
addition of 10 to 11 over 24 min
8n NaOH used for preparation of 10
10 equiv of 4-fluoroaniline (11)/10
5 equiv of 4-fluoroaniline (11)/10
addition of aliquat 336 (5 mol%)
addition of iron powder (2.0 mmol)
addition of diazonium salt to NaOH and 11
[a] Standard conditions: An aqueous solution of 10 [prepared from 4-
chlorophenyldiazonium chloride, (0.4m, 2.00 mmol, 5.00 mL) and aque-
ous sodium hydroxide (4n, 3 mL), 62% yield] was added dropwise over
12 min to 4-fluoroaniline (11, 25.0 mmol, 2.40 mL, 12.5 equiv) under air
at 758C. [b] Yield based on diazotate 10 determined by 1H NMR spec-
troscopy using dimethyl terephthalate [1.00 mmol, d=8.10 ppm (s, 4H)]
as internal standard. [c] Yield of diazotate intermediate: 64%; yield of 12
based on diazonium salt: 52%.
[a] Yields of 2-aminobiphenyls and regioisomers (p-14, p-15, m-23, m-24)
after purification by column chromatography. Regioselectivity for the 2-
position/3-position>20:1, in case no yield is given for the regioisomer.[27]
Finally, an experiment showed that the desired aminobi-
phenyl 12 can even be obtained through the direct addition
of 4-chlorophenyldiazonium chloride to a mixture of aque-
ous sodium hydroxide and 4-fluoroaniline, avoiding the in-
deriving from the donor-substituted anilines 4-anisidine (13,
R2 =OMe) and 4-phenetidine (13, R2 =OEt).
termediate preparation of
a solution of diazotate 10
(entry 15). Up to this point, the diazotate-based arylation
demonstrated a remarkable robustness. Additionally, amino-
biphenyl 12 was formed with unreached regioselectivities of
more than 20:1 related to its regioisomer in all reac-
tions.[26,27] The main difference with respect to previously in-
vestigated literature-known Gomberg–Bachmann reac-
tions[21] appears to be the increased base concentration. In
this way, the equilibrium between the aryl diazonium salt 1
and the aryl diazotate 3 (Scheme 1) can be shifted largely
towards the diazotate 3 and otherwise prevailing ionic side
reactions of diazonium ions with anilines are effectively sup-
pressed.[28,29] Supported by the identification of the diazo-
tates in NMR experiments,[24] we therefore propose that not
diazo anhydrides 4, such as in classic Gomberg–Bachmann
reactions, but more nucleophile-resistant diazotates 3 or di-
azohydroxides 2 represent the major intermediates of this
reaction type.[20,29,30] Slightly modified standard conditions
were then applied to determine the scope and limitations of
the biaryl synthesis (Table 2). Halogens, hydrogen, and ac-
ceptor substituents in 4-position of the aniline (as in biphen-
yls 14–22 and 25–27) were well tolerated and the products
were formed with unchangingly high regioselectivities
(>20:1).[27] Reduced selectivities, which partially account for
lower yields, were only observed for biphenyls 23 and 24,
In principle, acceptor substituents on the aniline (e.g., 4-
aminobenzonitrile 13, R2 =CN) could similarly lead to a de-
crease in selectivity, since the cyclohexadienyl radical adduct
(compare 8, Scheme 1), arising from the undesired addition
of aryl radicals in 3-position of 13, again receives better sta-
bilization.[31] In previous work, in which the arylation of 4-
anisidine (13, R2 =OMe) had to be conducted under acidic
conditions to avoid side reactions, the radical-stabilizing
effect of the methoxy group clearly predominated the influ-
ence of the protonated amino functionality, and m-23 was
consequently formed as major product.[18a] In contrast,
under the basic conditions described herein, it has been pos-
sible for the first time to advantageously exploit the highly
radical-stabilizing effect of the amino group to effectively
direct the arylation into the ortho position of the anili-
ne.[9c,27]
Structural variations of the diazotate 3 led to the conclu-
sion that lipophilic atoms or groups represent the preferred
substituents on the aromatic core. Aryl diazotates bearing
polar functional groups (e.g., R1 =4-NO2 or 4-CN) gave in-
creasing yields of undesired azo coupling compounds and
triazenes. This observation further supports the proposed re-
action course via diazohydroxides 2 or diazotates 3, because
these intermediates are likely to require lipophilic substitu-
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Arylation of Anilines with Aryl Diazotates
COMMUNICATION
ents to allow their entry into the organic (aniline-contain-
ing) phase for the later generation of aryl radicals.[32] The
phase-transfer step itself is confirmed by the successful ary-
lation of benzene (biphenyl 28) under otherwise identical
conditions.
For a comparison of para-substituted anilines and benzene
as radical acceptors, a competition experiment was conduct-
ed by using a mixture of 4-fluoroaniline (11) and benzene as
aromatic substrates. This experiment shows that 4-fluoroani-
line (11), in contrast to what one would expect from the
yields reported in Table 2, is about five times more reactive
towards aryl radicals than benzene, although it possesses
only two (activated) ortho positions compared to the six
equivalent sites of benzene (ratio of reaction rate per aro-
matic site is 16:1).[33] Taking into account literature-known
rate constants, anilines can be integrated into the reactivity
row of commonly used substrates for aryl radicals as fol-
lows: benzene (5ꢄ105 mÀ1 sÀ1),[12] para-substituted anilines
(2ꢄ106 mÀ1 sÀ1),[33] nonactivated alkenes and furan (2–3ꢄ
107 mÀ1 sÀ1), and activated alkenes (1–3ꢄ108 mÀ1 sÀ1).[34]
Beneficially, mainly with regard to an application of the
radical arylation on a larger scale, the intermediate prepara-
tion of the diazotate solution can be avoided by a modified
experimental procedure (Table 1, entry 15).[35] The results
from a comparison of both variants, each conducted with
five aminobiphenyls, are summarized in Table 3. For a
Scheme 2. Synthesis of Boscalidꢅ and Bixafenꢅ from 2-aminobiphenyls.
pared by classical palladium-catalyzed cross-coupling reac-
tions. Through the radical arylation described herein, the
same compounds are now available from much simpler
starting materials and by using cheap sodium hydroxide in-
stead of a precious catalyst.[39] Further applications of 2-ami-
nobiphenyls in heterocyclic,[40] organometallic,[41] and medic-
inal[42] chemistry have also been reported.
In summary, aryl diazotates were found to be valuable
starting materials for the direct arylation of unprotonated or
unprotected anilines. Owing to the highly radical-stabilizing
effect of the free amino group, which until now could not be
exploited effectively in Gomberg–Bachmann reactions, the
radical arylation proceeded with so far unreached regiose-
lectivity. This new synthetic access to 2-aminobiphenyls for-
À
mally proceeds in the sense of a C H activation, but without
the requirements to use catalysts and to previously prepare
bromo- or iodoarenes or even more elaborate precursors.[1]
Table 3. Comparison of variants A and B.
2-Amino- A: Addition of the diazotate B: Addition of the diazonium
biphenyl solution to the aniline
(compare Table 2)
[%][a,b]
salt solution to the aniline and
NaOH (one-pot procedure)
Experimental Section
[%][a,b]
[%][a,c]
Preparation of the aryl diazotate by diazotization (aryl diazonium chlor-
68
64
41
12
83[d]
54/10
51
53[d]
35/7
42
ide) and addition of base:
A degassed solution of sodium nitrite
(20.0 mmol, 1.38 g) in water (10 mL) was added dropwise to an ice-
cooled degassed solution of the aniline (20.0 mmol) in hydrochloric acid
(3n, 20 mL) and water (20 mL) over a period of 15 min. The clear solu-
tion was stirred for 20 more minutes at 08C. An aliquot of this 0.4m aryl
diazonium chloride solution (2.00 mmol, 5.00 mL) was treated with a pre-
cooled aqueous solution of sodium hydroxide (4n, 3 mL). The resulting
solution/suspension of the aryl diazotate can be used for the aryl–aryl
coupling.
o-15/p-15 61/19
17
19
20
52
43
60
42
62
34
39
[a] Yield after purification by column chromatography. [b] For compar-
sion: yield based on the diazotate intermediate [yield for the diazotate
determined by gas evolution: 62% (A) and 64% (B)]. [c] Yield based on
the diazonium salt. [d] Reaction on a 100 mmol scale (50-fold); yield de-
termined as in Table 1, entry 15.
Radical arylation of anilines with a previously prepared aryl diazotate:
The previously prepared solution/suspension of the aryl diazotate was
added dropwise to the aniline derivative (20.0–25.0 mmol) at 75–958C
under vigorous stirring over a period of 10–15 min. After the addition
was complete, the mixture was left to stir for 10 more minutes. The re-
sulting reaction mixture was then extracted with organic solvents (e.g. di-
ethyl ether or ethyl acetate, 3ꢄ75 mL). The combined organic phases
were washed with saturated aqueous sodium chloride and dried over
sodium sulfate. The solvent was removed under reduced pressure and the
resulting product was dried in vacuo. Depending on the product, further
purification was carried out by destillation in vacuo or column chroma-
tography on silica gel.
better insight, the yields of the one-pot variant were calcu-
lated on the basis of the diazotate and the diazonium salt.
By measuring the gas evolution in reactions of variant B, we
could further show that the diazonium salt, upon entry into
the reaction mixture, is immediately converted under loss of
nitrogen.[22,36] An accumulation of reactive intermediates,
such as diazo anhydrides, can therefore be ruled out.[35] By
applying variant B, the synthesis of aminobiphenyl 12 was fi-
nally carried out on a 50-fold (100 mmol) scale leading to an
unchanged yield.
An important field for the application of 2-aminobiphenyl
derivatives is crop protection.[37,38] Biphenyls 15 and 18,
which represent the key intermediates for Boscalidꢅ (29)[37]
and Bixafenꢅ (30)[38] (Scheme 2), currently have to be pre-
Acknowledgements
We would like to thank the Deutsche Forschungsgemeinschaft (DFG) for
generous financial support. We are further grateful to Amelie L. Bartu-
Chem. Eur. J. 2012, 00, 0 – 0
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M. R. Heinrich et al.
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Keywords: anilines · aryl diazotates · biaryls · Gomberg—
Bachmann reaction · radical reactions
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Arylation of Anilines with Aryl Diazotates
COMMUNICATION
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with 4-fluoroaniline (ca. 20ꢄ); 3,4-dichlorophenylboronic acid com-
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alyst is not taken into account.
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ed on the basis of the known value for benzene (k=4.5ꢄ105 mÀ1 sÀ1
,
see reference [12]).
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Received: February 9, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
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M. R. Heinrich et al.
Radical Reactions
G. Pratsch, T. Wallaschkowski,
M. R. Heinrich* .............. &&&& — &&&&
The Gomberg–Bachmann Reaction for
the Arylation of Anilines with Aryl
Diazotates
Simply aqueous sodium hydroxide is
sufficient to exclude ionic side reac-
tions and to prepare 2-aminobiphenyls
from aryl diazotates and anilines
through a new variant of the Gom-
berg–Bachmann reaction (see scheme).
The metal-free reaction under basic
conditions allows to exploit the highly
radical-stabilizing effect of the anilineꢀs
free amino function for the first time,
which leads to a so far unreached
regioselectivity.
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These are not the final page numbers!