Improved synthesis of pyridyl-biaryl ring systems via benzidine rearrangements

Article abstract of DOI:10.1016/j.tetlet.2014.04.126

The acid-catalyzed benzidine rearrangement of diazo compounds is known to involve several rearrangements with the major pathway being a [5,5] sigmatropic rearrangement to provide 4,4′-diaminobiaryls. A limitation of this rearrangement has been poor conversions with pyridyl systems. Herein, we address this long standing issue to furnish hetero-biaryls via a pyridinium salt in the presence of trimethylsilyl iodide.

Full text of DOI:10.1016/j.tetlet.2014.04.126

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Improved synthesis of pyridyl–biaryl ring systems via benzidine
rearrangements
⇑
⇑
Gulice Y. C. Leung , Anthony D. William, Charles W. Johannes
Organic Chemistry, Institute of Chemical and Engineering Science (ICES), Agency for Science, Technology and Research A⁄STAR, 11 Biopolis Way, Helios, #03-08, Singapore
138667, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
The acid-catalyzed benzidine rearrangement of diazo compounds is known to involve several rearrange-
ments with the major pathway being a [5,5] sigmatropic rearrangement to provide 4,40-diaminobiaryls. A
limitation of this rearrangement has been poor conversions with pyridyl systems. Herein, we address this
long standing issue to furnish hetero-biaryls via a pyridinium salt in the presence of trimethylsilyl iodide.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 5 March 2014
Revised 11 April 2014
Accepted 30 April 2014
Available online xxxx
Keywords:
Benzidine rearrangement
Diazo compounds
[5,5] sigmatropic rearrangement
Hetero-biaryls
Pyridinium salt
There has been a long and controversial development of the
benzidine reaction since the first discovery reported by Hoffman
in 1863 on unsubstituted simple biaryl systems, and very lately
by Cho and co-workers with substituent(s) at the ortho or meta
positions.1,2 Wildgrube and co-workers were the first to report
on the pyridyl–aryl benzidine rearrangement which suffered from
poor conversions due to tautomerization.3 Thus, despite more than
a century of attention by the synthetic community, only a few
rather inefficient routes to heterobiaryls exist4 and hence most
mechanistic studies have been limited to the naphthyl or phenyl
systems reviewed by Mamantov.5a There has been renewed inter-
est in the benzidine rearrangement for the synthesis of chiral
naphthyl ligands for catalysis and mechanistic investigations to
determine the potential toxicity of azo dyes.5b,c
The hetero-biaryl moiety is a common functionality found in
many pharmaceutical bioactive molecules6 (Fig. 1). The current
state of the art methods for their preparation is to employ transi-
tion metal catalyzed cross-coupling reactions as developed by
Suzuki.7 However, this method has several limitations such as,
sourcing of an appropriate functionalized boronic acid or ester,
chemoselectivity of the coupling in the presence of other halogen
atoms and expensive Pd catalysts.8 These requirements diminish
optimal atom economy and generate waste, thus compromising
O
F
N
N
N
N
N
O
O
NH2
N
N
N
N
H
HN
RBX-11760
antibiotic
O
N
N
NH2
O
N
O
HN
N
NH2
PIM Kinase inhibitor
HN
NH2
FLT3 Kinase inhibitor
Figure 1. Bioactive molecules with hetero-biaryl systems.
some of the 12 principles of green chemistry.9 In the context of
an internal drug development effort, we were interested in the
investigation of the benzidine rearrangement as
a potential
improvement to construct pyridyl–aryl linkages without using a
boronic acid and particularly palladium that poses a potential reg-
ulatory hurdle.10 Herein, we report our preliminary success on
expanding the scope of this rearrangement to provide hetero-aryl
systems in reasonable yields.
A review of the literature indicated several unproductive
pathways such as tautomerization and disproportionation, which
prevent correct orientation for [5,5] sigmatropic rearrangement
of the phenylhydrazinylpyridine to provide the benzidine
rearrangement product 3. We envisioned that protection of the
nitrogen on the pyridine might shift the equilibrium from the
⇑
Corresponding authors. Tel.: +65 67998518; fax: +65 68745870 (G.Y.C.L.); tel.:
+65 67998501; fax: +65 68745870 (C.W.J.).
E-mail addresses: leung_yiu_chung@ices.a-star.edu.sg
(G.Y.C.
Leung),
Charles_johannes@ices.a-star.edu.sg (C.W. Johannes).
http://dx.doi.org/10.1016/j.tetlet.2014.04.126
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
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2
G. Y. C. Leung et al. / Tetrahedron Letters xxx (2014) xxx–xxx
thermodynamically stable hydrazono tautomer of 2, and also pre-
vent disproportionation by-products (Scheme 1). The preliminary
results of our investigation are summarized in Table 1.
Disproportionation
N
Protection
and
N
Reduction
N
N
1
N
N
Consistent with the reported literature, unsubstituted phenyl-
azopyridine 1 (Table 1, entry 1) afforded the target compound 3
in only 15% yield without the use of a pyridinium salt. Interest-
ingly, alkyl and acyl pyridinium salts led to unidentifiable mixtures
of compounds with no desired benzidine 3 (Table 1, entries 2 and
3). Sulfonamide pyridinium salts were more successful with a
notable three fold improvement in yield using the para-nosyl
pyridinium salt. The two fold difference between tosyl and para-
nosyl pyridinium salts has not been investigated (Table 1, entry
5). Silyl pyridinium salts derived from silyl triflates provided no
improvement, however TMS-pyridinium salts derived from TMSI
gave the best yield of 52% (Table 1, entry 8). At this point no further
studies were undertaken to determine why TMSOTf was signifi-
cantly worse than TMSI.11
H2N
NH2
Reduction
X
H
N
H
N
N
H
H
H
N
P
N
N
N
N
H
2
Tautomerization
H
N
H2N
N
H
N
3
NH2
Unproductive pathways
4,4'-azabenzidine
Scheme 1. Tautomerization of N-phenyl-N0-pyridin-2-ylhydrazine.
At this point, no further optimization studies were conducted
and the TMSI conditions were used to explore the substitution
effect for the hetero-aryl benzidine rearrangement. In addition to
[5,5] sigmatropic rearrangements to provide 4,40-benzidine prod-
ucts, [3,5] and [1,3] sigmatropic rearrangements can provide diph-
enyline and o-semidine products. To explore if these
rearrangements could be selective and to understand if substitu-
tion on the pyridyl versus phenyl ring had an effect on the product
distribution, several substrates were synthesized.12 The key diazo
intermediates 1a–g were prepared in moderate to good yields by
reacting a substituted 2-aminopyridine with nitrosobenzene deriv-
atives.13 The rearrangement results are listed in Table 2.
Consistent with unsubstituted 1, 4-substituted aminopyridines
1a and 1b (Table 2, entry 1) furnished [5,5]-sigmatropic rearrange-
ment products 3a and 3b in moderate yields. No other competing
rearrangement products such as 4 or 5 were observed, thus indi-
cating that the 4-position has relatively little impact on the reac-
tion pathways. 5-Substituted aminopyridines 1c–e, which block
the benzidine rearrangement pathway provided only [3,5]-sigma-
tropic diphenyline products 4c–e.14 However, similar substitution
to prevent the [5,5] rearrangement at the 4 position of the phenyl
ring completely suppressed diphenyline formation. Only minor
Table 1
N-substitution effect on hetero-benzidine rearrangement
H2N
N
N
SnCl2,
HCl-EtOH
110 o
RX
N
N
N
N
R
N
2
1
X
C
3
NH2
Entry
2a
3 Yield (%)b
1c
2
3
4
5
6
7
8
N/A
15
R = Me; X = I
NAd
NAd
21
R = Ac; X = Cl
R = Ts; X = Cl
R = Ns; X = Cl
R = TBS; X = OTf
R = TMS; X = OTf
R = TMS; X = I
48
14
12
52
a
Conditions: diazo compound (1 equiv), RX (1.1 equiv), rt, 8 h, isolated yield; for
entries 2–5, CH2Cl2; entries 6–8, n-hexane as solvent.
b
Conditions: SnCl2 (1.3 equiv), concd HCl, EtOH, 110 °C, 2 h, isolated yield.
Control with no protecting group.
Unknown compounds at TLC baseline that could not be isolated.
c
d
Table 2
Substrate scope of the benzidine rearrangementa
X
H2N
Conditions
R
N
NH2
X
X
H2N
X
N
N
N
N
N
N
H
5
R
NH2
NH2
1
3
4
Entry
1
Substrate
Product
H2N
Yield (%)b
X
X
3a X = Br
3b X = I
54
46
N
N
N
N
NH2
1a X = Br
1b X = I
X
4,4'-benzidine
NH2
4c X = Cl
4d X = Br
4e X = I
52
48
40
N
N
N
N
2
3
1c X = Cl
X
1d
1e
X = Br
X = I
NH2
diphenyline
H2N
5f
5
(1f recovery 90%)
N
N
N
N
N
H
Cl
1f
Cl
o-semidine
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G. Y. C. Leung et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
Table 2 (continued)
Entry
Substrate
Product
Yield (%)b
Br
Br
H2N
N
4
5g
37
N
N
N
N
H
Cl
1g
Cl
o-semidine
Br
N
NH2
6 (recover 40%)
a
Conditions: (1) diazo compound (1 equiv), TMSI (1.1 equiv), rt, 8 h; (2) SnCl2, EtOH–HCl, 110 °C.
Isolated yield.
b
H
N
H
N
X
H
H
P
N
H2N
I
P
H2N
N
N
I
I
[ ]
k1
[5,5]
NH2
X
X
4,4'-benzidine
X
NH2
X
H
N
H
N
H
H
P
H
5
X
N
[II]
N
N
N
P
I
I
k2
H
H
[3,5]
N
H
N
H
NH2
Reduction
P
H
H
NH2
2
H+
X
1
HN
diphenyline
NH
H
kdisproportionation
H
N
H
N
H
H
N
V
H
[
]
X
P
H
N
III
[
]
N
P
R
4'
I
H
X
k3
I
N
2
[1,3]
N
N
H
NH2
X
o-semidine
H
N
H
H
N
H
N
X
H
H
H
H
P
X
[IV]
N
N
P
I
H
X
k4
[1,3]
N
I
N
N
H
NH2
X
X
o-semidine
X
Scheme 2. Simplified mechanistic proposal for the formation of 4 and 5.
amounts of o-semidene 5f were observed, and 90% of 1f was recov-
ered indicating that disproportionation pathways were also shut
down.15 5-Bromo-2-(4-chlorophenyl)diazenylpyridine (1g), which
blocks both positions required for the benzidine rearrangement,
provided o-semidine 5g in 37% yield along with 40% of the dispro-
portionation fragment, 5-bromo-2-aminopyridine (6) (Table 2,
entry 4). Interestingly this suggests that the 5 position of the ami-
nopyridine ring overrides the influence of the substitution at the 4
position on the phenyl ring.
It is apparent that while the [5,5] sigmatropic rearrangement
proposed in Scheme 2 is the major pathway when the 5 and 40
positions are unsubstituted, there are competing and alternate
processes depending on the location of the substituents on the
phenylhydrazinylpyridine 2. Based on the previous mechanistic
studies proposed by Shine16 on the bis-aryl system, we hypothe-
size the following plausible mechanistic considerations depicted
in Scheme 2 for the effect of substitution on the pyridyl and aryl
rings. There are as few as five competing pathways (I–V) for the
intermediate bis-substituted phenylhydrazinylpyridine 2. When
the pyridyl is unsubstituted or substituted at the 4 position
the reaction occurs predominately through pathways I and V
(k1 > kdis >> k2, k3, k4). When the substitution is such that benzidine
rearrangement is blocked on the pyridyl ring, pathway II [3,5] pre-
dominates (k2 > kdis >> k3, k4 >> k1). However the same substitution
on the phenyl ring either shuts down pathway III [1,3] or dispro-
portionation V occurs (kdis > k3 > k4, k2 >> k1). When both rings are
substituted to prevent [5,5] rearrangement pathway IV [1,3] is
now preferred along with disproportionation (k4 = kdis > k2,
k3 >> k1). These preliminary results that there are subtle effects
from the substitution that may affect the mechanism for these pyr-
idyl–aryl rearrangements. Further substrate scope studies and
more extensive experiments will need to be conducted in order
to determine the underpinning mechanistic rationale. In addition,
the roles of the counterion (OTf vs I) and the difference between
nosyl and tosyl versus silyl will need to be studied in more depth.
In conclusion, we have developed a method using pyridinium
salts to provide a threefold improvement in yield to construct
various substituted phenylpyridines. Importantly, this method
circumvents the use of expensive boronic acids and palladium
catalysts. Work in this area as well as detailed mechanistic studies
will be reported in due course.
Acknowledgments
We thank Ms. Doris Tan (ICES) for high-resolution mass spec-
trometric (HRMS) assistance. Financial support for this work was
provided by the Agency for Science, Technology and Research
(A⁄STAR).
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15. We attempted to exchange the chloride in 1f to an electron- donating group
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