Cobalt(III)-catalyzed synthesis of indazoles and furans by C-H bond functionalization/addition/cyclization cascades

Article abstract of DOI:10.1021/ja5116452

The development of operationally straightforward and cost-effective routes for the assembly of heterocycles from simple inputs is important for many scientific endeavors, including pharmaceutical, agrochemical, and materials research. In this article we describe the development of a new air-stable cationic Co(III) catalyst for convergent, one-step benchtop syntheses of N-aryl-2H-indazoles and furans by C-H bond additions to aldehydes followed by in situ cyclization and aromatization. Only a substoichiometric amount of AcOH is required as an additive that is both low-cost and convenient to handle. The syntheses of these heterocycles are the first examples of Co(III)-catalyzed additions to aldehydes, and reactions are demonstrated for a variety of aromatic, heteroaromatic, and aliphatic derivatives. The syntheses of both N-aryl-2H-indazoles and furans have been performed on 20 mmol scales and should be readily applicable to larger scales. The reported heterocycle syntheses also demonstrate the use of directing groups that have not previously been applied to Co(III)-catalyzed C-H bond functionalizations. Additionally, the synthesis of furans demonstrates the first example of Co(III)-catalyzed functionalization of alkenyl C-H bonds.

Full text of DOI:10.1021/ja5116452

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Article
Cobalt(III)-Catalyzed Synthesis of Indazoles and Furans by
C–H Bond Functionalization/Addition/Cyclization Cascades
Joshua R Hummel, and Jonathan A. Ellman
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 10 Dec 2014
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Cobalt(III)-Catalyzed Synthesis of Indazoles and Furans by
C–H Bond Functionalization/Addition/Cyclization Cascades
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Joshua R. Hummel and Jonathan A. Ellman*
Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States
Supporting Information Placeholder
ABSTRACT: The development of operationally straightforward and cost effective routes for the assembly of heterocycles from
simple inputs is important for many scientific endeavors, including pharmaceutical, agrochemical and materials research. In this
Article we describe the development of a new air-stable cationic Co(III)-catalyst for convergent, one step bench-top syntheses of N-
aryl-2H-indazoles and furans by C–H bond additions to aldehydes followed by in situ cyclization and aromatization. Only a sub-
stoichiometric amount of AcOH is required as a low cost and convenient to handle additive. The syntheses of these heterocycles are
the first examples of Co(III)-catalyzed additions to aldehydes, and reactions are demonstrated for a variety of aromatic,
heteroaromatic, and aliphatic derivatives. The syntheses of both N-aryl-2H-indazoles and furans have been performed on 20 mmol
scales and should readily be applicable to larger scales. The reported heterocycle syntheses also demonstrate the use of directing
groups that have not previously been applied to Co(III)-catalyzed C–H bond functionalizations. Additionally, the synthesis of
furans demonstrates the first example of cobalt(III)-catalyzed functionalization of alkenyl C–H bonds.
. INTRODUCTION
examples of Co-catalyzed additions of C–H bonds to carbonyl
compounds and represent the first use of azo18–19 and oxime
directing groups with Co(III) catalysis (Figure 1). Moreover, the
C–H bond functionalization of α,β-unsaturated oximes to give
furans provides the first example of Co(III)-catalyzed
functionalization of alkenyl C–H bonds.20 Both heterocycle
syntheses utilize the same air-stable cationic Co(III) catalyst, and
reactions can be performed on the bench-top and on large scale.
Remarkable progress in transition-metal-catalyzed C–H bond
functionalization has enabled the direct generation of nucleophilic
partners without requiring pre-functionalization.1,2 Strategies for
the addition of C–H bonds to polarized π-bonds are particularly
efficient and atom economical for the assembly of heteroatom
substituted products.3 Due to the vast number of diverse
aldehydes that are commercially available, aldehydes potentially
represent the most versatile of the polarized π-bond inputs.
However, C–H bond additions to aldehydes are reversible with
the alcohol products only favored when destabilized, highly
electron-deficient aldehydes are used.4 For typical aldehydes,
good conversion to the alcohol product can only be achieved by
trapping the alcohol to prevent reversibility, for example, through
protection5 or oxidation.6 Recently, we have reported a general
strategy to access important classes of heterocycles by cyclative
capture of the initially formed alcohol intermediate via reaction
with the directing group for C–H functionalization (Figure 1).7 In
this approach the alcohol can either react as a leaving group with
the directing group serving as a nucleophile as represented by
indazole synthesis, or the alcohol can act as a nucleophile with the
directing group serving as an electrophile as depicted for furan
synthesis.
While our cyclative capture approaches provide efficient and
convergent access to heterocycles, this chemistry is limited by the
expensive Rh(III) C–H functionalization catalysts that we have so
far employed. Due to the high cost of the more extensively
developed catalyst systems based upon the precious metals Rh,
Pd, Ag, Ir, Pt and Au, it is not surprising that C–H bond
functionalization using the earth abundant first row metals such as
Mn,8 Fe,9 Co,10–12 Ni13 and Cu,14 has increasingly been
investigated as an attractive alternative based on availability and
cost.15
Figure 1: Rhodium and cobalt-catalyzed heterocycle synthesis via
aldehyde addition followed by cyclative capture.
. RESULTS AND DISCUSSION
Seminal reports by Kanai, Matsunaga, and co-workers have
established that the high-valent preformed cobalt complex
[Cp*Co(C6H6)][PF6]2 (4) catalyzes the addition of 2-
phenylpyridyl11g and indole11f C–H bonds to sulfonyl protected
imines. We therefore envisioned that a cationic Cp*Co(III) system
could also be designed for additions to aldehydes with cyclative
capture to obtain heterocycles. To evaluate the potential of high
valent Co-catalysts for these transformations, we chose to
investigate the addition of azobenzene (1a) to benzaldehyde (2a)
(Table 1). The initial attempt utilizing Kanai’s and Matsunaga’s
In this Article we report the development of a new Co catalyst
for the synthesis of 2-aryl indazoles and furans (Figure 1). These
structural motifs are prevalent in drugs and natural products,16–17
and for 2-aryl indazoles, exhibit interesting spectrophotometric
properties.7a The transformations reported herein are the first
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Page 2 of 9
preformed catalyst [Cp*Co(C6H6)][PF6]2 (4) resulted in a poor
tetrakis(pentafluorophenyl)borate can be conveniently performed
1
2
3
4
5
6
7
8
yield of the desired product (entry 1).
on a multi-gram scale to provide the desired catalyst 5 (Scheme
1). A biphasic mixture of benzene/H2O was selected as the solvent
of choice for this reaction to partition KPF6 into the aqueous
phase while avoiding any potential exchange of the benzene
ligand on the parent [Cp*CoIII(C6H6)] complex.
We next evaluated a series of silver halide abstractors with
[Cp*CoCl2]2 as the precatalyst to generate cationic Co(III) in situ.
AgPF6 provided similar results to those observed with the
preformed catalyst (entry 2), and with AgSbF6 or AgOAc little or
no product was obtained (entries 3 and 4, respectively). However,
switching to the non-coordinating AgB(C6F5)4 significantly
increased the yield (entry 5), and the addition of a slight excess of
AgB(C6F5)4 resulted in further improvement (entry 6). In previous
reports on Co(III) catalysis the addition of catalytic amounts of
acetate base was beneficial.11d–f During our optimization, we
found that the addition of 20 mol % of AgOAc also proved to be
advantageous to the reaction, resulting in a near quantitative yield
(entry 7).21 Furthermore, although lower concentrations were
tolerated, high concentration (2.0 M) was selected for added
convenience and efficiency.
Scheme 1. Synthesis of [Cp*Co(C6H6)][B(C6F5)4]2 (5)
Me
Co
4
Me
Co
5
Me
Me
Me
Me
Me
Me
Me
Me
KB(C6F5)4
[PF6]2
[B(C6F5)4]2
9
benzene/H2O (1:1)
60 oC, 4 h
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8.25 mmol
4.64 g
10.9 g
81% yield
Preliminary evaluation of 5 in the C–H functionalization
cascade to 3a established a large increase in reactivity over 4
(Table 2, entries 1 vs. 2). In analogy to the observations for
[Cp*CoCl2]2/AgB(C6F5)4 in Table 1, the addition of silver acetate
resulted in a dramatic improvement in the reaction yield (entries 3
and 4). We therefore sought to replace the precious metal additive
AgOAc with earth abundant first row metal acetate salts.
We first investigated Cu(OAc)2 because this additive had
previously been observed to result in higher yields for Rh(III)-
catalyzed transformations, including in transformations where
Cu(II) did not serve as an oxidant.22 While promising results were
observed at 10 mol % (71%, entry 5), a significant reduction in
yield was obtained at a higher loading (entry 6). Interestingly,
although 10 mol % of Cu(OAc)2(H2O)4 did not significantly
influence reaction outcome (entry 7), at 20 mol % the tetrahydrate
performed substantially better than anhydrous copper (II) acetate
(entries 6 vs. 8). Based upon this observation, water was evaluated
as an additive demonstrating that this transformation was not
sensitive to moderate amounts of moisture (entries 9–11). In fact,
water was slightly beneficial when 1.0 equivalent was employed
providing 3a in 53% yield. Turning our attention to other protic
additives we found that AcOH proved highly effective (entry 12),
and with these conditions achieved our goal of completely
eliminating all precious metal additives from the reaction system.
Table 1. Optimization of Reaction Conditions for N-aryl-
2H-Indazole Synthesis with [Cp*CoCl2]2
a
Entry Co(III) source
(mol %)
Ag salt
(mol %)
Acetate additive Yield
(mol %)
--
--
--
--
--
--
(%)b
2
3
1
1
4 (10)
--
2
3
4
5
6
7
8
9
10
11d
12
a
[Cp*CoCl2]2 (5)
[Cp*CoCl2]2 (5)
[Cp*CoCl2]2 (5)
[Cp*CoCl2]2 (5)
[Cp*CoCl2]2 (5)
[Cp*CoCl2]2 (5)
[Cp*CoCl2]2 (2.5)
[Cp*CoCl2]2 (1)
[Cp*CoCl2]2 (2.5)
[Cp*CoCl2]2 (2.5)
--
AgPF6 (20)
AgSbF6 (20)
AgOAc (20)
AgB(C6F5)4 (20)
AgB(C6F5)4 (25)
AgB(C6F5)4 (25)
AgB(C6F5)4 (12.5) AgOAc (10)
AgB(C6F5)4 (5) AgOAc (4)
AgB(C6F5)4 (12.5) KOAc (10)
AgB(C6F5)4 (12.5) AgOAc (10)
--
51
61
AgOAc (20)
97 (91)c
63
44
54
45
--
AgB(C6F5)4 (25)
AgOAc (20)
Conditions: 2a (1.0 equiv), 1a (2.0 equiv) in 1,4-dioxane (2.0 M) for 24
b
h. Determined by GC analysis relative to tetradecane as an external
standard. Isolated yield at 0.20 mmol scale. d Reverse stoichiometry: 2a
c
(2.0 equiv), 1a (1.0 equiv).
Table 2. Optimization of Reaction Conditions for Indazole
Synthesis with Catalyst 5 a
The application of lower catalyst loadings resulted in a reduced
yield, providing 63% yield with 2.5 mol % of [Cp*CoCl2]2 (entry
8) and 44% yield when only 1 mol % [Cp*CoCl2]2 was employed
(entry 9). We decided to continue evaluation at 2.5 mol % of
[Cp*CoCl2]2 due to the difficulty in evaluating minor differences
at the near quantitative yield observed at higher catalyst loading.
The use of KOAc as an alternative to AgOAc resulted in a slightly
lower yield (entries 8 vs. 10), as did the reversal of stoichiometry
(entry 11). Finally, no reaction occurred when only Ag salts and
no [Cp*CoCl2]2 was added (entry 12), indicating that Cp*Co(III)
is essential for C–H bond functionalization.
Although a high yield of indazole 3a was obtained under the
optimized Co-catalyzed conditions (entry 7, Table 1), our goal of
identifying a cost effective earth abundant catalyst system was
only partially realized because a significant mol % of the precious
metal silver was still required. In particular, 25 mol % of
AgB(C6F5)4 was necessary to abstract the chlorides to generate the
cationic Co(III) catalyst, with 20 mol % more silver contributed
by the AgOAc additive needed to achieve high yields.
Entry Preformed Co(III) catalyst Additive
Temp
(oC)
130
130
130
130
130
130
130
130
130
130
130
130
100
100
130
130
130
130
Yield
(%)b
2
31
82
72
71
25
75
50
45
53
27
85
87
(mol %)
4 (10)
5 (10)
5 (10)
5 (10)
5 (10)
5 (10)
5 (10)
5 (10)
5 (10)
5 (10)
5 (10)
5 (10)
5 (10)
5 (10)
5 (10)
5 (10)
5 (5)
(mol %)
--
--
1
2
3
4
5
6
7
8
AgOAc (10)
AgOAc (20)
Cu(OAc)2 (10)
Cu(OAc)2(20)
Cu(OAc)2(H2O)4 (10)
Cu(OAc)2(H2O)4 (20)
H2O (50)
H2O (1.0 equiv)
H2O (2.0 equiv)
AcOH (10)
AcOH (10)
AcOH (10)
AcOH (50)
PivOH(10)
AcOH (5)
9
10
11
12
13
14c
15
16
17
18
a
90(83)d
71
80
67
68
As a first step to eliminating any use of Ag salts, we developed
an independent synthesis of the optimal catalyst
[Cp*Co(C6H6)][B(C6F5)4]2 (5) that avoids the use of costly
metals. We selected [Cp*Co(C6H6)](PF6)2 (4) as a viable starting
point because Kanai and Matsunaga had prepared this complex
without the use of Ag salts or other expensive reagents.11g Anion
metathesis of complex 4 and commercially available potassium
5 (5)
PivOH (5)
Conditions: 2a (1.0 equiv), 1a (2.0 equiv) in 1,4-dioxane (2.0 M) for 24
h. Determined by GC analysis relative to tetradecane as an external
b
standard. c Reaction performed on the bench-top under nitrogen. d Isolated
yield at 0.20 mmol scale.
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Table 3. Azobenzene Substrate Scope a,b
Additional reaction parameters were investigated to enhance the
1
2
3
4
5
6
7
8
practicality of the transformation. First, the reaction temperature
was explored, and a comparable yield was observed at a
temperature below the solvent boiling point (entries 13 and 14).
Furthermore, rigorous glovebox conditions were not required,
which allowed reactions to be conveniently set up on the bench-
top (entry 14).
In previous reports of C–H functionalization, pivalic acid has
proven to be superior to other organic acids.23 However, when
PivOH was used in place of AcOH, a similar yield was obtained
(entries 12 vs. 16). This trend was also observed at lower acid and
catalyst loading (entries 17 vs. 18). Ultimately, acetic acid was
selected as the additive of choice due to lower cost.
R2
R1
R2
5 (10 mol %)
AcOH (10 mol %)
N
O
R1
N
N
+
H
Ph
N
1,4-dioxane (2.0 M)
100 oC, 24 h
Ph
1
2a
3
N
N
N
NO2
N
+
O2N
Ph
Ph
3b
3b'
Co: 10% (12%)c,d
Rh: 62% combined yield (rr 9:1)f
9
Co: 48% (52%)c,d
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OMe
Having identified practical reaction conditions that were free of
precious metals for the synthesis of 3a, we next evaluated a series
of unsymmetrical azobenzenes to determine the influence of steric
and electronic parameters on the regioselectivity of this
transformation (Table 3). In addition, the original conditions
developed to generate cationic Cp*Co(III) in situ (Table 1) were
also evaluated for each substrate to provide a comparative
analysis of these two catalyst systems.
MeO
N
N
N
N
+
Ph
Ph
3c'
3c
Co: 45% (56%)c,d
Co: 22% (21%)c,d
Rh: 61% combined yield (rr 9:1)f
Me
CF3
Me
N
N
N
N
The major regioisomer obtained from the reaction of the para-
N
N
OH
nitro
substituted
azobenzene,
(E)-1-(4-nitrophenyl)-2-
CF3
Me
Ph
Me
Ph
Ph
phenyldiazene, resulted from C–H functionalization on the more
electron-rich aromatic ring, providing fully separable
regioisomers 3b and 3b’ in a 4.6:1 ratio when the preformed
catalyst 5 was used. Comparable results were seen when cationic
Cp*Co(III) was generated in situ and the AgOAc additive was
included, providing a 4.4:1 ratio of regioisomers 3b and 3b’. In a
similar fashion, the meta-methoxy substituted azobenzene, (E)-1-
(3-methoxyphenyl)-2-phenyldiazene, also underwent C–H
functionalization on the more electron-rich aryl ring, furnishing
products 3c and 3c’ in 2.1:1 ratio of separable regioisomers with
preformed catalyst 5/AcOH and 2.7:1 ratio with
[Cp*CoCl2]2/AgB(C6F5)4/AgOAc. Notably, for both catalyst
systems reaction on the meta-methoxy substituted aromatic ring
only occurred at the less hindered of the two ortho sites to give
regioisomer 3c. These results are consistent with the yields and
selectivity that we previously observed with Rh(III), although
higher regioselectivities were observed with this precious metal
catalyst.7a
Several 3,5-disubstituted azobenzenes containing both electron-
withdrawing and electron-donating functionalities were also
evaluated. Indazoles 3d and 3e were obtained as single
regioisomers in good yield, establishing that steric effects
dominate the regioselective outcome of this Cp*Co(III)-catalyzed
reaction. With Rh(III) catalysis high regioselectivities albeit with
slightly lower yields were previously observed for these
substrates. In addition, a cleavable phenolic derivative was
employed to access indazoles 3f and 3g in reasonable though
lower yield than for the corresponding azobenzene lacking the
hydroxyl substituent (see 3d).7a For 3f and 3g, Rh(III) catalysts
had previously provided somewhat higher yields.
3e
3d
3f
Co: 84% (73%)c
Rh: 61%f
Co: 67% (75%)c
Co: 50% (53%)c
Rh: 53%g
Rh: 68%e
Me
OH
Me
N
N
N
N
R
Br
F3C
Me
Me
Ph
Ph
3g
3h
Co (R = H): 63% (74%)c
Co: 47% (59%)c
Rh (R = OH): 46%e
Rh: 60%e
Me
Me
N
N
N
N
MeO2C
Br
Me
Me
Me
Me
Ph
Ph
3i
3j
86% (78%)c
95% (84%)c
R
N
N
N
N
R
Me
Me
Me
Me
Ph
Ph
3k
3l (R = OMe): 70% (64%)c
Co (R = H): 71% (68%)c
c
Rh (R = OH): 62%e
(R = CF3): 54% (65%)
3m
Me
Me
Me
N
N
N
N
R
R
Me
Me
Ph
Ph
3n
3o
Co (R = H): 77% (86%)c
Co (R = H): 69% (84%)c
Rh (R = OH): 60%e
Rh (R = OH): 76%e
A series of 3,5-dimethyl substituted azobenzenes were then
applied to the selective introduction of functionality to the
indazole core (3h–3o, Table 3). Indazoles containing electron-
poor (3h–3i, 3m), electron-neutral (3g, 3j–3k, 3n–3o), and
electron-rich (3l) substituents were all obtained in good yields.
Moreover, functionality could be placed regiospecifically at the 5-
(3g–3k), 6- (3l–3n) and 7-positions (3o) of the indazole ring. In
cases where the same or closely related indazole products had
previously been prepared using Rh(III) catalysis, comparable
yields were observed (3g–h, 3k, 3n–3o).
a
Co(III) conditions: 2a (0.20 mmol), azobenzene 1 (0.40 mmol), 5 (10
mol %) and AcOH (10 mol %) in 1,4-dioxane (2.0 M) at 100 oC for 24 h.
Isolated yields after silica gel chromatography.
b
c
Co(III) in situ
conditions: 2a (0.20 mmol), azobenzene 1 (0.40 mmol), [Cp*CoCl2]2 (5
mol % of Co dimer), AgB(C6F5)4 (25 mol %), and AgOAc (20 mol %) in
1,4-dioxane (2.0 M) at 130 oC for 24 h. Ratio of fully separable
d
e
regioisomers. Rh(III) conditions: azobenzene 1 (0.20 mmol), 2a (0.40
mmol), [Cp*RhCl2]2 (5 mol % of Rh dimer), AgSbF6 (20 mol %), and
MgSO4 (100 mg) in tetrahydrofuran (0.2 M) at 110 oC for 24 h. f Reaction
g
was conducted in 1,4-dioxane (0.2 M). Reaction was conducted in 1,4-
dioxane (1.0 M).
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Table 4. Aldehyde Substrate Scope for N-aryl-2H-Indazole Synthesisa,b
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o
a Co(III) conditions: aldehyde 2 (0.20 mmol), 1a (0.40 mmol), 5 (10 mol %) and AcOH (10 mol %) in 1,4-dioxane (2.0 M) at 100 C for 24 h. b Isolated
c
yields after silica gel chromatography. Co(III) in situ conditions: aldehyde 2 (0.20 mmol), 1a (0.40 mmol), [Cp*CoCl2]2 (5 mol % of Co dimer),
AgB(C6F5)4 (25 mol %), and AgOAc (20 mol %) in 1,4-dioxane (2.0 M) at 130 C for 24 h. d Rh(III) conditions: azobenzene 1 (0.20 mmol), aldehyde 2
o
(0.40 mmol), [Cp*RhCl2]2 (5 mol % of Rh dimer), AgSbF6 (20 mol %), and MgSO4 (100 mg) in tetrahydrofuran (0.2 M) at 110 oC for 24 h. e Reaction was
conducted in 1,4-dioxane (0.2 M). f Reaction was conducted in 1,4-dioxane (1.0 M).
A variety of aldehydes were next evaluated (Table 4). Both
electron-poor (3p–t) and electron-rich (3v–x) aldehydes coupled
efficiently. Indazoles bearing diverse functionality such as
trifluoromethyl (3p), methyl ester (3q), nitro (3r), fluoro (3s),
chloro (3t), bromo (3u), methyl (3v–3w), and methoxy (3x)
substituents were obtained in good to excellent yields. Moreover,
ortho (3s), meta (3t, 3w) and para (3p–r, 3u, 3v, 3x) substitution
patterns were well tolerated. Heterocycles such as an indole (3y),
a thiophene (3z), and a furan (3aa) could be introduced in
excellent to moderate yields. Even additions to the alkyl
aldehydes cyclohexanecarboxaldehyde and isovaleraldehyde
proceeded to give indazoles 3ab and 3ac, respectively, in
reasonable yields. Notably, in the case of substrate 3aa bearing a
furanyl substituent, the Ag-free conditions developed for
preformed catalyst 5 provided a noticeably higher yield. On the
other hand, for substrates 3ab and 3ac derived from alkyl
aldehydes, in situ preparation of the Co catalyst with use of the
AgOAc additive gave better results, thus demonstrating the
complementary nature of these two catalyst systems. We had
previously evaluated many of these aldehydes for Rh(III)-
catalyzed indazole synthesis (3a, 3p–3s, 3v, 3x, 3ab). Although a
direct comparison cannot be made because different azobenzenes
were employed in most cases, it is readily apparent that both
Co(III) and Rh(III) catalysts show a comparable high level of
functional group compatibility.
We next explored the possibility of extending this Co(III)-
catalyzed aldehyde addition and cyclative capture approach to
include the synthesis of highly functionalized furans 7 from α,β-
unsaturated oximes 6 (Table 5). For the optimization studies we
employed the oxime as the limiting reagent because aldehydes are
generally readily available and inexpensive while the oxime must
be prepared from the corresponding α,β-unsaturated ketone. For
convenience and practicality, we also focused on preformed
catalyst 5 and Ag free conditions. The use of 10 mol % of AcOH
with 1,4-dioxane as the solvent was first employed because these
conditions were optimal for indazole synthesis (entry 1). While a
good yield was obtained, considerable improvement in yield to
83% was observed upon replacing 1,4-dioxane with THF (entry
2). A significant decrease in yield resulted when the reaction was
conducted below the solvent boiling point (entries 3 and 4).
However, use of DCE provided a comparable yield at both 100 oC
o
and 80 C (entries 5 and 6, respectively). The lower temperature
was selected for further experiments to allow for large scale
reactions to be conducted under reflux instead of in a sealed tube
(vide infra). Finally, removing the AcOH catalyst resulted in
much lower conversion (entry 7).
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to aromatic aldehydes, this transformation exhibited a broad scope
Table 5. Optimization of Reaction Conditions for Furan
Synthesis using Catalyst 5a
1
2
3
4
and was compatible with fluoro (7b), chloro (7c–7d), bromo (7e),
methyl ester (7f), methyl (7g), and trifluoromethyl (7j–l)
functionality. Moreover, a good yield was obtained for sterically
hindered ortho (7b) and meta (7c, 7g) functionalities. Unactivated
alkyl aldehydes were also tolerated affording furans 7h and 7i in
moderate yield.
5
6
7
8
9
For almost all of the furans that we had previously prepared
with Rh(III) catalysis, Co(III) provided comparable yields. The
one exception is for tetrasubstituted furans such as 7l, for which
Rh(III)-catalysis provided considerably higher yields.24
To evaluate the scalability these C–H functionalization cascades
and to further demonstrate the robust nature of catalyst 5, 20
mmol scale reactions were performed on the bench-top under
reflux (Scheme 2). Indazole 3z was accessed in 74% yield (4.08
g), comparable to the small-scale procedure (Table 3).25
Additionally, furan 7j was synthesized in 72% yield (4.34 g),
which was a nearly identical yield to that obtained on smaller
scale.
Entry
Solvent
AcOH
Temp
(oC)
100
100
80
65
100
80
Yield
(%)b
64
83
74
56
79
80 (67)c
25
loading
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
--
1
2
3
4
5
6
7
Dioxane
THF
THF
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
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
THF
DCE
DCE
DCE
80
a Conditions: 6a (1.0 or 2.0 equiv), 2a (1.0 or 2.0 equiv) in solvent (2.0 M)
b
for 24 h. Determined by GC analysis relative to tetradecane as an
external standard. c Isolated yield at 0.20 mmol scale.
Scheme 2. Gram-Scale Indazole and Furan Synthesis using
Catalyst 5
The substrate scope was explored with a range of α,β-
unsaturated oximes 6 and aldehydes 2 (Table 6). Oximes lacking
R3 substitution resulted in trisubstituted furans 7a–7k in good to
excellent yields. Tetrasubstituted furan 7l with a fused bicyclic
framework was also prepared, albeit in lower yield. With respect
Table 6. Furan Substrate Scopea,b
R1
O
R1
R2
R3
5 (10 mol %)
AcOH (10 mol %)
R2
R3
OMe
O
N
+
H
R4
1,2-dichloroethane
80 oC, 24 h
6
2
7
R4
Me
O
Me
O
Me
Ph
Me
Ph
Ph
Ph
O
O
F
We performed several experiments to provide insight into the
mechanism for aldehyde additions followed by cyclative capture
and focused these studies on indazole synthesis. First, several
competition experiments were performed at low conversion to
determine the effect of electronics upon rate of conversion
(Scheme 3).
Cl
Cl
7a
7b
7c
7d
Co: 67%
Rh: 52%c
Co: 69%
74%
Co: 64%
Rh: 67%c
Rh: 65%c
Me
Me
Me
O
Me
Ph
Ph
Ph
Ph
Substituted azobenzenes were first explored (Scheme 3a)
because this component is involved in each step of the catalytic
cycle (vide infra). For all of the competition experiments,
azobenzene 1b proceeded to highest conversion affording
indazole 3d. Electron-rich methoxy and methyl-substituted
azobenzenes (indazoles 3l and 3n, respectively) gave only
modestly lower conversion than the unsubstituted derivative. In
contrast, the azobenzene bearing a trifluoromethyl group, gave
dramatically lower conversion to indazole 3m. We hypothesize
that two factors are primarily responsible for the dramatically
lower conversion to 3m. First, the electron-deficient
trifluoromethyl group may slow the rate of C–H bond activation
based upon studies on the effect of electronics on concerted-
metallation-deprotonation for related Cp*Rh(III) complexes.26
Second, the alcohol intermediate resulting from aldehyde addition
cyclizes by intramolecular nucleophilic displacement of the
hydroxyl group by either an SN1 or SN2 process. This cyclization
would be expected to be slower when the electron-deficient
trifluoromethyl group is present.
O
O
O
Me
Br
CO2Me
7e
68%
7f
7g
7h
Co: 67%
53%
Co: 48%
Rh: 41%d
Me
Rh: 76%c
Me
Me
Me
Ph
Ph
Ph
O
O
O
O
CF3
CF3
Co: 84%
CF3
7i
Co: 40%
Rh: 52%d
7j
7k
7l
Co: 73%
Co: 25%
Rh: 53%c
Rh: 76%c
Rh: 71%c
a
Co(III) conditions: O-methyl oxime 6 (0.20 mmol), aldehyde 2 (0.40
mmol), 5 (10 mol %) and AcOH (10 mol %) in 1,4-dichloroethane (2.0 M)
b
c
for 24 h. Isolated yields after silica gel chromatography. Rh(III)
conditions: O-methyl oxime 6 (0.20 mmol), aldehyde (0.40 mmol),
[Cp*RhCl2]2 (5 mol % of Rh dimer), and AgSbF6 (20 mol %) in
tetrahydrofuran (0.3 M) at 90 oC for 24 h. d Reaction was conducted using
[Cp*RhCl2]2 (10 mol % of Rh dimer) and AgSbF6 (40 mol %).
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Scheme 3. Azobenzene and Aldehyde Competition
Experiments to Analyze Electronic Effects
Scheme 4. Reversibility of Co(III)-Catalyzed C–H
Functionalization using Deuterated Azobenzenes
1
2
3
4
5
6
7
8
(a)
Me
(39%)
D
Me
(a)
(56%)
H
Me
Me
D
D
N
H
N
N
N
Me
N
Me
D
D
5 (10 mol %)
AcOH
N
D
(39%)
O
D
D
N
D
1b (1.0 equiv)
N
Me
5 (10 mol %)
AcOH (10 mol %)
(10 mol %)
(56%)
Me
Me
3d Ph
+
D
H
Ph
Me
1f
1,4-dioxane
65 oC, 1 h
2a
+
+
(2.0 equiv)
(39%)
H
1,4-dioxane
55 oC, 1 h
(32%)
D
(1.0 equiv)
Me
X
9
N
N
+
Me
Me
O
X
N
D
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
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
19% conversion
N
H
Ph
N
1 (1.0 equiv)
Me
Ph
2a
D
(1.0 equiv)
D
(32%)
Ph
Substrate
3l
OMe
0.32
3n
Me
0.64
3m
CF3
0.010
D
X
Ratio (3d:3X)
(b)
Me
(55%)
H
(39%)
D
D
Me
D
(b)
D
N
N
N
5 (10 mol %)
AcOH
(10 mol %)
N
Me
N
N
N
N
H
(55%)
N
Me
D
1a (2.0 equiv)
N
Ph
Ph
D
(39%)
5 (10 mol %)
AcOH (10 mol %)
+
+
1g
1,4-dioxane
65 oC, 1 h
O
O
3a
+
(2.0 equiv)
1,4-dioxane
55 oC, 1 h
(33%)
D
(38%)
H
H
Ph
H
+
Me
Me
O
19% conversion
X
N
X
2a
2
H
Ph
N
D
(0.5 equiv)
(0.5 equiv)
2a
(1.0 equiv)
H
Ph
Substrate
X
Ratio (3a:3X)
3x
OMe
0.40
3v
Me
0.81
3p
CF3
0.59
(38%)
To assess the reversibility of Co(III)-catalyzed aldehyde
insertion, the aldehyde addition product 8a was prepared
independently and then subjected to the reaction conditions in the
presence of 2c (Scheme 5). A mixture of indazoles 3a and 3v was
obtained. Even though we had previously shown that 4-
methylbenzaldehyde is converted to the product more slowly than
benzaldehyde (see Scheme 3), a significant percentage of indazole
3v is still produced. Furthermore, azobenzene (1a) was observed
in the final reaction mixture, albeit in only 3% yield. These results
conclusively indicate that the Co(III)-catalyzed C–H bond
addition to aldehydes is reversible, which is consistent with other
metal-catalyzed C–H bond additions to aldehydes.28
A series of aromatic aldehydes with different electronic
properties were also subjected to competition experiments
(Scheme 3b). Benzaldehyde (2a) gave higher conversion than
both electron-rich (indazoles 3x and 3v) and -deficient (indazole
3p) aldehydes. These results suggest that competing effects may
lead to a substrate dependent change in the rate-limiting step. The
electron-rich aldehyde 4-methoxybenzaldehyde has increased
resonance stabilization, and therefore a lower equilibrium for the
alcohol product resulting from C–H addition to the aldehyde.
However, donating substituents would also be expected to
facilitate cyclization by nucleophilic displacement of the hydroxyl
group. On the other hand, the electron-deficient 4-
trifluoromethylbenzaldehyde should result in a more favorable
equilibrium for the alcohol product, but might also slow
cyclization (vide supra). Regardless of electronic effects, it is
important to note that good yields of indazoles 3 are obtained in
nearly all cases (see Tables 3 and 4).
The reversibility of the cyclometallation step was next evaluated
by subjecting site specifically deuterated azobenzene 1f to the
reaction conditions (Scheme 4a). After stopping the reaction at
low conversion, a significant level of protio-deutero scrambling
had occurred in both the recovered starting material and product.27
A similar result was obtained for azobenzene 1g deuterated solely
on the aromatic ring with 3,5-dimethyl substitution (Scheme 4b).
These results clearly indicate that while the steric hindrance
introduced by 3,5-disubstitution completely prevents indazole
formation on this disubstituted ring (see Table 3),
cyclometallation readily occurs as evidenced by the extensive
protio-deutero scrambling.
Scheme 5. Reversibility of Co(III)-Catalyzed Aldehyde
Insertion using a Synthetic Intermediate
A
potential mechanistic pathway
for
this
C–H
functionalization/addition/cyclization cascade is depicted in
Scheme 6.29 Thermal loss of the benzene from 5 provides the
active catalyst. Coordination of azobenzene 1 is followed by
reversible formation of cobaltacycle 9.30 Reversible aldehyde
coordination and migratory insertion affords cobaltacycle 11.
Protonation of this metallacycle releases the alcohol intermediate
8 and regenerates the active catalyst. Cyclative capture of 8 then
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proceeds via an intramolecular nucleophilic substitution reaction
with concomitant release of H2O to furnish 12. This species then
rearomatizes to afford the desired indazole 3.
REFERENCES
1
2
3
4
5
6
7
8
(1) For select recent reviews on C–H functionalization, see: (a)
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Scheme 6. Proposed Mechanism of Co(III)-Catalyzed C–H
Functionalization/Addition/Cyclization Cascade
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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33
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35
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37
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45
46
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52
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54
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A. J. Am. Chem. Soc. 2013, 135, 7122. (b) For furan synthesis, see: Lian,
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For an early example of cyclative capture in the Re-catalyzed synthesis of
isobenzofurans, see: Kuninobu, Y.; Nishina, Y.; Nakagawa, C.; Takai, K.
J. Am. Chem. Soc. 2006, 128, 12376.
. CONCLUSION
In summary, we have developed the first examples of cobalt-
catalyzed C–H bond functionalization with additions to
aldehydes. By employed azo and oxime directing groups, which
have not previously been applied to Cp*Co(III)-catalyzed C–H
bond functionalization, cyclative capture and aromatization is
then achieved to enable the single step, convergent assembly of N-
aryl-2H-indazoles and furans, respectively. A wide range of aryl,
hetero, and alkyl aldehydes participate in these reactions to
provide efficient access to highly substituted heterocycles. These
transformations can be performed on the bench-top, under
standard reflux conditions, and on large scale.
Successful implementation of these practical conditions
necessitated that we develop a new air-stable cationic catalyst,
[Cp*Co(C6H6)][B(C6F5)4]2 (5). Additionally, while AgOAc was
initially identified as a key additive for obtaining acceptable
reaction yields, after extensive evaluation we established that this
precious metal additive could be replaced with sub-stoichiometric
quantities of AcOH as a very low cost and simple to handle
alternative. The air-stable cobalt catalyst and convenient bench-
top reaction conditions should hopefully be applicable to other C–
H bond functionalization reactions.
(8) For a review of Mn-catalyzed C–H functionalization, see: Wang, C.
Synlett 2013, 24, 1606. (b) also see references 5b and 5d.
(9) For recent examples of C–H functionalization catalyzed by low-
valent iron complexes, see: (a) Shang, R.; Ilies, L.; Asako, S.; Nakamura,
E. J. Am. Chem. Soc. 2014, 136, 14349. (b) Fruchey, E. R.; Monks, B. M.;
Cook, S. P. J. Am. Chem. Soc. 2014, 136, 13130. (c) Ilies, L.; Matsubara,
T.; Ichikawa, S.; Asako, S.; Nakamura, E. J. Am. Chem. Soc. 2014, 136,
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Ed. 2014, 53, 11065. (e) Matsubara, T.; Asako, S.; Ilies, L.; Nakamura, E.
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Am. Chem. Soc. 2013, 135, 17755. (g) Shang, R.; Ilies, L.; Matsumoto, A.;
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L.; Daugulis, O. Angew. Chem., Int. Ed. 2014, 53, 10209. (b) Grigorjeva,
L.; Daugulis, O. Org. Lett. 2014, 16, 4684. (c) Grigorjeva, L.; Daugulis,
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Supporting Information
Experimental procedures and characterization data. This content
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
jonathan.ellman@yale.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Support has been provided by the National Institutes of Health
(R01-GM69559).
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T.; Sakata, K.; Matsunaga, S.; Kanai, M. J. Am. Chem. Soc. 2014, 136,
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1
2
3
4
5
6
7
8
(19) For selected recent examples of azobenzene C–H functionalization
with Cp*Rh(III), see: (a) Wangweerawong, A.; Bergman, R. G.; Ellman,
J. A. J. Am. Chem. Soc. 2014, 136, 8520. (b) Ryu, T.; Min, J.; Choi, W.;
Jeon, W. H.; Lee, P. H. Org. Lett. 2014, 16, 2810. (c) Wang, H.; Yu, Y.;
Hong, X.; Tan, Q; Xu, B. J. Org. Chem. 2014, 79, 3279. (d) Lian, Y.;
Hummel, J. R.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2013,
135, 12548. (e) Zhao, D.; Wu, Q.; Huang, X.; Song, F.; Lv, T.; You, J.
Chem.–Eur. J. 2013, 19, 6239. (f) Maralirajan, K.; Cheng, C.-H. Chem.–
Eur. J. 2013, 19, 6198. (g) also see reference 7a.
(20) For Co()-catalyzed alkenyl C–H functionalization, see:
Yamakawa, T.; Yoshikai, N. Org. Lett. 2013, 15, 196.
(21) Cationic Cp*Co with the non-coordinating B(C6H5)4 counterion in
combination with AgOAc is presumably successful because Ag+ and
Cp*Co2+ bind with comparable strength to acetate such that only partial
exchange occurs.
(22) For an examples where Cu(OAc)2 was beneficial for redox neutral
Rh(III)-catalyzed C–H functionalization reactions, see: (a) Liu, B.; Zhou,
T.; Li, B.; Xu, S.; Song, H.; Wang, B. Angew. Chem., Int. Ed. 2014, 53,
4191. (b) Li, B.-J.; Wang, H.-Y.; Zhu, Q.-L.; Shi, Z.-J. Angew. Chem., Int.
Ed. 2012, 51, 3948. (c) Tsai, A. S.; Brasse, M.; Bergman, R. G.; Ellman, J.
A. Org. Lett. 2011, 13, 540.
(23) For selected examples employing pivalic acid as an additive in Pd-
catalysis, see: (a) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
16496. In Cp*Rh(III)-catalysis, see: (b) Zhang, X.; Li, Y.; Shi, H.; Zhang,
L.; Zhang, S.; Xu, X.; Liu, Q. Chem. Commun., 2014, 50, 7306. (c)
Schipper, D. J.; Hutchinson, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132,
6910.
(24) Acetophenone O-methyl oxime was evaluated under the optimized
conditions but gave a mixture of products. For the Re-catalyzed synthesis
of isobenzofurans, see reference 7e.
(25) Indazole 3a was also prepared on 20 mmol scale providing a yield
of 75% (4.04 g). See Supporting Information for details.
(26) For a study demonstrating the effect of electronics on concerted-
metallation-deprotonation for related Cp*Rh(III) complexes, see: Li, L.;
Brennessel, W. W.; Jones, W. D. Organometallics, 2009, 28, 3492.
(27) To demonstrate that Co(III) is required for protio-deutero
scrambling to occur, a control reaction was run in which azobenzene 1f
was subjected to the reaction conditions in the absence of catalyst 5.
Under these conditions no protio-deutero exchange occurred. See
Supporting Information for details.
(28) The reversibility of Rh(III)-catalyzed C–H bond addition to
aldehydes has been previously demonstrated. (a) Chen, K.; Li, H.; Lei, Z.-
Q.; Li, Y.; Ye, W.-H.; Zhang, L.-S.; Sun, J.; Shi, Z.-J. Angew. Chem., Int.
Ed. 2012, 51, 9851. (b) Zhang, X.-S.; Li. Y.; Li, H.; Chen., K.; Lei, Z.-Q.;
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(29) For relevant mechanistic studies demonstrated for Rh(III)-
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(16) (a) Nasonex (mometasone furoate), Zantac (ranitidine HCl),
lapatinib, and furadantin monohydrate are approved drugs containing a
furan moiety. Detailed information on these drug candidates including
compound structure, bioactivity, published studies, and information
regarding ongoing clinical trials, applications, and usage can be obtained
at PubChem (http://pubchem.ncbi.nlm.nih.gov/). (b) also see Katritzky, A.
R. Comprehensive Heterocyclic Chemistry III, 1st ed., Elsevier,
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(17) (a) Niraparib and pazopanib are 2-substituted 2H-indazoles
currently in clinical trials. Detailed information on these drug candidates
including compound structure, bioactivity, published studies, and
information regarding ongoing clinical trials, applications, and usage can
be obtained at PubChem (http://pubchem.ncbi.nlm.nih.gov/). (b) For
leading references on pharmaceutical applications and syntheses of 2-
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