Gold(i)-catalysed high-yielding synthesis of indenes by direct Csp3-H bond activation

Article abstract of DOI:10.1039/c8ob02056f

A catalytic, practical and high-yielding procedure for the synthesis of indenes by direct C_sp³-H activation under gold(i) catalysis was developed. The scope of the protocol was determined by synthesizing some electron-neutral, electr

Full text of DOI:10.1039/c8ob02056f

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Org. Biomol. Chem., 2018, DOI: 10.1039/C8OB02056F.
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Gold(I)-Catalysed High-Yielding Synthesis of Indenes by Direct
3
Csp -H Bond Activation
Pradip D. Nahide,a J. Oscar C. Jiménez-Halla,a Katarzyna Wrobel,a César R. Solorio-Alvarado,a*
Rafael Ortiz Alvaradob* and Berenice Yahuaca-Juárezb
A catalytic, practical and high-yielding procedure for the synthesis of indenes by direct Csp3-H activation under gold(I)
catalysis was developed. The scope of the protocol was determined by synthesizing some electron-neutral, electron-poor
as well as electron-rich derivatives including the dibenzofurane and carbazole heterocycles. The mechanism of this
reaction was elucidated by theoretical calculations using a ONIOM(M08-HX/mixed-basis:PM6) hybrid scheme. Thereby we
found a pericyclic transformation involving a [1,5]-H shift generating a gold(I)-carbene that evolves to the indene
derivative. In comparison with several reports, our protocol presents a direct activation of the Csp3-H bond.
Received 00th February 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
the context of this development, the contributions from Sanz,10
Toste11 and Echavarren12 (Scheme 1A-C) are noteworthy as high
impact and archetypal examples. All these protocols proceed via
two-step cyclo-isomerisations of the starting material: 1) formation
of a cyclopropyl gold(I)-carbene or an oxonium gold(I)-vinylidene
and 2) evolution of this intermediate into the corresponding
indene.
Introduction
The indenes are compounds of great importance in organic
synthesis.1 They appear or are frequently found in naturally
occurring compounds,2 pharmaceutical drugs,3 organic dyes,4 and
pigments5 among the most typical applications (Fig. 1).
HO
O
OH
OH
Taking advantage of the recently introduced gold(I)-catalysed Csp3-H
bond activation into synthetic organic chemistry,13 we have used
this strategy for the synthesis of the indene nucleus. In the
envisioned process, the direct Csp3-H bond activation proceeds via a
concerted instead of two-step reaction. As shown, after cyclization,
a gold(I)-carbene is formed without a cyclopropane or oxonium
intermediate (Scheme 1D).
OH
H
H
OH
Me
HO
O
H
Me
Ph
HO
HO
O
OH
Me
Cl
HO
OH
O
Me
Cl
HO
indenestrol
(+)-indacrinone
(+)-hematoxyline
(±)-pallindol
Cl
OH
Cl
nPr
O
N
Et
MeO
OH
O
N
Intermediate
Me
Me
Cycloisomerization
MeO
O
1st step
O
N
Et
A) Sanz
N
O
OMe
HO
[AuCl(Ph3P)L*] /AgSBF6
H
O
O
∗
MeOH
human prostate
cancer inhibitors
Ph
Anti-Alzheimer disiase agent
MT2-selective antagonist ligand
DCM, 23 C
AuL
O
Et
H
Au(I)-carbene
Et
N
CN
B) Toste
N
N
R1
R1
Et
R1
Et
R4
R3
H
HOOC
O
R4
R4
R3
F3C
PAuCl / AgBF4
O
Me
R2
OMe
R2
3
R2
OMe
solution-processable pigment
organic dye for solar cell
R3
DCM, 23 C
LAu
oxonium
Au(I)-vinylidene
Figure 1. Examples highlighting the relevance of the indene core.
C) Echavarren
To date, several procedures for the synthesis of indenes have been
reported. Among the most representative ones, those involving
metal-free,6 transition metal-free7 or metal-catalyzed8 conditions
have been extensively described. Particularly, the gold(I)-catalysed
cyclo-isomerisation of enynes9 has been a broadly exploited tool for
building up different organic architectures such as indenes. Within
R
R
O
R
N
AuL
Cat A
O
Cl Au
Cl
with Cat A
with Cat B
tBu
Au(I)-carbene
R
SbF6
tBu
O
PHAu NCPh
No C-H activation
at this 1st stage
3
Cat B
D) This work
Intermediate
1st step
Concerted
Direct Csp3-H activation-Cyclization
AuL
H
H
C1 (20 mol%)
H
DCE, 105 ºC
C1= [L-Au-CNMe][SbF6
L= JohnPhos
]
Csp3-H activation
occurs at this 1st stage
Scheme 1. Selected gold(I)-catalysed synthesis of indenes.
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Regarding this transformation, the gold(I)-catalysed Csp3-H bond We started with the addition of phenylmagnesium bromide to the
activation described under redox-neutral conditions13 gives rise to 2-aminobenzophenone to get 1, with 70% yield. The following
the formation of a gold(I)-carbene14 as the necessary key step to reduction installed the desired Csp3-H bond to be activated
promote such activation. In those studies,13d-f the activation generating 2 with excellent yield of 85%. Next, the Sandmeyer-type
occurred via [1,n]-H migration leading to the formation of a iodination16 furnished
3 in 71%. A consecutive Sonogashira
carbocation that evolved by cyclization and protodeauration. alkynylation with 2-methylbut-3-yn-2-ol produced 4 in 55% of yield,
Herein we described our development for the direct Csp3-H bond which upon basic treatment, finally gave rise to 5 in 89%.
activation under gold(I) catalysis.
Once the alkyne 5 was obtained, we proceeded to synthesize the
starting materials 6 – 17 by a second Sonogashira alkynylation
(Scheme 4).
R
R
I
or
R
(1.5 equiv)
Pd(PPh3)Cl2 (2 mol%)
CuI (1 mol%)
I
Results
or
H
Ph
Ph
Ph
Et3N, 80 C, 3 h
3
5
6 -17
Ph
Ph
Inspired by the recent gold(I)-catalysed redox-neutral Csp3-H bond
activation reports, we hypothesized that starting materials such as
6 – 17 could give rise to indenes of the type 18 – 29. Thus, we
describe here our own gold(I)-catalysed Csp3-H bond activation
approach, in which we anticipate, based upon the alkyne design,
that the transformation would proceed via [1,5]-H shift. The
convergent retrosynthetic analysis of this hypothesis is outlined in
Scheme 2.
Ph
Me
Me
Me
H
H
H
H
Ph
5, 89%a
Ph
Ph
Ph
6, 78%b
Ph
Ph
7, 93%
Ph
Ph
8, 76%
Me
OMe
OMe
OMe
H
R
Me
R
Au(I)
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
6 - 17
9, 62%
10, 90%
Cl
11, 88%
18 - 29
Cl
I
H
H
H
H
+
Ph
Ph
R
Ph
Ph
Ph
Ph
12, 85%
13, 93%
14, 91%
Ph
Ph
5
F
Scheme 2. Retrosynthesis of indenes 18 – 29.
O
N
Ts
H
In the retrosynthesis, the final indenes 18 – 29 are the products of
the gold(I)-catalysed Csp3-H bond activation of the alkynes 6 – 17,
which were obtained from the Sonogashira alkynylation15 between
alkyne 5 and different commercially available aryl iodides.
Ph
15, 96%
Ph
H
H
16, 78%
17, 91%
Ph
Ph
Ph
Ph
Scheme 4. Synthesis of the starting alkynes 6-17. aThis compound was
synthesized by the Sonogashira alkynylation of
3 and TMS-acetylene
Thus, the synthesis of the starting alkyne 5 was envisioned as a
linear five-step synthesis described in Scheme 3.
followed by basic desilylation in methanol. bThis compound was synthesized
using the iodide 3 and phenylacetylene.
Et3SiH
CF3COOH
NH2
Ph
NH2
NH2
PhMgBr
H
OH
Ph
1, 70%
THF,
23 ºC, 12 h
DCM,
23 ºC, 2 h
In this way, different alkynyl triphenylmethanes containing a single
Csp3-H bond as well as distinct electronic-nature aryl groups were
synthesized. Thus, electron-neutral (6), electron-rich (7 – 12) and
electron-poor (13 – 15) derivatives were obtained in moderate to
excellent overall yields (62-96%). Moreover, the terminal alkyne 5
was prepared in 89% of yield. Finally, two more derivatives
containing heterocycles (16 and 17) were obtained in 78 and 91% of
yield, respectively, for testing the further scope of this reaction.
Ph
O
Ph
Ph
2, 85%
1) NaNO2
H2SO4,
2) KI / H20
/
23 ºC to
60 ºC, 3 h
OH
1.5 equiv
OH
Pd(PPh3)Cl2
(2 mol%)
I
CuI (1 mol%)
KOH
H
H
H
Et3N,
80 ºC, 3 h
Toluene
120 ºC, 3 h
With the starting alkynes 6 – 17 synthesized, we carried out the
optimization of the reaction conditions to prove the hypothesis of
our new activation mode of the Csp3-H bond. Alkyne 6 was used as
model compound, and different cationic gold(I)-complexes17 were
tested as the catalyst sources (Table 1).
Ph
5, 89%
Ph
Ph
Ph
Ph
Ph
4, 55%
3, 71%
Scheme 3. Synthetic route for accessing the alkyne (5).
2 | Org. Biomol. Chem., 2018, 00, 1-3
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Table 1. Optimization of the new gold(I)-catalysed Csp3-H bond reaction was observed (entries 3 – 5). To our delight, with further
activation mode in the synthesis of 1,1,2-triarylindenes.
increase of temperature to 90 °C while keeping 10 mol% of C1, we
found the desired indene 18 with 48% of the reaction progress, as
detected by GC (entry 6). This experiment confirmed our hypothesis
showing the feasibility of Csp3-H bond activation. Trying to enhance
the reaction yield, we tested 15 mol% of C1 at 105 °C; after 12
hours we still found remaining starting material in the mix. Then,
the amount of catalyst was further increased by adding extra 5
mol%, which enabled us to obtain the desired indene 18 in 78% of
yield after additional 12 hours (entry 7). From this experiment, we
were able to set the catalytic charge of C1 at 20 mol% and the
temperature at 105 °C, since less amount of catalyst or lower
temperature did not result in full consumption of the starting
material. To confirm that these selected conditions were
appropriate, in the next reaction 20 mol% of C1 at 105 °C was
directly applied. Gratifyingly, the reaction was completed within
two hours with more than 99% of yield (GC analysis) and the
H
Au(I)L (mol%)
H
Solvent, Temperature
18
6
Temp
(˚C)
Yield
(%)a
Entry
Au(I)L (mol %) Solvent
1
2
C1 (5)
C1 (5)
MeCN
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
23
23
n.r.
n.r.
n.r.
n.r.
n.r.
48 b
78c
>99 c
9
3
C1 (10)
C1 (5)
23
4
60
1
structure was confirmed by H and 13C NMR (entry 8). Some other
5
C1 (5)
80
gold(I) catalysts such as C2 to C7 were assayed by using the
optimised conditions in entry 8. By doing so, the yields from 9 to
81% were obtained (entries 9-14). Finally, a control experiment was
carried out in the absence of catalyst to discard a thermally-
activated [1,5]-H migration19 and to confirm that a metal-catalysed
Csp3-H bond activation took place. In this experiment, 18 was not
detected by NMR even after 24 hours.
6
C1 (10)
C1 (15 + 5)
C1 (20)
C2 (20)
C3 (20)
C4 (20)
C5 (20)
C6 (20)
C7 (20)
-
90
7
105
105
105
105
105
105
105
105
105
8
9
10
11
12
13
14
15
81
At this point, it was determined that the optimal conditions were
those in entry 8. Thereby, we proceeded to explore the scope of our
new developed Csp3-H bond activation procedure (Scheme 5).
25
30
45
R
H
SbF6
11
C1 (20 mol%)
R
P
Au NCMe
H
DCE, 105 ºC
n.r.
C1
6-17
H
18-29
SbF6
SbF6
H
H
P
Au NCMe
P
Au NCMe
P
Au NTf2
Me
Me
Me
AuL=
C1
C2
C3
18, 98%, 2 h
19, 97%, 2.5 h
20, 92%, 3 h
H
H
H
iPr
N
iPr
Me
Me
SbF6
SbF6
N
tBu3P Au NTf2
OMe
OMe
OMe
P
Au NCMe
P
Au NCMe
i
Pr
iPr
Au
C7
MeCN
BF4
N
C6
C5
C4
21, 98%, 2.5 h
22, 96%, 2 h
23, 89%, 3.5 h
O
H
H
H
Cl
All the reactions were carried out without the use of inert atmosphere yet in
sealed tubes. aThe reaction yields were determined by GC. b48% of the
reaction advance was determined by GC. cThe structure was confirmed by 1H
NMR and 13C NMR. n.r. = no reaction observed. DCE= 1,2-dichloroethane.
MeCN= acetonitrile.
Cl
24, 93%, 18 h
25, 88%, 3.5 h
26, 91%, 2.5 h
H
H
H
F
N
O
Ts
The high reactivity of the cationic gold(I)-complex C1 (Echavarren
catalyst)18 is well known.12b-c Thereby, we decided to start the
optimization by using 5 mol% of C1 in acetonitrile and 1,2-
dichloroethane at room temperature (Table 1, entries 1 and 2).
After 12 hours in such mild conditions, we found no reaction in any
of the two solvents. Since slight decomposition of the starting
material was observed in the presence of acetonitrile, 1,2-
dichloroethane (DCE) was selected for further experiments. The
attempts of increasing the catalyst amount to 10 mol% as well as
heating the mixture to 60 °C or 80 °C were unsuccessful and still, no
27, 93%, 3.5 h
28, 91%, 18 h
29, 95%, 3 h
Scheme 5. Scope for the new gold(I)-catalysed Csp3-H bond activation mode
in this work.
This developed procedure yields 1,1,2-triarylindenes. The explored
scope focused mainly in the electronic effects at the 2-aryl position
of the indene. According to the results, our protocol supported the
electron-neutral phenyl group giving rise to 18 in 99% yield in only 2
hours. Also, different electron-rich aryls containing one or two
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methyl groups proceeded with excellent 92 to 98% of yield (19 to of the cationic gold(I)-complex C1 to 6 to provide I. The Csp3-H bond
21) in no more than 3 hours of reaction. The presence of methoxy activation takes place at this point through a [1,5]-H shift defined by
groups at the 2-aryl moiety furnished 22 and 23 in 96 and 89% of
yield in only 3.5 hours. Even the bulky 1-naphtyl substituent
produced 24 for a very good 93% of yield after 18 hours. This result
showed that the reaction is kinetically sensitive to steric hindrance
but chemically feasible. The scope was expanded to electron-poor
aryls containing 3-chloro (25), 4-chloro (26) and 4-fluoro (27)
obtaining high yields ranging from 88 to 93%. Finally, the
dibenzofurane and carbazole heterocycles were perfectly enabled
in the reaction giving rise to 28 and 29 in 91 and 95% yield,
respectively, after 18 hours. The former results confirmed that
bulky substituents slow down the reaction time, nevertheless they
do not have a negative impact in the reaction yield.
the transition state TSI→II, which affords the stabilized carbocation
II. The energy barrier of this step is high enough (28.7 kcal
mol−1) to
⋅
explain the need of heating up (105 °C) the reaction to proceed. In
this six-membered ring TS, the metal centre abstracts and, downhill,
delivers the hydrogen to the vicinal carbon of the double bond. The
positive charge remains delocalized through the carbon backbone
in II, which defined an endothermic reaction by 18.6 kcal
the next step, the new ring is formed through the C-C bond
formation in TSII→III leading to carbene III (exothermic step: 22.5
mol− and is
⋅
mol−1. In
−
1
kcal
faster than the reverse energy barrier (10.1 kcal
back to I. Next, III evolves via [1,2]-H shift21 giving rise to IV which is
more exothermic by 17.1 kcal
mol−1. The energy barrier of this
step is calculated through TSIII→IV
H‡ = 15.1 kcal mol−1) and it is
⋅ ⋅
mol−1). This energy barrier takes only 7.1 kcal
1
⋅
mol− ) for turning
−
⋅
Based upon these results, we can highlight some relevant aspects of
our procedure: 1) the hypothesis about the new gold(I)-catalysed
Csp3-H bond activation mode to synthesize 1,1,2-triarylindenes from
the alkynyl triphenylmethanes 6-17 was validated, 2) the procedure
is high-yielding, 3) short reaction times ranging from 2 to 3.5 hours
were observed for mono-annular aryls, 4) the bis- or tris-annular
aryls with a relevant steric bulkiness only slowed down the kinetics
of reaction but did not affect its yield, 5) this developed protocol
tolerates electron-poor, electron-rich and electron-neutral aryls as
well as heterocycles.
(
ꢀ
⋅
important to make notice about the role of the acetonitrile acting
as a base for assisting this reaction step in the transition state. We
also located an analogous of TSIII→IV without the acetonitrile
1
influence and this was almost 6.0 kcal
⋅
mol− higher in energy than
the former one. Finally, gold(I)-complex C1 delivers back the
electron-pair to the indene ring and releases product 18 which is
1
−
4.8 kcal
⋅
mol− more favoured. Overall, this process has a total
1
reaction energy of
ꢀHR =
−
29.3 kcal
⋅
mol−
.
Our procedure represents a new and direct activation mode for
which the initial formation of gold(I)-carbene as key intermediate to
activate the Csp3-H bond does not occur. Instead, a pericyclic [1,5]-H
migration takes place giving rise to the direct Csp3-H bond
activation-cyclization intermediate, which contains the gold(I)-
At this point, we considered of main relevance to describe the
reaction pathway, which gives rise to the synthesized indenes in the
developed procedure. Accordingly, we carried out theoretical
calculations at the (SMD:dichloroethane)ONIOM(M08-HX/mixed-
basis:PM6) level for proposing a plausible reaction mechanism (see
Supporting Information for further details). Figure 2 shows the carbene. This carbene progresses to the final indene via [1,2]-H shift
whereas Au(I) catalyst is regenerated.
calculated energy profile (for free energy values, see Figure S9 in
Supporting Information). The reaction starts with the coordination
Figure 2. Energy profile of the calculated reaction mechanism between C1 and 6 to obtain 18. Relative energies are expressed as enthalpy values.
The JohnPhos phosphine was used as ligand (L) in our calculations.
4 | Org. Biomol. Chem., 2018, 00, 1-3
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migration-cyclization giving rise to a gold(I)-carbene. This
evolves by [1,2]-H shift with concomitant loss of the gold(I)-
complex to furnish the desired triarylindenes. To the best of
our knowledge, in contrast with previous procedures where
the formation of the gold(I)-carbene as first step is necessary
to activate the Csp3-H bond, in the present development this
key step proceeds directly without any intermediate.
Considering the aforementioned mechanic studies as well as the
experimental results obtained and the know chemistry of gold(I)
catalysis,20 we have compiled the following mechanistic proposal
(Scheme 6).
H
H
AuL
C1
18
Conflicts of interest
6
There are no conflicts to declare.
H
AuL
AuL
Acknowledgements
H
We are grateful to CONACyT (CB-2013/220836) for financial
support. We acknowledge the facilities of the DCNyE, the Chemistry
Department, and the National Laboratory UG-CONACyT
(LACAPFEM) of the University of Guanajuato for full
characterization. We thank CONACyT for fellowships to P.D.N.
IV
I
[1,2]-H
[1,5]-H
LAu
AuL
Notes and references
H
H
III
II
1
2
T. Chanda and M. S. Singh, Org. Biomol. Chem. 2016, 14,
8895-8910.
Scheme 6. Mechanistic pathway for the direct gold(I)-catalysed Csp3-H bond
activation mode in the 1,1,2-triarylindenes synthesis.
a) Studies in Natural Products Chemistry, Vol. 51, Chapter 8,
Naseem Ahmed. 383-434. b) (+)-indacrinone: J. P. Genet, T.
Ayad and V. Ratovelomanana, Chem. Rev. 2014, 114, 2824-
2880. c) (+)-hematoxcyline: J. S. Yadav, A. K. Mishara and S.
Das, Tetrahedron 2014, 70, 7560-7566. d) (±)-pallindol: M. H.
Keylor, B. S. Matsuura and C. R. J. Stephenson, Chem. Rev.
2015, 115, 8976-9027.
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Su, H. Jiang, W. Shan and X. Li, J. Med. Chem. 2012, 55, 8483-
8492. b) MT2-selective antagonist ligands: X. Zhang, Z. Wang,
The catalytic cycle starts with coordination of C1 to alkyne affording
I. Then the Csp3-H bond activation takes place via [1,5]-H shift
yielding II which affords the gold(I) carbene III. This carbene evolves
via [1,2]-H shift giving rise to IV. Finally, the loss of the gold(I)
complex leads to the formation of the indene derivative and
concomitantly the catalyst regeneration.
3
Q. Huang, Y. Luo, X. Xie and W. Lu, RSC Adv. 2014, 4, 25871-
25874.
Conclusions
4
5
Organic dye for solar cells: Y. D. Lin and T. J. Chow, J. Mater.
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Solution-processable pigment: Y. Zou, T. Yuan, H. Yao, D. J.
Frazier, D. J. Stanton, H. J. Sue and L. Fang, Org. Lett. 2015,
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In summary, we have developed a catalytic, high-yielding
procedure, and a new activation mode for the direct gold(I)-
catalysed Csp3-H bond activation of alkynyl triphenylmethanes
to get 1,1,2-triarylindenes. The procedure supports all types of
electronic nature groups at the 2-indenyl position including
electron-rich, -poor and -neutral aryls as well 2-heteroaryls.
The short reaction times, generally found in mono-annular
aryls, and the nearly quantitative yields are particularly
important features of this protocol. Bulky substituents such as
naphthyl, dibenzofurane or carbazole only slow down the
kinetics of reaction, but they do not negatively impact in the
chemical yield.
6
7
8
The reaction mechanism was elucidated by theoretical
calculations using a hybrid ONIOM level. It was determined
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that the operating mechanism involves
a
Csp3-H bond
activation as a key step, which proceeds via a pericyclic [1,5]-H
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9, 117-120. Using Fe: a) C. R. Liu, F. L. Yang,
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