Highly Enantioselective Synthesis of Indazoles with a C3-Quaternary Chiral Center Using CuH Catalysis

Article abstract of DOI:10.1021/jacs.0c04286

C3-substituted 1H-indazoles are useful and important substructures in many pharmaceuticals. Methods for direct C3-functionalization of indazoles are relatively rare, compared to reactions developed for the more nucleophilic N1 and N2 positions. Herein, we report a highly C3-selective allylation reaction of 1H-N-(benzoyloxy)indazoles using CuH catalysis. A variety of C3-allyl 1H-indazoles with quaternary stereocenters were efficiently prepared with high levels of enantioselectivity. Density functional theory (DFT) calculations were performed to explain the reactivity differences between indazole and indole electrophiles, the latter of which was used in our previously reported method. The calculations suggest that the indazole allylation reaction proceeds through an enantioselectivity-determining six-membered Zimmerman-Traxler-type transition state, rather than an oxidative addition/reductive elimination sequence, as we proposed in the case of indole alkylation. The enantioselectivity of the reaction is governed by both ligand-substrate steric interactions and steric repulsions involving the pseudoaxial substituent in the six-membered allylation transition state.

Full text of DOI:10.1021/jacs.0c04286

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Article
Highly Enantioselective Synthesis of Indazoles with
a C3-Quaternary Chiral Center Using CuH Catalysis
Yuxuan Ye, Ilia Kevlishvili, Sheng Feng, Peng Liu, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c04286 • Publication Date (Web): 14 May 2020
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Highly Enantioselective Synthesis of Indazoles with a C3-Quaternary
Chiral Center Using CuH Catalysis
Yuxuan Ye,1 Ilia Kevlishvili,2 Sheng Feng,1 Peng Liu,2* and Stephen L. Buchwald1*
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1Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
2Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
ABSTRACT: C3-substituted 1H-indazoles are useful and important substructures in many pharmaceuticals. Methods for direct C3-
functionalization of indazoles are relatively rare, compared to reactions developed for the more nucleophilic N1 and N2 positions.
Herein, we report a highly C3-selective allylation reaction of 1H-N-(benzoyloxy)indazoles using CuH catalysis. A variety of C3-allyl
1H-indazoles with quaternary stereocenters were efficiently prepared with high levels of enantioselectivity. Density functional theory
(DFT) calculations were performed to explain the reactivity differences between indazole and indole electrophiles, the latter of which
was used in our previously reported method. The calculations suggest that the indazole allylation reaction proceeds through an
enantioselectivity-determining six-membered Zimmerman-Traxler-type transition state, rather than an oxidative addition/reductive
elimination sequence, as we proposed in the case of indole alkylation. The enantioselectivity of the reaction is governed by both
ligand-substrate steric interactions and steric repulsions involving the pseudoaxial substituent in the six-membered allylation
transition state.
INTRODUCTION
The functionalization of nitrogen-containing heterocycles is
a key area of research in organic synthesis due to the importance
of these molecules in pharmaceutical applications.1 In
particular, the preparation of indazole derivatives is of great
interest as a result of their versatile pharmacological activities2
and their utility as indole bioisosteres in medicinal chemistry
(Figure 1a).3 The direct alkylation of indazoles is one of the
most efficient methods to derivatize these molecules for
medicinal chemistry studies. Conventionally, indazoles are
employed as nucleophiles in these transformations, and either
the N1- or N2-isomer is formed, depending on the reaction
conditions.4,5 Direct C3-alkylation processes, however, are rare
due to the lack of nucleophilicity at the C3-position, even when
the N1- or N2-position is protected (Figure 1b).6
Recently, we developed a method to prepare chiral alkylated
indoles through a CuH-catalyzed nucleophilic alkylation
reaction.7 By employing N-(benzoyloxy)indoles as
electrophiles and with the appropriate choice of ligand,
selective N-alkylation or C3-alkylation was achieved (Figure
1c). Compared to conventional alkylation reactions, wherein
indoles are used as nucleophiles,8 the regioselectivity of this
alkylation protocol was dictated by the catalyst, rather than the
intrinsic nucleophilicities of the indole.9 We envisioned that this
umpolung strategy10 could be expanded to other nitrogen-
containing heterocycles, allowing us to achieve unconventional
regioselectivity in the functionalization process of these
heterocyclic molecules. Specifically, in the case of indazoles,
we were hopeful that by employing N-(benzoyloxy)indazoles as
electrophiles, the typically observed N1- or N2-regioselectivity
in the nucleophilic substitution reactions could be overrode, and
C3-alkylated indazoles might be accessed (Figure 1d).
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(d) Proposed indazole C3-functionalization using electrophilic indazole reagent
enantioselectivity with the increasing steric hindrance of alkyl
1
2
3
4
5
6
substituents on the allenes. Methyl- (3a), ethyl- (3g), isobutyl-
(3l), and cyclopropyl- (3h) substituted indazoles were prepared
from the corresponding allenes with decreasing enantiomeric
ratios (99.5:0.5 to 92:8). In addition, an indazole derivative with
a fused dihydropyran (3i) was prepared from a chromane-
derived allene efficiently.
R*
R1
N
L*CuH, olefins
N
R1
N
OR
R = COMes
unconventional C3-selectivity
N
H
electrophile
Figure 1. (a) Indazole-containing biologically active
molecules. (b) Regioselectivity of conventional indazole
alkylation reactions. (c) CuH-catalyzed asymmetric alkylation
of indole electrophiles. (d) Proposed CuH-catalyzed
asymmetric C3-allylation of indazole electrophiles. Mes:
mesityl group.
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RESULTS AND DISCUSSION
Initially, we attempted the coupling of a variety of readily
accessible alkenes with indazole 1a under the conditions
previously developed for indole alkylation.7 Less than 5% yield
of the alkylated indazole products were formed in the cases of
styrene (Figure 2a). However, when cyclohexylallene was
employed,11 it reacted efficiently with the indazole electrophile
1a, providing the corresponding allyl indazole product (3s) in
good yield with a high level of enantioselectivity. Notably, the
reaction proceeded with excellent C3-regioselectivity. It is
interesting that only the branched allyl indazole was formed, as
the same reaction with the indole electrophile 6 produced the
corresponding allyl indole product (6a) with exclusive
selectivity for the linear isomer (Figure 2a). In addition, unlike
the indole alkylation reaction,7 wherein selective N-alkylation
could be achieved using DTBM-SEGPHOS ligand, no N-allyl
indazole product was observed with all the ligands tested (see
the Supporting Information). The intriguing reactivity
differences between indazole and indole electrophiles have
important implications on the mechanisms of these reactions
and were studied in detail with the aid of density functional
theory (DFT) calculations (vide infra).
We further investigated the reactivity of other types of
allenes in this reaction (Figure 2b). A monoalkyl-substituted
allene with a substituent sterically smaller than cyclohexyl
reacted efficiently albeit with decreased enantioselectivity (3t).
A monoaryl-substituted allene could be coupled efficiently
(3u). Furthermore, a 1,1-dialkylallene was successfully reacted
with 1a in moderate yield and useful enantioselectivity (3v).
Finally, 1-aryl-1-alkylallene underwent the reaction with high
efficiency, providing C3-allyl indazole (3a) in excellent yield
and with a high level of enantioselectivity. However, neither
1,3-disubstituted allenes nor 1,1,3-trisubstituted allenes were
suitable substrates.
We considered 1-aryl-1-alkylallenes attractive coupling
partners because the corresponding C3-allyl indazole products
with an acyclic quaternary stereocenter are potentially valuable
molecules in medicinal chemistry, and challenging to access
using existing methods.12 Therefore, a variety of 1-aryl-1-
alkylallenes are tested in the reaction with N-
(benzoyloxy)indazole electrophiles (Table 1). Substituents
including 4-methoxy (3b), 2-fluoro (3c), 4-bromo (3g), 3-
chloro (3i), 4-trifluoromethyl (3j), and 2-methyl (3k) on the
phenyl ring of the allenes are well tolerated. Allenes containing
heterocycles, such as furan (3d), 2-methoxypyridine (3e), and
N-Ts-pyrrole (3f), are also compatible in the reaction. We
Reactions were conducted on 0.10 mmol scale. Yields were
determined by H NMR or GC analysis of the crude reaction
mixture. The absolute stereochemistry was signed by analogy
to 3a and confirmed by DFT calculations.
1
observed
a
slight decrease in both efficiency and
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Figure 2. (a) Comparison of indazole and indole electrophiles
with styrene and allene pronucleophiles. (b) Test of allenes with
different substitution patterns in the indazole allylation reaction.
The reaction is broadly tolerant of substituents appended to
the indazole electrophiles, including 4-methoxy (3j), 4-fluoro
(3k), 5-chloro (3l), 6-methylsulfonyl (3n), 6-chloro (3o), 6-
1
2
3
4
carbomethoxy (3p), and 7-methyl (3q). Moreover,
a
Table 1. Substrate Scope for the C3-Allylation of Indazole
Electrophiles with 1-Aryl-1-Alkyl Allenes.a
benzoindazole electrophile was also found to be a competent
coupling partner in this transformation (3r).
5
To briefly demonstrate the potential synthetic utility of these
coupling products, indazole 3b was converted to a primary
alcohol in good yield under hydroboration-oxidation process
(Scheme 1a). Furthermore, the terminal double bond of 3b
could be easily reduced to an ethyl group, generating a
stereocenter containing both methyl and ethyl substituents with
excellent enantioselectivity (Scheme 1b). An Ullmann coupling
reaction of 3a with an aryl iodide was performed successfully
as well. Although transition-metal-catalyzed N-arylation of
indazoles usually generates a mixture of N1- and N2-arylated
products,13 high N1-selectivity (N1:N2>20:1) of 3b was
observed in this case, presumably due to the steric hindrance of
the C3-substituent (Scheme 1c).
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Scheme 1. Further Functionalizations of Allylated
Indazoles.a
Me
OMe
OMe
(b)
Me
Me
PtO2
N
N
1 atm H2
N
N
3b
H
H
4b
85% yield, 100% es
I
BH3•THF
(a)
NaOH, H2O2
OMe
Me
HO
Me
CO2Et
N
N
CuI, DMEDA
OMe
(c)
N
N
CO2Et
H
4a
71% yield, 100% es
4c
95% yield, 100% es, N1/N2 > 99:1
aReactions were conducted on 0.20 mmol scale. See the
Supporting Information for detailed conditions.
As mentioned earlier, we noted prominent differences in
reaction outcomes between indazole and indole electrophiles
under copper hydride catalysis. To obtain more mechanistic
understanding of the origin of reactivity differences, we
computed the energy profiles of allylation reactions of 1a and 6
with 1-phenyl-1-methylallene 2a using density functional
theory (DFT) calculations (Figure 3). Both reactions initiate via
the hydrocupration of allene 2a with copper hydride 7 with a
15.9 kcal/mol activation energy (TS1a, see the Supporting
Information, Figure S1, for other less favorable hydrocupration
pathways). This step leads to the irreversible formation of the
Z-isomer of the terminal allylic copper species (8). Complex 8
can rapidly isomerize to form either diastereomers of the
tertiary benzylic copper intermediate (9), which undergoes
subsequent isomerization to afford the thermodynamically
more stable E-isomer of the terminal allylic copper (10).14 In the
presence of the indole electrophile 6, the most favorable
reaction pathway proceeds through the SN2’ type oxidative
addition (TS3’, ΔG‡ = 23.3 kcal/mol with respect to 10), leading
to the formation of C3-allyl indole product with linear
selectivity, which is consistent with the experimental results
(Figure 2b). The competing SN2 type oxidative addition TS4’
aAll yields represent average isolated yields of two runs,
performed with 0.50 mmol of indazole electrophile. b60 ºC.
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leading to the N-allyl indole product is disfavored by 5.9
kcal/mol. These results are consistent with the previously
studied ligand effects, where Ph-BPE ligand promoted the
formation of C3-alkylated product.7
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Figure 3. A. Energy profiles of the allylation of indazole (1a) and indole (6) electrophiles. B. Optimized structures of the C3-oxidative
addition with indazole (TS3) and indole (TS3’) substrates. C. Calculated N-O bond dissociation enthalpies (BDEs) of 1a and 6.
it forgoes the generation of the less stable Cu(III)
intermediate. Furthermore, this transition state is stabilized by
the presence of dative Cu–N2 bond, which is not available
with the indole substrate. This model is consistent with the
branched regioselectivity as well as the observed
In the reaction with the indazole electrophile (1a), we found
that the SN2’ oxidative addition (TS3) requires a higher
activation barrier of 28.0 kcal/mol with respect to 10, when
compared to the reaction with indole (TS3’), and the product
enantioselectivity in the reaction (Figure 4). The indazole
is thermodynamically destabilized by 3.6 kcal/mol (12 versus
electrophile 1a can add at either face of the C=C bond of 8 or
12’). Since the C3 oxidative additions are endergonic, the
10 (TS2a-d). Here, the C−C bond formation and the
transition states are more product-like and exhibit significant
dissociation of 2,4,6-trimethylbenzoate anion are concerted
N–O bond elongations (Figure 3B). The computed kinetic and
processes, leading directly to 3H-indazole complexes (11a-d),
which form the 1H-indazole product upon tautomerization.
The enantioselectivity of the C3-allylation product is
determined in the indazole addition step (TS2). Among the
four competing transition states, TS2c and TS2d originating
from the Z-allyl complex 8 are both disfavored (3.3 and 8.0
kcal/mol higher than TS2a, respectively) due to the
pseudoaxial placement of the bulky phenyl group, which leads
to increased repulsions with the indazole ring (Figure 4B). In
TS2a and TS2b, the smaller methyl group is placed at the
pseudoaxial position and thus the steric repulsions about the
forming C−C bond are decreased. From intermediate 10, the
addition of the indazole to form product (S)-3a through TS2b
thermodynamic trends can therefore be attributed to the
cleavage of a stronger N–O bond in the indazole electrophile,
which is supported by calculated BDEs where the cleavage of
the N–O bond in 1a requires 9.0 kcal/mol higher energy than
the corresponding bond cleavage in 6 (Figure 3C). In addition
to the relatively high calculated energy barrier, this oxidative
addition pathway would lead to the linear allylation products,
which are inconsistent with the branched selectivity observed
in experiment.
Our DFT calculations revealed a more feasible mechanism
with indazole 1a via a Zimmerman-Traxler type six-member
transition state (TS2a).15 This mechanism is favored because
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is 5.4 kcal/mol less favorable than the addition to form (R)-3a
To further verify the mechanistic model, we calculated the
enantioselectivities of the allylation reaction with allenes
containing substituents of varying degrees of steric hindrance.
The enantioselectivities were computed from transition states
TSa and TSc arising from the same facial addition of 1a to
the E- and Z-isomers of the corresponding allylic copper
species (Figure 5). The calculated enantioselectivity trend is
in a good qualitative agreement with the experimental data
(Figure 2). While reactions with allenes 2a and 2s are both
highly enantioselective, using a less bulky primary alkyl
allene (2t) almost completely diminishes the predicted er.
Although this computed value is underestimated when
compared to the observed er, both computational and
experimental results demonstrated the role of steric effects of
allene substituents on the er of the allylation product.
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2
3
4
5
6
7
8
through TS2a. The relative instability of TS2b arises from
unfavorable steric repulsions between the (S,S)-Ph-BPE
ligand and the 2,4,6-trimethylbenzoate leaving group. In
TS2b, the bulky leaving group is placed in the quadrant
occupied by a “proximal” phenyl group on the ligand (Figure
4C). By contrast, in TS2a, the leaving group is in a less
occupied quadrant with a “distal” phenyl group. The increased
ligand-substrate steric repulsions in TS2b are evidenced by
the more significant distortion of the Ph-BPE ligand in TS2b
than in TS2a (ΔΔEdist-Ph-BPE = 3.7 kcal/mol, see Figure S2).
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Cu(OAc)2 (5 mol%)
RL
RS
RL
RS
(S,S)-Ph-BPE (6 mol%)
N
+
N
•
N
DMMS (4.0 equiv)
THF (0.5 M), 12 h
1a
OR
N
O
H
R =
Mes
CuL*
CuL*
RL
RS
N
N
N
RS
RL
N
OR
OR
TSc (disfavored)
TSa (favored)
RS
RL
allene
2a
predicted er
99.7:0.3
96:4
observed er
99.5:0.5 (3a)
98.5:1.5 (3s)
75:25 (3t)
Me
H
Ph
Cy
2s
(CH2)3OPiva
H
2t
42:58
Figure 5. aRL=n-Pr was used in calculations as a model of the
3-pivaloyloxypropyl group in 2t. Computed
enantioselectivities with different allene substrates.
CONCLUSIONS
In summary, we developed a method for the preparation of
C3-allyl indazoles bearing quaternary stereocenters in high
yield with excellent levels of enantioselectivity using CuH
catalysis. Key to the success of this unique C3-selectivity in
indazole allylation reaction is the use of an umpolung
strategy: in contrast to the conventional use of indazoles as
nucleophiles,
electrophilic
indazoles
(N-
(benzoyloxy)indazoles) are employed as electrophiles in the
reaction. With the aid of DFT calculations, we discussed the
fundamental reactivity differences between the indazole and
the previously reported indole electrophiles. In addition, a
mechanistic model was developed to account for the branched
selectivity of the allyl indazole products, and explain the
observed enantioselectivity in the reaction. Expanding this
polarity reversal strategy to achieve novel reactivities in other
nitrogen-containing heterocycle functionalization reactions is
currently underway.
ASSOCIATED CONTENT
Supporting Information.
The supporting Information is available free of charge on
the ACS Publications website.
Figure 4. The origin of enantioselectivity in the C3-allylation
with the indazole electrophile 1a.
Experimental details and computational data (PDF)
Spectroscopic data (PDF)
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Derivatization at C-3 of Indazoles. J. Org. Chem. 2006, 71, 5392–
5395.
(6) A rare example of direct C3-alkylation using indazoles as
nucleophiles: Campetalla, S.; Palmieri, A.; Petrini, M. Synthesis of
3-(Tosylalkyl)indazoles and their Desulfonylation Reactions-A New
Entry to 3-Substituted Indazoles by an Unprecedented Friedel-Crafts
Process. Eur. J. Org. Chem. 2009, 3184–3188.
(7) Ye, Y.; Kim, S.-T.; Jeong, J.; Baik, M.-H.; Buchwald, S. L.
CuH-Catalyzed Enantioselective Alkylation of Indole Derivatives
with Ligand-Controlled Regiodivergence. J. Am. Chem. Soc. 2019,
141, 3901–3909.
(8) (a) Chen, J. B.; Jia, Y. X. Recent Progress in Transition-Metal-
Catalyzed Enantioselective Indole Functionalizations. Org. Biomol.
Chem. 2017, 15, 3550−3567. (b) Bandini, M.; Eichholzer, A.
Catalytic Functionalization of Indoles in a New Dimension. Angew.
Chem., Int. Ed. 2009, 48, 9608−9644.
(9) (a) Lakhdar, S.; Westermaier, M.; Terrier, F.; Goumont, R.;
Boubaker, T.; Ofial, A. R.; Mayr, H. Nucleophilic Reactivities of
Indoles. J. Org. Chem. 2006, 71, 9088−9095. (b) Otero, N.;
Mandado, M.; Mosquera, R. A. Nucleophilicity of Indole
Derivatives: Activating and Deactivating Effects Based on Proton
Affinities and Electron Density Properties. J. Phys. Chem. A 2007,
111, 5557−5562.
AUTHOR INFORMATION
Corresponding Author
1
2
3
4
5
6
7
8
*sbuchwal@mit.edu
*pengliu@pitt.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
9
The authors thank Solvias AG for donations of ligands
used in this project. We are grateful to the National
Institutes of Health (R35-GM122483, R35-GM128779).
The content is solely the responsibility of the authors and
does not necessarily represent the official views of the
National Institute of Health. We thank Yujing Zhou, Drs.
Richard Liu, Scott McCann, and Christine Nguyen for their
advice on the preparation of this manuscript. We
acknowledge Drs. Peter Müller (MIT) and Charlene Tsay
(MIT) for X-ray crystallographic analysis. We thank the
National Institutes of Health for a supplemental grant for
the purchase of supercritical fluid chromatography (SFC)
equipment (GM058160-17S1). I.K. is grateful to the
University of Pittsburgh and the Pittsburgh Quantum
Institute for fellowships. DFT calculations were performed
at the Center for Research Computing at the University of
Pittsburgh and the Extreme Science and Engineering
Discovery Environment (XSEDE) supported by the NSF.
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(10) Seebach, D. Methods of Reactivity Umpolung. Angew. Chem.
Int. Ed. Engl. 1979, 18, 239–258.
(11) For asymmetric allylation using allyl copper species, see: (a)
Holmes, M.; Schwartz, L. A.; Krische, M. J. Intermolecular Metal-
Catalyzed Reductive Coupling of Dienes, Allenes, and Enynes with
Carbonyl Compounds and Imines. Chem. Rev. 2018, 118, 6026–
6052. (b) Liu, R. Y.; Yang, Y.; Buchwald, S. L. Regiodivergent and
Diastereoselective CuH-Catalyzed Allylation of Imines with
Terminal Allenes. Angew. Chem. Int. Ed. 2016, 55, 14077–14080. (c)
Tsai, E.; Liu, R. Y.; Yang, Y.; Buchwald, S. L. A Regio- and
Enantioselective CuH-Catalyzed Ketone Allylation with Terminal
Allenes. J. Am. Chem. Soc. 2018, 140, 2007–2011.
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TOC
R3
R2
R3
R1
N
•
R1
N
R2
N
N
OR
H
R = (2,4,6-trimethyl)benzoyl
L*CuH
17 examples
electrophiles
up to 96% yield, 99.5:0.5 er
C3/(N1+N2) > 20:1
C3-selectivity
branched/linear > 20:1
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