Enantioselective Twofold C?H Annulation of Formamides and Alkynes without Built-in Chelating Groups

Article abstract of DOI:10.1002/anie.202001267

Twofold C?H annulation of readily available formamides and alkynes without built-in chelating groups was achieved. Ni?Al bimetallic catalysis enabled by a bulky BINOL-derived chiral secondary phosphine oxide (SPO) ligand proved to be critical for high reactivity and high selectivity. This reaction uses readily available formamides as starting materials and provides a concise synthetic pathway to a broad range of chiral ferrocenes in 40–98 % yield and 93–99 % ee.

Full text of DOI:10.1002/anie.202001267

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Accepted Article
Title: Enantioselective Twofold C-H Annulation of Formamides and
Alkynes without Built-in Chelating Groups
Authors: Hao Chen, Yin-Xia Wang, Yu-Xin Luan, and Mengchun Ye
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Enantioselective Twofold CH Annulation of Formamides and
Alkynes without Built-in Chelating Groups
Hao Chen, Yin-Xia Wang, Yu-Xin Luan, Mengchun Ye*
Dedicated to the 70th anniversary of Shanghai Institute of Organic Chemistry
Abstract: Twofold CH annulation of readily available formamides
and alkynes without built-in chelating groups was achieved,
providing a series of chiral ferrocenes in 4098% yield and 9399%
ee. Bulky chiral SPO ligand-enabled NiAl bimetallic catalysis
proved to be critical to high reactivity and high selectivity.
activation[11] or intermolecular chelated CH bond activation.[12]
To avoid case-by-case substrate preparation in intramolecular
reactions and the requirement for extra chelating groups in
intermolecular reactions, the development of non-chelated
twofold CH annulation for synthesis of chiral ferrocenes is
highly desirable. In this context, herein, we report the first
asymmetric non-chelated twofold CH annulation of readily
available formamides and alkynes for synthesis of chiral
Transition metal-catalyzed oxidative annulation of twofold CH
bonds with -unsaturated compounds provides a concise and
economical pathway to various cyclic compounds that are
difficult to be prepared by traditional cycloaddition reactions such
as Diels-Alder reactions.[1,2] This type of reaction not only allows
the formation of two bonds and one ring in one step, but also
eliminates pre-functionalizations of substrates, significantly
enhancing atom and step economy. According to whether to use
built-in chelating groups, twofold CH annulation can be divided
into two subgroups: chelated annulation and non-chelated
annulation (Scheme 1a). The former uses chelating groups to
initiate CH bond activation, significantly facilitating the reaction.
With this strategy, a number of chelated twofold CH oxidative
annulations have been achieved during the past decades.[3,4]
Even most recently, two asymmetric examples on chelated
[13]
ferrocenes (Scheme 1c). Chiral secondary phosphine oxide
(
SPO)-enabled NiAl bimetallic catalysis proved to be an
[
14,15]
efficient catalytic system for the reaction,
providing a series
of chiral ferrocenes with up to 98% yield and up to 99% ee.
[
5]
twofold CH annulations were reported by Wang and Li
[
6]
groups , who both used amides as chelating groups and chiral
Cp-Rh as efficient catalysts, achieving good to excellent yield
and ee (Scheme 1b). However, from the viewpoint of atom and
step economy, the latter would undoubtedly be a more attractive
pathway because it avoids extra manipulations of chelating
groups such as pre-installation and post-removal in the former,
thereby allowing the use more readily available substrates.
However, the absence of chelating groups cause quite big
difficulty for CH bond activation, leading to only scarce
examples on non-chelated twofold CH annulations reported in
recent years,[
7,8]
which lagged far behind the former. Given
higher atom- and step-economy of the latter, the development of
more efficient non-chelated twofold CH annulation would be in
high demand. In particular, owing to the lack of proper chiral
ligands, its asymmetric version still remains an elusive challenge.
On the other hand, enantioselective synthesis of ferrocenes
via CH activation has attracted much attention during recent
years because it proves to be a more atom- and step-
economical pathway than traditional methods.[9,10] However, all
reported versions were limited to either intramolecular CH bond
Scheme 1. Enantioselective transition metal-catalyzed oxidative annulations
via twofold CH bond activation.
Inspired by Nakao and Hiyama’s elegant work on direct
annulation of formamides and alkynes,[8] we proposed to use
readily available ferrocene-based formamide 1a and alkyne 2a
as model substrates (Scheme 2). However, there existed three
major challenges: 1) the reported method suffered from severe
limitation of substrates. Only one type of steric-demanding
formamides were compatible, whereas other formamides
[*]
H. Chen, Y.-X. Wang, Y.-X. Luan, M. Ye
State Key Laboratory and Institute of Elemento-Organic Chemistry,
College of Chemistry, Nankai University, Tianjin 300071 (China)
E-mail: mcye@nankai.edu.cn
[8]
including arylformamides were completely ineffective; 2) the
scope of ligands was quite limited, and only bulky tri(tert-
butyl)phosphine was efficient ligand; 3) chiral ligands for nickel-
catalyzed CH activation are quite scarce.[16] To address these
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challenges, we proposed to use SPO-bridging Ni-Al bimetallic
system to promote this reaction, and thus a rigid 6-membered
nickelacycle could accelerate the second CH activation by
increasing steric hindrance of SPO ligand (see Scheme S1).
Herein, the Al(III) would act as dual roles: one was the same
Lewis acid activator as that in Nakao’s reaction, the other was
an anchoring site of SPO ligand. Following this hypothesis, we
of either the nickel(II) species or the nickel(II) together with Zn
still catalyzed the reaction well with excellent ee but lower yield.
investigated our previously reported Taddol-derived SPO (L
1
) for
the reaction.[15b] With AlMe
or not, traditional phosphines and
3
carbenes did not produce 3a, except some side products from
hydrocarbomoylation[17] and decarbonylation. However, to our
delight, chiral SPO (L ) greatly promoted this reaction in the
1
presence of proper Lewis acids. In the presence of Ni(cod)
2
(10
i
mol%), AlBu
3
(40 mol%) and SPO L
1
(10 mol%), the planar
chiral product 3a was successfully obtained in 58% yield and 50%
ee (see Scheme S1).
Scheme 2. Ligand optimization. 1a (0.10 mmol), 2a (0.25 mmol), toluene (0.5
1
mL), under N
2
for 12 h. Yield was determined by H NMR analysis with CH
2
Br
2
1
as the internal standard and ee was determined by chiral HPLC analysis. Ar =
,5- Bu C H ; Ar = 3,5-Me C H . [a] 20 mol% of L15 under N for 1 h.
2 6 3 2 6 3 2
t
2
3
To further improve enantioselectivity, various chiral SPOs
such as Taddol-derived (L and L ), diamine-derived (L L ),
and BINOL-derived SPOs (L L10) were tested, however, only
1
2
3
6
7
moderate yield and ee were observed (Scheme 2). Notably,
when substituents on the naphthyl ring of BINOL varied from H
Scheme 3. Scope of alkynes. Reaction conditions: 1a (0.2 mmol), 2 (0.5
mmol), toluene (1.0 mL) under N for 1 h. Yield of isolated products and ee
2
n
(
L
7
), Me (L
8
), Et (L
9
), to Pr (L10), the corresponding yield and ee
increased gradually, suggesting that the steric hindrance of the
substituent played a critical role in enhancing the yield and the
ee. In view of this fact, we decided to introduce more bulky
groups into the naphthyl ring of BINOL, for example, silyl (L11
and L12) and (bisaryl)methyl (L13L15). As expected, the most
bulky SPO (L15) gave the best yield and ee (98% yield and 96%
ee). When using 20 mol% of ligand, the ee was further improved
was determined by chiral HPLC analysis. [a] Additional IPr (10 mol%) was
added. [b] 3r as a major isomer was determined by H NMR.
1
With the optimized conditions in hand, various diaryl alkynes
were investigated first (Scheme 3). Results showed that methyl
on para or meta position on the phenyl ring of the alkyne did not
have a strong influence on the reaction (3b and 3c), whereas
ortho-methyl led to no reaction, probably because sterically
hindered arylalkynes could not insert into NiH or NiC bond.
Other mono- or di-substituted groups on para or meta position
were also well tolerated. For example, bulky tert-butyl (3d), 3,4-
dimethyl (3f) and indolyl (3g) provided the corresponding
to 99%, and the reaction was complete within one hour. Control
i
experiments showed that AlBu
3
was indispensable (see Table
S7), and other alkylalumilums or Lewis acids gave lower
efficiency. The absence of Ni(cod) gave no reaction, but the use
2
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products in 9498% yield and 9799% ee. Notably, due to steric
hindrance, 3,5-dimethylphenyl (3e) only gave 40% yield but still
good ee (93%). In addition, the reaction showed good
compatibility for various electron-donating groups (OMe and
including acetyl, benzoyl and tert-butoxycarbonyl led to no
reaction. Gratifyingly, easily removable protecting groups such
as methoxymethyl (MOM, 4d) and trimethylsilylethoxymethyl
(SEM, 4e) proved to be well compatible, providing the
corresponding product in 96% yield (98% ee) and 98% yield (99%
ee), respectively, within less than 10 minutes. For investigating
the compatibility of substituted groups on the ferrocene ring, we
synthesized methyl (4f), and functionalized groups such as
trimethylsilyl (4g), ethoxycarbonyl (4h) and tri(n-butyl)tin (4i).
Results showed that all of them were tolerated well, providing
7294% yield and 9899% ee.
Although ferrocene-based chiral pyridines have proved to be
useful chiral bases or ligands, traditional synthetic methods often
required lengthy synthetic routes along with late-stage chiral
resolution.[18] To achieve a shorter pathway, we explored direct
transformation of our products. Gram-scale reaction afforded
product 4d in 93% yield (1.25 g), which was then treated by
reduction and hydrolysis, providing the corresponding ferrocene-
based chiral pyridine 5 with intact 98% ee in 32% yield over two
steps (Scheme 5a). This result showed that our reaction could
provide a concise method for enantioselective synthesis of
various ferrocene-based chiral pyridines.
OCF
3
3
, 3h3j) and electron-withdrawing groups (F, CF , and
CO Me, 3k3o) on para or meta position, affording the
2
corresponding products in 8297% yield and 9499% ee.
Different from ortho-methyl group, ortho-fluoro on the phenyl ring
of the alkyne was well compatible, providing the desired product
in 84% yield and 95% ee (3m). However, dialkyl alkynes were
not well compatible with the conditions, providing only trace
amounts of products even by prolonging reaction time or
increasing loadings of nickel. We reasoned that the facile
cyclometallation of dialkyl alkynes with the nickel could inhibit
the reactivity of the nickel in both two CH bond activations.
Therefore, sterically-hindered N-heteocyclic carbene (IPr) was
added to prevent such side reactions. Pleasingly, good yield and
ee was then obtained for dialkyl alkynes (3p and 3q).
Nevertheless, this system was not similarly suitable for diaryl
alkynes and even mono-aryl alkynes, which could be attributed
to steric repulsion between the alkyne and the ligand. Only less
bulky phenyl and methyl alkyne proved to be effective under the
optimal conditions of diaryl alkynes, affording 3r as a major
isomer (53% yield, 4:1 isomer ratio).
Scheme 4. Scope of formamides. Reaction conditions: 1 (0.2 mmol), 2a (0.5
mmol), toluene (1.0 mL) under N
2
for 10 min to 2 h. Yield of isolated products.
[
a] 120 C. MOM = methoxymethyl. SEM = trimethylsilylethoxymethyl.
Scheme 5. Synthetic utility, mechanistic experiments and
a proposed
mechanism.
Next, the scope of formamides was investigated (Scheme 4).
There was no reaction for formamide bearing free NH bond, but
the substrate can be fully recovered. Various formamides with
aryl or alkyl N-protecting groups such as ethyl (4a), benzyl (4b),
phenyl (4c) worked well in the reaction, providing the
corresponding products in 5095% yield and 9899% ee,
whereas the use of electron-withdrawing protecting groups
To gain insight into this reaction, additional mechanistic
experiments were conducted (Scheme 5b). During the reaction
of deuterated formamide (1a-d) with 1,2-diphenylethyne (2a)
6
3
using less reactive SPO L and AlMe , compound 6 from
hydrocarbomoylation and alkene 7 can be isolated together with
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the desired 3a, and the formyl D was completely transferred into
compounds 6 and 7 (eq (1)). In addition, parallel reactions
showed no isotope effect (eq (2)), excluding formyl CH bond
cleavage from the rate-determining step. On basis of these
information and our previous work,[15b] a plausible mechanism
was proposed in Scheme 5c. The bifunctional SPO coordinated
to the nickel and the aluminum concurrently at the beginning.
Then the in-situ formed catalyst coordinated to formamide and
activated the formyl CH bond, providing the nickelacycle (A).
The subsequent insertion of the alkyne and the direct reductive
elimination would produce the byproduct 6, otherwise the
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E
Ar mechanism.[ The second insertion
19]
of the alkyne and the followed reductive elimination would
provide the desired product 3a. The stereochemical model
showed that R -type CH activation of the intermediate (B) was
p
favored in the confined space by the bulky chiral L15 ligand (see
Page S39).
In summary, we have developed the first asymmetric oxidative
annulation of twofold CH bonds and alkynes without built-in
chelating groups, providing
a concise synthesis of chiral
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ferrocenes from readily available formamides. Bulky BINOL-
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reaction. Various diaryl alkynes and dialkyl alkynes were well
tolerated, affording a series of chiral ferrocenes in 4098% yield
and 9399% ee. Two-step transformations of products produced
useful ferrocene-based chiral pyridines. The SPO/Ni/Al system
could be widely used in other twofold CH activations in future.
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[
Acknowledgements
We thank the National Natural Science Foundation of China
(
91856104, 21871145 and 21672107), the Tianjin Applied Basic
Research Project and Cutting-Edge Technology Research Plan
19JCZDJC37900) and “the Fundamental Research Funds for
(
the Central Universities”(63191601) for financial support for
financial support.
[
8]
9]
2011, 133, 3264.
Keywords: nickel • aluminum • annulation • formamide •
[
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Angewandte Chemie International Edition
10.1002/anie.202001267
COMMUNICATION
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COMMUNICATION
Hao Chen, Yin-Xia Wang, Yu-Xin, Luan,
Mengchun Ye*
Page No. – Page No.
Enantioselective Twofold CH
Annulation of Formamides and
Alkynes without Built-in Chelating
Groups
Text for Table of Contents
A highly enantioselective annulation of twofold CH bonds with alkynes without built-in chelating groups has been developed via
BINOL-derived secondary phosphine oxide (SPO)-enabled Ni-Al bimetallic catalysis. This reaction used readily available formamides
as starting materials, provided a concise synthetic pathway to a broad range of chiral ferrocenes in 4098% yield and 9399% ee.
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