A Rhodium-Catalyzed [3 + 2] Annulation of General Aromatic Aldimines/Ketimines and N-Substituted Maleimides

Article abstract of DOI:10.1021/acs.orglett.8b02671

A new class of rhodium-catalyzed, C-H activation triggered [3 + 2] annulations of aromatic aldimines or ketimines and maleimides was reported in this study. A broad scope of general imines without electron-withdrawing groups were successfully activated an

Full text of DOI:10.1021/acs.orglett.8b02671

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Rhodium-Catalyzed [3 + 2] Annulation of General Aromatic
Aldimines/Ketimines and N-Substituted Maleimides
Chengfeng Zhu,† Jichao Luan,† Jun Fang, Xu Zhao, Xiang Wu, Yougui Li, and Yunfei Luo*
Anhui Province Key Laboratory of Advanced Catalytic Materials and Reaction Engineering, School of Chemistry and Chemical
Engineering, Hefei University of Technology, Hefei, 230009, China
S
* Supporting Information
ABSTRACT: A new class of rhodium-catalyzed, C−H activation triggered [3 + 2] annulations of aromatic aldimines or
ketimines and maleimides was reported in this study. A broad scope of general imines without electron-withdrawing groups
were successfully activated and could effectively react with N-substituted maleimide to afford pericyclic, multichiral centered
amines in good yields and with excellent diastereoselectivity.
Scheme 1. Transition Metals Catalyzed [3 + 2] Annulations
of Imines and Electron-Deficient Olefins
ycloaddition and annulation reactions have long received
Cmuch interest, and significant progress has been achieved
due to their widely synthetic applications in broad research
areas such as organic synthesis,1 material science, and biology.2
C−H activation,3 an emerging synthetic strategy which tackles
the C−H bond of substrates without prefunctionalization, has
been implanted in annulation reactions,4 and particularly
intense effort has been made on the [3 + 2] annulation5−9
reactions in which aromatic imine substrates were used to yield
synthetically useful indanyl/indenyl amine or amide5−8 (see
Scheme 1). Quite a few successful protocols including
enantioselective versions8 have been reported. However, C−
H activation triggered [3 + 2] annulation reactions are still in
their infancy in terms of synthetic applications due to the
limitations in both substrates and electrophiles, which usually
have to be provided with high reactivity. For example, active
aromatic ketimines bearing electron-withdrawing groups, such
as phosphonyl,5q acyl,5s or sulfonyl7 groups and highly reactive
alkynes5j,m,l,p,8b or allenes,8a8c are the most used combinations
of substrates and electrophiles in these types of reactions.
Incorporation of both general imine substrates without an
activating group and active olefins into this protocol remains
underexplored.
The only example was reported by Ackerman’s group, in
which general aromatic ketimines and acrylates underwent [3
+ 2] annulations in the presence of a manganese catalyst.6
Interestingly, aldimines, the less hindered substrates, appeared
to be a challenge in this [3 + 2] annulation reaction.6,10 Most
recently, Kim’s group demonstrated that aldimines having a
tosyl group and electron-deficient olefins could be effectively
catalyzed by a cationic rhodium catalyst to form a [3 + 2]
annulation product (see Scheme 1).7
effectively utilized as substrates and maleimides bearing an
active CC double bond as electrophiles.
Aiming to develop a [3 + 2] annulation of general imines
and active olefins, our study commenced with a very stable
cyclic ketimine 1, in which a heterocyclic structure of 2H-
benzo[b][1,4]oxazine was featured, and maleimide 2 to
investigate the reaction. We found that the reaction only
worked with Cp*RhCl2 and a copper acetate system after a
Herein, we report a new class of rhodium-catalyzed, C−H
activation initiated [3 + 2] annulation reactions, in which a
broad scope of general aromatic ketimines and aldimines were
Received: August 21, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02671
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Scheme 2. Scope of Cyclic Ketimines and Maleimides
a
The reactions were carried out with the following conditions: 0.30 mmol of 1 and 0.36 mmol of 2 in the presence of 2.5 mol % Cp*RhCl2 dimer
b
c
and 20 mol % copper acetate in 2.0 mL of solvent stirred at 50 °C for 15 h. All the yields are isolated yields. 200 mol % copper acetate, 2.5 equiv
of maleimides, and 70 °C of reaction temperature were applied to the reaction.
combinatorial screen of different metal catalysts, solvents, and
additives (see Supporting Information (SI) for details). With
the optimal conditions in hand, the substrate scopes of cyclic
ketimines (1a−j) were examined with maleimides having three
representative N-substituents of hydride, alkyl, and aryl groups
(2a−d, see Scheme 2). The results show that this new
methodology generally workes with 2-aryl-2H-benzo[b][1,4]-
oxazine type ketimine substrates, which could undergo [3 + 2]
annulations with N-H, N-Me, and N-aryl substituted
maleimides smoothly to afford products 3 in good yields
(51−88%) and with excellent diastereoselectivity (the relative
configuration was confirmed by single-crystal diffraction on
3aa).
According to the result shown in Scheme 2, the electron-
donating group generally benefits from the reactions and gave
a relatively better yield while the electron-withdrawing group
has the opposite effect. For example, substrates 1b, 1d, and 1j,
in which each or both aromatic rings of the benzoxazine
structure has/have methyl groups, could afford the correspond-
ing products in better yields (81% of 3bc, 78% of 3db, and
81% of 3jc) than that of the unsubstituted substrates 1a and
halogenated substrates 1e, 1f, and 1g (52% of 3ac, 57% of 3ec,
62% of 3fa, and 51% of 3gc). Moreover, for these less active
substrates, sometimes an increased copper acetate loading and
a higher temperature were applied to achieve a moderate yield
(3cb and 3gc). The impact of N-substituting groups of the
maleimide to the reactions is not obvious.
protocol is compatible with this type of substrate, although the
yield dropped apparently compared with that obtained on
substrate 3. It was found that an increase of the copper acetate
loading could promote the yields to some extent. The final
optimal usage of copper acetate for the acyclic ketimines is 2.0
equiv, and the results are shown in Scheme 3.
Initially, phenylacetone ketimine 4a was examined with
various N-substituted maleimides and provided the desired
products in moderate yields of 57−75% (see 5aa−5ah,
Scheme 3). The drop in yields sometimes comes from the
decomposition of substrates. Later, the scope of acyclic
ketimines was examined and the result shows that the
methodology is general to various aryl ketimines. A single
diastereoisomer of products was formed smoothly, and the
yields range from moderate to good (5bc−5db, Scheme 3).
Importantly, it should be highlighted that ketimine (5c),
generated from 2-naphthyl ketone and which could yield
regioisomers,6 gave the single regioisomer (see 5cb and 5cc)
and diastereoisomer product. This is probably due to the mild
reaction temperature. This novel result significantly increases
its potential usage in synthetic chemistry. When there was a
meta substituting group in the substrate (5d), the activation
site of arene exclusively went to the less hindered position that
is opposite to the substituting group (5dc and 5db). This
result is consistent with the selectivity of metalation that is
reported in the literature.11
As the α-branched chiral amines possess a large percentage
of core structures in drugs and natural products, it is important
that aldimines could be adapted to this protocol. However,
aldimines, which are less hindered than ketimines and are
To explore the generality of this methodology, PMP group
protected acyclic ketimines 4a−d were prepared and tested
with the same conditions. We were pleased to find that this
B
DOI: 10.1021/acs.orglett.8b02671
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Organic Letters
Letter
Scheme 3. [3 + 2] Annulation of Acyclic Ketimines and N-
Substituted Maleimides
Scheme 4. [3 + 2] Annulation of Acyclic Ketimines and N-
Substituted Maleimides
a b
,
a b
,
a
The reaction was carried out with the same conditions as those used
b
c
in Scheme 3. All yields were isolated yields. Combined yield of two
regioisomers.11
Scheme 5. Stoichiometric Reactions of the Rhodacycle
a
The reaction was carried out with the following conditions: 0.30
mmol of 4 and 0.36 mmol of 2 in the presence of 5.0 mol %
Cp*RhCl2 dimer and 200 mol % copper acetate in 2.0 mL of solvent
b
stirred at 50 °C for 15 h. All yields were isolated yields.
supposed to be the least challenging substrates, have turned
out to be problematic in this type of reaction, for a β-hydride
elimination would occur to generate the CN double bond
again.10
Gratifyingly, this protocol is also applicable to aromatic
aldimines (6a−e), affording the desired products in good
yields (61−85%) with excellent regio- and diastereoselectivity
(Scheme 4). An exception was 6f, from which a pair of
inseparable regioisomers in a ratio of 5:1 was obtained. This
could be attributed to the fact that the meta-fluoro group could
not differentiate the two possible sites significantly.11 The 2-
naphthyl substituted aldimine substrate yielded single
regioisomer products (7ba and 7bb) similar to its ketimine
analogs (5cb and 5cc in Scheme 4). This success again makes
this protocol synthetically useful. Moreover, to the best of our
knowledge, there is no literature precedent for the rhodium-
catalyzed [3 + 2] annulations of aldimines having no electron-
withdrawing groups and electron-deficient olefins.
Interestingly, a straightforward insertion of the unsaturated
bond of the electrophiles into the rhodium−carbon bond of
the rhodacycle complex, the most commonly proposed
carborhodation step,5j,m,n,p,9d is unlikely to occur in this
reaction system according to the results of stoichiometric
reactions of the rhodacycle 8 and maleimide 2b (eq 1, Scheme
5). The reaction only proceeded when extra imine substrate
was present in the reaction.12 An unprecedented metathesis
reaction of the rhodacycle 8a and free imine 6b (eq 2, Scheme
5), which could only occur with the presence of copper acetate,
afforded the rhodacycle 9, suggesting that extra imine substrate
along with copper acetate played a very crucial role in the
carborhodation step in the reaction.12
In summary, we have developed a [3 + 2] annulation
reaction of aromatic imine substrates and maleimides via a
rhodium catalyzed C−H activation strategy. This protocol is
applicable to a broad scope of imines including cyclic/acyclic
ketimines and aldimines, in which an activation moiety such as
an acyl or a sulfonyl group was not required. The wide
substrate scope along with good yields and high diaster-
oselectivity make this protocol synthetically attractive. Further
studies in regard to the reaction mechanism and new reactions
relative to this reaction are currently ongoing in our laboratory.
C
DOI: 10.1021/acs.orglett.8b02671
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02671.
■
S
Experimental procedures, compounds data, and spectra
(PDF)
Accession Codes
CCDC 1863180−1863182 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yunfluo@hfut.edu.cn.
ORCID
Chengfeng Zhu: 0000-0002-9676-6750
Xiang Wu: 0000-0001-5428-9063
Yunfei Luo: 0000-0001-9366-118X
Author Contributions
†C.Z. and J.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Hefei University of Technology and the
NSFC (Project Nos. 21401037 and 21672049) for financial
support for this work. Y.L. thanks Prof. Jianliang Xiao at the
University of Livperool in the U.K. for the key suggestions of
rhodium chemistry and Prof. George O’Doherty at Northeast-
ern University in Boston for valuable discussions.
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DOI: 10.1021/acs.orglett.8b02671
Org. Lett. XXXX, XXX, XXX−XXX