Rh(II)-Catalyzed Chemoselective Oxidative Amination and Cyclization Cascade of 1-(Arylethynyl)cycloalkyl)methyl Sulfamates

Article abstract of DOI:10.1021/acs.orglett.7b01558

A Rh(II)-catalyzed chemoselective oxidative amination and cyclization cascade of 1-(arylethynyl)cycloalkyl)methyl sulfamates has been presented. For a cyclopropyl or cyclobutyl moiety containing alkynyl sulfamates, the reactions underwent a metallonitrene

Full text of DOI:10.1021/acs.orglett.7b01558

Letter
pubs.acs.org/OrgLett
Rh(II)-Catalyzed Chemoselective Oxidative Amination and
Cyclization Cascade of 1‑(Arylethynyl)cycloalkyl)methyl Sulfamates
Dong Pan, Yin Wei, and Min Shi*
State Key Laboratory of Organometallic Chemistry, University of Chinese Academy of Sciences, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A Rh(II)-catalyzed chemoselective oxidative
amination and cyclization cascade of 1-(arylethynyl)cyclo-
alkyl)methyl sulfamates has been presented. For a cyclopropyl
or cyclobutyl moiety containing alkynyl sulfamates, the
reactions underwent a metallonitrene-initiated alkyne oxidation
along with cyclopropyl ring expansion or alkoxyl moiety
migration to give cyclobutane-fused or methylenecyclobutane-
containing heterocycles. In the case of a cyclopentyl or
cyclohexyl moiety containing sulfamate, the reaction under-
went a direct C−H bond insertion event to afford the corresponding nitrogen-containing heterocyclic product.
atalytically generated metallonitrenes or metal carbenes are
highly versatile species and have shown broad applications
Scheme 1. Previous Work and This Work
C
in modern organic synthetic chemistry.1 Since nitrogen atom is
essential to life science, considerable attention has thus been paid
to the development of synthetic methods for its incorporation
into organic molecules. The metallonitrene chemistry would
offer great potential to build structurally complex nitrogen-
containing molecules and has attracted much attention over the
past decades.2 Besides the typical C−H amination3 and alkene
aziridination,4 the cascade reactions of metallonitrene with
alkynyl derivatives show more efficiency in multibond formations
through the generation of an α-iminometal carbene intermediate.
Metal carbene/alkyne cascades have a long history. Hoye5 and
Padwa6 did pioneering works on catalytic carbene/alkyne
cascade metathesis reactions with alkynyl-tethered diazo
compounds. Since then, various cascade reactions of metal
carbene/alkyne have been developed.7 For example, May’s
group8 recently reported a carbene cascade reaction terminating
in C−H insertion (Scheme 1a). As a comparison, the application
of metallonitrene chemistry to cascade reactions with alkynyl
derivatives has been demonstrated by the pioneering studies of
Blakey and co-workers.9 They showed that α-iminometal
carbenes could be generated via Rh-catalyzed metallonitrene-
initiated alkyne oxidation, and the α-iminometal carbenes could
be terminated in an array of reactions, such as oxygen-ylide
formation, [2,3]-Wittig rearrangement,9d aromatic substitution,
and cyclopropanation9b as well as intermolecular trapping by a
variety of allyl ethers (Scheme 1b).9a
with an ortho-cyclopropane would be generated from metal-
lonitrene I via a Rh-catalyzed metallonitrene-initiated alkyne
oxidation. Intermediate II could be terminated by a cyclopropane
ring-expanding process to give product III along with the
regeneration of Rh catalyst according to Tang’s previous work.11
Based on this hypothesis, we utilized the sulfamic ester 1a for
the initial examination using [Rh2(esp)2] (2.5 mol %) as the
catalyst and PhI(OAc)2 (1.3 equiv) as the oxidant with 2.6 equiv
of MgO as a base at room temperature in dichloromethane
(DCM) under argon atmosphere. We were pleased to find that
the desired ring-expanding product 2a was given in 71% NMR
yield within 8 h (Table 1, entry 1). This result inspired us to
further explore the better conditions for this reaction, and the
results are summarized in Table 1. First, we screened various
rhodium catalysts such as [Rh2(oct)4], [Rh2(OAc)4],
With these termination methods of carbene/alkyne cascade
reactions in mind, we wondered if it could be terminated by an
alkyl migration process. On the basis of our ongoing investigation
on the chemical transformations of strained small rings,10 we
designed 1-(arylethynyl)cycloalkyl)methyl sulfamates for a
metallonitrene-initiated metal carbene/alkyne cascade. As
shown in Scheme 1c, the α-iminometal carbene II tethered
Received: May 23, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01558
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Letter
a
Table 1. Optimization of the Reaction Conditions
b
entry
cat. (mol %)
oxidant
base
solvent
yield (%)
1
Rh2(esp)2
Rh2(oct)4
Rh2(OAc)4
Rh2(Piv)4
Rh2(TFA)4
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
PhI(OAc)2
MgO
MgO
MgO
MgO
MgO
MgO
MgO
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
toluene
benzene
DCM
DCM
DCM
71
<5
<5
15
<5
<5
74
58
77
<5
<5
70
56
2
PhI(OAc)2
3
PhI(OAc)2
4
PhI(OAc)2
5
PhI(OAc)2
6
PhIO
7
PhI(O2CtBu)2
PhI(O2CtBu)2
PhI(O2CtBu)2
PhI(O2CtBu)2
PhI(O2CtBu)2
PhI(O2CtBu)2
PhI(O2CtBu)2
PhI(O2CtBu)2
PhI(O2CtBu)2
8
9
CaO
10
11
12
13
Cs2CO3
LiOtBu
CaO
CaO
c
d
14
CaO
85 (80)
15
16
CaO
NR
NR
Rh2(esp)2
CaO
a
Unless otherwise specified, all reactions were carried out using 1a (0.2 mmol), oxidant (0.26 mmol), catalyst (2.5 mol %), and base (0.52 mmol) in
b
c
solvent (4.0 mL), rt, 8 h. Yield was determined by 1H NMR spectroscopic data using mesitylene as an internal standard. 50 mg 4 Å MS was added.
d
Isolated yield.
a,b
[Rh2(O2CtBu)4], and [Rh2(TFA)4] (Table 1, entries 1−5).
[Rh2(esp)2] was found to be the best one for this cascade
reaction.12 Then, PhI(O2CtBu)2 was identified as the more
efficient oxidant compared to PhI(OAc)2 and PhIO (Table 1,
entries 6 and 7).12b We also found that CaO served as the best
basic additive to scavenge the carboxylic acid byproduct
generated from PhI(O2CtBu)2 (Table 1, entries 8−11). Next,
we examined the solvent effects in this reaction and found that
DCM was the best choice (Table 1, entries 12 and 13). With the
addition of 4 Å MS (50 mg for 0.2 mmol of 1a), 2a could be
obtained in 85% NMR yield along with 80% isolated yield (Table
1, entry 14). Furthermore, the catalyst and oxidant were both
necessary for this reaction (Table 1, entries 15 and 16).
Scheme 2. Substrate Scope of 1
With the optimal conditions in hand, we next investigated the
generality of this reaction using a variety of substrates 1b−1l
(Scheme 2). Regardless of whether electron-donating or
electron-withdrawing groups were introduced on the aromatic
R1 group, the reactions proceeded smoothly, affording the
desired products 2b−2l in moderate to good yields. The
electron-donating groups could be methyl, phenyl, and the
methoxyl at the para- or meta-position, affording the
corresponding products 2b, 2c, and 2e in 82, 84, and 86% yields
upon heating at 100 °C, respectively. Naphthyl moiety was also
compatible, giving 2d in 72% yield upon heating, as well. The
halogen substituents were also tolerated at the para- or ortho-
position, furnishing the desired products 2f, 2g, 2h, and 2i in
good yields at room temperature. Substrates 1j and 1l with
strongly electron-withdrawing groups, nitryl group, and
trifluoromethyl group could also provide the desired products
2j and 2l in 72 and 83% yields. Besides, substrate 1k having an
ester moiety on the benzene ring gave the corresponding product
2k in 78% yield under the standard conditions. It should be noted
that substrate, in which R1 = Me, was also tested under the
optimal condition, but none of the desired product was isolated.
The structure of 2h was further confirmed by X-ray diffraction.13
Moreover, further examination of substrates 3 containing a
cyclobutyl moiety was also conducted. Upon investigation of
a
Unless otherwise specified, all reactions were carried out using 1 (0.2
mmol), PhI(O2CtBu)2 (0.26 equiv), Rh2(esp)2 (2.5 mol %), CaO
(0.52 mmol), and 4 Å MS (50 mg) in DCM (4.0 mL), rt, 8 h.
b
c
Isolated yields are provided. The reaction was performed at 100 °C
in a sealed tube, 8 h.
substrate 3a, we found that, in this case, the alkoxyl moiety
migration could take place via α-iminometal carbene, giving the
cyclobutyl group fused six-membered heterocyclic product 4a in
moderate yield rather than the ring expansion product. The
structure of 4a was further confirmed by X-ray diffraction.13 This
result suggests that the highly strained cyclopropane is essential
for the ring expansion alkyl migration process.
These alkoxyl moiety migration reaction conditions have also
been optimized (see Table S1 in the Supporting Information).
We chose 1.3 equiv of PhI(O2CtBu)2 as the oxidant, 2.5 mol % of
[Rh2(esp)2] as the catalyst, 2.6 equiv of CaO as a base, and 4 Å
MS as the additive and carried out the reaction at room
temperature in DCM for 8 h, giving the desired product 4a in
B
DOI: 10.1021/acs.orglett.7b01558
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Letter
53% NMR yield along with 48% isolated yield. The substrate
scope was then explored. As summarized in Scheme 3, the
unambiguously determined by X-ray diffraction.13 In the case of
substrate 9a with no substituent at the carbon atom, the reaction
only produced complex product mixtures under identical
conditions (eq 3).
a,b
Scheme 3. Substrate Scope of 3
On the basis of the previous reports and the control
experiments mentioned above, a plausible reaction mechanism
has been outlined in Scheme 4 to explain the different reaction
Scheme 4. Proposed Reaction Mechanism
a
Unless otherwise specified, all reactions were carried out using 3 (0.2
mmol), PhI(OPiv)2 (1.3 equiv), Rh2(esp)2 (2.5 mol %), CaO (0.46
b
mmol), and 4 Å MS (50 mg) in DCM (4.0 mL), rt, 8 h. Isolated
yields are provided.
reactions proceeded smoothly with various substrates 3b−3l,
allowing the facile synthesis of product 4 in moderate yields. The
substrates bearing an electron-withdrawing or an electron-
donating group on the aromatic ring underwent the cascade
cyclization efficiently to deliver the desired products 4b−4l in
yields ranging from 34 to 48%. Of note, for substrate 3h with a
bromo substituent at the ortho-position, corresponding product
4h was formed in 34% yield, perhaps due to the steric effect. All
kinds of halogen substituents on the aromatic ring were tolerable,
affording the desired products 4f, 4g, and 4i in moderate yields.
The lower yield of 4 compared with that of 2 was considered to
be due to the instability of product 4 under the oxidative reaction
conditions.
On the other hand, in the cases of substrates 5a and 7a bearing
a cyclopentyl or cyclohexyl group, we found that they did not
undergo metallonitrene-initiated α-iminometal carbene cycliza-
tion. Instead, a direct C−H bond insertion reaction took place to
give the corresponding heterocyclic products 6a and 8a as anti-
configuration in 34 and 64% yields, respectively, under the
standard conditions (eqs 1 and 2). The structure of 8a was
outcomes. Oxidation of substrate 1a or 3a (5a or 7a) initiates the
formation of iminoiodinane intermediate A, which undergoes
exchange with dirhodium catalyst to generate the metallonitrene
intermediate B. When n = 2 or 3, a direct C−H bond insertion
event takes place to afford the heterocyclic product 6a or 8a
because the flexible five- or six-membered carbocycle has lower
C−H bond energy (n = 2, E = 97.6 kcal/mol; n = 3, E = 97.6 kcal/
mol)14 and easily undergoes C−H abstraction in view of the
entropy effect compared to the strained small carbocycle. When
n = 0 or 1, C−H bond activation is difficult to achieve because the
C−H bond has higher energy (n = 0, E = 102.5 kcal/mol; n = 1, E
= 100.0 kcal/mol),14 and the bond angles are not in the proper
range for C−H abstraction in the case of a strained small ring. In
these cases, intermediate C or α-iminometal carbene D is
generated. For substrate 1a (n = 0), cyclopropyl intermediate D′
undergoes ring expansion to form intermediate E′ due to the
highly strained cyclopropane ring energy (n = 0, Estrain = 27.5
kcal/mol).15 The π character of the ring bonds of a cyclopropane
provides the kinetic opportunity to initiate the unleashing of the
strain.16 Then, elimination of Rh catalyst from intermediate E′
affords product 2a. However, in the case of 3a (n = 1), the
corresponding intermediate D″ undergoes the more electron-
rich alkoxyl group migration to afford intermediate E″ instead of
a ring enlargement because the four-membered ring (n = 1, Estrain
= 26.3 kcal/mol)15 is not as highly strained as that of
cyclopropane and has no π character of the ring bonds. The
elimination of Rh catalyst from intermediate E″ gives product 4a.
Therefore, the cycloalkyl ring size plays a significant role in the
chemoselectivity of this metallonitrene-initiated metal carbene/
alkyne cascades, giving diversified cyclization products.
In summary, we have disclosed a novel chemoselective Rh(II)-
catalyzed intramolecular cyclization reaction of 1-(arylethynyl)-
cycloalkyl)methyl sulfamates, affording diversified nitrogen-
containing heterocyclic products in moderate to good yields
depending on different cycloalkyl ring sizes under mild
C
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alkynyl sulfamate, direct C−H bond insertion with metal-
lonitrene takes place to give the corresponding alkyne-containing
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oxidation cascade along with cyclopropyl ring expansion occurs
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along with the alkoxyl group migration occurs to give
methylenecyclobutane-containing six-membered heterocyclic
product. Further investigations on expanding the scope and
applications of this method are underway in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01558.
Experimental procedure and characterization data for all
compounds (PDF)
X-ray data for 2h (CIF)
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Org. Chem. 1990, 55, 4518. (b) Korkowski, P. F.; Hoye, T. R.; Rydberg,
D. B. J. Am. Chem. Soc. 1988, 110, 2676.
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K. E.; Zhi, L. Tetrahedron Lett. 1989, 30, 2633.
X-ray data for 4a (CIF)
X-ray data for 8a (CIF)
́ ́
(7) (a) Cambeiro, F.; Lopez, S.; Varela, J. A.; Saa, C. Angew. Chem., Int.
AUTHOR INFORMATION
■
Ed. 2012, 51, 723. (b) Panne, P.; Fox, J. M. J. Am. Chem. Soc. 2007, 129,
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Corresponding Author
*E-mail: mshi@mail.sioc.ac.cn.
ORCID
Yin Wei: 0000-0003-0484-9231
Min Shi: 0000-0003-0016-5211
Notes
The authors declare no competing financial interest.
(10) Chen, G.-Q.; Zhang, X.-N.; Wei, Y.; Tang, X.-Y.; Shi, M. Angew.
Chem., Int. Ed. 2014, 53, 8492.
ACKNOWLEDGMENTS
■
(11) (a) Xu, H.; Zhang, W.; Shu, D.; Werness, J. B.; Tang, W. Angew.
Chem., Int. Ed. 2008, 47, 8933. (b) Liu, R.; Zhang, M.; Winston-
McPherson, G.; Tang, W. Chem. Commun. 2013, 49, 4376.
We are grateful for the financial support from the National Basic
Research Program of China [(973)-2015CB856603], the
Strategic Priority Research Program of the Chinese Academy
of Sciences (Grant No. XDB20000000), the National Natural
Science Foundation of China (20472096, 21372241, 21572052,
20672127, 21421091, 21372250, 21121062, 21302203, and
20732008).
́
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Macmillan, S. N.; Lancaster, K. M.; Mack, J. B. C.; Du Bois, J.; Berry, J.
F.; Musaev, D. G. J. Am. Chem. Soc. 2016, 138, 2327. (b) Zalatan, D. N.;
Du Bois, J. J. Am. Chem. Soc. 2009, 131, 7558.
(13) See Supporting Information for the complete experimental details
and corresponding CIF data.
(14) Luo, Y. R. Handbook of Bond Dissociation Energies in Organic
Compounds; Science Press: Beijing, 2003; p 28.
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