Rhodium(III)-Catalyzed [3+2] Annulation of 5-Aryl-2,3-dihydro-1H-pyrroles with Internal Alkynes through C(sp2)-H/Alkene Functionalization

Article abstract of DOI:10.1002/anie.201407175

This study describes a new rhodium(III)-catalyzed [3+2] annulation of 5-aryl-2,3-dihydro-1H-pyrroles with internal alkynes using a Cu(OAc)₂ oxidant for building a spirocyclic ring system, which includes the functionalization of an aryl C(sp²)-H bond and addition/protonolysis of an alkene C=C bond. This method is applicable to a wide range of 5-aryl-2,3-dihydro-1H-pyrroles and internal alkynes, and results in the assembly of the spiro[indene-1,2′-pyrrolidine] architectures in good yields with excellent regioselectivities.

Full text of DOI:10.1002/anie.201407175

Angewandte
Chemie
DOI: 10.1002/anie.201407175
Heterocycle Synthesis
Rhodium(III)-Catalyzed [3+2] Annulation of 5-Aryl-2,3-dihydro-1H-
2
À
pyrroles with Internal Alkynes through C(sp ) H/Alkene
Functionalization**
Ming-Bo Zhou, Rui Pi, Ming Hu, Yuan Yang, Ren-Jie Song, Yuanzhi Xia,* and Jin-Heng Li*
2
À
Abstract: This study describes a new rhodium(III)-catalyzed
[3+2] annulation of 5-aryl-2,3-dihydro-1H-pyrroles with inter-
nal alkynes using a Cu(OAc)2 oxidant for building a spirocyclic
However, annulation methods[6,7] using this C(sp ) H func-
tionalization strategy for the construction of five-membered
carbocycles, particularly the annulation methods in the
presence of oxidants,[6] are uncommon. These transformations
are focused on aryl carbonyl compounds and their derivatives,
including benzadehydes, arylketones, benzamides, and aryl
imines, and their reaction with alkynes (Scheme 1a).[6,7]
ring system, which includes the functionalization of an aryl
2
À
=
C(sp ) H bond and addition/protonolysis of an alkene C C
bond. This method is applicable to a wide range of 5-aryl-2,3-
dihydro-1H-pyrroles and internal alkynes, and results in the
assembly of the spiro[indene-1,2’-pyrrolidine] architectures in
good yields with excellent regioselectivities.
À
However, approaches involving the cleavage of the C C
p bond of alkenes for the annulation of 2p components
remain an unexploited area.[8] We report a new, highly
selective rhodium(III)-catalyzed [3+2] annulation of 5-aryl-
2,3-dihydro-1H-pyrroles with internal alkynes for the selec-
tive synthesis of spiro[indene-1,2’-pyrrolidines] (Scheme 1b).
This method achieves C(sp ) H functionalization, the inser-
T
he 1-azaspiro[4.4]nonanes, including spiro[indene-1,2’-pyr-
rolidines], are used in many bioactive natural products,
pharmaceuticals, and pesticides, as they have important
pharmacological and pesticidal properties,[1] including inhib-
ition of the hepatitis C virus (HCV),[1a] inhibition of b-
secretase (BACE-1),[1b] agonism of the nicotinic acetylcholine
receptors (mAChR),[1c–d] as well as herbicidal activity[1e] and
anticancer activity[1f–k] (Figure 1). The routes most commonly
used to build the 1-azaspiro[4.4]nonane ring system are the
formation of a cyclopentane ring onto a pre-existing pyrro-
lidine ring and the formation of a pyrrolidine ring onto a pre-
existing cyclopentane ring.[2,3] However, these transforma-
tions often require multiple synthetic steps, thus limiting the
functional group choice. Therefore, a new strategy for the
facile one-pot assembly and derivatization of the 1-azaspiro-
[4.4]nonane ring system is highly desirable.
2
À
À
tion of an alkyne, the addition of a C C double bond, and
a protonolysis.
We began our investigations by optimizing the reaction
conditions for the annulation of 3,5-diphenyl-1-tosyl-2,3-
dihydro-1H-pyrrole (1a) with 1,2-diphenylethyne (2a)
(Table 1). Extensive screening of various reaction parameters
revealed that 5 mol% [{Cp*RhCl2}2], 20 mol% AgSbF6,
Transition-metal-catalyzed cycloaddition reactions have
emerged as powerful and step-economic methodologies for
the construction of complex cyclic compounds in organic
synthesis.[4–8] The transition-metal-catalyzed cycloadditon of
aromatic compounds with 2p components (e.g., alkenes,
allenes, and alkynes) involving the functionalization of the
2
À
C(sp ) H bonds is promising, as it exhibits a high efficiency
and provides opportunities to discover new reactions.[5–7]
Figure 1. Examples of important 1-azaspiro[4.4]nonanes.
[*] M.-B. Zhou, R. Pi, M. Hu, Y. Yang, R.-J. Song, Prof. Dr. J.-H. Li
State Key Laboratory of Chemo/Biosensing and Chemometrics
College of Chemistry and Chemical Engineering
Hunan University, Changsha 410082 (China)
E-mail: jhli@hnu.edu.cn
Prof. Dr. J.-H. Li
State Key Laboratory of Applied Organic Chemistry
Lanzhou University, Lanzhou 730000 (China)
Dr. Y. Xia
College of Chemistry and Materials Engineering
Wenzhou University, Wenzhou 325035 (China)
[**] We thank the NSFC (No. 21172060) and HPNSFC (No. 13JJ2018)
for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407175.
Scheme 1. [3+2] annulation routes to carbocycles. Cp*=C5Me5, Ts=4-
toluenesulfonyl.
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Table 1: Screening for optimal reaction conditions.[a]
(entries 1 and 16). However, without additional H2O a longer
reaction time was required (approximately 24 h) to complete
the reaction (entry 17). Gratifyingly, a reaction on a one gram
scale of 1a was successfully performed in good yield
(entry 18).
After determining the optimal reaction conditions, the
scope of this rhodium(III)-catalyzed annulation protocol with
respect to the 5-aryl-1-tosyl-2,3-dihydro-1H-pyrroles 1 and
alkynes 2 was investigated (Table 2 and Table 3).[9] As shown
in Table 2, we first applied these optimal reaction conditions
Entry
Variation from the standard conditions
Yield [%]
1
2
3
4
5
6
7
8
none
at 608C
at 1008C
[{Cp*RhCl2}2] (2 mol%)
[{Cp*RhCl2}2] (10 mol%)
without [{RhCpCl2}2]
AgSbF6 (30 mol%)
AgSbF6 (10 mol%)
without AgSbF6
82
70
67
71
81
0
80
52
0
Table 2: Variation of internal alkynes (2).[a]
9
10
11
12
13
14
15
16
17
18[b]
AgOAc, Ag2CO3, or AgOTf instead of AgSbF6
Cu(OAc)2·H2O (2 equiv)
Cu(OAc)2·H2O (0.6 equiv)
without Cu(OAc)2·H2O
MeOH instead of CH2ClCH2Cl2
tAmOH instead of CH2ClCH2Cl2
H2O (6 equiv)
trace
82
66
16
trace
36
75
78
80
without H2O for 24 h
none
[a] Reaction conditions: 1a (0.15 mmol), 2a (0.18 mmol), [{Cp*RhCl2}2]
(5 mol%), AgSbF6 (20 mol%), Cu(OAc)2·H2O (1.2 equiv), H2O
(3 equiv), and CH2ClCH2Cl (2 mL) at 808C under Ar for 12 h. The d.r.
value is 1.1:1 as determined by 1H NMR analysis. [b] 1a (1 g) for 48 h.
1.2 equivalents Cu(OAc)2, and 3 equivalents H2O in
CH2ClCH2Cl at 808C for 12 hours was the best set of
conditions for the annulation of 1a with 2a, thus providing
the desired spiro[indene-1,2’-pyrrolidine] 3aa in 82% yield
(entry 1). The reaction temperatures were found to affect the
reaction, as the yield of 3aa decreased from 82% at 808C to
70% at 608C (entry 2) and to 67% at 1008C (entry 3). For the
amounts of [{Cp*RhCl2}2] and AgSbF6 used, we found that
5 mol% [{Cp*RhCl2}2] and 20 mol% AgSbF6 were preferred
for the annulation reaction (entry 1 versus entries 4, 5, 7, and
8). Notably, a rhodium catalyst was necessary for successful
annulation, as its absence resulted in no detectable amount of
3aa (entry 6). In addition, the reaction did not proceed
without silver salts (entry 9) because the formation of an
active cationic rhodium species requires a silver salt to trap
the Cl anions from the rhodium catalyst.[6] The use of other
silver salts, including AgOAc, Ag2CO3, and AgOTf, showed
relatively lower reactivity (entry 10). Subsequently, the
amount of Cu(OAc)2 was examined (entries 11–13). The
reaction yield when using 2 equivalents Cu(OAc)2 was
identical to that of 1.2 equivalents Cu(OAc)2, whereas the
yield decreased from 82 to 52% when using 0.6 equivalents
Cu(OAc)2 (entry 1 versus entries 11 and 12). It should be
noted that the reaction can take place without Cu(OAc)2,
albeit with a lower yield (entry 13). The screening of solvents
revealed that MeOH and tAmOH, two reported efficient
solvents for the rhodium-catalyzed annulation,[5–7] were less
efficient than CH2ClCH2Cl for the annulation of 1a
(entries 14 and 15). Notably, the presence of H2O accelerated
the reaction (entries 1, 16, and 17). In the presence of
additional H2O 1a was consumed completely within 12 hours
[a] Reaction conditions: 1a (0.15 mmol), 2 (0.18 mmol), [{Cp*RhCl2}2]
(5 mol%), AgSbF6 (20 mol%), Cu(OAc)2·H2O (1.2 equiv), H2O
(3 equiv,) and CH2ClCH2Cl (2 mL) at 808C under Ar 12 h. The d.r. value is
given within parentheses. [b] 4-Methyl-N-(4-oxo-2,4-diphenylbutyl)ben-
zenesulfonamide (4a), a ring-opening product from 1a and H2O, was
isolated in about 60% yield.[9]
to the annulation of 1a with a variety of symmetrical or
unsymmetrical internal alkynes (2b–m), thus affording
a broad array of spiro[indene-1,2’-pyrrolidines] (3ab–am) in
good yield. In the presence of 1a, [{Cp*RhCl2}2], AgSbF6,
Cu(OAc)2, and H2O, the 1,2-diarylethynes 2b–g, bearing Me,
MeO, Cl, and Br groups on the aromatic rings, afforded the
products 3ab–ag in 69–81% yield. Importantly, halogen
substituents were well-tolerated under the optimal reaction
conditions, thereby making the [3+2] annulation protocol
more useful in organic synthesis because of the potential to
further modify at the halogenated positions (3ad and 3af).
The annulation of the unsymmetrical internal alkynes 2h–m
2
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Table 3: Variation of 5-Aryl-2,3-dihydro-1H-pyrroles (1).[a]
also afforded 3ah–am in good yields with excellent levels of
regiocontrol. Several substituents, including OMe, OAc, and
Cl, were compatible with the optimal reaction conditions. The
reaction of 1-phenylpropyne (2h) with 1a regiospecifically
delivered 3ah in 71% yield.[10] We were pleased to find that
the alkynes 2k–m, containing OMe, OAc, and Cl groups,
respectively, on the alkyl moiety also had high reactivity and
afforded 3ak–am in 70–74% yield. However, the aliphatic
internal alkyne 2n and the aliphatic terminal alkyne 2o were
not viable substrates in the construction of the spiro[indene-
1,2’-pyrrolidines] 3an and 3ao, respectively.
We next turned our attention to applying the optimal
redaction conditions to the annulation of various 5-aryl-2,3-
dihydro-1H-pyrroles (1) with either 2a, 2g, or 2h (Table 3).
The pyrroles 1b–g, which contain several substituted aryl
groups, including 4-MeC6H4, 4-ClC6H4, 4-BrC6H4, 4-
NO2C6H4, 3-ClC6H4, and naphthalen-1-yl, were compatible
with the optimal reaction conditions, and gave 3ba–ga, 3cg,
3ch, 3dh, and 3 fh in good yields. Moreover, the electronic
properties of the substituted aryl groups had no distinct effect
on the reaction. While the 4-MeC6H4-substituted pyrrole 1b
delivered 3ba in 77% yield, 1e, containing an electron-
withdrawing NO2 group, afforded 3ea in 72% yield. The
chloro-substituted pyrroles 1c and 1 f were also successfully
reacted with the alkynes 2a, 2g or 2h, providing 3cg, 3ch, 3 fa
and 3 fh in good yields and excellent regioselectivities. The
pyrrole 1h, containing two substituents—a 3-phenyl group
and a 4-methyl group—provided 3ha in 66% yield.[9] 2-
Phenyl-3a,4,5,6,7,7a-hexahydro-1H-indole (1i) was also
a viable substrate, thus giving 3ia in 68% yield. Several
substituents on the pyrrole nitrogen atom (Ts, PhCO, Boc,
and H) were examined (3ja–ma and 3jh), and only the N-
tosyl-substituted substrate 1j smoothly delivered the spiro[in-
dene-1,2’-pyrrolidine] ring system (3ja and 3jh). The sub-
strates 1n and 1o were unsuitable for the annulation reaction
(3na and 3oa). Notably, the optimal reaction conditions were
applicable to the pyrroles 1p–s, which bore a Me, Cl, or Br
group on the aromatic ring of the 5-phenyl moiety (3pa–sa).
When using 1p to react with 2a, [{Cp*RhCl2}2], AgSbF6,
Cu(OAc)2, and H2O, the reaction afforded 3pa in 75% yield.
Interestingly, the chloro- (1q) and bromo-substituted pyrroles
(1r) were well-tolerated and provided the corresponding 3qa
and 3ra in 74 and 72% yield, respectively. The more sterically
hindered 3,5-dimethyl-substituted pyrrole 1s was annulated
with 2a smoothly to deliver 3sa in 78% yield. Notably, the
annulation was applicable to the assembly of the polycyclic
aromatic spirocyclic ring 3ta in good yield using the
naphthalen-1-yl-substituted pyrrole 1t.
[a] Reaction conditions: 1 (0.15 mmol), 2 (0.18 mmol), [{Cp*RhCl2}2]
(5 mol%), AgSbF6 (20 mol%), Cu(OAc)2·H2O (1.2 equiv), H2O
(3 equiv), and CH2ClCH2Cl (2 mL) at 808C under Ar for 12 h. The d.r.
value is given within parentheses. [b] N-(4-Oxo-4-phenylbutyl)benzamide
(4k) was isolated in 61% yield. [c] tert-Butyl 4-oxo-4-phenylbutylcarba-
mate (4l) was obtained in 66% yield. [d] 5-Phenyl-3,4-dihydro-2H-pyrrole
(5m) was obtained in 72% yield. [e] 1,2-Diphenylethanone (6n; 43%
yield) and benzil (7n; 22% yield) from 1n were isolated. [f] Greater than
89% of 1o was recovered. Boc=tert-butoxycarbonyl.
Based on the above results,[9] as well as previous
studies,[5–8] the mechanism outlined in Scheme 2 is proposed.
Initially, [{Cp*RhCl2}2] is easily converted into the active
[Cp*Rh3+X2] species (X = Cl, SbF6, OAc) by a Ag+ species.[5,6]
2
À
Subsequently, the C(sp ) H bond of 1a is cleaved by the
[Cp*Rh3+X2] species to form the rhodium intermediate A.
The complexation of A with alkyne 2a produces the
intermediate B, and subsequent insertion of 2a into the aryl
2
À
C(sp ) Rh bond of B gives the intermediate C. Within
2
À
intermediate C, the addition of the vinyl C(sp ) Rh bond to
the C C double bond of the pyrrole moiety leads to the
À
Scheme 2. Possible mechanism.
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reoselectivity[10] as a result of the complex of the Rh species
À
with the nitrogen atom). Finally, cleavage of the C Rh bond
´
of D through protonolysis produces 3aa and regenerates the
active [Cp*Rh3+X2] species with the aid of Cu(OAc)2.
In summary, we have developed the first rhodium(III)-
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catalyzed [3+2] annulation of 5-aryl-2,3-dihydro-1H-pyrroles
2
À
with internal alkynes through aryl C(sp ) H/alkene function-
alization. This new method is general for the construction of
the spiro[indene-1,2’-pyrrolidine] ring system with excellent
functional-group tolerance and good control of selectivity.
Moreover, DFT calculations were carried out to better
understand the exclusive regioselectivity observed.[9] Studies
on the detailed mechanism and applications of this annulation
method are currently underway in our laboratory.
[5] For special reviews on the cycloaddition reaction involving the
À
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ketimines with alkynes toward indenamine-based spirocycles:
g) M. Nagamoto, T. Nishimura, Chem. Commun. 2014, 50, 6274.
Received: July 14, 2014
Published online: && &&, &&&&
Keywords: alkynes · annulation · heterocycles · rhodium ·
.
spiro compounds
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[9] Detailed data, including the deuterium-labelling experiments
and an intermolecular kinetic isotope effect experiment (see
Scheme S1 in the Supporting Information), the DFT calcula-
tions, the crystallographic data of 3ah, 2D NMR spectra of the
two isomers of 3ah, and 2D NMR spectra of 3ha, are summar-
ized in the Supporting Information.
[10] CCDC 971156 (3ah) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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4
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Angew. Chem. Int. Ed. 2014, 53, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Heterocycle Synthesis
M.-B. Zhou, R. Pi, M. Hu, Y. Yang,
R.-J. Song, Y. Xia,*
J.-H. Li*
&&&& — &&&&
Rhodium(III)-Catalyzed [3+2] Annulation
of 5-Aryl-2,3-dihydro-1H-pyrroles with
Spiral bound: A new [3+2] annulation
protonolysis to assemble a spirocyclic
2
À
Internal Alkynes through C(sp ) H/
route to spiro[indene-1,2’-pyrrolidines] is
ring system. The method has a broad
range of functional-group tolerance and
excellent regioselectivity. Ts=4-toluene-
sulfonyl.
2
À
Alkene Functionalization
described. This method includes C(sp )
H functionalization, insertion of an
=
alkyne, addition of a C C bond, and
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!