RhII-catalyzed [3+2] cycloaddition of 2 H-azirines with N-sulfonyl-1,2,3-triazoles

Article abstract of DOI:10.1002/chem.201406460

Rh^II-catalyzed intermolecular [3+2] cycloaddition of 2 H-azirines with N-sulfonyl-1,2,3-triazoles is disclosed, in which a series of fully functionalized pyrroles is produced via rhodium azavinyl carbene intermediates. A distinct feature of this reaction is that the azavinyl carbene serves as a [2 C] equivalent, instead of as [1 C] or aza-[3 C] synthons, which have been reported previously in cyclopropanations and [3 + n] cycloadditions. Moreover, this methodology has also been successfully applied in the total synthesis of URB447 as well as the formal synthesis of Atorvastatin (Lipitor).

Full text of DOI:10.1002/chem.201406460

DOI: 10.1002/chem.201406460
Communication
&
Synthetic Methods
RhII-Catalyzed [3+2] Cycloaddition of 2H-Azirines with N-Sulfonyl-
1,2,3-Triazoles
Yun-Zhou Zhao, Hai-Bin Yang, Xiang-Ying Tang,* and Min Shi*[a]
Abstract: RhII-catalyzed intermolecular [3+2] cycloaddition
of 2H-azirines with N-sulfonyl-1,2,3-triazoles is disclosed,
in which a series of fully functionalized pyrroles is pro-
duced via rhodium azavinyl carbene intermediates. A dis-
tinct feature of this reaction is that the azavinyl carbene
serves as a [2C] equivalent, instead of as [1C] or aza-[3C]
synthons, which have been reported previously in cyclo-
propanations and [3+n] cycloadditions. Moreover, this
methodology has also been successfully applied in the
total synthesis of URB447 as well as the formal synthesis
of Atorvastatin (Lipitor).
Pyrroles and their derivatives are one of the most important
classes of nitrogen-containing heterocycles with diverse bio-
logical properties and synthetic applications.[1] For example,
highly functionalized pyrroles are subunits of heme, chloro-
phyll, bile pigments, vitamin B12, and pyrrole alkaloids derived
from nature.[2] Another well-known man-made representative
Scheme 1. Cycloadditions of Rh–azavinyl carbenes with unsaturated com-
pounds.
is Atorvastatin (Lipitor), which is used primarily for lowering
blood cholesterol and for the prevention of events associated
with cardiovascular disease.[3] Motivated by these significance
effects, intensive investigations have been conducted to devel-
op practical, useful, and step-economic methodologies to the
pyrrole architecture.[4] Accordingly, the discovery of novel strat-
egies for the synthesis of fully functionalized pyrroles with
good functional-group tolerance through simple operation is
highly desirable.
the use of an azavinyl carbene as a [2C] synthon in a formal
cycloaddition reaction has not yet been achieved. As the major
part of our research efforts in developing new methodologies
for the construction of heterocycles, we previously developed
the intramolecular CÀH functionalization of pyrroyl-/indolyltria-
zoles and the tandem ring extension/intermolecular Diels–
Alder cycloaddition of methylene cyclopropane tethered tria-
zoles.[8] To continue our research in this area, we have started
to develop new synthetic methods for heterocycles through
azavinyl carbene chemistry. Herein, we report a novel RhII-cata-
lyzed intermolecular [3+2] cycloaddition of 2H-azirines[9] with
N-sulfonyl-1,2,3-triazoles, which serve as [2C] equivalents
(Scheme 1C).
N-sulfonyl-1,2,3-triazoles, the precursors of Rh–azavinyl car-
benes, have been the focus of research interest in recent years,
as introduced by the leading groups of Fokin, Gevorgyan, Mur-
akami, and Davies.[5] Since these initial studies, a variety of
useful transformations have been reported.[6,7] As [1C], [3C], or
aza-[3C] equivalents, azavinyl carbenes are particularly attrac-
tive for use in cyclopropanations, [3+n] and [4+3] cycloaddi-
tions (Scheme 1A and B) to produce cyclic derivatives, espe-
cially N-heterocycles. However, to the best of our knowledge,
2H-azirines, easily derived from the corresponding ketones
through the Neber reaction,[10] have been investigated inten-
sively in the synthesis of heterocycles.[9] Notably, Park and co-
workers[11] have demonstrated an elegant synthesis of pyri-
dines by a vinyl carbene-mediated ring-opening of 2H-azirines,
in which the vinyl carbene served as a [3C] synthon. Interest-
ingly, in our work, upon treatment of 4-phenyl-1-tosyl-1H-
1,2,3-triazole, 1a, with ethyl 3-methyl-2H-azirine-2-carboxylate,
2a, in the presence of a dirhodium complex, a fully substituted
pyrrole derivative, 3aa, was obtained and its structure was un-
ambiguously determined by X-ray diffraction, confirming that
[a] Y.-Z. Zhao, H.-B. Yang, Prof. Dr. X.-Y. Tang, Prof. Dr. M. Shi
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai, 200032 (China)
E-mail: siocxiangying@mail.sioc.ac.cn
mshi@mail.sioc.ac.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406460.
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Table 2. Scope of the RhII-catalyzed tandem rearrangement.[a]
Scheme 2. Park’s pyridine synthesis.
only two carbon atoms of the azavinyl carbene were incorpo-
rated into the pyrrole ring (Scheme 2).[12]
Based on our previous work, solvents usually were critical in
Rh-catalyzed ring-opening reactions of triazoles;[8] therefore,
solvent effect was first investigated and it was revealed that
CH2Cl2 was the best solvent to promote the formation of 3aa,
giving 51% yield (Table 1, entries 1–5). Next, by using CH2Cl2 as
Entry
R1
R2
Product
Yield [%]
1
2
3
4
5
6
7
C6H5
C6H5
C6H5
4-Me-C6H4
3-Me-C6H4
4-MeO-C6H4
4-F-C6H4
Bs
3ba
3ca
3da
3ea
3fa
3ga
3ha
80
77
78
90
73
74
65
Ms
SO2Ph
Bs
Bs
Bs
Bs
Table 1. Optimization of the reaction conditions.[a]
8
3ic
23[c]
Entry
Cat.
Solvent
T [8C]
t [h]
Yield[b] [%]
1
2
3
4
5
6
7
8
[Rh2(Piv)4]
[Rh2(Piv)4]
[Rh2(Piv)4]
[Rh2(Piv)4]
[Rh2(Piv)4]
[Rh2(Oct)4]
[Rh2(tfa)4]
[Rh2(OAc)4]
[Rh2(esp)4]
[Rh2(esp)4]
[Rh2(esp)4]
[Rh2(esp)4]
DCE
toluene
CHCl3
90
90
90
90
90
90
90
90
90
80
70
60
2
2
2
2
2
2
2
2
33
25
0
R3
Et
R4
9
CO2Et
CO2Et
CO2tBu
CO2Bn
COPh
4-Cl-C6H4
CO2Et
H
3bb
3bc
3bd
3be
3bf
81
92
73
75
hexane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
40
51
46
trace
47
56
59
69
57
10
11
12
13
14
15
16
17
iPr
Me
Me
Me
Me
C6H5
C6H5
C6H5
86
3bg
3bl
3bm
3bn
60
81[d]
77[d]
80
9
2
10
11
12
10
18
48
Me
[a] Conditions: 1 (0.3 mmol), 2 (0.2 mmol), [Rh2(esp)2] (2 mol%), anhydrous
CH2Cl2 (2.0 mL) were heated at 708C in a sealed tube for 18 h. [b] Isolated
yields. [c] Another imine byproduct, 3i’, derived from a carbene-induced
1,2-H shift was obtained in 30% yield. [d] The reaction was run in CH2Cl2
(2.0 mL) at 908C in a sealed tube for 3 h.
[a] Conditions: 2a (0.20 mmol), 1a (0.30 mmol), Rh cat. (2 mol%), and sol-
vent (2.0 mL) were heated in a sealed tube until consumption of 2a was
apparent by TLC. [b] Isolated yields. DCE=1,2-dichloroethane.
solvent, the performance of various rhodium complexes was
investigated. Changing catalysts from the initially used
[Rh2(Piv)4] to [Rh2(Oct)4], [Rh2(OAc)4], or [Rh2(esp)2] (Piv=Piva-
late, Oct=Octanoate, esp=a,a,a’,a’-tetramethyl-1,3-benzene-
dipropionate), we found that 3aa was produced in the highest
yield (56%) when [Rh2(esp)2] was used (Table 1, entries 6, 8,
and 9). Conversely, [Rh2(tfa)4] (tfa=trifluoroacetate) showed
very low catalytic activity in the reaction (Table 1, entry 7).
After evaluation of the reaction temperature (Table 1, en-
tries 10–12), it was found that the yield of 3aa increased to
69% if conducting the reaction at 708C (Table 1, entry 11).
When the reaction was carried out at 608C, the reaction time
needed to be prolonged to 48 h, affording 3aa in 57% yield
(Table 1, entry 12).
products, 3ba–3da, in 77–80% yields (Table 2, entries 1–3).
Employing different aryl-ring-substituted (R1) triazoles, 1e–1h,
as substrates, the reactions went on smoothly to deliver the
desired products, 3ea–3ha, in 65–90% yields, and the elec-
tronic properties of the substituents did not have significant
impact on the reaction outcomes (Table 2, entries 4–7). When
a triazole substituted with a n-butyl group (R1) was employed
as the substrate, the corresponding pyrrole derivative, 3ic, was
obtained in low yield, because another byproduct, 3i’, was
also formed in 30% yield by a carbene-induced 1,2-H shift
(Table 2, entry 8).[13] Next, a series of 3-alkyl-2H-azirines, 2, were
also examined, and we found that different substituents at R3
(methyl, ethyl, or isopropyl groups) and R4 (ester, carbonyl, or
aryl groups) were all well tolerated under the standard reaction
conditions and the desired products, 3bb–3bg, were obtained
in 60–92% yields (Table 2, entries 9–14). R3 could also be
a phenyl substituent, instead of alkyl groups. For instance,
when 3-phenyl-2H-azirines with ethyl ester, H, or methyl sub-
stituents (R4) were employed as substrates, the reactions all
proceeded smoothly to yield pyrrole derivatives, 3bl–3bn, in
With the optimized reaction conditions in hand (Table 1,
entry 11), we next examined the substrate scope and limita-
tions of this reaction by using various triazoles, 1, and different
3-alkyl-2H-azirines, 2, (Table 2). For substrates 1b–d, in which
the nitrogen atom was protected by Bs (4-bromobenzene-1-
sulfony), Ms (methanesulfonyl), and benzenesulfonyl groups,
the reactions proceeded smoothly to give the corresponding
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77–81% yields (Table 2, entries 15–17). In addition, the identifi-
cation of 3bm was further established by single-crystal X-ray
analysis.[14]
an azavinyl carbene intermediate, A, in the presence of the RhII
catalyst. This Fisher-type carbine, A, readily accepts nucleophil-
ic attack from the nitrogen atom of 2H-azirine, giving the key
zwitterionic intermediate, B, which is shared by both reaction
pathways. For pyrrole synthesis (path a), intermediate B under-
goes a proton elimination and proto-demetalation to produce
aza cyclopropene intermediate C. Following a ring expansion,
intermediate D is obtained. Aromatization of intermediate D
results in the final pyrrole product, 3. On the other hand, if the
reaction goes through path b, a ring-opening process of inter-
mediate B takes place to produce intermediate E, which then
delivers the final pyrazine derivatives after a 6p electrocycliza-
tion.[11] The reactivity of intermediate B is greatly affected by
the properties of R3 and R4. In most cases, path a is the domi-
nate process. However, if R3 is electronegative or R4 is a sterical-
ly bulky group, the azirine ring is more unstable or strained
and the ring-opening process is also possible; that can account
for the formation of both 3 and 4 in these reactions.
To further evaluate the generality of this method, we synthe-
sized several 3-aryl-2H-azirines and treated them with 1b in
the presence of [Rh2(esp)2],[15] and the results are shown in
Table 3. Very surprisingly, 2H-pyrazine derivatives, 4, could be
Table 3. 3-Aryl-2H-azirines 2 variations.[a,b]
Entry R3
R4
Product Yield [%] Product Yield [%]
1
2
3
4
Ph
4-NO2-C6H4 CO2tBu 3bi
CO2tBu 3bh
80
48
36
81
4bh
4bi
4bj
4bk
7
35
55
12
4-Br-C6H4
4-Br-C6H4
CO2tBu 3bj
CO2Et 3bk
To demonstrate the synthetic utility of this RhII-catalyzed
[3+2] cycloaddition, we turned our efforts to synthesizing
[a] Conditions: 1 (0.3 mmol), 2 (0.2 mmol), [Rh2(esp)2] (2 mol%), anhy-
drous CH2Cl2 (2.0 mL) were heated at 908C for 3 h. [b] Isolated yields.
URB447
([4-amino-1-(4-chlorobenzyl)-2-methyl-5-phenyl-1H-
pyrrol-3-yl](phenyl)methanone), which is a mixed CB1 antago-
nist/CB2 agonist and can be used to lower food intake and
body-weight gain in mice without it entering the brain or an-
tagonizing central CB1-dependent responses.[19] The formal
[3+2] cycloaddition of triazole 1a and azirine 2 f afforded the
fully substituted pyrrole derivative 3af. This was followed by
selective protection and then alkylation with 4-chlorobenzyl
bromide to deliver intermediate 5 in 49% yield. Finally, the
target molecule URB447, 6, was synthesized by removal of the
tosyl (Ts) and Boc groups in a single step upon heating 5 in
HClO4 and AcOH at 908C (Scheme 4).
obtained along with pyrrole derivatives, 3. For substrates 2h–
2j, in which R4 was tert-butyl ester and R3 was a phenyl group
substituted with Ph, para-NO2, or ortho-Br, the reactions all
produced products 3bh–3bj along with 4bh–4bj in high total
yields (Table 3, entries 1–3). Substrate 2k, with a less sterically
bulky ethyl ester (R4) and a para-Br–phenyl group (R3), led to
the formation of 3bk and 4bk in 81% and 12% yields, respec-
tively (Table 3, entry 4). The structures of the pyrrole and 2H-
pyrazine derivatives were further confirmed by X-ray diffraction
analysis of 3bj[16] and pyrazine 4bj’, which was derived from
the deprotection of 4bj.[17,18] The electronic and steric effects
observed in this reaction indicate that the electronegativity or
steric hindrance of substituents in substrates, 2, produce
a combined impact on the reaction outcomes. Therefore, we
hypothesize that the two reaction pathways share a common
cationic intermediate, which controls the product’s
distribution.
A plausible mechanism for the formation of pyrrole and 2H-
pyrazine is outlined in Scheme 3. N-sulfonyltriazole 1 generates
Scheme 4. Total synthesis of URB447.
Additionally, the formal synthesis of Atorvastatin (Lipitor)
was performed. As shown in Scheme 5, the reaction of 1j and
2c afforded 3jc in 67% yield. Then, after deprotection the free
amine, derivative 7 was obtained (74% yield from 3jc). We
next tried to convert the free amine group to the correspond-
ing bromide by means of deamination[20] and bromination. It
turned out to be successful and the desired bromide, 8, was
delivered in 77% yield from 7. The following Suzuki coupling
and transamidation[21] with aniline delivered 4-acylamino pyr-
role derivative 9, which is the key synthetic intermediate to the
Scheme 3. Proposed mechanism.
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Scheme 5. Formal synthesis of Lipitor.
target Atorvastatin (Lipitor).[3c] The H and 13C NMR spectrosco-
py data of the synthesized URB447 and precursor of Lipitor
were in good agreement with those reported in the
literature.[3b,19]
1
In summary, we have developed a practical synthesis of fully
substituted pyrroles by means of formal [3+2] cycloaddition of
N-sulfonyl-1,2,3-triazoles with 2H-azrines. This is the first exam-
ple where N-sulfonyl-1,2,3-triazoles are used as [2C] synthons
in a formal cycloaddition reaction. Notably, the potential of
this novel protocol has been demonstrated by successful total
synthesis of URB447 as well as the formal synthesis of Atorvas-
tatin (Lipitor). The substrate scope is broad and a wide range
of functional groups are tolerated, which gives promising use-
fulness to this pyrrole synthesis for the construction of other
important pyrrole-containing drugs. Further potential applica-
tions and mechanistic investigations of this methodology are
currently underway in our laboratory.
Acknowledgements
We are grateful for financial support from the National Basic
Research Program of China ((973)-2015CB856603), the Shang-
hai Municipal Committee of Science and Technology
(11JC1402600), and the National Natural Science Foundation of
China (20472096, 21372241, 21361140350, 20672127,
21102166, 21121062, 21302203, and 20732008).
Keywords: 2H-azirines
rhodium · triazoles
· azavinyl carbenes · pyrroles ·
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Communication
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Received: December 12, 2014
Published online on && &&, 0000
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communication
COMMUNICATION
&
Synthetic Methods
Y.-Z. Zhao, H.-B. Yang, X.-Y. Tang,* M. Shi*
&& – &&
RhII-Catalyzed [3+2] Cycloaddition of
2H-Azirines with N-Sulfonyl-1,2,3-
Triazoles
Fully functional: A novel RhII-catalyzed
intermolecular [3+2] cycloaddition of
2H-azrines with N-sulfonyl-1,2,3-triazoles
is disclosed. The reaction, in which aza-
vinyl carbene serves as a [2C] equiva-
lent, produces a series of fully function-
alized pyrroles via rhodium azavinyl car-
bene intermediates.
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Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!