Construction of fused heterocyclic architectures by formal [4+l]/[3+2] cycloaddition cascade of sulfur ylides and nitroolefins

Article abstract of DOI:10.1002/anie.200904766

[Chemical equation presented] Under control: A format [4+1]/[3+2] cycloaddition cascade of sulfur ylides and alkene-tethered nitroolefins has been developed, and provides an efficient synthesis of fused polycyclic heterocyclic compounds in good to excelle

Full text of DOI:10.1002/anie.200904766

Communications
DOI: 10.1002/anie.200904766
Cascade Reaction
Construction of Fused Heterocyclic Architectures by Formal
[4+1]/[3+2] Cycloaddition Cascade of Sulfur Ylides and Nitroolefins**
Liang-Qiu Lu, Fang Li, Jing An, Ji-Ji Zhang, Xiao-Lei An, Qiu-Lin Hua, and Wen-Jing Xiao*
Over the last 50 years, seminal research from the groups of
Franzen,[1] Corey,[2] Trost,[3] Aggarwal,[4] and Dai[5] have
established sulfur ylides[6] as valuable and versatile inter-
mediates in synthetic chemistry. As a consequence, sulfur
ylides are widely utilized for the construction of epoxide,
aziridine, and cyclopropane architectures. Recently, studies
by Tang and co-workers[7] and others[8] have significantly
extended the scope of the ylide-initiated reactions and
outlined the first examples of tandem reactions initiated by
sulfur ylides to furnish a range of functionalized cyclic
compounds beyond three-membered rings. Despite the
advances, the search for unprecedented ylide-based multiple
cascade reactions continues, with the goal of increasing the
diversity of possible substrates and the architectural complex-
ity of products in a step-economical fashion.[9] Recently, our
laboratory implemented a new reaction of sulfur ylides with
nitroolefins to afford diverse and structurally complex
oxazolidin-2-ones, wherein a transiently generated cyclic
nitronate was involved.[10] On this basis, we became interested
in the possibility of using the above mentioned cyclic nitro-
nate as a suitable 1,3-dipole to react with electron-deficient
components in situ, and in doing so create multiple bonds,
rings, and stereocenters in a single transformation. Herein, we
report a successful execution of this idea and describe the first
intermolecular [4+1]/intramolecular [3+2] cycloaddition cas-
cade of sulfur ylides and alkene-tethered nitroolefins.[11] This
novel and catalyst-free strategy allows rapid access to
functionalized 2,3,5-trioxa-2a-azapentaleno[1,6-ab]naphtha-
lenes, 2,3-dioxa-5-thia-2a-azapentaleno[1,6-ab]naphthalenes,
and isoxazolo[4,3,2-hi][2,1]benzisoxazoles in a highly concise
fashion (Scheme 1); and these products are versatile synthons
for the construction of densely functionalized chromans,
thiochromans, amino acids, amino alcohols, and other impor-
tant heterocycles.[12]
Scheme 1. Concept of the formal [4+1]/[3+2] cycloaddition cascade.
Four bonds, three rings, five consecutive stereogenic centers, and one
quaternary carbon center are formed from versatile synthons. The
products are densely functionalized rings.
We initially studied the reaction of dimethyl (2-oxo-2-
phenylethyl)sulfonium ylide (1a) with (E)-ethyl 3-(2-((E)-2-
nitrovinyl)phenoxy)acrylate (2a) in acetonitrile at 08C for
12 hours, at which point the reaction mixture was warmed to
room temperature and stirred for an additional eight hours.
To our delight, the proposed cycloaddition cascade was
indeed facile and afforded ethyl 1-(phenylcarbonyl)-
4,4a,9b,9c-tetrahydro-1H-2,3,5-trioxa-2a-azapent-aleno[1,6-
ab]naphthalene-4-carboxylate (4a) as a major isolable prod-
uct in 43% yield with great diastereocontrol (Table 1,
Table 1: Optimization of the reaction conditions for the cycloaddition
cascade.[a]
[*] L.-Q. Lu, Dr. F. Li, J. An, J.-J. Zhang, X.-L. An, Q.-L. Hua,
Prof. Dr. W.-J. Xiao
Entry
Solvent
Conc. [m]
t [h]
Yield [%][b]
d.r.[c]
n.d.[d]
>95:5
>95:5
n.d.
>95:5
>95:5
>95:5
>95:5
>95:5
Key Laboratory of Pesticide & Chemical Biology
Ministry of Education, College of Chemistry
Central China Normal University
152 Luoyu Road, Wuhan, Hubei 430079 (China)
Fax: (+86)027-6786-2041
1
2
3
4
5
6
7
CH3OH
CH3CN
THF
toluene
CH2Cl2
CHCl3
CHCl3
CHCl3
CHCl3
0.1
0.1
0.1
0.1
0.1
0.1
0.05
0.02
0.02
15
20
18
24
20
20
20
24
18
26
43
68
32
79
81
86
89
85
E-mail: wxiao@mail.ccnu.edu.cn
Homepage: http://chem-xiao.ccnu.edu.cn/
[**] We are grateful to the National Science Foundation of China
(20672040 and 20872043) and the Program for Academic Leader in
Wuhan Municipality (200851430486) for the support of this
research. We thank Dr. Richard Pederson and Dr. Joel Austin for
fruitful discussions.
8
9[e]
[a] Reaction conditions: 1a (0.55 mmol), 2a (0.5 mmol), and solvent (5–
25 mL). [b] Yield of isolated product. [c] Determined by 1H NMR
methods. [d] n.d.=not determined. [e] 1-(2-Chlorophenyl)thiourea
(20 mol%) was used.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904766.
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entry 2). The structure and relative configuration of 4a were
unambiguously established by X-ray crystallographic analy-
sis.[13]
lenge in modern organic synthesis.[14] As highlighted in
entries 9 and 10 in Table 2 nitroolefins 2i and 2j, both
having a methyl group in the a-position, can readily
participate in this reaction and afford the corresponding
quaternary carbon-containing adducts 4i and 4j in 75 and
83% yields, respectively.
As exemplified in Table 3, a wide array of sulfur ylides was
suitable for this cascade strategy. The electronic nature of the
aryl ring of the sulfur ylides had little effect on the reaction
efficiency and stereoselectivity (Table 3, entries 1–9). Incor-
poration of alkyl and alkoxy substituents at the ortho or
para position revealed that steric variation of the ylide
component can be tolerated (Table 3, entries 2–4). Further-
more, a heterocycle-derived ylide (Table 3, entry 10) was
readily tolerated in this cascade cycloaddition. The scope of
this reaction was also significantly extended to the use of
alkyloxy- and alkyl-acyl ylides. For example, ethyloxyacyl
As shown in Table 1, the use of different solvents has a
pronounced effect on the reaction efficiency, although
excellent levels of diastereoselectivity were observed for a
diverse range of reaction media (Table 1, entries 1–6). Nota-
bly, this cascade sequence worked very well in chloroform
(CHCl3) to afford 4a in 81% yield (Table 1, entry 6). A brief
survey of substrate concentrations indicated that 0.02m was
ideal (Table 1, entry 8). As expected, an improved reaction
rate was observed when an hydrogen-bonding donor catalyst,
1-(2-chlorophenyl)thiourea,[10] was employed; however, the
yield of the product was slightly decreased in this case
(Table 1, entry 9).
With the optimal conditions in hand, the scope of the
nitroolefins was explored. As highlighted in Table 2, the
reaction displayed excellent gener-
Table 2: [4+1]/[3+2] Cycloaddition cascade of sulfur ylide 1a with representative nitroolefins.[a]
ality and significant structural var-
iation in the nitroolefin component
was tolerated. Typically, methyl and
methoxy substituents were incorpo-
rated onto the aryl ring at the meta-
or para-positions, relative to the
oxygen atom, without loss in reac-
tion efficiency or diastereocontrol
(Table 2, entries 2–4). Variation in
the electronic contribution of the
aryl architecture was also possible.
Relatively electron-deficient para-
chloro- or para-bromo-substituted
substrates were successfully utilized
in this reaction (Table 2, entries 5
and 6). Moreover, it was found that
the aryl framework could be
extended to naphthalene-derived
substrates, generating product 4g
in 86% yield (Table 2, entry 7). As
expected, sulfur-tethered 2h proved
to be a viable reaction partner
Entry Nitroolefin
Product
R2
R3 Yield [%][b] d.r.[c]
1
2
3
4
5
6
2a
2b
2c
2d
2e
2 f
4a
H
H
H
H
H
H
H
89
91
92
99
94
97
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
4b 4-MeO
4c 5-MeO
4d 4-Me
4e 4-Cl
4 f 4-Br
7
2g
4g
4h
86
>95:5
(Table 2, entry 8), affording
a
densely functionalized thiochro-
man. Notably, the nitroolefin bear-
ing either E enoates (Table 2,
entries 1–7, 9 and 10) or Z enoates
(Table 2, entry 8) were utilized in
this cascade reaction without signif-
icant loss in reaction efficiency.[13] In
addition to the substrates with an
aryl framework, an aliphatic linear
substrate was also tolerated
(Table 2, entry 10). Therefore, in
only one operation two simple,
acyclic molecules (1a and 2j) were
8[d]
2h
85
>95:5
9[e]
2i
2j
4i
4j
H
H
Me 75
Me 83
>95:5
>95:5
10[f]
converted into
a fused tricyclic
compound bearing five contiguous
stereogenic centers in 83% yield.
The construction of the quaternary
[a] Reaction conditions: 1a (0.55 mmol), 2 (0.5 mmol), and CHCl3 (25 mL), 08C to RT, 24 h. [b] Yield of
isolated product. [c] Determined by 1H NMR methods. [d] The structure of 4h was further confirmed by
X-ray analysis; see reference [13]. [e] 08C for 4.5 h, and then 508C for 40 h. [f] 08C for 10 h, and then
carbon center still remains a chal- 628C for 4 days.
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Table 3: [4+1]/[3+2] Cycloaddition cascade of representative sulfur
ylides with nitroolefin 2a or 2i.[a]
Entry
Sulfur ylide
1
Product
4
Yield
[%][b]
d.r.[c]
R1
R3
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Ph
4a
4k
4l
4m
4n
4o
4p
4q
4r
H
H
H
H
H
H
H
H
H
H
Me
Me
89
92
90
93
90
90
90
94
90
97
82
75
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
95:5
4-MeOC6H4
2-MeOC6H4
4-MeC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
3-BrC6H4
4-NO2C6H4
2-furanyl
EtO
In summary, a new and powerful process combination of
an intermolecular [4+1] and an intramolecular [3+2] cyclo-
addition has been developed for the rapid and selective
construction of fused heterocyclic compounds. This mild and
operationally simple cascade cycloaddition has been accom-
plished with a wide range of sulfur ylides and alkene-tethered
nitroolefins. All five consecutive stereogenic centers could be
stereospecifically controlled in this reaction. Complete dia-
stereoselectivity and excellent reaction efficiency were
obtained in all cases examined.
9[d]
10
11[e]
12[f]
1j
1k
1l
4s
4t
4u
>95:5
>95:5
>95:5
Me
[a] Reaction conditions: 1 (0.55 mmol), 2a or 2i (0.5 mmol), and CHCl3
(25 mL), 08C to RT, 24 h. [b] Yield of isolated product. [c] Determined by
1H NMR methods. [d] 08C for 16 h, and then 628C for 4 days (1.2 equiv
of 1i). [e] 08C for 9 h, and then 50–558C for 36 h (2.0 equiv of 1k). [f] 08C
for 6 h, and then 628C for 36 h (12.5 equiv of 1l).
Experimental Section
Representative procedure: 2a (0.5 mmol) and CHCl3 (10 mL) were
added to a 50 mL flask. The solution of 1a (0.55 mmol) in CHCl3
(15 mL) was then slowly added at 08C using a syringe pump, and the
resulting reaction mixture was stirred at 08C for 12 h at which point
2a was consumed as determined by TLC analysis. At this stage the
reaction mixture was warmed up to room temperature and stirred for
12 h. Upon the completion of reaction, which was monitored by TLC
analysis, the solvent was removed under reduced pressure. The crude
product was purified by flash chromatography on silica gel (n-hexane/
ethyl acetate 10:1!5:1) to give pure 4a in 89% yield with greater
than 95:5 d.r.
ylide (1k) and acetyl ylide (1l) were employed in the reaction
of 2i and provided the corresponding 4t and 4u with a
functionalized quaternary carbon center in high yields and
excellent diastereoselectivities (Table 3, entries 11 and 12).
A demonstration of the synthetic manipulation of the
cycloaddition products is presented in Equation (1).
Azapentaleno[1,6-ab]naphthalene 4a was subjected to hydro-
ꢀ
genolysis with Raney Ni to readily cleave N O bonds and to
afford chroman 5 bearing an attractive pyrroline ring in high
yield.[12]
Received: August 26, 2009
Published online: November 10, 2009
Keywords: cascade reaction · cycloaddition · nitroolefins ·
.
sulfur ylides
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