Nitrones as trapping reagents of α,β-unsaturated carbene intermediates - [1,2]oxazino[5,4-b]indoles by a platinum-catalyzed intermolecular [3+3] cycloaddition

Article abstract of DOI:10.1002/adsc.201300338

Some readily available Boc-protected 2-(3-methoxy-1-propynyl)anilines and nitrones in platinum-catalyzed reactions deliver [1,2]oxazino[5,4-b]indoles. Twelve examples with yields of 41-95% are reported. Different substituents like nitro, trifluoromethyl,

Full text of DOI:10.1002/adsc.201300338

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DOI: 10.1002/adsc.201300338
Nitrones as Trapping Reagents of a,b-Unsaturated Carbene
Intermediates – [1,2]Oxazino[5,4-b]indoles by a Platinum-
G
Catalyzed Intermolecular [3+3] Cycloaddition
Weibo Yang,a Tao Wang,a Yang Yu,a Shuai Shi,a Tuo Zhang,a
and A. Stephen K. Hashmia,*
a
Organisch-Chemisches Institut, Ruprecht-Karls-Universitꢀt Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg,
Germany
Fax : (+49)-6221-54-4205; e-mail: hashmi@hashmi.de (homepage: http://www.hashmi.de)
Received: April 20, 2013; Published online: May 17, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300338.
Abstract: Some readily available Boc-protected 2-
(3-methoxy-1-propynyl)anilines and nitrones in
platinum-catalyzed reactions deliver [1,2]oxazino-
m]cycloaddition reactions in which a,b-unsaturated
carbene intermediates serve as 1,3-dipoles have been
investigated.[1c] With regard to the generation of such
a,b-unsaturated carbene intermediates, the 1,2-acyl-
ACHTUNGTRENNUNG[5,4-b]indoles. Twelve examples with yields of 41–
95% are reported. Different substituents like nitro,
trifluoromethyl, fluoro, bromo, and ester groups are
tolerated. With regard to the mechanism, this reac-
tion probably combines an initial intramolecular
cyclization/elimination to vinylcarbenoid species
and a subsequent stepwise intermolecular [3+3]cy-
cloaddition with the nitrones.
ACHTUNGTRENoNGNU xy migration of propargylic ester derivatives has
become an important pathway (Scheme 1, a).[2] An-
other classical method involving diazoacetate com-
pounds in the presence of rhodium or copper catalysts
has also been extensively investigated (Scheme 1,
b).[3] Recently, Iwasawa and his co-workers first devel-
oped an alternative method for the generation of a,b-
unsaturated carbene intermediates from propargylic
ethers, which then underwent [3+2]cycloaddition re-
actions.[4a] Subsequently, based on this strategy
(Scheme 2), Tangꢁs research group employed conju-
gated dienes as trapping reagent for the a,b-unsatu-
rated carbene intermediate in which the cyclohepta-
Keywords: alkynes; amines; indoles; nitrones; plati-
num
AHCTUNGTREG[NNNU b]indoles can be synthesized in high regioselectivity
Platinum- or gold-catalyzed intermolecular cycloaddi- through a [4+3]cycloaddition reaction.[5]
tions[1] have attracted much attention as an efficient
Inspired by these intriguing studies and in continua-
method to facilitate construction of natural products tion of our work on the synthesis of indole deriva-
and pharmaceuticals from relatively simple organic tives,[6] we attempted to explore novel [n+m]cycload-
fragments or reactive intermediates. Various [n+ dition reactions by utilizing nitrones[7] as remarkable
Scheme 1. Catalytic generation of a,b-unsaturated carbene intermediates.
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Scheme 2. Trapping of the a,b-unsaturated carbene intermediates.
Table 1. Optimization studies on the platinum-catalyzed
[3+3]cycloaddition reaction.[a]
1,3-dipole reagents for the trapping of the a,b-unsatu-
rated carbene. The nitrones are easily accessible from
hydroxylamine derivatives. It should be noted that
there is only one example of a nitrone/a,b-unsaturat-
ed carbene cycloaddition: Doyleꢁs group has recently
described
a
dirhodium(II) carboxylate-catalyzed
formal [3+3]cycloaddition reaction involving nitrones
as trapping reagent for a,b-unsaturated carbene inter-
mediates generated in situ by Rh-catalyzed diazo de-
composition.[8] However, to the best of our knowl-
edge, there are no examples of platinum-catalyzed
[3+3]cycloaddition reactions of nitrones and a,b-un-
saturated carbene intermediates generated from prop-
argylic ethers. Here we report this new type of trans-
formation as an efficient synthesis of various useful
Entry
Catalyst
Time
Yield
[1,2]oxazinoACHTUNGTRENNUNG[5,4-b]indole derivatives, important build-
ing blocks for the total synthesis of natural products
1
2
3
4
IPrAuCl/AgNTf2
SPhosAuNTf2
PtCl2, Xphos
PtCl2, dppe
PtCl2
24 h
24 h
24 h
24 h
24 h
3 h
21%
13%
35%
15%
20%
86%
86%
trace
(Scheme 3).[9]
In order to achieve this novel intermolecular
[3+3]cycloaddition reaction, our initial efforts fo-
cused on the model reaction of 1a and 2a with differ-
ent gold catalysts. In the presence of IPrAuCl/AgNTf2
as the catalyst in 1,4-dioxane at 808C without an inert
atmosphere, after 24 h we indeed obtained the inter-
molecular [3+3]cycloaddition product 3a in 21% iso-
lated yield (Table 1, entry 1). Furthermore, the major
product 4 was formed through 5-endo-dig cyclization
of 1a in a yield of 62%. By using the SPhosAuNTf2 as
the catalyst, both the desired product 3a and by-prod-
5
6
PtCl2, P
PtCl2, P(C6F5)3
PdCl2A(PPh3)2
ACHTNUGRTEN(NGNU C6F5)3
7[b]
8
G
3 h
24 h
R
[a]
Reaction conditions: substrate A (100 mmol), substrate B
(200 mmol), [catalyst] (10 mol%), [ligand] (20 mol%), sol-
vent (1 mL), Na2CO3 (1.5 equiv.), in air. The reaction was
monitored by TLC.
[b]
Reaction was protected with N2.
uct 4 were generated, albeit with much lower yields
(entry 2). Based on the previous work of Iwasawa
et al.[4] and Tang et al.,[5] we switched to the PtCl2 as
catalyst with Xphos as ligand, the yield of the target
product 3a was increased to some extent (entry 3).
Neither the presence of dppe as ligand nor the ab-
sence of a phosphane ligand led to a distinct increase
of the yield (entries 4 and 5). Tangꢁs successful report
of a Pt-catalyzed [4+3]cycloaddition reaction with
PACHTNUTRGNEUN(G C6F5)3 as efficient ligand encouraged us to employ
it to improve the yield of the desired product.[5] To
our delight, with this ligand the reaction afforded 3a
with a very respectable 86% yield in 3 h (entry 6).
Control experiments indicated that the yield does not
improve when a protective atmosphere is used
Scheme 3. Bioactive compounds with
b]indole core structure.
a [1,2]oxazinoACTHUNTGNRUEGN[5,4-
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Nitrones as Trapping Reagents of a,b-Unsaturated Carbene Intermediates
(entry 7). In addition, this reaction is ineffective with CF3 and Br all favour the reaction and generate the
PdCl
G
[3+3]cycloaddition products in good to excellent
With the optimal conditions established for this yields (entries 1–3). Abnormally, a nitrone bearing
platinum-catalyzed formal [3+3]cycloaddition pro- a 4-fluoro substituent could also react under the stan-
cess, we turned our attention to investigate the sub- dard conditions, however a lower yield was obtained
strate scope of this reaction with different propargylic (entry 4). It is important to mention that propargylic
ethers and nitrones (Table 2). Various functional ethers with electron-donating substitutents on the
groups including NO2, CF3, CH3, Br, F and COOCH3 benzene ring can react smoothly and afford the corre-
were compatible in this catalytic system. The nitrones sponding products with quite higher yields compared
with electron-withdrawing substitutents such as NO2, to those obtained with electron-withdrawing substitu-
Table 2. Scope and limitations of platinum-catalyzed [3+3] cycloaddition reaction.
Entry
Substrate
Product
Time
3 h
Yield
86%
1
2
3
4
1.5 h
88%
2 h
90%
3 h
41%
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Weibo Yang et al.
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Table 2. (Continued)
Entry
Substrate
Product
Time
5 h
5
64%
6
5 h
53%
75%
81%
71%
90%
7
5 h
8
4 h
9
4 h
10
1.5 h
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Nitrones as Trapping Reagents of a,b-Unsaturated Carbene Intermediates
Table 2. (Continued)
Entry
Substrate
Product
Time
1.5 h
Yield
95%
11
12
1.5 h
89%
[a]
Reaction conditions: propargylic ethers (100 mmol), nirones (200 mmol), [catalyst] (10 mol%), [ligand] (20 mol%), solvent
(1 mL), Na2CO3 (1.5 equiv.), in air. The reaction was monitored by TLC.
tents on the benzene ring. As can be seen from substrates with an electron-donating CH3 group on
entry 6, when we employed the propargylic ether the benzene ring gave 3j, 3k and 3l in 89–95% in
bearing a COOCH3 substituent on the benzene ring, 1.5 h (entries 10–12).
a moderate isolated yield of 53% was obtained in 5 h.
As 1,4-amino alcohols are biologically important
Switching to the substrate with a chloro substituent moieties,[10] we treated 3a with SmI2 (Scheme 4). By
À
on the benzene ring, due to the increase in the nucle- reductive cleavage of the N O bond, the highly func-
ophilicity of the aniline nitrogen atom, the yield can tionalized 1,4-amino alcohol 5 can be obtained in
reach up to 71–81% (entries 7–9). Remarkably, the 74% isolated yield in a very short time (10 min).
A plausible mechanism for the Pt-catalyzed formal
[3+3]cycloaddition reaction is depicted in Scheme 5.
The triple bond was firstly activated by the platinum
catalyst, followed by a 5-endo-dig cyclization. Then
the unsaturated Pt-carbene intermediate
B was
formed via elimination of the methoxy group, another
resonance form is the dipolar intermediate C. A nu-
cleophilic attack by the nitrone at the g-position of C
generates the iminium ion intermediate D, which sub-
sequently cyclizes and affords the final product 3 with
regeneration of the platinum catalyst.
Scheme 4. Ring-opening of [1,2]oxazinoACTHNUTRGNE[NUG 5,4-b]indole as an
access to 1,4-amino alcohol.
Scheme 5. Plausible mechanism for Pt-catalyzed formal [3+3]cycloaddition reaction.
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Weibo Yang et al.
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1371; Angew. Chem. Int. Ed. 2013, 52, 1329–1332;
c) X.-Z. Shu, D. Shu, C. M. Schienebeck, W. Tang,
Chem. Soc. Rev. 2012, 41, 7698–7711.
In summary, an unprecedented Pt-catalyzed formal
[3+3]cycloaddition reaction was explored. This novel
transformation involves the nitrone 1,3-dipole as trap-
ping reagent for a,b-unsaturated carbenes generated
in situ from propargylic ether derivatives. Notably,
this work not only extends the Pt-catalyzed intermo-
lecular [n+m]cycloaddition reactivity mode,[11] but
also opens up new perspectives for synthetic applica-
[3] a) M. P. Doyle, M. A. McKervey, T. Ye, Modern Cata-
lytic Methods for Organic Synthesis with Diazo Com-
pounds: From Cyclopropanes to Ylides, Wiley-Inter-
science, New York, 1998; b) H. M. L. Davies, J. R.
Denton, Chem. Soc. Rev. 2009, 38, 3061–3071.
[4] a) K. Saito, H. Sogou, T. Suga, H. Kusama, N. Iwasawa,
J. Am. Chem. Soc. 2011, 133, 689–691; for related work,
see: b) H. Kusama, Y. Miyashita, J. Takaya, N. Iwasa-
wa, Org.Lett. 2006, 8, 289–292; c) H. Kusama, M. Ebi-
sawa, H. Funami, N. Iwasawa, J. Am. Chem. Soc. 2009,
131, 16352–16353; d) K. Ishida, H. Kusama, N. Iwasa-
wa, J. Am. Chem. Soc. 2010, 132, 8842–8843.
tions especially for the synthesis of [1,2]oxazino
b]indole derivatives. Importantly, these [1,2]oxazino-
[5,4-b]indole derivatives can easily provide access to
ACHTUNGTNER[NUNG 5,4-
ACHTUNGTRENNUNG
1,4-amino alcohols. Further studies on the other Pt-
catalyzed intermolecular [n+m]cycloaddition modes
and the application of this methodology for the syn-
thesis of natural products are under investigation in
our laboratory.
[5] D. Shu, W. Song, X. Li, W. Tang, Angew. Chem. 2013,
125, 3319–3322; Angew. Chem. Int. Ed. 2013, 52, 3237–
3240.
[6] a) A. S. K. Hashmi, W. Yang, F. Rominger, Adv. Synth.
Catal. 2012, 354, 1273–1279; b) A. S. K. Hashmi, W.
Yang, F. Rominger, Chem. Eur. J. 2012, 18, 6576–6580.
[7] For a review on nitrones as 1,3-dipole reagents for cy-
cloaddition reactions, see: a) K. Rꢄck-Braun, T. H. E.
Freysoldt, F. Wierschem, Chem. Soc. Rev. 2005, 34,
507–516; for subsequent work on this subject: b) F. Car-
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Y. Yu, J. Zhang, Angew. Chem. 2009, 121, 5613–5616;
Angew. Chem. Int. Ed. 2009, 48, 5505–5508; d) F. Liu,
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122, 6819–6822; Angew. Chem. Int. Ed. 2010, 49, 6669–
6672; e) Y. B. Kang, X.-L. Sun, Y. Tang, Angew. Chem.
2007, 119, 3992–3995; Angew. Chem. Int. Ed. 2007, 46,
3918–3921; f) I. S. Young, M. A. Kerr, Angew. Chem.
2003, 115, 3131–3134; Angew. Chem. Int. Ed. 2003, 42,
3023–3026; g) R. Shintani, S. Park, W.-L. Duan, T. Hay-
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Chem. Int. Ed. 2007, 46, 5901–5903; h) S. A. Gawade, S.
Bhunia, R-S. Liu, Angew. Chem. 2012, 124, 7955–7958;
Angew. Chem. Int. Ed. 2012, 51, 7835–7838; i) J. Yang,
Synlett 2012, 23, 2293–2297; j) for the platinum-cata-
lyzed reaction involving nitrones, see: S. Bhunia, C.-J.
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Experimental Section
tert-Butyl 1-(3-Nitrophenyl)-2-phenyl-1,2-dihydro-
[1,2]oxazino
ACHTUNGTRENNUNG[5,4-b]indole-5(4H)-carboxylate (3a);
Typical Procedure
To
a mixture of PtCl2 (2.7 mg, 0.01 mmol, 10 mol%),
P
ACHTUNGTRENNUNG
0.15 mmol) was added dry dioxane (0.5 mL). After the mix-
ture had been stirred for 5 min, a 1,4-dioxane solution
(0.5 mL) of 1a (26.1 mg, 0.10 mmol) and (Z)-N-(3-nitroben-
zylidene)aniline oxide (48.0 mg, 0.20 mmol) was added to
the mixture. After the mixture had been stirred at 808C for
3 h and removal of the solvent under vacuum, the residue
was purified by column chromatography (petrol ether-ethyl
acetate: 10/1) to give the desired product; yield: 40.4 mg
(86%).
Acknowledgements
W. Yang, T. Wang, Y. Yu, S. Shi and T. Zhang are grateful to
the CSC for fellowships. Gold salts were generously donated
by Umicore AG & Co. KG.
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Chen, Adv. Synth. Catal. 2010, 352, 1904–1908.
[10] Y. H. Jung, J. D. Kim, Arch. Pharmacal Res. 2005, 28,
382–390.
[11] a) For PtCl2-catalyzed [6+2]cycloadditions, see: A. Te-
naglia, S. Gaillard, Angew. Chem. 2008, 120, 2488–2491;
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