Six-membered cyclic nitronates as 1,3-dipoles in formal [3 + 3]-cycloaddition with donor-acceptor cyclopropanes. synthesis of new type of bicyclic nitrosoacetals

Article abstract of DOI:10.1021/ol303292c

The first formal [3 + 3]-cycloaddition of nitronates with donor-acceptor cyclopropanes is reported. The reaction is catalyzed by ytterbium trifluoromethanesulfonate and leads to hitherto unknown bicyclic nitrosoacetals, possessing two annelated six-member

Full text of DOI:10.1021/ol303292c

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Six-Membered Cyclic Nitronates as
1,3-Dipoles in Formal [3 þ 3]-Cycloaddition
with DonorꢀAcceptor Cyclopropanes.
Synthesis of New Type of Bicyclic
Nitrosoacetals
Evgenia O. Gorbacheva,†,‡ Andrey A. Tabolin,*,† Roman A. Novikov,†
Yulia A. Khomutova,† Yulia V. Nelyubina,§ Yury V. Tomilov,† and Sema L. Ioffe*,†
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
Leninsky prosp. 47, Moscow 119991, Russian Federation, Higher Chemical College,
D.I. Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9,
Moscow 125047, Russian Federation, and A.N. Nesmeyanov Institute of Organoelement
Compounds, Russian Academy of Sciences, Vavilov str. 28, Moscow 119991,
Russian Federation
iof@ioc.ac.ru
Received November 30, 2012
ABSTRACT
The first formal [3 þ 3]-cycloaddition of nitronates with donorꢀacceptor cyclopropanes is reported. The reaction is catalyzed by ytterbium
trifluoromethanesulfonate and leads to hitherto unknown bicyclic nitrosoacetals, possessing two annelated six-membered rings.
In the recent years there has been extensive develop-
ment in the chemistry of donorꢀacceptor cyclopropanes
(DACs).1 The reactivity of the banana σ-bond C,C of these
substrates is comparable to that of the π-bond C,C of
Michael acceptors. Homo-Michael nucleophilic addition
accompanies cyclopropane ring opening (Scheme 1, eq 1).2
Formal [3 þ 2]-cycloadditions ([3 þ 2]-annelations) with
multiple bonds where DACs act as 1,3-dipoles is another
intriguing field (eq 2). Such transformations involved a
wide range of dipolarophiles, including silylenolates,3
siloxy-alkynes,4 indoles,5 aldehydes,6 imines,7 pyridines,8
nitriles.9
† N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of
Sciences.
‡ D.I. Mendeleev University of Chemical Technology of Russia.
§ A.N. Nesmeyanov Institute of Organoelement Compounds, Russian
Academy of Sciences.
(1) (a) Mel’nikov, M. Ya.; Budynina, E. M.; Ivanova, O. A.; Trushkov,
I. V. Mendeleev Commun. 2011, 21, 293. (b) Carson, C. A.; Kerr, M. A.
Chem. Soc. Rev. 2009, 38, 3051. (c) Yu, M.; Pagenkopf, B. L. Tetra-
hedron 2005, 61, 321. (d) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003,
103, 1151.
(2) Recent examples: (a) Zhou, Y.-Y.; Wang, L.-J.; Li, J.; Sun, X.-L.;
Tang, Y. J. Am. Chem. Soc. 2012, 134, 9066. (b) Emmett, M. R.; Grover,
H. K.; Kerr, M. A. J. Org. Chem. 2012, 77, 6634. (c) Chen, G.-Q.; Tang,
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J. I. Org. Lett. 2011, 13, 5338. (f) Emmett, M. R.; Kerr, M. A. Org. Lett.
2011, 13, 4180. (g) Espejo, V. R.; Li, X.-B.; Rainier, J. D. J. Am. Chem.
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2081. (i) Lifchits, O.; Charette, A. B. Org. Lett. 2008, 10, 2809.
Our interest in DAC chemistry is encouraged by their
annelation capability due to the possible involvement of
cyclic nitronates 1 (see Scheme 2) as the reaction partners.
(3) (a) de Nanteuil, F.; Waser, J. Angew. Chem., Int. Ed. 2011, 50,
12075. (b) Fang, J.; Ren, J.; Wang, J. Tetrahedron Lett. 2008, 49, 6659.
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2007, 129, 9631.
r
10.1021/ol303292c
XXXX American Chemical Society

Recently a similar transformation, namely homocycload-
dition of DACs with nitrones, was described by Kerr et
al.10 Further studies from that and other groups deepened
the reaction understanding allowing the synthesis of var-
ious tetrahydro-1,2-oxazines,11 including those in asym-
metric mode.12
catalyzed by scandium triflate. Use of nickel perchlorate
decreased the reaction rate. Copper(II) triflate allowed
acceleration but led to some decomposition products even
in the presence of the acid scavenger, 2,6-di-tert-butyl-4-
methylpyridine. Traditional Lewis acids (SnCl4, TiCl4) led
only to the decay products. AgBF4 failed to catalyze the
reaction. Of note is the importance of molecular sieves or
Utilization as 1,3-dipoles in [3 þ 2]-cycloaddition is one
of the most explored reactivities of nitronates.13 In the
1990s Denmark’s and Rosini’s groups accomplished sev-
eral total syntheses based on similar transformations.13,14
This approach began with the synthesis of cyclic nitronates
1 (Scheme 2). Its cycloaddition with alkenes further led to
the formation of bicyclic nitrosoacetals 2. Reductive un-
masking of the amine group triggered the formation of
various amino-alcohol derivatives 3, which were further
transformed into target products. Undoubtedly [3 þ 2]-
cycloaddition itself can provide only nitrosoacetals 2 con-
taining a five-membered isoxazolidine ring. Consequently
successful involvement of nitronates 1 in a reaction with
DACs should open the access to nitrosoacetals 4, includ-
ing hitherto unknown bicyclic ones possessing two six-
membered rings.
use of nonhydrated Lewis acids: Yb(OTf)3 6H2O in the
˚
absence of MS 4A decreases the yield of annelation
3
product 7aa to 39%, presumably due to partial hydrolysis
of starting nitronate 5a.
Table 1. Formal [3 þ 3] Cycloaddition of Nitronates 3 with
DAC 4
Our study started from the model reaction of
1,2-oxazine-N-oxide 5a with DAC 6a (Table 1). Upon
treatment with catalytic amounts of ytterbium triflate in
the presence of molecular sieves, transformation proceeded
to target 7aa in pretty good yield with excellent stereo-
selectivity.15 Lewis acid screening (see Supporting Informa-
tion for details) revealed that the reaction can be equally
yield,
5
6
7
R1
R2
R3
R4
R5
%
7:70
a
b
c
a
a
a
a
a
b
c
aa Ana
ba ClPhb
ca Ph
da An
ea An
ab An
ac An
ad An
H
H
H
H
Me
Me
Me Ph
Me Ph
91
61
67
85
80
92
77
70
only 7
only 7
3.5:1
11:5:1c
only 7
only 7
only 7
only 7
Scheme 1. Reactivity Modes of DonorꢀAcceptor Cyclopro-
Ph
H
H
H
Ph
Ph
Ph
panes
d
e
n-Pr
-(CH2)4-
a
a
a
H
H
H
Me
Me
Me
Me ClPh
Me An
Me Thd
d
a An = 4-MeOC6H4-. b ClPh = 4-ClC6H4-. c Unknown adduct.
d Th = 2-thienyl.
Scheme 2. Cyclic Nitronates in Total Synthesisa
a * = chiral center.
B
Org. Lett., Vol. XX, No. XX, XXXX

The applicability of the reaction was tested on an array
of nitronates 5 and DACs 6 (Table 1, Figure 1). Good
yields were achieved for products shown in the Table 1,
while the stereoselectivity depended on the nitronate
structure. 6,6-Dimethyl substituted substrates 5a,b gave
products 7aaꢀad,ba as single diastereomers. 6-Monosub-
stituted substrates 5c,d led to a diastereomeric mixture of
products 7 and 70 with the same relative configuration at
bridgehead carbon C-4a and ring carbons C-2 and C-4.
3-Methyl substituted nitronate 5f (Figure 1) failed to
undergo the annelation even in refluxing toluene apparently
due to steric reasons. 6-Alkoxy-substituted nitronates 5g,h
led to a complex mixture of products.
Figure 2. ORTEP drawing for 7ba.
Figure 1. Nitronates, tried in [3 þ 3]-annelation unsuccessfully.
Scheme 3. Conformational Equilibrium of Nitrosoacetals 5
Target product composition was established by means
of elemental analyses or HRMS. Structures were deter-
mined by 2D NMR and X-ray data (for 7ba,ca,da,ea,70ca,
Figure 2). Nitrosoacetals 7aaꢀad,ba at room temperature
1
exhibit two sets of signals in H and 13C NMR that are
attributed to the conformation equilibrium (Figure 3,
Scheme 3). The dominant is the double chair conformation
7-1 with trans-ring junction. Other conformations to be
expected are those with a cis-junction: 7-2 and 7-3. Both of
these arise from nitrogen and ring inversions. Coupling
constant analysis reveals that the minor conformation is
7-2. Such domination of the trans-junction in nitrosoace-
tals 7aaꢀad,ba,ea is intriguing because such a structure
lacks the stabilizing anomeric interaction in the OꢀNꢀO
moiety. Indeed, 6-ring-5-ring-annelated nitrosoacetals 8
are known to adopt a conformation with the cis-junction,
with the NꢀO bond of the six-membered ring being
pseudoaxial with respect to the five-membered ring.16
(6) (a) Benfatti, F.; de Nanteuil, F.; Waser, J. Org. Lett. 2012, 14, 386.
(b) Pohlhaus, P. D.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127, 16014.
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Wang, J.; Yu, M.; Pagenkopf, B. L. Adv. Synth. Catal. 2006, 348, 2385.
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(b) Yu, M.; Pagenkopf, B. L. Org. Lett. 2003, 5, 5099.
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(b) Dias, D. A.; Kerr, M. A. Org. Lett. 2009, 11, 3694. (c) Hu, B.; Zhu, J.;
Xing, S.; Fang, J.; Du, D.; Wang, Z. Chem.;Eur. J. 2009, 15, 324.
(d) Ganton, M. D.; Kerr, M. A. J. Org. Chem. 2004, 69, 8554. (e) Young,
I. S.; Kerr, M. A. Org. Lett. 2004, 6, 139.
(12) (a) Kang, Y.-B.; Sun, X.-L.; Tang, Y. Angew. Chem., Int. Ed.
2007, 46, 3918. (b) Sapeta, K.; Kerr, M. A. J. Org. Chem. 2007, 72, 8597.
(c) Sibi, M.; Ma, Z.; Jasperse, C. P. J. Am. Chem. Soc. 2005, 127, 5764.
(13) (a) Sukhorukov, A. Yu.; Dilman, A. D.; Ioffe, S. L. Khim. Get.
Soed. 2012, 54. Engl.: Chem. Het. Comp. 2012, 48, 49. (b) Ioffe, S. L.
Nitrile oxides, nitrones, and nitronates in organic synthesis, 2nd ed.; Feuer,
H., Ed.; John Wiley & Sons: Hoboken, NJ, 2008; Chapter 3, p 541.
(c) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137.
Figure 3. Part of 1H NMR spectra for 7ac.
In conclusion here we reported the synthesis of bicyclic
nitrosoacetals 7 by means of ytterbium triflate mediated
annelation of cyclic nitronates 5 with DACs 6. Our next
Org. Lett., Vol. XX, No. XX, XXXX
C

efforts will be focused on broadening the reaction scope,
including stereochemical regularities, and investigation of
the chemistry of adducts 7.
Supporting Information Available. Experimental pro-
cedures, analytical data and copies of NMR spectra,
cif files for compounds 7ba,ca,da,ea,70ca. This mate-
rial is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. The work was supported by the
Russian Foundation for Basic Research (Grant 12-03-00278).
(16) (a) Shitkin, V. M.; Khudak, V. I.; Chlenov, I. E.; Tartakovskii,
V. A. Izv. Akad. Nauk. SSSR, Ser. Khim. 1974, 1908 (Engl.: Bull. Akad.
Sci. USSR, Div. Chem. Sci. 1974, 23, 1836). (b) Shitkin, V. M.; Chlenov,
I. E.; Tartakovskii, V. A. Izv. Akad. Nauk. SSSR, Ser. Khim. 1977, 211
(Engl.: Bull. Akad. Sci. USSR, Div. Chem. Sci. 1977, 26, 187). (c) Denmark,
S. E.; Thorarensen, A.; Swiss, K. A. Acta Crystallogr., Sect. C 1996, C52,
2558. (d) Kuster, G. J.; Kalmoua, F.; de Gelder, R.; Scheeren, H. W.
Chem. Commun. 1999, 855. (e) Denmark, S. E.; Baiazitov, R. Y. J. Org.
Chem. 2006, 71, 593.
(14) Selected seminal publications: (a) Denmark, S. E.; Baiazitov,
R. Y.; Nguyen, S. T. Tetrahedron 2009, 65, 6535. (b) Denmark, S. E.;
Montgomery, J. I. Angew. Chem., Int. Ed. 2005, 44, 3732. (c) Denmark,
S. E.; Juhl, M. Helv. Chim. Acta 2002, 85, 3712. (d) Denmark, S. E.;Hurd,
A. J. Org. Chem. 2000, 65, 2875. (e) Denmark, S. E.; Martinborough, E. A.
J. Am. Chem. Soc. 1999, 121, 3046. (f) Denmark, S. E.; Dixon, J. A. J. Org.
Chem. 1998, 63, 6167. (g) Righi, P.; Marotta, E.; Rosini, G. Chem.;Eur. J.
1998, 4, 2501.
(15) IntriguinglyannelationofDACwithcyclicnitronesgave no adducts;
see: Carson, C. A.; Kerr, M. A. Angew. Chem., Int. Ed. 2006, 45, 6560.
The authors declare no competing financial interest.
D
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