Transition-metal-catalyzed ring expansion of diazocarbonylated cyclic N -hydroxylamines: A new approach to cyclic ketonitrones

Article abstract of DOI:10.1021/ol502029z

Novel C-ethoxycarbonyl cyclic ketonitrones are synthesized from the Ag- or Cu-catalyzed ring expansion of β-diazo cyclic hydroxylamines. The latter are themselves easily obtained by the addition of lithiated ethyl diazoacetate onto cyclic nitrones. The regioselective metal-catalyzed rearrangement of β-diazo cyclic hydroxylamines proved highly efficient and resulted in a synthetically useful ring expansion to produce 6- or 7-membered ring functionalized nitrones. The outcome of the two steps, i.e. nucleophilic addition of α-diazoesters to nitrones and ring expansion, is a formal nitrone homologation.

Full text of DOI:10.1021/ol502029z

Letter
pubs.acs.org/OrgLett
Transition-Metal-Catalyzed Ring Expansion of Diazocarbonylated
Cyclic N‑Hydroxylamines: A New Approach to Cyclic Ketonitrones
Evelyn Lieou Kui, Alice Kanazawa,* Jean-Franco̧ is Poisson, and Sandrine Py*
Univ. Grenoble Alpes, DCM, F-38000 Grenoble, France
CNRS, DCM, F-38000 Grenoble, France
S
* Supporting Information
ABSTRACT: Novel C-ethoxycarbonyl cyclic ketonitrones are
synthesized from the Ag- or Cu-catalyzed ring expansion of β-
diazo cyclic hydroxylamines. The latter are themselves easily
obtained by the addition of lithiated ethyl diazoacetate onto
cyclic nitrones. The regioselective metal-catalyzed rearrange-
ment of β-diazo cyclic hydroxylamines proved highly efficient and resulted in a synthetically useful ring expansion to produce 6-
or 7-membered ring functionalized nitrones. The outcome of the two steps, i.e. nucleophilic addition of α-diazoesters to nitrones
and ring expansion, is a formal nitrone homologation.
iazo compounds are highly versatile intermediates in
mixture of diastereoisomeric hydroxylamines 3f and 3g (trans/
Dorganic synthesis. In particular, they are precursors of cis = 60:40) was obtained from nitrone 1f,7 albeit in excellent
overall yield (93%) (Table 1, entry 3). The noncarbohydrate
nitrone 48 (MiPNO, Table 1, entry 4) was readily converted
into 8 in good yield and with excellent diastereoselectivity
(76%, dr >99:1), in line with the total diastereocontrol
previously observed in the addition of Grignard reagents to
this nitrone.9
metal carbenoids that can undergo powerful synthetic trans-
formations.1 We recently reported the synthesis of β-diazo N-
hydroxylamines by addition of lithiated α-diazoesters on a
variety of nitrones.2 From carbohydrate-derived cyclic nitrones
1, the expected N-hydroxypyrrolidines 3a−c were obtained in
high yields and excellent diastereoselectivities (Scheme 1).
The addition of ethyl lithiodiazoacetate was next extended to
six-membered-ring nitrones. From 3,4-dihydroisoquinoline N-
oxide 510 the expected β-diazo N-hydroxylamine 9 was
obtained in 78% yield.11 In the case of the arabinopyranose-
derived nitrone 612 the nucleophilic addition was also found to
proceed efficiently (97% yield), although in a 64:36 ratio of
diastereomers (Table 1, entry 6). The cis N-hydroxypiperidine
10a was the major diastereomer, in contrast with previous
reports on organometallic additions on this nitrone, yielding
preferentially trans hydroxylamines.3d,e,13 Interestingly, the
cyclic ketonitrone 714 was smoothly transformed into the
corresponding α-quaternary β-diazo N-hydroxypiperidine 11, in
good yield (79%) and excellent diastereoselectivity.6 This
represents a unique example of organometallic addition on a 6-
membered ring ketonitrone.15
The reactivity of β-diazo hydroxylamines has not been
reported to date. As they could represent excellent precursors
of oxazetidines16 by intramolecular O−H-insertion of a
transient carbenoid, we studied their reactivity in the presence
of metal catalysts. A variety of metal complexes are known to
induce decomposition of the diazo functionality, with extrusion
of gaseous dinitrogen and formation of highly reactive metal
carbenoids. The latter can evolve through different processes
including X−H insertion,17 1,2-hydride shift, and 1,2-C → C or
1,2-X → C bond migration (e.g., X = O, N, S, Si). Although
Scheme 1. Previous work2
Intrigued by the reactivity of these novel highly function-
alized diazoester derivatives, we decided to investigate their
transformation in the presence of metal catalysts. We report
herein an extension of the scope of preparation of cyclic β-diazo
N-hydroxylamines from nitrones and the first study on their
transformation in the presence of metal catalysts, granting
access to novel, homologated cyclic nitrones conjugated to an
ester function.
Variously substituted cyclic nitrones3 were treated with ethyl
lithiodiazoacetate (1.5 equiv) in THF at −78 °C (Table 1),
according to our reported protocol. From nitrone 1d4 or 1e,5
the corresponding β-diazo N-hydroxypyrrolidines 3d and 3e
were readily obtained in good yields, as single trans
diastereomers (Table 1, entries 1 and 2).6 In contrast, a
Received: July 11, 2014
Published: August 19, 2014
© 2014 American Chemical Society
4484
dx.doi.org/10.1021/ol502029z | Org. Lett. 2014, 16, 4484−4487

Organic Letters
Letter
Table 1. Scope of Nucleophilic Addition of Ethyl
Diazoacetate on Cyclic Nitrones
Scheme 2. Preliminary Result and Proposed Pathway
In order to optimize this unprecedented ring expansion,
other catalysts were screened (see Supporting Information for
complete screening). Copper and silver complexes21 have been
described to promote NH-insertion and, in some cases, ring
expansion.22 In the present process, they were found to be the
most efficient to generate nitrone 12 from 3a in high yields
(Table 2). In particular, the tetrakis(acetonitrile)copper(I)
Table 2. Selected Results on Catalyst Screening
a
b
entry
1
catalyst
solvent
temp
rt
time
yield (%)
Rh2(OAc)4
Cu(OTf)2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhCF3
30 min
45 min
<5 min
<5 min
50 min
1.25 h
53
77
86
96
82
83
97
c
2
rt
3
Cu(CH3CN)4BF4
Cu(CH3CN)4PF6
AgBF4
rt
d
4
rt
6
rt
7
AgOBz
rt
8
AgOTf
rt
20 min
120 h
e
9
no catalyst
no catalyst
40 °C
80 °C
0
10
50 min
57
a
The reactions were performed in the presence of 10 mol % catalyst
b
unless otherwise stated. Isolated yield after column chromatography.
c
d
15 mol % catalyst. With 0.5 mol % catalyst, nitrone 12 was isolated
e
in 86% yield (40 min). Starting material was totally recovered.
hexafluorophosphate [Cu(CH3CN)4PF6] was an excellent
catalyst, producing rapidly the desired nitrone 12 in 96%
yield (<5 min) with a 10 mol % catalyst loading, and in 86%
yield (40 min) with 0.5 mol % catalyst. Catalysis with AgOTf
(10 mol %) delivered 12 in 97% yield in 20 min. Thermal
decomposition of 3a was also examined: while no trace of
nitrone 12 was detected in refluxing CH2Cl2 after several days
(Table 2, entry 9), the ring-expanded nitrone was isolated in
57% yield by heating 3a at 80 °C during 50 min in
trifluorotoluene (Table 2, entry 10).23
With these results in hand, Cu(CH3CN)4PF6 and AgOTf
were selected as catalysts to evaluate the substrate scope (Table
3). As in the case of N-hydroxypyrrolidine 3a, all other five-
membered ring β-diazo-hydroxylamines 3 underwent Ag- and
Cu-mediated ring expansion to 6-membered ring cyclic
nitrones in excellent yields (68−100%) (Table 3, entries 1−
13). Nitrones 13−17 were isolated as single products and
exhibited good stability. The diastereoisomeric N-hydroxypyr-
rolidines 3f and 3g were both transformed into the same
nitrone 17 in good yields, upon Ag- or Cu-catalysis. In general,
reactions mediated by Cu(CH3CN)4PF6 catalysis were faster
than those mediated by AgOTf. In addition, with 2 mol %
copper catalyst the reaction efficiency was maintained (Table 3,
entry 9).
a
b
Isolated yield after column chromatography. Determined by
1
integration of representative signals in H NMR.
examples of chemo- and regioselective rearrangements of
carbenoids generated from diazo compounds have been
reported,18 most often several processes compete, leading to
mixtures of products.1
Dirhodium tetraacetate, the most popular catalyst for
carbenoid formation,1a,19 was tested first on N-hydroxypyrro-
lidine 3a. The six-membered ring nitrone 12 was the only
isolated product, with no trace of oxazetidine. The formation of
the nitrone 12 can be explained by generation of the Rh(II)
carbenoid A, from which 1,2-migration of nitrogen would take
place to afford an ammonium ylide intermediate B (Scheme 2).
Then, ring enlargement would occur producing a six
membered-enehydroxylamine C that tautomerizes to 12.20
A
concerted mechanism for the conversion of metallocarbenoid A
to intermediate C is also plausible.
4485
dx.doi.org/10.1021/ol502029z | Org. Lett. 2014, 16, 4484−4487

Organic Letters
Letter
nitrone 19 could be obtained in 78% yield, by increasing the
amount of silver triflate to 1 equiv (Table 3, entry 15). Using
Cu(CH3CN)4PF6 (10 mol %) as the catalyst, nitrone 19
formed in only 35 min (60%, Table 3, entry 16). This result
confirms the superiority of the copper catalyst over silver
triflate, a trend already observed for the 5 → 6-membered ring
expansions. Again, when diastereomeric N-hydroxypiperidines
10a and 10b were treated with the Ag- or Cu-catalysts, the
starting materials were consumed much faster with the latter
(minutes instead of hours). However, from these β-diazo
hydroxylamines, nitrone 20 was isolated in higher yield with the
silver catalyst (96% from 10a, 64% from 10b). The lower yields
in the Cu-catalyzed ring expansion of these N-hydroxy-
piperidines is due to competing insertion of the transient
carbenoid in a benzylic C−H bond of the C-3 benzyloxy-
substituent in hydroxylamines 10a or 10b (see Supporting
Information).1c,f Unfortunately, nitrone 21 that was expected to
arise from ring expansion of hydroxylamine 11 was not isolated
from treatment of 11 with AgOTf or Cu(CH3CN)4PF6, neither
with a 10 mol % (not shown) nor with a 100 mol % (Table 3,
entries 21, 22) loading. The only products that could be
identified from the reaction mixture resulted from CH-insertion
(see Supporting Information). This side reaction, which was
never observed from β-diazo N-hydroxy pyrrolidines, occurs
competitively from O-benzyl-protected β-diazo N-hydroxy-
piperidines (Table 3, entries 18 and 20−22), as the formation
of 7-membered rings is energetically demanding.
Table 3. Formation of Ketonitrones 13−20 Mediated by
a
Ag(I) and Cu(I) Catalysts
In summary, the efficient addition of α-diazo esters to cyclic
nitrones, followed by metal-catalyzed ring expansion, results in
homologation to new C-ethoxycarbonyl cyclic ketonitrones. In
contrast to the well-documented preparation of aldonitrones,3
methods for the preparation of cyclic ketonitrones are scarce
and suffer from low yields.14,24,25 This novel approach for their
synthesis opens new opportunities for development of the rich
chemistry of nitrones. Further applications of these novel
structures to access cyclic amino acids and bioactive alkaloids
are currently ongoing in our laboratory. We are also
investigating the factors that influence the selectivity of these
reactions depending on the nature of the catalysts.
ASSOCIATED CONTENT
■
S
* Supporting Information
Characterization data, full experimental procedures, and copies
1
of H and 13C NMR spectra of all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
a
Corresponding Authors
All reactions were performed in dichloromethane, at room temper-
b
ature, with 10 mol % catalyst, unless otherwise stated. [Ag]: AgOTf;
[Cu]: Cu(CH3CN)4PF6. Isolated yield after chromatography. 2 mol
% cat. 100 mol % cat. 24% imine resulting from dehydration of 9 was
isolated as a side product. CH-insertion competes favorably with ring
*E-mail: alice.kanazawa@ujf-grenoble.fr.
*E-mail: sandrine.py@ujf-grenoble.fr.
c
d
e
f
g
Notes
expansion (see Supporting Information).
The authors declare no competing financial interest.
We next turned our attention to the more challenging
conversion of N-hydroxypiperidines 9−11 into 7-membered-
ring ketonitrones. When the β-diazo hydroxylamine 9 was
treated with 10 mol % AgOTf (Table 3, entry 14) the expected
nitrone 19 was isolated in only 36% yield, accompanied by
ethyl 2-diazo-2-(3,4-dihydroisoquinolin-1-yl)acetate (24%) aris-
ing from dehydration of 9. However, the 7-membered-ring
ACKNOWLEDGMENTS
■
E.L.K. is grateful to the Universite
́
de Grenoble for a doctoral
allocation. M. Carbo Lopez (DCM) is thanked for a gift of
nitrone 4. We acknowledge support from ICMG FR 2607,
Grenoble, through which NMR and MS analyses have been
performed.
4486
dx.doi.org/10.1021/ol502029z | Org. Lett. 2014, 16, 4484−4487

Organic Letters
Letter
(17) Zhu, S.-F.; Zhou, Q.-L. Acc. Chem. Res. 2012, 45, 1365−1377.
(18) (a) Vitale, M.; Lecourt, T.; Sheldon, C. G.; Aggarwal, V. K. J.
Am. Chem. Soc. 2006, 128, 2524−2525. (b) Xu, X.; Qian, Y.; Zavalij, P.
Y.; Doyle, M. P. J. Am. Chem. Soc. 2013, 135, 1244−1247.
(19) (a) Padwa, A. Chem. Soc. Rev. 2009, 38, 3072−3081. (b) Wee,
A. G. H. Curr. Org. Synth. 2006, 3, 499−555. (c) Davies, H. M. L.;
Walji, A. M. In Modern Rhodium-Catalyzed Organic Reactions; Evans, P.
A., Ed.; Wiley: 2005; pp 301−340.
(20) For related ring expansions involving β-diazo amines, see:
(a) Liu, J.-M.; Young, J.-J.; Li, Y.-J.; Sha, C.-K. J. Org. Chem. 1986, 51,
1120−1123. (b) Chen, S.; Zhao, Y.; Wang, J. Synlett 2006, 1705−
1710.
REFERENCES
■
(1) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. In Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds; Wiley: New
York, 1998. Selected reviews: (b) Padwa, A.; Weingarten, M. D. Chem.
Rev. 1996, 96, 223−269. (c) Davies, H. M. L.; Beckwith, R. E. J. Chem.
Rev. 2003, 103, 2861−2903. (d) Davies, H. M. L.; Hedley, S. J. Chem.
Soc. Rev. 2007, 36, 1109−1119. (e) Lebel, H.; Marcoux, J.-F.;
Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977−1050.
(f) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417−424.
(g) Zhang, Z.; Wang, J. Tetrahedron 2008, 64, 6577−6605. (h) da
Silva, F. C.; Jordao, A. K.; da Rocha, D. R.; Ferreira, S. B.; Cunha, A.
C.; Ferreira, V. F. Curr. Org. Chem. 2012, 16, 224−251.
(2) Lieou Kui, E.; Kanazawa, A.; Poisson, J.-F.; Py, S. Tetrahedron
Lett. 2013, 54, 5103−5105.
(21) (a) Bachmann, S.; Fielenbach, D.; Jørgensen, K. A. Org. Biomol.
Chem. 2004, 2, 3044−3049. (b) Zhao, X.; Zhang, Y.; Wang, J. Chem.
Commun. 2012, 48, 10162−10173.
(3) For reviews on the synthesis of enantiopure cyclic nitrones, see:
(a) Revuelta, J.; Cicchi, S.; Goti, A.; Brandi, A. Synthesis 2007, 485−
504. (b) Brandi, A.; Cardona, F.; Cicchi, S.; Cordero, F. M.; Goti, A.
Chem.Eur. J. 2009, 15, 7808−7821. For recent reports describing
carbohydrate-derived nitrones syntheses, see: (c) Tsou, E.-L.; Yeh, Y.-
T.; Liang, P.-H.; Cheng, W.-C. Tetrahedron 2009, 65, 93−100.
(d) Wang, W.-B.; Huang, M.-H.; Li, Y.-X.; Rui, P.-X.; Hu, X.-G.;
Zhang, W.; Su, J.-K.; Zhang, Z.-L.; Zhu, J.-S.; Xu, W.-H.; Xie, X.-Q.; Jia,
Y.-M.; Yu, C.-Y. Synlett 2010, 488−492. (e) Chan, T.-H.; Chang, Y.-F.;
Hsu, J.-J.; Cheng, W.-C. Eur. J. Org. Chem. 2010, 5555−5559.
(f) Chang, Y.-F.; Guo, C.-W.; Chan, T.-H.; Pan, Y.-W.; Tsou, E.-L.;
Cheng, W.-C. Mol. Diversity 2011, 15, 203−214. (g) Zhao, W.-B.;
Nakagawa, S.; Kato, A.; Adachi, I.; Jia, Y.-M.; Hu, X.-G.; Fleet, G. W. J.;
Wilson, F. X.; Horne, G.; Yoshihara, A.; Izumori, K.; Yu, C.-Y. J. Org.
Chem. 2013, 78, 3208−3221.
(22) (a) Xu, H.; Zhang, W.; Shu, D.; Werness, J. B.; Tang, W. Angew.
Chem., Int. Ed. 2008, 47, 8933−8936. (b) Liu, R.; Zhang, M.; Winston-
McPherson, G.; Tang, W. Chem. Commun. 2013, 49, 4376−4378.
(c) Barluenga, J.; Riesgo, L.; Lopez, L. A.; Rubio, E.; Tomas, M. Angew.
Chem., Int. Ed. 2009, 48, 7569−7572.
(23) Hansen, S. R.; Spangler, J. E.; Hansen, J. H.; Davies, H. M. L.
Org. Lett. 2012, 14, 4626−4629.
(24) van den Broek, L. A. G. M. Tetrahedron 1996, 52, 4467−4478.
(25) For recent reports on metal-catalyzed 7- and 8-membered ring
ketonitrones synthesis, see: (a) Nakamura, I.; Okamoto, M.; Sato, Y.;
Terada, M. Angew. Chem., Int. Ed. 2012, 51, 10816−10819.
(b) Nakamura, I.; Sato, Y.; Takeda, K.; Terada, M. Chem.Eur. J.
2014, 20, 10214−10219.
(4) (a) Closa, M.; Wightman, R. H. Synth. Commun. 1998, 28, 3443−
3450. (b) Cicchi, S.; Corsi, M.; Brandi, A.; Goti, A. J. Org. Chem. 2002,
67, 1678−1681.
(5) (a) Pillard, C.; Desvergnes, V.; Py, S. Tetrahedron Lett. 2007, 48,
6209−6213. See also ref 3c.
(6) The configuration of β-diazo hydroxylamines was determined by
NOESY experiments; see Supporting Information.
(7) Cicchi, S.; Marradi, M.; Vogel, P.; Goti, A. J. Org. Chem. 2006, 71,
1614−1619.
(8) (a) Thiverny, M.; Philouze, C.; Chavant, P.-Y.; Blandin, V. Org.
Biomol. Chem. 2010, 8, 864−872. (b) Thiverny, M.; Demory, E.;
Baptiste, B.; Philouze, C.; Chavant, P.-Y.; Blandin, V. Tetrahedron:
Asymmetry 2011, 22, 1266−1273.
(9) (a) Thiverny, M.; Farran, D.; Philouze, C.; Blandin, V.; Chavant,
P. Y. Tetrahedron: Asymmetry 2011, 22, 1274−1281. (b) Demory, E.;
Farran, D.; Baptiste, B.; Chavant, P. Y.; Blandin, V. J. Org. Chem. 2012,
77, 7901−7912.
(10) Murahashi, S.; Mitsui, H.; Shiota, T.; Tsuda, T.; Watanabe, S. J.
Org. Chem. 1990, 55, 1736−1744.
(11) Compound 9 was somewhat unstable and evolved into ethyl-2-
diazo-2-(3,4-dihydroquinolin-1-yl)acetate, upon standing.
(12) Tamura, O.; Toyao, A.; Ishibashi, H. Synlett 2002, 1344−1346.
See also refs 3d−f.
(13) (a) Xu, W.-Y.; Iwaki, R.; Jia, Y.-M.; Zhang, W.; Kato, A.; Yu, C.-
Y. Org. Biomol. Chem. 2013, 11, 4622−4639. (b) Zhao, H.; Wang, W.-
B.; Nakagawa, S.; Jia, Y.-M.; Hu, X.-G.; Fleet, G. W. J.; Wilson, F. X.;
Nash, R. J.; Kato, A.; Yu, C.-Y. Chin. Chem. Lett. 2013, 24, 1059−1063.
(14) Racine, E.; Bello, C.; Gerber-Lemaire, S.; Vogel, P.; Py, S. J. Org.
Chem. 2009, 74, 1766−1769.
(15) For reviews on nucleophilic additions to nitrones, see:
(a) Merino, P. C. R. Chimie 2005, 8, 775−788. (b) Lombardo, M.;
Trombini, C. Curr. Org. Chem. 2002, 6, 695−713. See also: (c) Delso,
I.; Tejero, T.; Goti, A.; Merino, P. J. Org. Chem. 2011, 76, 4139−4143.
(d) Delso, I.; Melicchio, A.; Isasi, A.; Tejero, T.; Merino, P. Eur. J. Org.
Chem. 2013, 5721−5730.
(16) (a) Hanquet, G. In Asymmetric Synthesis of Nitrogen Heterocycles;
Wiley-VCH: Weinheim, 2009. (b) Capriati, V.; Florio, S.; Luisi, R.;
Salomone, A.; Cuocci, C. Org. Lett. 2006, 8, 3923−3926. (c) Luisi, R.;
Capriati, V.; Florio, S.; Piccolo, E. J. Org. Chem. 2003, 68, 10187−
10190.
4487
dx.doi.org/10.1021/ol502029z | Org. Lett. 2014, 16, 4484−4487