Catalytic migratory oxidative coupling of nitrones

Article abstract of DOI:10.1021/ol201629n

A Cu(I)-catalyzed migratory oxidative coupling between nitrones and heterocycles or a methylamine is described. Selective C-C bond-formation proceeds through cleavage of two C(sp³)-H bonds concomitant with C=N double bond-migration. The reaction provides an alternating nitrone moiety, allowing for further synthetically useful transformations. Radical clock studies suggest that the nucleophilic addition of nitrones to an oxidatively generated carbocation is a key step.

Full text of DOI:10.1021/ol201629n

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4288–4291
Catalytic Migratory Oxidative Coupling
of Nitrones
Shogo Hashizume, Kounosuke Oisaki,* and Motomu Kanai*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
oisaki@mol.f.u-tokyo.ac.jp; kanai@mol.f.u-tokyo.ac.jp
Received June 17, 2011
ABSTRACT
A Cu(I)-catalyzed migratory oxidative coupling between nitrones and heterocycles or a methylamine is described. Selective CꢀC bond-formation
proceeds through cleavage of two C(sp3)ꢀH bonds concomitant with CdN double bond-migration. The reaction provides an alternating nitrone
moiety, allowing for further synthetically useful transformations. Radical clock studies suggest that the nucleophilic addition of nitrones to an
oxidatively generated carbocation is a key step.
The pursuit of novel catalytic methodologies to functio-
nalize unactivated CꢀH bonds is one of the most attractive
subjects in current synthetic organic chemistry.1 Cross-
dehydrogenative coupling (CDC) reactions pioneered by
Li et al.2 are direct oxidative CꢀC bond-formations from
two different CꢀH bonds in the presence of terminal
oxidants (hydrogen acceptors). CDC eliminates the need
for preactivation and cumbersome functional group ma-
nipulations of substrates thereby contributing to environ-
mentally benign, streamlined synthesis.3,4 Although
various CDC reactions have been reported to date, there
remains much room for improvement, especially in the
extension to practical complex molecule synthesis. Re-
ported conditions usually include precious metals, high
temperature, oxidants producing stoichiometric amounts
of hazardous waste, and narrow substrate scope.2,5 Here
we report a catalytic migratory oxidative coupling reaction
between nitrones (imine N-oxides) and O-/N-heterocycles
or an alkylamine as a novel CDC, producing alternating
nitrones, that can be used for synthetically useful transfor-
mations. This reaction is promoted by an inexpensive and
abundant copper catalyst at room temperature, using tert-
butyl hydroperoxide (TBHP) as the terminal oxidant.6
Our study began with the unexpected finding that a
migratory coupling product 3ac was produced from ni-
trone 1a under oxidative conditions in the presence of a
copper catalyst in THF (2c), even at room temperature. In
this reaction, multiple events proceeded sequentially: (1)
(1) (a) Topics in Current Chemistry; Yu, J.-Q., Shi, Z.-J., Eds.; Springer:
New York, 2010; Vol. 292. (b) Dick, A. R.; Sanford, M. S. Tetrahedron
2006, 62, 2439. (c) Davies, H. M. L.; Du Bois, J.; Yu, J. -Q. Chem. Soc.
Rev. 2011, 40, 1855.
(2) (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (b) Scheuermann, C. J.
Chem. Asian. J. 2010, 5, 436. (c) Klussmann, M.; Sureshkumar, D.
Synthesis 2011, 353. (d) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev.
2011, 111, 1780.
(3) Discussions of the benefit of constant oxidation level escalation in
complex molecule synthesis: (a) Baran, P. S.; Maimone, T. J.; Richter,
J. M. Nature 2007, 446, 404. (b) Burns, N. Z.; Baran, P. S.; Hoffmann,
R. W. Angew. Chem., Int. Ed. 2009, 48, 2854. (c) Ishihara, Y.; Baran,
P. S. Synlett 2010, 1733.
(5) Representative examples of metal-catalyzed CDC forming C-
(sp3)-C(sp3) bonds: (a) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127,
3672. (b) Li, Z.; Li, C.-J. Eur. J. Org. Chem. 2005, 3173. (c) Zhang, Y.; Li,
C.-J. Angew. Chem., Int. Ed. 2006, 45, 1949. (d) Li, Z.; Li, C.-J. J. Am.
Chem. Soc. 2006, 128, 56. (e) Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed.
2008, 47, 7075. (f) Li, Z.-P.; Yu, R.; Li, H.-J. Angew. Chem., Int. Ed. 2008,
47, 7497. (g) Lin, S.; Song, C.-X.; Cai, G.-X.; Wang, W.-H.; Shi, Z.-J. J.
Am. Chem. Soc. 2008, 130, 12901. (h) Young, A. J.; White, M. C. J. Am.
Chem. Soc. 2008, 130, 14090. (i) Dubs, C.; Hamashima, Y.; Sasamoto,
N.; Seidel, T. M.; Suzuki, S.; Hashizume, D.; Sodeoka, M. J. Org. Chem.
~
2008, 73, 5859. (j) Richter, H; Mancheno, O. G. Eur. J. Org. Chem. 2010,
4460. (k) Yang, F.; Li, J.; Xie, J.; Huang, Z.-Z. Org. Lett. 2010, 12, 5214.
(l) Xie, J.; Huang, Z.-Z. Angew. Chem., Int. Ed. 2010, 49, 10181.
(6) For CDCs using copper catalyst and TBHP: (a) Li, Z.; Li, C.-J.
J. Am. Chem. Soc. 2004, 126, 11810. (b) Li, Z.; Li, C.-J. Org. Lett. 2004,
6, 4997. (c) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 6968. (d) Li, Z.;
Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8928. Also
see refs 2, 5a, 5b, 5d, 5e, 5k, and 5l.
(4) (a) Godula, K.; Sames, D. Science 2006, 312, 67. (b) Davies,
H. M. L.; Manning, J. R. Nature 2008, 451, 417. (b) McMurray, L.;
O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40, 1885. (c) Gutekunst,
W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976. (d) Wencel-Delord,
€
J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, doi:10.1039/
c1cs15083a.
r
10.1021/ol201629n
Published on Web 07/18/2011
2011 American Chemical Society

cleavage of both the benzylic CꢀH bond of 1a and the
methylene CꢀH bond adjacent to an oxygen atom of
THF, (2) double bond-migration of 1a, and (3) the site-
selective CꢀC bond formation. The synthetic utility and
reactivity of nitrones have previously been studied due to
their unique structural features such as densely presented
functional groups and easy availability; however, the
above conversion is not found among any classical
transformation.7 This finding led us to explore the novel
reactivity of nitrones under oxidative coupling conditions.
We optimized the migratory oxidative coupling reaction
between nitrone 1b (prepared via condensation of methyl
pyruvatewithN-benzyl hydroxylamine) and pinacol acetal
2a in the presence of copper catalysts and TBHP, affording
3ba (Table 1). First, screening of copper salts as a catalyst
revealed that copper halides and cationic copper salts were
less suitable than copper carboxylates, among which cop-
per benzoate (CuOBz) produced the best results (entries
1ꢀ4).8 Reducing the amount of TBHP to 2.0 equiv and
decreasing the reaction time suppressed undesirable side
reactions and improved the yield (entry 5). Polar solvents
generally afforded better yields, and dimethylsulfoxide
(DMSO) was the optimum solvent (entry 6). Investigation
of the ligand effects on copper revealed that specific
bidentate ligands comprising pyridyl moieties enhanced
the reactivity. The best yield was obtained with 1,10-
phenanthroline (1,10-phen) as the ligand (entries 7ꢀ9).
Decreasing the catalyst loading to 5 mol %, however,
produced a less satisfactory yield (entry 10). We then
studied the effects of additives to enhance the reactivity.
Table 1. Optimization of Reaction Conditionsa
Cu cat.
time
additives
(mol %)
yieldb
[%]
entry (mol %)
solvent [h]
1c CuCl (20)
CH3CN 24 none
8
13
16
20
40
55
8
2c Cu(OAc)2 (20)CH3CN 24 none
3c CuOAc (20) CH3CN 24 none
4c CuOBz (20) CH3CN 24 none
5
6
7
8
9
CuOBz (10) CH3CN
CuOBz (10) DMSO
CuOBz (10) DMSO
CuOBz (10) DMSO
CuOBz (10) DMSO
6
8
6
6
4
5
5
none
none
TMEDA(12)
2,20-bipy. (12)
1,10-phen.(12)
1,10-phen.(6)
57
76
66
10 CuOBz (5)
11 CuOBz (5)
12 CuOBz (5)
13 CuOBz (5)
DMSO
DMSO
1,10-phen. (6), pyridine (20) 61
64
DMSO 0.5 1,10-phen. (6), NaHCO3 (20) 75d
DMSO 1.5 1,10-phen.(6), K2CO3(20)
a Standard conditions: 1 (0.10 mmol), 2 (0.50 mmol), Cu catalyst
(0.005ꢀ0.02 mmol), TBHP (0.20 mmol), and solvent (0.5 mL) at rt for
0.5ꢀ24 h. b Determined by 1H NMR using an internal standard. c Using 3.0
equiv of TBHP. d Isolated yield. TMEDA = N,N,N0,N0-tetramethylethyle-
nediamine, 2,20-bipy. = 2,20-bipyridine, 1,10-phen. = 1,10-phenanthroline.
In addition, the reaction in the absence of base cocatalyst
was tolerant of substrate 1c containing fairly acidic methylene
protons, giving 3ca. The product 3ca is a potentially versatile
precursor of biologically relevant aspartic acid analogs.
Cyclic ethers, such as tetrahydrofuran (2c), 1,4-dioxane
(2d), oxepane (2e), cyclopentylmethyl ether (2f), and oxetane
(2g) were competent substrates as well. Because direct func-
tionalizations of medium-sized ether rings are rare, the result
giving 3ag would offer novel synthetic route and derivatiza-
tion of more complex (poly)cyclic ethers, which are observed
in many bioactive molecules.9 In the case of 2f, two regioi-
somers, 3af and 3af0, were produced in a moderate ratio with
tertiary ether 3af as the major product. Direct introduction of
a strained oxetane ring (2g) will be useful for medicinal
chemistry applications.10 The expected coupling product
was produced at the initial stage of the reaction between 2g
and 1a. In case of extended reaction time, however, a ring-
opening reaction proceeded to produce alcohol 3ag. In
contrast, the oxetane ring remained intact in the reaction
between 2g and pyruvate-derived nitrone 1b to give 3bg.
In addition to simple cyclic ethers, the reaction was
applicable to protected 1,2-diol 2h and morpholine 2i.
Densely functionalized 3ah and 3ai were produced in a
convergent manner through a simple operation. The unique
regioselectivity of this system is noteworthy. In cases of 2i,
oxidative coupling proceeded at the R-carbon of a nitrogen
atom with complete regioselectivity. Both cyclic amines 2j
€
Bronsted base cocatalysts markedly enhanced the reactiv-
ity (entries 11ꢀ13). Finally, product 3ba was obtained in
75% isolated yield with a shorter reaction time (0.5 h) by
adding 20 mol % of NaHCO3 (entry 13).
Under these optimized conditions, substrate scope was
tested (Figure 1). Compared with previously reported room
temperature CDCs,5aꢀc,i,j,l the substrate scope of the current
reaction is quite broad. The reaction was not very sensitive
to steric factors of the substrates, for both the nitrone (R =
Me, CH2CO2Me) and cyclic acetal (R-Me, 2b). Products
containing tetrasubstituted carbons, including 3bb contain-
ing highly congested contiguous tetrasubstituted carbon
centers, were obtained in moderate to high yields.
(7) Previously reported synthetic utilities of nitrones are categorized
into the following four main transformations. [2 þ 3] Cyclization
reaction: (a) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96,
137. (b) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863. (c)
Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887. Cyclization with
cyclopropane opening reaction: (d) Young, I. S.; Kerr, M. A. Angew.
Chem., Int. Ed. 2003, 42, 3023. (e) Stevens, A. C.; Palmer, C.; Pagenkopf,
B. L. Org. Lett. 2011, 13, 1528. Kinugasa reaction: (f) Kinugasa, M.;
Hashimoto, S. J. Chem. Soc., Chem. Commun. 1972, 466. (g) Miura, M.;
Enna, M.; Okuro, K.; Nomura, M. J. Org. Chem. 1995, 60, 4999. (h) Lo,
M. M.-C.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 4572. (i) Marco-
Contelles, J. Angew. Chem., Int. Ed. 2004, 43, 2198. Used as an
electrophile: (j) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem.
Soc. 1999, 121, 11245. (k) Pinet, S.; Pandya, S. U.; Chavant, P. Y.;
Ayling, A.; Vallee, Y. Org. Lett. 2002, 4, 1463. (l) Garret, M. R.; Tarr,
J. C.; Johnson, J. S. J. Am. Chem. Soc. 2007, 129, 12944. Recently a
CDC reaction using nitrones was reported: (m) Murarka, S.; Studer, A.
Org. Lett. 2011, 13, 2746.
(9) Review of the synthesis of a medium-sized ether ring: (a) Yet, L.
Tetrahedron 1999, 55, 9349. (b) Yet, L. Chem. Rev. 2000, 100, 2963.
(10) Intriguing properties of oxetanes in medicinal chemistry:
€
Burk-hard, J. A.;Wuitschik, G.;Rogers-Evans, M.; Muller, K.;Carreira,
E. M. Angew. Chem., Int. Ed. 2010, 49, 9052.
(8) Iron salts were also studied as catalysts, but the results were less
satisfactory than when using copper catalysts.
Org. Lett., Vol. 13, No. 16, 2011
4289

Scheme 1. Conversions of Coupling Products
The pseudoreplication feature starting from nitrones 1 to
products 3 containing an alternating nitrone functionality is
also unique in this catalysis. Thus, products 3 are syntheti-
cally useful intermediates for further conversions (Scheme 1).
Functional group transformation of the nitrone to an
amine derivative was conducted in two steps; treatment of
3aa with acetyl bromide at ꢀ78 °C followed by hydrolysis
afforded 4, which was converted into non-natural R-amino
acid derivative 5, through hydrogenolysis. Nitrone itself is
also a reactive functional group for further structural
diversification.7 1,3-Dipolar cycloaddition between 3ba
and electron-deficient alkyne produced isoxazoline 6 in
92% yield. Nitrones can be used as an electrophile for the
addition of organometallic reagents. Thus, the addition of a
zinc acetylide species7k to 3ba proceeded in 90% yield.
To get insight into the reaction mechanism, “radical
clock” experiments were conducted (Scheme 2). The cou-
pling reaction with 1a using 2m, possessing a Δ5,6 CdC
double bond, mainly proceeded at the acetal C-1. In this
case, however, the cyclopentanone derivative 3am0 was
concomitantly produced as a minor product through
cyclization between C-1 and C-5, followed by intermole-
cular CꢀC bond-formation at C-6 (eq 1). The coupling
reaction of acetal 2n, containing a neighboring cyclopro-
pane moiety, proceeded without any ring-opening (eq 2).
Figure 1. Catalytic migratory oxidative coupling between nitrones
1 and heterocycles 2aꢀ2k or N,N-dimethylaniline 2l. Isolated
yield is shown for each run unless otherwise noted. Diastereomeric
Scheme 2. Radical Clock Experiments
1
ratio (dr) was determined from H NMR of diastereo-mixture.
b
aReaction was conducted without NaHCO3. Yield was calcu-
1
c
lated from H NMR (see Supporting Information). Using 10
equiv of 2. d Obtained as a mixture of geometrical isomers (6.6:1
ratio). eUsing 3.0 equiv of TBHP. fCombined yield of diastereo-
mixture. PMP = p-methoxyphenyl.
and 2k and acyclic amine 2l were effective substrates in the
coupling with amines, affording 1,2-diamine derivatives. In
general, the diastereoselectivity was not high (1:1 to 2.4:1)
and requires further improvement.
These two results suggested that the present reaction does
not include attack of carbon radical species, which are
catalytically generated from heterocycles in situ, to nitrones
(“radicalic pathway”, Scheme S1, Supporting Informa-
tion).11 If a radical was generated at the acetal methine
carbon, ring-opening of cyclopropane must have been
also observed, because the estimated rate constant for the
(11) Nitrones, oximes, imines, and Michael acceptors are excellent
carbon radical acceptors. For O2/alkylborane-initiated radical reac-
tions: (a) Kabalka, G. W.; Brown, H. C.; Suzuki, A.; Honma, S.; Arase,
A.; Itoh, M. J. Am. Chem. Soc. 1970, 92, 710. (b) Miyabe, H.; Ueda, M.;
Naito, T. J. Org. Chem. 2000, 65, 5043. (c) Liu, J.-Y.; Jang, Y.-J.; Lin,
W.-W.; Liu, J.-T.; Yao, C.-F. J. Org. Chem. 2003, 68, 4030. For
dialkylzinc-initiated radical reactions: (d) Akindele, T.; Yamada, K.-i.;
Tomioka, K. Acc. Chem. Res. 2009, 42, 345. Also see Supporting
Information for our detailed investigations.
4290
Org. Lett., Vol. 13, No. 16, 2011

ring-opening of cyclopropylmethyl radical is much larger
than that of cyclization of 5-hexenyl radical (k = 1.3 ꢁ 108
ꢀ1 sꢀ1 and 1.0 ꢁ 105 Mꢀ1 sꢀ1, respectively, at 25 °C).12
Scheme 3. Possible Catalytic Cycle
M
We propose a possible catalytic cycle of the migratory
oxidative coupling reaction partly based on those results
(Scheme 3). First, a Fenton reaction between Cu(I) and
TBHP produces tert-butyloxy radical (or hydroxy radical)
and Cu(II).13 The base cocatalyst, which exhibited marked
acceleration effects, might contribute to increase the con-
centration of precursor for radical generation (CuOOtBu)
by producing peroxide anion (tBuOOꢀ) that is more
coordinating to Cu(I) than TBHP.14 The thus-generated
radical is reactive enough to subtract a hydrogen atom
from a C(sp3)ꢀH bond R to a heteroatom of coupling
partners 2 to afford carbon radical 8. A “radicalic path-
way” is not probable, based on the radical clock studies
described above. As an alternative pathway, we propose
the “polar pathway” involving oxonium/iminium inter-
mediate 9 generated by fast one-electron oxidation of
8 by Cu(II).15 Subsequent nucleophilic attack of nitrone
1 to 9 affords product 3. This polar mechanism is
consistent with all the experimental results, including
the regioselectivity discussed in scope and limitations
(Figure 1, 3ai).
manner starting from C(sp3)ꢀH bonds without preactiva-
tion; (2) the reaction proceeded under mild conditions to
produce densely functionalized R-amino acid derivatives,
acting as versatile synthetic intermediates for further con-
versions. The experimental results supported that this
reaction proceeds via a “polar mechanism”. Further stu-
dies, especially with regard to the improvement of stereo-
selectivity, are ongoing in our laboratory.
In conclusion, we developed a catalytic migratory oxi-
dative coupling between nitrones and heterocycles or an
alkylamine by identifying a novel reactivity of nitrones.
Due to the following two characteristics, this catalysis will
significantly expand the utility of CDC reactions: (1) the
molecular complexity was rapidly increased in a convergent
Acknowledgment. This work was supported by JSPS
(Grant in-Aid for Young Scientists S) and the Funding
Program for Next Generation World-Leading Research-
ers from JSPS. We also thank Noriaki Takasu in our
laboratory for supplying the substrates.
(12) (a) Lal, D.; Griller, D.; Husband, S.; Ingold, K. U. J. Am. Chem.
Soc. 1974, 96, 6355. (b) Mailard, B.; Forrest, D.; Ingold, K. U. J. Am.
Chem. Soc. 1976, 98, 7024.
(13) Detailed mechanism of Fenton reaction is still under debate. For
recent discussion: Rachmilovic-Calis, S.; Masarwa, A.; Meyerstein, N.;
Meyerstein, D.; van Ekdik, R. Chem.;Eur. J. 2009, 15, 8303 and
references therein.
(14) Results of other mechanistic investigations are consistent with
our proposed mechanism. See Supporting Information for details.
Supporting Information Available. Experimental pro-
cedures, syntheses and characterization of all new pro-
ducts, and supporting data for mechanistic insights. This
material is available free of charge via the Internet at
http://pubs.acs.org.
ꢀ
(15) Boess, E.; Sureshkumar, D.; Sud, A.; Wirtz, C.; Fares, C.;
Klussmann, M. J. Am. Chem. Soc. 2011, 133, 8106.
Org. Lett., Vol. 13, No. 16, 2011
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