One-Pot Synthesis of O-Allylhydroxylamines through the Organocatalytic Oxidation of Tertiary Allylic Amines Followed by a [2,3]-Meisenheimer Rearrangement

Article abstract of DOI:10.1002/chem.201406173

A cheap, green, and highly efficient one-pot method for the synthesis of O-protected allylic alcohols is described. By utilizing 2,2,2-trifluoroacetophenone as the organocatalyst and H₂O₂ as the oxidant, a variety of allylic amine N-

Full text of DOI:10.1002/chem.201406173

DOI: 10.1002/chem.201406173
Full Paper
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Organocatalysis
One-Pot Synthesis of O-Allylhydroxylamines through the
Organocatalytic Oxidation of Tertiary Allylic Amines Followed by
a [2,3]-Meisenheimer Rearrangement
Alexis Theodorou, Dimitris Limnios, and Christoforos G. Kokotos*[a]
Abstract: A cheap, green, and highly efficient one-pot
method for the synthesis of O-protected allylic alcohols is
described. By utilizing 2,2,2-trifluoroacetophenone as the or-
ganocatalyst and H2O2 as the oxidant, a variety of allylic
amine N-oxides were synthesized, which upon heating are
converted to the final products through a [2,3]-Meisenheim-
er rearrangement.
Introduction
One of the most important methods for the synthesis of allylic
alcohol products is the [2,3]-Meisenheimer rearrangement, first
reported in 1919.[1] This consists of the rearrangement of an al-
lylic amine N-oxide to the corresponding O-allylhydroxylamine.
Significant efforts have been devoted to the rearrangement
itself,[2] for the synthesis of natural products and potential anti-
viral agents.[3] The vast majority of literature reports involve
the use of stoichiometric amounts of oxidants, mostly meta-
chloroperbenzoic acid (mCBPA), for the first key step, that is,
the oxidation of tertiary amines to the corresponding N-
oxides.[4] Such methods may be inexpensive, but often gener-
ate large amounts of waste, thus making purification a difficult
task. The asymmetric variant of this transformation has also
been reported;[5,6] however, most reports involved the use of
chiral auxiliaries or chiral substrates leading to lower selectivi-
ties.[5] There is a single report for the asymmetric catalytic reac-
tion, in which the chiral induction occurs at the rearrangement
step.[6]
Scheme 1. Approaches for the synthesis of O-allylhydroxylamines.
organocatalytic oxidation of silanes to silanols.[7a] Following our
initial contribution, the same catalyst was found to promote
both the oxidation of azines and tertiary amines to N-oxides[7b]
and olefins to epoxides.[7c] Herein, optimization reactions were
carried out to establish the optimum conditions for the model
Table 1. Optimization of the reaction conditions.
Results and Discussion
The past two years, we have been involved in the develop-
ment of a green, environmentally friendly, organocatalytic oxi-
dation protocol and its application in various transformations.[7]
Herein, we present the first organocatalytic one-pot approach
for the synthesis of O-allylhydroxylamines, by utilizing hydro-
gen peroxide exclusively as the green oxidant (Scheme 1).
Previously, 2,2,2-trifluoacetophenone was proven to be the
optimum catalyst, among a series of activated ketones, for the
Entry
Catalyst
[mol%]
MeCN
[equiv]
H2O2
[equiv]
Solvent
Yield[a]
[%]
1
2
3
4
5
6
7
8
9
10
10
10
10
10
5
10
10
10
10
2
2
2
2
2
2
1.2
2
2
2
2
2
2
2
2
1.1
2
2
CH2Cl2
THF
27
20
21
44
99(92)[b]
85
MeOH
EtOAc
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
84
43[c]
45[d]
7[e]
[a] A. Theodorou, Dr. D. Limnios, Prof. Dr. C. G. Kokotos
Laboratory of Organic of Chemistry, Department of Chemistry
University of Athens
10
2
2
[a] Yield determined by GC–MS. [b] Yield of the product isolated after
column chromatography. [c] A temperature of 1008C was applied. [d] The
reaction time was 15 min for the rearrangement step. [e] An initial tem-
perature of 1208C was applied.
Panepistimiopolis 15771, Athens (Greece)
E-mail: ckokotos@chem.uoa.gr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406173.
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reaction of the synthesis of O-allyl-N,N-dibenzylhydroxylamine
(Table 1).[8] Initially, the reaction conditions for the second step
were kept constant (heating to 1208C for 30 min) and the oxi-
dation step was studied. Utilizing 10 mol% catalyst loading
and 2 equiv of MeCN and H2O2, respectively, several solvents
were tested; dichloromethane, THF, methanol, and ethyl ace-
tate did not prove to be suitable solvents (Table 1, entries 1–4).
tert-Butanol proved the best solvent, providing the desired
product in excellent yield (Table 1, entry 5). Reducing the cata-
lyst loading to 5 mol% led to a reduced yield (Table 1, entry 6).
Similar results were observed when the amounts of
(4c). When the substitution on the double bond is not at the
terminal position, like amine 1i, then prolonged heating (2 h)
is required for the rearrangement to occur, affording product 5
in high yield. Moreover, the long unsaturated chain of geraniol
could be embedded on amine 1j and, when subjected to the
reaction conditions, provided tertiary alcohol 6 in good yield.
Introducing two allylic groups on amine 1k resulted in product
7 being isolated in a mediocre yield. Lastly, when allylic amine
1l, based on (S)-(À)-perillyl alcohol, was utilized, product 8 was
isolated in 83% yield as a mixture of diastereomers (65:35).
MeCN and H2O2 were decreased to 1.2 and
1.1 equivalents, respectively (Table 1, entry 7). Next,
Table 2. Substrate scope of the oxidation.
the rearrangement conditions were investigated.
Reducing the temperature from 120 to 1008C or
the heating time from 30 to 15 min led to signifi-
cantly lower yields (Table 1, entries 8 and 9). Finally,
when the temperature was set to 1208C from the
beginning of the reaction, only traces of the prod-
uct were observed (Table 1, entry 10). It has to be
highlighted that the rearrangement did not occur,
even when the reaction mixture was left stirring at
room temperature for additional reaction time
(20 h).
Substrate
Product
Having in hand the ideal reaction conditions, we
turned our focus to exploring the substrate scope
of this method (Table 2). There is a literature report
in which, depending on the oxidation system and
the substrate utilized, a mixture of oxidation of
amine (N-oxide) and alkene (epoxide) is obtained.[3i]
Although our oxidation protocol can perform both
the oxidation of tertiary amines[7b] and alkenes,[7c]
in all substrates utilized in this study, no epoxide
was detected, thus providing excellent selectivity
for the oxidation of tertiary amines (see also the
Supporting Information). Initially, a number of di-
benzyl allylic amines (1a–d), bearing mono-, di-, or
nonsubstituted short and long aliphatic chains[8]
were tested, providing the corresponding products
in very high yields (2a–d). The amine bearing the
simple allyl moiety provided the product 2a in the
highest yield, whereas monosubstituted amines 1b
and 1d produced—in slightly lower yields—the al-
lylic alcohols 2b and 2d, respectively, which con-
tain a stereogenic center. Furthermore, doubly sub-
stituted alkenes on the w-position led to allylic al-
cohol 2c having a quaternary carbon. Replacing
the benzyl moiety with that of cyclohexyl had no
effect on the reaction outcome, affording product
3 in almost quantitative yield. In addition, utilizing
non-symmetrical amines, like amines having
a phenyl substituent on the nitrogen atom, thus
creating steric bulkiness, provided the correspond-
ing O-allylhydroxylamines (4a–c) in slightly lower
yields. As before, various substitution patterns on
the allylic moiety were well-tolerated, leading to
primary (4a), secondary (4b), and tertiary alcohols
[a] A reaction temperature of 1208C for 2 h was applied.
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In an effort to test more classes of substrates, allylic amine
1m was synthesized (Table 3). To our surprise, an additional re-
arrangement took place. Literature reports indicate such an ad-
ditional rearrangement could occur only at extended heating
and with a change of solvent.[9] However, in our case, this hap-
pened only when an aromatic or a conjugated aromatic
moiety was utilized at the terminal substituent of the allylic
amine (Table 3). Presumably, the reason for this additional
[1,3]-shift lies with the stability of the extended conjugated ar-
omatic system of the final products.
ing groups like 4-OMe led to a decreased yield (9e). Replacing
the n-propyl moiety with benzyl resulted in a similar yield
(product 10). O-Cinnamyl-N,N-dipropylhydroxylamine (1s) pro-
vided the corresponding product 11 in mediocre yield, indicat-
ing that cyclic allylic amines can be employed successfully.
When an extensive aromatic conjugated system (amine 1t)
was utilized, product 12 was obtained in good yield, but as
a mixture of diastereomers. Finally, the presence of a methyl
substituent at the b-position to the nitrogen (amine 1u)
proved problematic, because a mixture of products was ob-
tained, seemingly indicating the steric difficulty of the second
rearrangement to take place. However, this proved that the ini-
tial [2,3]-Meisenheimer is followed by a [1,3]-shift to afford
products 9–14, rather than a direct [1,2]-Meisenheimer rear-
rangement of the generated N-oxide. Further evidence for this
was the fact that when the mixture of 13 and 14 was subject-
ed to the same reaction conditions, product 13 was the only
product observed in the crude reaction mixture (see the Sup-
porting Information). Furthermore, when amine 1o was sub-
jected to the same reaction conditions,
Although Majumdar and Jana reported that all kinds of allyl-
ic amines provide this additional shift at elevated temperatures
for extended reaction times,[9] we only observed this shift on
conjugated allylic systems (Table 3). Initially, various phenyl-
substituted allylic amines (1m–r) were tested, leading to allylic
alcohols 9a–e and 10 in high yields. Electron-withdrawing sub-
stituents, such as 4-Cl or 4-NO2, provided the desired products
in slightly higher yields, with the exception of the sterically
hindered 2-NO2-phenyl moiety (9b–d). In contrast, ring-activat-
but heating occurred at 608C for 30 min,
the [2,3]-rearrangement was the main re-
Table 3. Additional rearrangement products of aryl-substituted aryl amines.
action pathway (see the Supporting In-
formation).
Conclusion
Substrate
Product
We have developed a green and efficient
one-pot protocol for the synthesis of O-
protected allylic alcohols starting from
tertiary allylic amines. All literature re-
ports utilize a stoichiometric oxidation,
isolation of the intermediate N-oxide fol-
lowed by the Meisenheimer rearrange-
ment. In just one case a catalytic second
step is reported. Our method constitutes
the first organocatalytic methodology to
provide access to these compounds, fo-
cusing on the initial oxidation step and
followed by a thermal rearrangement.
An extensive survey of substrate scope
was successfully carried out, tolerating
a variety of substituents on the amine
and the allylic moiety and providing the
products in moderate to high yields. In
the case of stabilized allylic tertiary
amines, an additional shift was observed
leading to the conjugated products. To
the best of our knowledge, this is the
first one-pot method utilizing a cheap
and commercially available metal-free
molecule for such a transformation. Fur-
ther investigation of the applications of
this method is currently under way.
[a] A reaction temperature of 1208C for 18 h was applied.
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Chem. Soc. Perkin Trans. 1 1999, 2327–2334; e) A. Arnone, P. Metrangolo,
B. Novo, G. Resnati, Tetrahedron 1998, 54, 7831–7842.
Experimental Section
[3] a) T. Kurihara, M. Doi, K. Hamaura, H. Ohishi, S. Harusawa, R. Yoneda,
Chem. Pharm. Bull. 1991, 39, 811–813; b) T. Kurihara, Y. Sakamoto, M.
Takai, K. Ohuchi, S. Harusawa, R. Yoneda, Chem. Pharm. Bull. 1993, 41,
1221–1225; c) T. Kurihara, Y. Sakamoto, M. Takai, K. Tsukamoto, T. Sakai,
S. Harusawa, R. Yoneda, Chem. Pharm. Bull. 1994, 42, 31–38; d) T. Kuri-
hara, Y. Sakamoto, H. Matsumoto, N. Kawabata, S. Harusawa, R. Yoneda,
Chem. Pharm. Bull. 1994, 42, 475–480; e) T. Kurihara, Y. Sakamoto, M.
Takai, H. Ohishi, S. Harusawa, R. Yoneda, Chem. Pharm. Bull. 1995, 43,
1089–1095; f) T. Kurihara, Y. Sakamoto, T. Kimura, H. Ohishi, S. Harusawa,
R. Yoneda, T. Suzutani, M. Azuma, Chem. Pharm. Bull. 1996, 44, 900–908;
g) R. Yoneda, Y. Sakamoto, Y. Oketo, S. Harusawa, T. Kurihara, Tetrahedron
1996, 52, 14563–14576; h) H. Yang, M. Sun, S. Zhao, M. Zhu, Y. Xie, C.
Niu, C. Li, J. Org. Chem. 2013, 78, 339–346; i) Y. Xie, M. Sun, H. Zhou, Q.
Cao, K. Gao, C. Niu, H. Yang, J. Org. Chem. 2013, 78, 10251–10263.
[4] a) V. Boekelheide, W. J. Linn, J. Am. Chem. Soc. 1954, 76, 1286–1291;
b) G. B. Payne, P. H. Deming, P. H. Williams, J. Org. Chem. 1961, 26, 659–
663; c) A. R. Gallopo, J. O. Edwards, J. Org. Chem. 1981, 46, 1684–1688;
d) R. W. Murray, R. Jeyaraman, J. Org. Chem. 1985, 50, 2847–2853;
e) W. W. Zajac Jr., T. R. Walters, M. G. Darcy, J. Org. Chem. 1988, 53, 5856–
5860; f) R. W. Murray, M. Singh, R. Jeyaraman, J. Am. Chem. Soc. 1992,
114, 1346–1351; g) L. Kaczmarek, R. Balicki, P. Nantka-Namirski, Chem.
Ber. 1992, 125, 1965–1966.
General procedure
Organocatalytic oxidation of tertiary allyl amines followed by
a Meisenheimer rearrangement: Allyl amine (1.00 mmol) was
placed in a round-bottom flask and dissolved in tert-butanol
(0.5 mL), followed by 2,2,2-trifluoro-1-phenylethanone (17.4 mg,
0.10 mmol). Aqueous buffer solution (0.5 mL, 0.6mK2CO3/4ꢁ10À5
m
ethylenediaminetetraacetic acid (EDTA) tetrasodium salt), acetoni-
trile (0.10 mL, 2.00 mmol), and 30% aqueous H2O2 (0.21 mL,
2.00 mmol) were added consecutively. The reaction mixture was
left stirring for 18 h at room temperature and then a reflux con-
denser was added and the reaction mixture was stirred at 1208C
for 30 min. The crude product was purified using flash column
chromatography (5% EtOAc in pet. ether) to afford the desired
product.
Acknowledgements
The authors gratefully acknowledge the Operational Program
“Education and Lifelong Learning” for financial support
through the NSRF program “ENISCYSH METADIDAK
TORWNEREYNHTWN” (PE 2431) co-financed by ESF and the
Greek State.
[5] a) M. T. Reetz, E. H. Lauterbach, Tetrahedron Lett. 1991, 32, 4481–4482;
b) D. Enders, H. Kempen, Synlett 1994, 969–971; c) J. E. H. Buston, I. Cold-
ham, K. R. Mulholland, Tetrahedron: Asymmetry 1998, 9, 1995–2009; d) A.
Guarna, E. G. Occhiato, M. Pizzetti, D. Scarpi, S. Sisi, M. van Sterkenburg,
Tetrahedron: Asymmetry 2000, 11, 4227–4238; e) J. Blanchet, M. Bonin, L.
Micouin, H.-P. Husson, Tetrahedron Lett. 2000, 41, 8279–8283.
[6] H. Bao, X. Qi, U. K. Tambar, J. Am. Chem. Soc. 2011, 133, 1206–1208.
[7] a) D. Limnios, C. G. Kokotos, ACS Catal. 2013, 3, 2239–2243; b) D. Lim-
nios, C. G. Kokotos, Chem. Eur. J. 2014, 20, 559–563; c) D. Limnios, C. G.
Kokotos, J. Org. Chem. 2014, 79, 4270–4276.
Keywords: alcohols · green chemistry · organocatalysis ·
oxidation · rearrangement
[8] For extensive optimization studies, as well as allylic amine preparation
procedures, see the Supporting Information.
[9] K. C. Majumdar, G. H. Jana, J. Org. Chem. 1997, 62, 1506–1508.
[1] J. Meisenheimer, Ber. Dtsch. Chem. Ges. 1919, 52, 1667–1667.
[2] a) S. G. Davies, G. D. Smyth, J. Chem. Soc. Perkin Trans. 1 1996, 2467–
2477; b) J. E. H. Buston, I. Coldham, K. R. Mulholland, Synlett 1997, 322–
324; c) R. Yoneda, L. Araki, S. Harusawa, T. Kurihara, Chem. Pharm. Bull.
1998, 46, 853–856; d) J. E. H. Buston, I. Coldham, K. R. Mulholland, J.
Received: November 21, 2014
Published online on && &&, 2015
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FULL PAPER
All in one pot: The organocatalytic oxi-
dation of tertiary allylic amines followed
by a Meisenheimer rearrangement leads
to protected hydroxylamines (see
scheme).
&
Organocatalysis
A. Theodorou, D. Limnios, C. G. Kokotos*
&& – &&
One-Pot Synthesis of O-
Allylhydroxylamines through the
Organocatalytic Oxidation of Tertiary
Allylic Amines Followed by a [2,3]-
Meisenheimer Rearrangement
Chem. Eur. J. 2015, 21, 1 – 5
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