Facile, efficient, and catalyst-free electrophilic aminoalkoxylation of olefins: Scope and application

Article abstract of DOI:10.1021/ja104168q

A new one-pot electrophilic aminoalkoxylation reaction using olefin, cyclic ether, amine, and N-bromosuccinimide has been developed. The olefinic substrates and the cyclic ether partners can be flexibly varied to produce a range of amino ether derivatives. This novel protocol has been applied in the facile and efficient synthesis of biologically active morpholine compounds.

Full text of DOI:10.1021/ja104168q

Published on Web 07/14/2010
Facile, Efficient, and Catalyst-Free Electrophilic Aminoalkoxylation of Olefins:
Scope and Application
Ling Zhou, Chong Kiat Tan, Jing Zhou, and Ying-Yeung Yeung*
Department of Chemistry, National UniVersity of Singapore, 3 Science DriVe 3, Singapore 117543
Received May 14, 2010; E-mail: chmyyy@nus.edu.sg
Table 1. Electrophilic Aminoalkoxylation of Cyclohexenea
Abstract: A new one-pot electrophilic aminoalkoxylation reaction
using olefin, cyclic ether, amine, and N-bromosuccinimide has
been developed. The olefinic substrates and the cyclic ether
partners can be flexibly varied to produce a range of amino ether
derivatives. This novel protocol has been applied in the facile and
efficient synthesis of biologically active morpholine compounds.
entry
R
X
yield (%)b
entry
R
X
yield (%)b
1
2
3
iPr
Br
Br
Br
Br
Br
Br
trace
trace
78
65
50
8
9
Ms Br
60
94
94
95
41
trace
p-NO2C6H4
C6H5SO2
Ns
Ns
Ns
Ns
Ns
Br
Br
Br
Cl
I
10e
11f
12
13
4
Ts
Ts
Ts
5c
6d
7
The limited supply of natural resources and the impact on
environmental pollution have been problems for the pharmaceutical
industry for decades. To address these problems, many research
endeavors to develop green and sustainable manufacturing processes
have been carried out.1 One of the recent focuses is on multicom-
ponent reactions (MCRs), which allow the quick assembly of several
simple components into complex structures in one pot. MCRs
require very careful design, and the usefulness of the reactions is
demonstrated by their numerous applications.2 Among MCRs,
electrophilic MCRs have been less reported, partly because of the
common incompatibility of electrophiles with the other components.
Herein we describe a facile, efficient, and catalyst-free one-pot
electrophilic aminoalkoxylation of olefins and its application in
morpholine synthesis.
23
60
p-MeOC6H4SO2 Br
a Reactions were carried out with cyclohexene (0.6 mmol), RNH2
(0.5 mmol), and NBS (0.6 mmol) in THF (4.0 mL). b Isolated yield.
c BF3 ·Et2O (0.2 mmol) was added. d Cu(OTf)2 (0.1 mmol) was added.
e THF (5.0 mmol) in CH2Cl2 (2.0 mL) was used instead of pure THF.
f The reaction was conducted on a 1.0 g scale.
efficiency (Table 1, entry 11); and (5) the yield was not affected
when the addition sequence of the components was changed.7
We had suspected that the reaction might proceed through the
addition of a preformed aminoalcohol to the bromonium cation ring
A. In fact, this pathway was ruled out simply by mixing THF,
NsNH2, and NBS at 25 °C, which showed no reaction after 24 h.7
Once the optimum conditions had been identified, various olefins
were subjected to investigation. The scope of the aminoalkoxylation
is indicated by the 13 examples listed in Table 2. All of the reactions
proceeded smoothly with good to excellent yields. In addition,
excellent chemoselectivities were observed, as the reaction occurred
on the electron-rich olefins (Table 2, 4b and 4k). In the cases of
trisubstituted cyclic (Table 2, 4a and 4b), acyclic (Table 2, entries
4d, 4e, and 4k), and benzylic (Table 2, 4f-i) olefins, the desired
positional selectivities (Markovnikov-type) were achieved. Interest-
ingly, 4l and 4m were isolated as the only stereoisomers when the
corresponding allylic substituted olefins were used.7 The X-ray
On the basis of electrophilic cascades,3 we reasoned that a cyclic
ether could act as the nucleophile in the opening of bromonium
cation ring A to yield intermediate B.4 The resulting oxonium cation
B could be captured by an amine and should provide the
corresponding aminoether derivative C. To test this hypothesis, we
examined the reaction cascade using cyclohexene, N-bromosuc-
cinimide (NBS), and primary amines in tetrahydrofuran (THF) at
room temperature. An alkylamine and arylamine were tested first,
and only trace amounts of products were observed (Table 1, entries
1 and 2). To our surprise, a 78% yield of the desired product was
obtained when benzenesulfonamide was used (Table 1, entry 3).
Poorer yields were observed when more electron-rich sulfonamides
were used (Table 1, entries 4, 7, and 8). Finally, the use of electron-
deficient p-nitrobenzenesulfonamide gave an excellent yield (Table
1, entry 9). There are several features in this novel electrophilic
aminoalkoxylation reaction: (1) unlike typical NBS electrophilic
reactions,5 the addition of a Lewis acid in this reaction led to a
decrease in reaction yield (Table 1, entries 5 and 6); (2) NBS was
found to be superior to other halogen sources (Table 1, entries 12
and 13); (3) the reaction proceeded equally smoothly when 10 equiv
of THF in CH2Cl2 was used as the cosolvent (Table 1, entry 10);6
(4) performing the reaction on a 1.0 g scale showed no change in
Table 2. Synthesis of Amino Ethers Using Various Olefinsa
a Reactions were carried out with olefin (0.6 mmol), NsNH2 (0.5
mmol), and NBS (0.6 mmol) in THF (4.0 mL). The product yields are
isolated yields.
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10.1021/ja104168q  2010 American Chemical Society
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C O M M U N I C A T I O N S
Table 4. Electrophilic Alkoxyetherification of Cyclohexenea
crystallographic structure of 4b confirmed the regio- and stereo-
selectivity of the reaction protocol.7
The scope of the aminoalkoxylation disclosed herein appears to
be quite broad in regard to not only the olefinic component but
also the cyclic ether partner.7 We carried out the reaction using
cyclohexene, NsNH2, and NBS in cyclic ethers having different
ring sizes (Table 3). Amino ether 5a was isolated in 79% yield
when ethylene oxide was used. Treatment of the substrates in
oxetane gave the desired product 5b in 82% yield, whereas 5c was
isolated in 97% yield when 3,3-dimethyloxetane was used as the
solvent. In addition to three- and four-membered-ring cyclic ethers,
a six-membered-ring tetrahydropyran was also found to be effective
in the reaction, giving 5d in 86% yield. Interestingly, aza-ether 5e
was isolated (91% yield) when 1,4-dioxane was used in the reaction;
aza-ethers are important building blocks in the synthesis of novel
aza-crown ethers.8
entry
oxygen nucleophile
product (R)
yield (%)
1b none
16a (2,4,6-tribromophenoxy)
16a (2,4,6-tribromophenoxy)
56
42
42
85
45
-
2c phenol
3
2,4,6-tribromophenol 16a (2,4,6-tribromophenoxy)
4d 4-nitrophenol
5d 2-nitrophenol
6d 4-tBu-phenol
16b (2,6,-dibromo-4-nitrophenoxy)
16c (4,6-dibromo-2-nitrophenoxy)
no desired product
7
8
AcOH
BzOH
16d (AcO)
16e (BzO)
48
33
a Reactions were carried out with cyclohexene 1 (0.6 mmol), oxygen
nucleophile (0.5 mmol), and NBS (0.6 mmol) in THF (4.0 mL). The
product yields are isolated yields. b TBCO (0.6 mmol) was used instead
of NBS. c Using 4.5 equiv of NBS. d Using 3.5 equiv of NBS.
Table 3. Synthesis of Amino Ethers Using Various Cyclic Ethers
preliminary results are listed in Table 4. In the case using phenol,
2,4,6-tribromophenol was initially formed and subsequently reacted
with intermediate B to yield 16a.7 In addition to phenols, carboxylic
acids were found to be effective in the reaction (Table 4, entries 7
and 8).13
In summary, we have developed a general, efficient, regio- and
stereoselective, and atom-economical electrophilic aminoalkoxy-
lation using olefin, cyclic ether, amine, and NBS. The reaction is
catalyst-free and readily scalable, and the experimental setup is
extremely convenient. The olefin and cyclic ether partners can be
flexibly varied to produce different kinds of amino ether derivatives.
Also, the introduction of nitrogen functionality without the use of
intrinsically hazardous organic azide would be of great interest to
the manufacturing sector.1 The synthetic utility of this novel MCR
has been illustrated with the efficient synthesis of a substituted
morpholine core 8, (()-phenmetrazine (12), (()-phendimetrazine
(13), and analogue 15. Other oxygen nucleophiles, including phenols
and carboxylic acids, were found to be viable nucleophilic
alternatives in the reaction. Further investigations of other applica-
tions, including the use of other nucleophilic partners, as well as
the study of the asymmetric version14 are underway.
To further demonstrate the usefulness of this protocol, we
attempted to synthesize substituted morpholines9 using the novel
electrophilic MCR strategy. Thus, a mixture of styrene, ethylene
oxide, NsNH2, and NBS in CH2Cl2 was stirred at 25 °C for 8 h,
affording amino ether 6 in 78% yield. Stirring 6 with K2CO3 in
MeCN at 25 °C followed by filtration furnished morpholine
derivative 7 in 96% yield. Subsequent deprotection of 7 gave the
free morpholine 8 quantitatively; 8 is the fundamental unit of many
norepinephrine-dopamine releasing agents.10 In a similar manner,
(()-phenmetrazine (12), which is a potent releaser of [3H]norepi-
nephrine (EC50 ) 50 nM) and [3H]dopamine (EC50 ) 131 nM),11
and the anorexigenic drug (()-phendimetrazine (Bontril) (13)12
were synthesized using ꢀ-methylstyrene (9) as the starting material.
Similarly, the trisubstituted analogue 15 was synthesized using cis-
2,3-epoxybutane (Scheme 1).
Acknowledgment. We gratefully acknowledge the National
University of Singapore (Grant 143-000-428-112) for funding of
this research. We thank Prof. Barry M. Trost (Stanford University)
for his valuable advice on this project.
Scheme 1. Synthesis of Substituted Morpholinesa
Supporting Information Available: Experimental procedures,
spectral data for reaction products, complete ref 9, and crystallographic
data (CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
References
(1) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.; Leazer,
J. L.; Linderman, R. J., Jr.; Lorenz, K.; Manley, J.; Pearlman, B. A.; Wells,
A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411.
(2) (a) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (b) Ganem,
B. Acc. Chem. Res. 2009, 42, 463. (c) Toure´, B. B.; Hall, D. G. Chem.
ReV. 2009, 109, 4439.
a Conditions: (a) NBS, CH2Cl2, 25 °C, 8 h; (b) K2CO3, MeCN, 25 °C,
6 h; (c) LiOH, n-C3H7SH, MeCN, 25 °C, 2 h; (d) HCHO, HCO2H, reflux,
(3) (a) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem.
Soc. 1997, 119, 11224. (b) Xiong, Z.; Corey, E. J. J. Am. Chem. Soc. 2000,
122, 4831. (c) Xiong, Z.; Corey, E. J. J. Am. Chem. Soc. 2000, 122, 9328.
(d) Mi, Y.; Schreiber, J. V.; Corey, E. J. J. Am. Chem. Soc. 2002, 124,
11290. (e) Zakarian, A.; Batch, A.; Holton, R. A. J. Am. Chem. Soc. 2003,
125, 7822. (f) Snyder, S. A.; Treitler, D. S. Angew. Chem., Int. Ed. 2009,
48, 7899.
8 h.
We also examined the use of other brominating sources, including
bromine, PyHBr3, nBu4NBr3, 2,4,4,6-tetrabromo-2,5-cyclohexadi-
enone (TBCO), and Et2SBr ·SbCl5Br,3f none of which were found
to be as effective as NBS.7 Interestingly, a 21% yield of the phenoxy
adduct 16a (Table 4, entry 1) and a 40% yield of the desired product
2 (Table 1, X ) Br, R ) Ns) were obtained when TBCO was
used; this led us to investigate the use of phenol partners, and the
(4) (a) Serguchev, Y. A.; Ponomarenko, M. V.; Lourie, L. F.; Chernega, A. N.
J. Fluorine Chem. 2003, 123, 207. (b) Braddock, D. C.; Millan, D. S.;
Pe´rez-Fuertes, Y.; Pouwer, R. H.; Sheppard, R. N.; Solanki, S.; White,
A. J. P. J. Org. Chem. 2009, 74, 1835.
(5) (a) Schmid, G. H.; Garrat, D. G. In The Chemistry of Double Bonded
Functional Groups; Patai, S., Ed.; Wiley: New York, 1977; Suppl. A, Part
2, p 725. (b) DeLaMare, P. B. D.; Bolton, R. Electrophilic Additions to
9
10246 J. AM. CHEM. SOC. VOL. 132, NO. 30, 2010

C O M M U N I C A T I O N S
Unsaturated Systems, 2nd ed.; Elsevier: New York, 1982; pp 136-197.
(c) Ruasse, M.-F. AdV. Phys. Org. Chem. 1993, 28, 207.
73-100. (c) Hajos, M.; Fleishaker, J. C.; Filipiak-Reisner, J. K.; Brown,
M. T.; Wong, E. H. F. CNS Drug ReV. 2004, 10, 23.
(6) Examples of solvent-intercepted cohalogenations: (a) Winstein, S.; Hend-
erson, R. B. J. Am. Chem. Soc. 1943, 65, 2196. (b) Dalton, D. R.; Dutta,
V. P.; Jones, D. G. J. Am. Chem. Soc. 1968, 90, 5498. (c) Snyder, S. A.;
Corey, E. J. J. Am. Chem. Soc. 2006, 128, 740.
(11) Rothman, R. B.; Katsnelson, M.; Vu, N.; Partilla, J. S.; Dersch, C. M.;
Blough, B. E.; Baumann, M. H. Eur. J. Pharmacol. 2002, 447, 51.
(12) Rothman, R. B.; Baumann, M. H. Curr. Top. Med. Chem. 2006, 6, 1845.
(13) Diphenyl disulfide was obtained when thiophenol was used.
(14) Asymmetric halogenation is still an exceedingly challenging research area.
For related kinetic studies that explain this challenge, see: Neverov, A. A.;
Feng, H. X.; Hamilton, K.; Brown, R. S. J. Org. Chem. 2003, 68, 3802,
and references cited therein.
(7) Full details appear in the Supporting Information.
(8) Ferdani, R.; Barbour, L. J.; Hu, J.; Djedovicˇ, N. K.; Gokel, G. W. J.
Supramol. Chem. 2001, 1, 305.
(9) Brands, K. M. J.; et al. J. Am. Chem. Soc. 2003, 125, 2129.
(10) (a) Rudnick, G.; Clark, J. Biochim. Biophys. Acta 1993, 1144, 249. (b)
Rudnick, G. In Neurotransmitter Transporters: Structure, Function and
Regulation; Reith, M. E. A., Ed.; Humana Press: Totowa, NJ, 1997; pp
JA104168Q
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