Stereoselective synthesis of morpholines via copper-promoted oxyamination of alkenes

Article abstract of DOI:10.1021/ol301984b

A new copper(II) 2-ethylhexanoate-promoted addition of an alcohol and an amine across an alkene (oxyamination) is reported. The alcohol addition is intramolecular, while coupling with the amine occurs intermolecularly. Several 2-aminomethyl morpholines we

Full text of DOI:10.1021/ol301984b

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Stereoselective Synthesis of Morpholines
via Copper-Promoted Oxyamination of
Alkenes
Fatima C. Sequeira and Sherry R. Chemler*
Department of Chemistry, The State University of New York at Buffalo, Buffalo,
New York 14260, United States
schemler@buffalo.edu
Received July 17, 2012
ABSTRACT
A new copper(II) 2-ethylhexanoate-promoted addition of an alcohol and an amine across an alkene (oxyamination) is reported. The alcohol
addition is intramolecular, while coupling with the amine occurs intermolecularly. Several 2-aminomethyl morpholines were synthesized in good
to excellent yields and diastereoselectivities.
The simultaneous addition of oxygen and nitrogen
across an alkene (aminooxygenation, oxyamination) is a
useful way to install the vicinal aminoalcohol moiety.1
Vicinal amino alcohols are useful in a number of applica-
A
number of reactions have been invented to enable this
important transformation,1 including those that con-
struct a heterocycle in the process.3 While the majority of
ring-forming oxyaminations construct nitrogen hetero-
cycles,3a,b,dÀk few reports of oxygen heterocycle synthesis
have appeared3c,l and only one of them is thought to
initiate with addition of oxygen to the alkene.3l An
alkyne oxyamination that likely initiates with intra-
molecular additionof the alcohol tothe alkynehas recently
been reported.4
We report herein a new copper(II) 2-ethylhexanoate-
promoted alkene oxyamination reaction that provides
2-aminomethyl-functionalized morpholines in good to
excellent yields and with generally high levels of diaste-
reoselectivity. This reaction likely proceeds by initial addi-
tion of the alcohol moiety to the alkene (vide infra).
Morpholines5 are frequently found in bioactive com-
pounds, thus new methods for their efficient and stereo-
selective synthesis are desirable. Substituted morpholines,
in particular, are useful scaffolds and property-enhancing
functional groups in drug discovery. In the past 20 years, a
number of concise and inventive methods for the synthesis
of variously substituted morpholines have been reported.6
Despite their demonstrated utility in drug discovery,7
tions including catalysis and medicinal chemistry.2
(1) Reviews: (a) Donohoe, T. J.; Callens, C. K. A.; Flores, A.; Lacy,
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McLeod, M. D. J. Chem. Soc., Perkin Trans. 1 2002, 2733–2746. Recent
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Chem. 2011, 3679–3684. (k) Paderes, M. C.; Belding, L.; Fanovic, B.;
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10.1021/ol301984b
XXXX American Chemical Society

however, no direct methods for the synthesis of amino-
methyl morpholines from alkenols have appeared.6c
We have recently reported that copper(II) carboxylates
promote and catalyze intramolecular alkene aminooxygena-
tion and diamination reactions.8,9 In these reactions, nitro-
gen heterocycles are formed via a mechanism involving cis-
aminocupration across the alkene.3k In these studies, all of
the alkene substrates were tethered to amine nucleophiles.
More recently, we have begun exploring copper-promoted
and -catalyzed intramolecular additions of alcohols to
alkenes.10 Both carboetherification and hydroetherification
reactions have been achieved where the reaction is thought to
initiate with a cis-oxycupration of the alkene.10 This paper
describes an expansion of this method to the alkene oxya-
mination reaction, and both five- and six-membered ring
oxygen-containing heterocycles have resulted (vide infra).
Our interest in the synthesis of morpholines led us to
explore the copper(II) 2-ethylhexanoate-promoted cycliza-
tion/amination reactions of β-hydroxy-N-allylsulfonamide
1a. Substrate 1a was synthesized from L-phenylalanine in
three steps and 78% overall yield as illustrated in eq 1.
In this reaction, we found that the higher boiling xylenes
proved to be a better solvent than PhCF3 at 130 °C, the
temperature these reactions performed best at (Table 1,
entries 1À3). We found the copper(II) loading could be
reduced from 3 to 2 equiv without diminishing the isolated
yield (Table 1, compare entries 3 and 4). Decreasing the
copper(II) loading to 1.5 equiv resulted in diminished
conversion (Table 1, entry 5).
Table 1. Optimization of the Alkene Oxyaminationa
entry
equiv of Cu(eh)2
solvent
yield (%)b
1c
2
3
PhCF3
PhCF3
xylenes
xylenes
xylenes
xylenes
45d
50d
85
3
3
3
4
2
87
5
6c
1.5
2
50d
80d
a Conditions: Substrate 1a (0.116 mmol) in solvent (0.1 M) was treated
with the specified amount of Cu(eh)2, Cs2CO3 (1 equiv), and TsNH2
(1.5 equiv) at 130 °C for 24 h unless otherwise noted. Only one diastereomer
(dr >20:1) was observed by 1H NMR. b Isolated yield unless otherwise
noted. c Reaction run at 120 °C. d Percent conversion based on 1H NMR
analysis of the crude mixture. The remainder of the material balance is
starting substrate. Cu(eh)2 = copper(II) 2-ethylhexanoate.
Upon treatment with copper(II) 2-ethylhexanoate
(3 equiv) in the presence of TsNH2, β-hydroxy-N-allylsul-
fonamide 1a underwent oxyamination to provide morpho-
line 2a as a single diastereomer (>20:1 dr) in 45% yield
(Table 1, entry 1). Bouyed by this promising initial result, we
optimized the product yield and copper(II) loading in this
reaction (Table 1). Copper(II) 2-ethylhexanoate [Cu(eh)2]
was chosen as the copper(II) source as it is very soluble in
nonpolar organic solvents where analogous alkene difunc-
tionalization reactions tend to perform well.3iÀk,10
Lowering the reaction temperature from 130 to 120 °C
resulted in lower conversion, as well (Table 1, compare
entries 4 and 6). No conversion to product was observed
under conditions where a catalytic amount of Cu(2-
ethylhexanoate)2 (20 mol %) and a stoichiometric amount
of MnO2 (3 equiv) was used as oxidant under otherwise
optimal reaction conditions (130 °C in xylenes). We have
previously used MnO2 successfully in analogous reactions
to turnover catalytic amounts of Cu(II).8,9c,10
Using the optimized reaction conditions (Table 1, entry 4),
we examined the copper(II)-promoted oxyamination reac-
tion of a number of β-hydroxy-N-allylsulfonamides (Table 2,
entries 1À8). Alkyl, phenyl, silyloxymethyl, and benzyl-
sulfidomethyl substituents were all tolerated in the reaction,
albeit the sulfide’s conversion was lower (Table 2, entry 5)
and the phenyl-substituted substrate 1i (Table 2, entry 8)
gave a comparably lower diastereoselectivity (dr = 6:1).
N-Nosyl- and N-mesyl-containing substrates 1g and 1h
reacted with similar efficiencies as the N-tosyl substrate 1a
(Table 2, entries 6 and 7).
Various nitrogen nucleophiles were explored as sum-
marized in Table 2, entries 9À15. Sulfonamide nucle-
ophiles including the easily desulfonylated nosyl and
2-trimethylsilylethylsulfonamide generally performed well
(Table 2, entries 9À12), but the reaction with methanesul-
fonamide gave a lower conversion and the copper(II)
loading had to be increased to 4 equiv for a reasonable
isolated yield (Table 2, entry 11). The benzamide nucleo-
phile also underwent the coupling; however, increased
copper(II) loading (3À4 equiv) was critical to obtaining
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(k) Bornholdt, J.; Felding, J.; Kristensen, J. L. J. Org. Chem. 2010, 75, 7454–
7457. (l) Ritzen, B.; Hoekman, S.; Verdasco, D. D.; van Delft, F. L.; Rutjes,
F. P. J. T. J. Org. Chem. 2010, 75, 3461–3464. (m) Bera, S.; Panda, G. ACS
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G. M.; Swanson, S.; Walker, A. J.; Wilkinson, M. U.S. Patent Appl.
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2005, 127, 11250–11251. (b) Zabawa, T. P.; Chemler, S. R. Org. Lett.
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B
Org. Lett., Vol. XX, No. XX, XXXX

a good diastereomeric ratio (Table 2, entries 13 and 15 and
see Supporting Information for diastereoselectivity as a
function of copper loading). Sodium azide could also be
used as nucleophile under the higher copper(II) loading
conditions (Table 2, entry 14). Anilines failed to function
as the amine component in these reactions (no reaction
observed, reactions not shown).
Table 2. Morpholine Synthesis Scopea
While most of the examples provide 2,5-disubstituted
morpholines 2, a brief examination using 2-substituted sub-
strate 3indicated that 2,6-disubstituted morpholines 4can also
be synthesized, albeit the reaction temperature had to be raised
to 150 °C to obtain moderate conversion (Table 2, entry 16).
The 1,1-disubstituted alkene 5 also underwent efficient
conversion, giving the highly substituted morpholine 6 in
91% yield, albeit as a 2:1 diastereomeric mixture (eq 2).
The relative stereochemistry of the major diastereomer of
morpholine 2n was assigned as 2,5-cis by X-ray crystal-
lography (Figure 1). All other 2,5-disubstituted morpholine
(major) products were assigned by analogy. The relative
stereochemistry of the 2,6-trans-disubstituted morpholine 4
was assigned by NOE (see Supporting Information).
Inthe absence ofanamine nucleophile, dioxygenationof
the alkene occurs to give a 1:1 mixture of 2-ethylhexanoic
esters 7 (Scheme 1). Saponification of this ester mixture
provided the 2-hydroxymorpholine 8 as a single diastereo-
mer (dr = >20:1), confirming that the diastereomeric
mixture originated from the ester configuration.
A proposed mechanism that accounts for the observed
diastereoselectivity is illustrated in Scheme 2. Coordina-
tion of alcohol 1a to the copper(II) 2-ethylhexanoate dimer
in the presence of Cs2CO3 likely results in monomer 9. This
first step is an analogy to similar reactions of the copper(II)
carboxylate with alkenylsulfonamides and the copper(II)
ligation is undefined as either one or two carboxylates may
be attached at the copper center.3k Thermally promoted cis-
oxycupration via transition state A then provides the un-
stable organocopper(II) intermediate 10. The diastereoselec-
tivity is rationalized by a chairlike transition state where the
vicinal tosyl and benzyl substituents adopt pseudoaxial
positions,11 much like in the final product 2 (e.g., Figure 1).
Intermediate 10 then undergoes CÀCu(II) homolysis to give
carbon radical 11.3k,10 Recombination of the radical with a
[Cu(II)] in the presence of TsNH2 then gives an organo-
copper(III) intermediate 12 that can undergo reductive
a Same conditions as Table 1, entry 4, unless otherwise noted. b Diaste-
reoselectivity obtained by analysis of the crude 1H NMR spectra. c Isolated
yields. d Reaction was run using 4 equiv of Cu(eh)2. e Reaction was run
using 3 equiv of Cu(eh)2. f Reaction was run at 150 °C.
(11) The SO2R group of sulfonamides in six-membered rings prefers to
be equatorial except when adjacent to a carbon bearing an alkyl substituent,
presumably due to mimimization of A1,3-strain: (a) Modarresi-Alam, A. R.;
Amirazizi, H. A.; Bagheri, H.; Rijanzadeh, H.-R.; Kleinpeter, E. J. Org.
Chem. 2009, 74, 4740–4746. (b) Toumieux, S.; Compain, P.; Martin, O. R.;
Selkti, M. Org. Lett. 2006, 8, 4493–4496. (c) Ragoussi, M.-E.; Walker,
S. M.; Piccanello, A.; Kariuki, B. M.; Horton, P. N.; Spencer, N.; Snaith,
J. S. J. Org. Chem. 2010, 75, 7347–7357.
elimination to form the CÀN bond of 2a.9 In the absence of
amine nucleophile, a carboxylate ligand is transferred, giving
the dioxygenated product 7 (Scheme 1).
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Rationalization of 2,6-trans-Selectivity
efficient than that of 1a, and the temperature of the
reaction had to be raised to 150 °C for increased conver-
sion, indicating steric demands proximal to the oxycupra-
tion bond formation in TS-B or TS-C decrease reactivity.
The synthesis of 2-aminomethyltetrahydrofurans was
briefly examined. 4-Pentenol underwent oxyamination
with TsNH2 and PhC(O)NH2, providing tetrahydrofurans
13a and 13b in 83 and 85% yield, respectively (eq 3).
1-Phenyl-4-pentenol 14 underwent oxyamination with
TsNH2 or PhC(O)NH2 to provide the 2,5-trans-tetra-
hydrofurans 15 with >20:1 diastereoselectivity (eq 4),
presumably via TS-D.
Figure 1. X-ray crystallography structure of 2,5-cis-2n.
Scheme 1. Dioxygenation in the Absence of Amine Nucleophile
Scheme 2. Proposed Oxyamination Reaction Mechanism
In summary, a new method for the stereoselective
synthesis of oxygen-containing heterocycles via alkene
oxyamination has been developed. This method offers
direct entry into aminomethyl-functionalized morpholines
and tetrahydrofurans and is a significant extension of
copper(II)-promoted alkene difunctionalization chemistry
both in the oxyamination transformation and in the ability
to synthesize morpholines. Use of these new synthons in
drug discovery should now be facile.
It is possible that some of the amine nucleophiles
could coordinate to the copper(II) prior to oxy-
cupration, which may explain the dependence of
the reaction diastereoselectivity on the amount of
copper(II) 2-ethylhexanoate promoter in the reac-
tion with benzamide. Such coordination could also
explain why anilines fail to couple with 1a via oxyami-
nation. (Under the reaction conditions, aniline might com-
plex too tightly with Cu(eh)2 and render it unreactive.)
Alternatively, the rate of CÀN bond-forming reductive
elimination (e.g., from 12, Scheme 2) is likely different with
different amine nucleophiles and could effect the observed
reaction diastereoselectivity (by allowing ring opening and
unselective ring closing when slow).10
Acknowledgment. We thank the National Institutes of
Health (GM078383) for support of this research, and
William W. Brennessel and the X-ray Crystallography
Facility at the University of Rochester for obtaining the
crystal structure of 2n.
Note Added after ASAP Publication. Reference 6p was
added and this paper was reposted on August 17, 2012.
Supporting Information Available. Procedures and
characterization data, NMR spectra for all new products,
and cif data for 2n. This material is available free of
charge via the Internet at http://pubs.acs.org.
The 2,6-trans-diastereoselectivity observed in morpholine
4 can be rationalized by either TS-B or TS-C, where either
the methyl or the alkene substituent must adopt a pseudoaxial
position on the chairlike transition state (Scheme 3). The
reaction of the R-methyl-substituted alcohol 3 was less
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX