Stereoselective synthesis of 2,5-disubstituted morpholines using a palladium-catalyzed hydroamination reaction

Article abstract of DOI:10.1039/c3cc44117b

A palladium-catalyzed hydroamination reaction is the key step in a stereoselective synthesis of 2,5-disubstituted and 2,3,5-trisubsituted morpholines from carbamate-protected aziridines. Aziridines are selectively attacked at the more substituted position by unsaturated alcohol nucleophiles using Lewis acid catalysts. Palladium-catalyzed hydroamination of the resulting aminoalkenes gives morpholines as a single diastereomer in excellent yield.

Full text of DOI:10.1039/c3cc44117b

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Stereoselective synthesis of 2,5-disubstituted
morpholines using a palladium-catalyzed
hydroamination reaction†
Cite this: Chem. Commun., 2013,
49, 6800
Received 31st May 2013,
Accepted 12th June 2013
Alicia McGhee, Brian M. Cochran, Torrey A. Stenmark and Forrest E. Michael*
DOI: 10.1039/c3cc44117b
www.rsc.org/chemcomm
A palladium-catalyzed hydroamination reaction is the key step in a morpholines, but the 2,5-disubstitution pattern gives low diastereo-
stereoselective synthesis of 2,5-disubstituted and 2,3,5-trisubsituted selectivity.13 To our knowledge, only Panda has reported a highly
morpholines from carbamate-protected aziridines. Aziridines are trans-diastereoselective 2,5-disubstituted morpholine synthesis, by
selectively attacked at the more substituted position by unsaturated using an iodoalkoxylation ring closing reaction.14
alcohol nucleophiles using Lewis acid catalysts. Palladium-catalyzed
Recently, we reported a facile synthesis of nitrogen hetero-
hydroamination of the resulting aminoalkenes gives morpholines as cycles that utilizes a mild palladium catalyzed hydroamination
a single diastereomer in excellent yield.
reaction as the key cyclization step.15,16 The success of this
hydroamination depends on the use of a tridentate ligand on
Morpholines are frequent structures in biologically active and pharma- palladium to prevent b-hydride elimination. Herein, we report
ceutically prescribed organic molecules.1–3 For example, reboxetine is a an extension of this method to the synthesis of morpholines in
prescribed antidepressant, fenpropimorph and amorolfine are used as a two-step, one-pot procedure (Scheme 1).
fungicides, and aprepitant is an antiemetic used in chemotherapy. As a
Retrosynthetically, the morpholine ring can be divided into
consequence of their ubiquity in pharmaceutical chemistry, countless two fragments: an aziridine and an allylic alcohol. Coupling of
methods for the syntheses of morpholines have been reported.1,3,4 the two could be accomplished by Lewis acid catalyzed ring
However, many existing routes require multiple steps and are poorly opening of the appropriately protected aziridine with allyl alcohol.
convergent, often relying on condensation of a 1,5-diol.5
Subsequent hydroamination would close the heterocyclic ring
Despite the large number of morpholine syntheses, synthetic and yield the desired morpholine. Two issues need to be resolved
routes to stereopure morpholines bearing a 2,5-disubstitution in carrying out this set of transformations: (1) the aziridine
pattern are particularly uncommon. Two main strategies have opening must proceed regioselectively and (2) the hydroamina-
been employed. In the first, two enantiopure reagents are coupled, tion reaction must be highly diastereoselective.
thereby guaranteeing the desired diastereomer. In this class, Myers
Regioselective ring opening of aziridines under acidic condi-
and Lanman6 and Breuning et al.7 reported the aminolysis of tions continues to be a challenging problem.17 Aziridines with
enantiopure epoxides with enantiopure aminoalcohols to generate aryl, vinyl, or alkynyl substituents at the 2-position are known to
2,5-disubstituted morpholines, and Rutjes et al. performed a reduc- give high selectivity for attack at the substituted position.18,19 On
tive amination on enantiopure cyanohydrins with enantiopure the other hand, alkyl-substituted aziridines usually are attacked at
aminoesters.8 Alternately, the morpholine ring can be closed in a the less hindered unsubstituted position or provide mixtures of
diastereoselective reaction of a single enantiopure starting material. regioisomers, even under Lewis acidic conditions.20 There are
Most of these methods are either cis-selective or poorly diastereo- very few examples of selective attack on monosubstituted alkyl
selective. Bandini et al.9 and Gharpure and Prasad10 have reported aziridines at the more substituted position.21
diastereoselective ring closures to give cis-substituted morpholines.
Portella et al. obtained 2,2,5-trisubstituted morpholines by iodoami-
nation of an aminoalkene, but with poor diastereoselectivity.12 Wolfe
has employed a ring-closing carboamination of alkenes to form
Department of Chemistry, University of Washington, Box 351700, Seattle, WA,
98195-1700, USA. E-mail: michael@chem.washington.edu; Fax: +1 206 616 4209;
Tel: +1 206 543 6519
† Electronic supplementary information (ESI) available: Full characterization
data and stereochemical assignments of the morpholines. See DOI: 10.1039/
c3cc44117b
Scheme 1 Preparation of 2,3,5-trisubstituted morpholines using a (PNP)PdCl2
catalyzed hydroamination reaction.
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Table 1 Opening of aziridines with allyl alcohol
Table 2 Morpholines prepared through hydroamination
Entry
R
Product
Yielda (%)
1
2
3
4
5
6
7
8
H
Me
Et
n-Bu
c-Hex
t-Bu
Bn11
Ph
3a
3b
3c
3d
3e
3f
68
77
81
75
80
62
46
66
3g
3h
a
Isolated yields.
Nevertheless, initial studies of the reaction of Cbz protected
aziridines 2 with allyl alcohol indicated that many Lewis acids were
effective at promoting the ring opening, including BF3ÁOEt2,
Sc(OTf)3, Zn(OTf)2, and Yb(OTf)3. The highest yields were obtained
upon treatment of the aziridine with 2 equivalents of allyl alcohol
in the presence of 10 mol% BF3ÁOEt2 at À78 1C. Under these
conditions, monosubstituted aziridines were opened in good yields
to give a single regioisomer, resulting from attack exclusively at the
more substituted position (Table 1).
a
b
Isolated yields. 0.25 equivalents of TMSOTf added.
substantial carbocationic character at the displacement site in
the SN2 transition state and is quite rare for aziridines, even
with Lewis acid activation.
Treatment of aminoalkene substrates 3 under previously
reported hydroamination conditions (5 mol% 1, 10 mol%
AgBF4, 1 equiv. MgSO4) afforded the corresponding morpho-
lines in excellent yields (Table 2).15 Disubstituted morpholines
bearing linear and branched alkyl groups as well as aryl groups
were formed as a single diastereomer. For some substrates the
addition of TMSOTf as co-catalytic acid was required for
complete conversion.16,22 Trisubstituted morpholines were
also formed as a single diastereomer from the cyclization of
disubstituted aminoalkene substrates (3k–n).23
(1)
(2)
Since the AgBF4 required for activation of the Pd precatalyst
is itself a mild Lewis acid, a one-pot ring-opening–hydroamina-
tion procedure was investigated. AgBF4 proved to be an effective
catalyst for the aziridine opening, thereby eliminating the need
to isolate the aminoalkene intermediate. After further optimization,
treatment of the aziridine with 20 mol% AgBF4 and 4 equivalents of
allyl alcohol at À78 1C to form the aminoalkene intermediate,
followed by addition of 5 mol% of the palladium catalyst and
(3)
(4)
Ring opening of several disubstituted aziridines also gave the
desired aminoalkene products (eqn (1)–(3)). Aziridines 2j and 2l each
gave a single regioisomeric product resulting from attack adjacent to
the phenyl group. In all cases, inversion of stereochemistry at the
substitution site was observed, giving the product as a single
diastereomer. Further confirmation of the stereospecificity of the
ring opening was obtained in the reaction of the enantioenriched
methyl substituted aziridine 2b (eqn (4)). No loss of enantiopurity
was observed in the aminoalkene product 3b by chiral HPLC.
The inversion of stereochemistry at the displacement site is
most consistent with SN2 attack on a Lewis acid coordinated
aziridine. The fact that displacement occurs selectively at the
more substituted position in 2-alkylaziridines is indicative of
Table 3 One-pot synthesis of morpholines
Entry
Substrate
R1
R2
Product
Yielda (%)
1
2
3
4
2c
2d
2e
Et
H
H
H
Me
4c
4d
4e
82
72
48
55
n-Bu
c-Hex
Me
2m
4m
a
Isolated yields.
c
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This stereochemical model also provides an explanation for the
difficulty in cyclizing anti-disubstituted aminoalkenes (3i–k). In
both chair conformations, the palladium–alkyl intermediate
must endure an unfavorable interaction.
In conclusion, we have developed a convergent, high-yield-
ing, and diastereoselective synthesis of 2,5-disubstituted and
2,3,5-trisubstituted morpholines, employing
a palladium-
catalyzed hydroamination as the key ring-forming step. A variety
of alkyl and aryl substituted aziridines can be used as starting
materials in either a two-step sequence, or a one-pot domino
reaction sequence.
We would like to thank the ACS PRF, NSF CAREER Award,
and the University of Washington for financial support.
Fig. 1 Proposed stereochemical rationale depicting the four possible palladium–
alkyl intermediates en route to the morpholine products.
Notes and references
1 equivalent MgSO4 at room temperature gave the desired morpho-
line product (Table 3) in a convenient one-pot procedure.24 The
overall yield from this procedure is comparable to that obtained
from the two-step sequence.
1 Review: R. Wijtmans, M. K. S. Vink, H. E. Schoemaker, F. L. van
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The stereochemistry of the disubstituted morpholine products was
determined to be trans based on H NMR coupling constants and
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1
NOESY data. The morpholine ring adopts a chair conformation, with
the 2- and 5-substituents in a trans-diaxial orientation. This conforma-
tion is preferred as it avoids A1,3 strain between the carbamate
protecting group on the nitrogen and the 5-methyl substituent
(B3.4–4.7 kcal molÀ1).25 The combined A values of the 2- and 5-alkyl
substituents (1.8–3 kcal molÀ1) are also further diminished by the
absence of one axial proton on each side due to the heteroatoms.
Notably, the observed trans stereoisomer is not the thermodynami-
cally preferred isomer in these carbamate-protected morpholines;
rather the cis isomer is more stable.
´
¨
5 K. Leijondahl, L. Boren, R. Braun and J. E. Backvall, Org. Lett., 2008,
10, 2027.
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8 B. Ritzen, S. Hoekman, E. D. Verdasco, F. L. van Delft and F. P. J. T.
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11 The benzyl-substituted aziridine rearranges through a phenonium
ion to give a regioisomeric byproduct in 32% yield. Alternate Lewis
acid catalysts and conditions did not prevent this side reaction.
12 J. Nonnenmacher, F. Grellepois and C. Portella, Eur. J. Org. Chem.,
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In the trisubstituted morpholine series, the syn-disubstituted
aminoalkenes (3l–n) cyclize quickly to place the new methyl stereo-
center trans to both existing stereocenters. NOESY data were
consistent with the morpholines (4l–n) adopting a mixture of a 13 M. L. Leathen, B. R. Rosen and J. P. Wolfe, J. Org. Chem., 2009,
twist-boat and a chair conformation.24 The twist-boat conformation
has been previously observed for trans 2,6- disubstituted piperazines,
74, 5107. Though the diastereoselectivity in formation of the
2,5-disubstituted morpholine was low, excellent diastereoselectivities
were observed for both the 2,3,5- and 3,5-substitution patterns.
and is the only way to avoid A1,3 strain between the carbamate 14 S. Bera and G. Panda, ACS Comb. Sci., 2012, 14, 1.
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substrates and 3i and 3j completely failed to cyclize.
Our proposed model to explain the stereoselectivity is depicted in
Fig. 1. Any such model must account for the preferred formation of
17 Review: X. E. Hu, Tetrahedron, 2004, 60, 2701.
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´
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formation of trisubstituted morpholines. Reversible cyclization of
the aminoalkene gives the key palladium–alkyl intermediate as one
of four possible conformations A–D.16 As previously noted, A1,3
strain predicts that axial–equatorial conformer D should be the
most stable, but it does not lead to the observed trans product.
Therefore, we propose that the protonolysis of the palladium–alkyl
complex must occur intramolecularly via transfer from the carba-
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23 See ESI† for synthesis of aminoalkene 3n.
24 See ESI† for details.
25 (a) R. W. Hoffmann, Chem. Rev., 1989, 89, 1841; (b) F. Johnson,
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R group, is the more stable and leads to the observed trans product.
6802 Chem. Commun., 2013, 49, 6800--6802
Chem. Rev., 1968, 68, 375.
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This journal is The Royal Society of Chemistry 2013