New strategy for the synthesis of substituted morpholines

Article abstract of DOI:10.1021/jo9007223

(Chemical Equation Presented) A four-step synthesis of cis-3,5- disubstituted morpholines from enantiomerically pure amino alcohols is described. The key step in the synthesis is a Pd-catalyzed carboamination reaction between a substituted ethanolamine de

Full text of DOI:10.1021/jo9007223

SCHEME 1. Synthetic Strategy
New Strategy for the Synthesis of Substituted
Morpholines
Matthew L. Leathen, Brandon R. Rosen, and John P. Wolfe*
Department of Chemistry, UniVersity of Michigan, 930 North
UniVersity AVenue, Ann Arbor, Michigan, 48109-1055
SCHEME 2. Synthesis of Substrates
jpwolfe@umich.edu
ReceiVed April 6, 2009
a Ligand ) (o-biphenyl)PtBu2. b Ligand ) P(tBu)3 ·HBF4. c Ligand )
(()-BINAP.
We recently reported a concise asymmetric synthesis of cis-
2,6-disubstituted piperazines that involves Pd-catalyzed car-
boamination reactions of N-allyl ethylenediamine derivatives.6,7
We felt that a similar strategy may be applied to the construction
of 3,5-disubstituted morpholines. As shown in Scheme 1,
enantiopure N-Boc amino alcohols (1) could be converted to
O-allyl ethanolamines 2 using standard methods. These com-
pounds would then be transformed to the desired heterocycles
3 through Pd-catalyzed coupling with an aryl or alkenyl halide.8
This strategy should provide access to a broad array of
enantiopure cis-3,5-disubstituted morpholines that are difficult
to generate using existing methods.
The substrates for the Pd-catalyzed carboamination reactions
were synthesized in three steps from commercially available
starting materials 1a-e as shown in Scheme 2. Treatment of
the N-protected amino alcohols with NaH and allyl bromide
afforded allyl ethers 4a-e. Cleavage of the Boc-group followed
by Pd-catalyzed N-arylation of the resulting amine trifluoroac-
etate salts provided 2a-f in moderate to good yield.9
A four-step synthesis of cis-3,5-disubstituted morpholines
from enantiomerically pure amino alcohols is described. The
key step in the synthesis is a Pd-catalyzed carboamination
reaction between a substituted ethanolamine derivative and
an aryl or alkenyl bromide. The morpholine products are
generated as single stereoisomers in moderate to good yield.
This strategy also provides access to fused bicyclic mor-
pholines as well as 2,3- and 2,5-disubstituted products.
In recent years drug discovery efforts have revealed several
interesting biologically active compounds that contain C-
substituted morpholine units.1,2 However, despite the medicinal
importance of these molecules, the development of new ap-
proaches to their synthesis remains relatively unexplored.1,3 For
example, few methods allow the preparation of 3,5-disubstituted
morpholines,4 and only two approaches to the stereoselective
synthesisofcis-3,5-disubstitutedderivativeshavebeendescribed.2a,5
Both of these strategies are limited in scope, as one affords
symmetrically disubstituted (meso) products5 and the other was
used only for the generation of one single compound (cis-3-
carbomethoxy-5-allylmorpholine).2a
At the beginning of our studies we elected to examine the
coupling of 2c with 2-bromotoluene under reaction conditions
(4) For stereoselective syntheses of trans-3,5-disubstituted morpholines, see:
(a) Leijondahl, K.; Boren, L.; Braun, R.; Ba¨ckvall, J.-E. Org. Lett. 2008, 10,
2027. (b) Dave, R.; Sasaki, N. A. Tetrahedron: Asymmetry 2006, 17, 388. (c)
Dave, R.; Sasaki, N. A. Org. Lett. 2004, 6, 15. (d) Takahata, H.; Takahashi, S.;
Kouno, S.-i.; Momose, T. J. Org. Chem. 1998, 63, 2224. For non-stereoselective
syntheses of 3,5-disubstituted morpholines, see: (e) Revesz, L.; Blum, E.; Wicki,
R. Tetrahedron Lett. 2005, 46, 5577. (f) Enders, D.; Meyer, O.; Raabe, G.;
Runsink, J. Synthesis 1994, 66. (g) Barluenga, J.; Najera, C.; Yus, M. Synthesis
1978, 911.
(5) D’hooghe, M. D.; Vanlangendonck, T.; To¨rnroos, K. W.; De Kimpe, N.
J. Org. Chem. 2006, 71, 4678.
(6) (a) Nakhla, J. S.; Wolfe, J. P. Org. Lett. 2007, 9, 3279. (b) Nakhla, J. S.;
Schultz, D. M.; Wolfe, J. P. Tetrahedron 2009, in press, DOI:, 10.1016/
j.tet.2009.04.017.
(7) For related syntheses of pyrrolidines, imidazolidin-2-ones, isoxazolidines,
and pyrazolidines via Pd-catalyzed carboamination reactions, see: (a) Ney, J. E.;
Wolfe, J. P. Angew. Chem., Int. Ed. 2004, 43, 3605. (b) Bertrand, M. B.; Neukom,
J. D.; Wolfe, J. P. J. Org. Chem. 2008, 73, 8851. (c) Fritz, J. A.; Wolfe, J. P.
Tetrahedron 2008, 64, 6838. (d) Lemen, G. S.; Giampietro, N. C.; Hay, M. B.;
Wolfe, J. P. J. Org. Chem. 2009, 74, 2533. (e) Giampietro, N. C.; Wolfe, J. P.
J. Am. Chem. Soc. 2008, 130, 12907.
(1) For a review on the synthesis and biological significance of C-substituted
morpholines, see: Wijtmans, R.; Vink, M. K. S.; Schoemaker, H. E.; van Delft,
F. L.; Blaauw, R. H.; Rutjes, F. P. J. T. Synthesis 2004, 641.
(2) For selected examples of biologically active cis-3,5-disubstituted mor-
pholines, see: (a) O’Neil, S. V.; Wang, Y.; Laufersweiler, M. C.; Oppong, K. A.;
Soper, D. L.; Wos, J. A.; Ellis, C. D.; Baize, M. W.; Bosch, G. K.; Fancher,
A. N.; Lu, W.; Suchanek, M. K.; Wang, R. L.; De, B.; Demuth, T. P., Jr. Bioorg.
Med. Chem. Lett. 2005, 15, 5434. (b) Allison, B. D.; Phuong, V. K.; McAtee,
L. C.; Rosen, M.; Morton, M.; Prendergast, C.; Barrett, T.; Lagaud, G.; Freedman,
J.; Li, L.; Wu, X.; Venkatesan, H.; Pippel, M.; Woods, C.; Rizzolio, M. C.;
Hack, M.; Hoey, K.; Deng, X.; King, C.; Shankley, N. P.; Rabinowitz, M. H.
J. Med. Chem. 2006, 49, 6371. (c) Josien, H. B.; Clader, J. W.; Bara, T. A.; Xu,
R.; Li, H.; Pissarnitski, D.; Zhao, Z. Chem. Abstr. 2006, 144, 129004 PCT Int.
Appl. WO 2006004880 A2, January 12, 2006;
(3) For recent approaches to the synthesis of C-substituted morpholines, see:
(a) Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Org. Lett. 2009, 11, 257. (b)
Penso, M.; Lupi, V.; Albanese, D.; Foschi, F.; Landini, D.; Tagliabue, A. Synlett
2008, 2451. (c) Wilkinson, M. C.; Bell, R.; Landon, R.; Nikiforov, P. O.; Walker,
A. J. Synlett 2006, 2151. (d) Lanman, B. A.; Myers, A. G. Org. Lett. 2004, 6,
1045. (e) Tiecco, M.; Testaferri, L.; Marini, F.; Sternativo, S.; Santi, C.; Bagnoli,
L.; Temperini, A. Tetrahedron: Asymmetry 2003, 14, 2651.
(8) For reviews on Pd-catalyzed carboamination reactions, see: (a) Wolfe,
J. P. Eur. J. Org. Chem. 2007, 571. (b) Wolfe, J. P. Synlett 2008, 2913.
10.1021/jo9007223 CCC: $40.75  2009 American Chemical Society
Published on Web 06/01/2009
J. Org. Chem. 2009, 74, 5107–5110 5107

TABLE 1. Synthesis of cis-3,5-Disubstituted Morpholinesa
that had proven optimal in related piperazine-forming carboami-
nation reactions.6 As shown in eq 1, the use of a catalyst
composed of Pd(OAc)2 and P(2-furyl)3 provided 3a in 66%
yield. The main side product observed in this reaction was 5a,
although small amounts of several other unidentified side
products were also detected. A survey of other ligands (e.g.,
PPh3, Dpe-phos) did not provide improved results, and our initial
choice of solvent (toluene) and base (NaOtBu) also proved
optimal.10
The results of our studies on the scope of 3,5-disubstituted
morpholine-forming carboamination reactions are illustrated in
Table 1. Several different 2-subsituted O-allylethanolamines
were effectively converted to the desired heterocycles, including
heteroatom-containing substrates derived from methionine (entry
7), serine (entry 8), and tryptophan (entry 9). Although the yields
in these reactions were modest (46-66%),11 the diastereose-
lectivities were uniformly high (>20:1 dr). The presence of
electron-neutral or slightly electron-deficient N-aryl groups on
the substrates was tolerated. However, efforts to employ a
morpholine precursor bearing an N-(p-methoxyphenyl) moiety
led to a poor yield of 3d due to competing N-arylation and Heck
arylation of the substrate (entry 3).12 Low yields were also
obtained when starting materials with N-p-cyanophenyl groups
were used, as competing Heck arylation of the substrate alkene
group was again problematic. Similarly, efforts to couple N-Boc-
protected substrate 4a with 1-bromo-4-tert-butylbenzene af-
forded only a Heck arylation product.
To further explore the utility of this method for the synthesis
of other substituted morpholines, reactions of several N-aryl
ethanolamine derivatives with different substitution patterns
were examined. As shown in Table 2, substrates 6a-d, which
were prepared by O-allylation of 2-(N-phenylamino)cyclohex-
anol or -cyclopentanol,13 were coupled with aryl bromides using
our optimized reaction conditions. These transformations af-
forded the desired bicyclic morpholines 7a-e in moderate to
good yields with excellent diastereoselectivities (>20:1 dr). We
also successfully converted 8 and 10 into 2,3-disubstituted
morpholine 9 and 2,5-disubstituted morpholine 11 (eq 2-3).
However, both 9 and 11 were produced with only modest (2:1)
diastereoselectivity.
a Conditions: 1.0 equiv substrate, 2.0 equiv R1Br, 2.0 equiv NaOtBu,
2 mol % Pd(OAc)2, 8 mol % P(2-furyl)3, toluene (0.4 M), 105 °C.
b Isolated yield (average of two experiments). All products were formed
1
with >20:1 dr as judged by H NMR analysis of crude products prior to
purification. c The reaction was conducted using 4.0 equiv of
ꢀ-bromostyrene, 4.0 equiv of NaOtBu, 4 mol % Pd(OAc)2 and 16 mol
% P(2-furyl)3.
(9) For a representative reaction sequence, chiral HPLC analysis indicated
complete retention of enantiomeric purity (99% ee) during the preparation of
substrate 2a from 1a. The Pd-catalyzed carboamination reaction of 2a to 3b
also proceeded with no erosion of ee.
(10) Use of other ligands provided greater amounts of 5a, led to formation
of side products resulting from Heck arylation of the starting material, or both.
See the Supporting Information for a table of results obtained with other
phosphines.
(11) Side products of general structure 5 were also observed in crude reaction
mixtures. NMR analysis indicated these side products were formed as ca. 10-
35% of the mixture. See the Supporting Information for further details.
(12) In some instances side products resulting from sequential N-arylation
and Heck arylation of the substrate were also isolated.
(13) The known trans-2-(N-phenylamino)cycloalkanols were prepared in one
step from aniline and cyclohexene oxide or cyclopentene oxide. See: (a) Wang,
Z.; Cui, Y.-T.; Xu, Z.-B.; Qu, J. J. Org. Chem. 2008, 73, 2270. (b) Arai, K.;
Lucarini, S.; Salter, M.; Ohta, K.; Yamashita, Y.; Kobayashi, S. J. Am. Chem.
Soc. 2007, 129, 8103. The cis-2-(N-phenylamino)cycloalkanols were prepared
in three steps from the epoxides. See the Supporting Information for further
details.
The nature of the aryl halide coupling partner had a significant
effect on the yield of the morpholine-forming reactions. Use of
electron-rich or electron-neutral derivatives provided acceptable
yields of the desired heterocycles. In addition, the coupling of
2a with an alkenyl halide (Table 1, entry 2) was also successful.
However, most attempts to employ electron-poor aryl bromides
led to complex mixtures of products, although the carboami-
nation reactions of 6c-d with 4-bromobenzophenone (Table
2, entries 4-5) and of 8 with 3-bromobenzonitrile (eq 2) gave
useful quantities of desired products. The coupling of 2c with
the sterically hindered 2-bromotoluene provided a 66% yield
of 3a (Table 1, entry 5), but 1-bromo-2-methylnaphthalene failed
to react with 2c under similar conditions.
5108 J. Org. Chem. Vol. 74, No. 14, 2009

TABLE 2. Synthesis of Bicyclic Morpholinesa
The mechanism of the morpholine-forming carboamination
reactions is likely similar to that of related transformations that
generate piperazines, pyrrolidines, and other nitrogen heterocy-
cles.6-8 As shown in Scheme 3, the key intermediate in the
conversion of 2 to 3 is palladium(aryl)(amido) complex 12,
which is produced by oxidative addition of the aryl bromide to
Pd(0) followed by Pd-N bond formation.14 The relative
stereochemistry of the substituted morpholine products is most
consistent with a pathway involving syn-aminopalladation of
12 through a boat-like transition state (13) to afford 14.15
Reductive elimination from 14 would provide the cis-3,5-
disubstituted morpholine products 3. This mechanism also
accounts for the conversion of 8 to cis-2,3-disubstituted mor-
pholine 9, and 10 to trans-2,5-disubstituted morpholine 11.
These products would arise from transition states 15 and 16,
respectively.16
As noted above in eq 1, we observed the formation of 3,4-
dihydro-2H-1,4-oxazine 5a as a side product in the Pd/P(2-
furyl)3 catalyzed coupling of 2c with 2-bromotoluene. This
compound is presumably generated via ꢀ-hydride elimination
from intermediate 14 to provide 17. This complex could then
be transformed into unsaturated heterocycle 5a by alkene
dissociation and subsequent Heck arylation17 of the resulting
product 18 (Scheme 4).
a Conditions: 1.0 equiv substrate, 2.0 equiv R1Br, 2.0-2.7 equiv
NaOtBu, 2 mol % Pd(OAc)2, 8 mol % P(2-furyl)3, toluene (0.3 M), 105
°C. b Isolated yield (average of two or more experiments). All products
were formed with >20:1 dr as judged by 1H NMR analysis of crude
products prior to purification.
SCHEME 3. Mechanism and Stereochemistry
We felt that it may be possible to optimize conditions so that
unsaturated compounds such as 5a would be generated as the
major products in coupling reactions between 2 and aryl
bromides. The mechanism outlined in Scheme 4 suggests that
catalysts or ligands that either slow C-C bond-forming reduc-
tive elimination, facilitate ꢀ-hydride elimination, or both, may
favor the conversion of 14 to 17, which in turn leads to
generation of 5. Thus, we examined the use of catalysts
supported by relatively electron rich monodentate ligands.18
After some experimentation, we discovered that use of (IPr)-
Pd(acac)Cl19 for the coupling of bromobenzene with 2c afforded
5b in 57% yield (eq 4). However, the scope of this reaction is
currently limited. For example, use of 2-bromotoluene as the
electrophile afforded only 21% yield of 5a. Purification of these
products is also difficult due to their hydrolytic lability.
Nonetheless, further optimization of conditions or use of this
transformation in tandem/sequenced reactions may improve
synthetic utility.
(14) (a) Barder, T. E.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 12003.
(b) Yamashita, M.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 5344.
(15) Chair-like transition states for intramolecular syn-aminopalladation
reactions that generate six-membered rings appear to be less favorable than boat-
like transition states due to poor overlap between the alkene π-system and the
Pd-N bond. For additional discussion of boat-like vs. chair-like transition states
in Pd-catalyzed carboamination reactions that afford piperazine products, see
ref 6b.
(16) The modest diastereoselectivities observed in the reactions of 8 and 10
are presumably due to relatively small differences in the energies of transition
states in which the substrate R-group is oriented in a psueduoaxial vs.
pseudoequatorial position. For further discussion, see ref 6b.
SCHEME 4. Formation of 3,4-Dihydro-2H-1,4-oxazine 5a
(17) (a) Heck, R. F. Synlett 2006, 2855. (b) Beller, M.; Zapf, A.; Reirmeier,
T. H. In Transition Metals for Organic Synthesis, 2nd ed.; Beller, M., Bolm, C.,
Eds; Wiley-VCH: Weinheim, Germany, 2004; pp 271-305.
(18) The rate of reductive elimination from Pd(II) decreases as ligand basicity
increases and ligand size decreases. However, steric effects can outweigh
electronic effects, as electron-rich ligands that are sterically bulky are known to
promote reductive elimination. For reviews, see: (a) Christmann, U.; Vilar, R.
Angew. Chem., Int. Ed. 2005, 44, 366. (b) Brown, J. M.; Cooley, N. A. Chem.
ReV. 1988, 88, 1031.
In conclusion, we have developed a concise asymmetric
synthesis of cis-3,5-disubstituted morpholines from readily
available enantiopure amino alcohol precursors. The modular
nature of this approach permits variation of the morpholine
J. Org. Chem. Vol. 74, No. 14, 2009 5109

reaction mixture was cooled to rt, quenched with saturated aqueous
NH4Cl (3 mL), and extracted with EtOAc (3 × 3 mL). The
combined organic layers were concentrated in vacuo and the crude
product was purified by flash chromatography on silica gel.
(-)-(3S,5R)-3-Benzyl-5-(2-methylbenzyl)-4-phenylmorpho-
line (3a). The representative procedure was employed for the
coupling of 2-bromotoluene with 2c. This procedure gave the title
compound (121 mg, 68%) as a yellow oil after purification by
chromatography with 5% EtOAc/hexanes as the eluant. This
substituents and also provides access to fused-ring morpholine
derivatives. In addition, we have demonstrated that modification
of catalyst structure can lead to potentially useful 3,4-dihydro-
2H-1,4-oxazine products. The strategies described above sig-
nificantly expand the range of substituted morpholines that can
be prepared in a concise, stereocontrolled manner.
material was judged to be of >20:1 dr by 1H NMR analysis before
1
and after purification. [R]23 - 3.1 (c ) 1.20, CH2Cl2). H NMR
D
(400 MHz, CDCl3) δ 7.43-7.37 (m, 2 H), 7.31-7.14 (m, 7 H),
7.14-7.07 (m, 4 H), 7.07-7.00 (m, 1 H), 3.71 (dd, J ) 5.4, 11.5
Hz, 1 H), 3.66-3.46 (m, 5 H), 2.81-2.66 (m, 4 H), 2.23 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ 147.5, 138.9, 137.0, 136.5, 130.4,
129.6, 129.5, 129.1, 128.5, 126.3, 126.3, 125.9, 121.7, 119.6, 69.6,
69.6, 57.9, 56.9, 37.0, 33.6, 19.6; IR (film) 1598 cm-1; MS (ESI)
358.2174 (358.2171 calcd for C25H27NO, M + H+).
Experimental Section
Representative Procedure for Synthesis of Morpholines
via Pd-Catalyzed Carboamination. A Schlenk tube was evacuated,
flame-dried, and backfilled with nitrogen. The tube was charged
with Pd(OAc)2 (2.3 mg, 0.01 mmol), P(2-furyl)3 (9.3 mg, 0.04
mmol), and NaOtBu (96.1 mg, 1.0 mmol). The tube was evacuated
and backfilled with nitrogen, then the aryl bromide (1.0 mmol) and
a solution of the amine substrate (0.50 mmol) in toluene (1.25 mL)
were added to the Schlenk tube (aryl bromides that were solids at
room temperature were added as solids following the addition of
NaOtBu). The mixture was heated to 105 °C with stirring until the
substrate was consumed as judged by GC analysis (12-18 h). The
Acknowledgment. The authors thank the NIH-NIGMS
(GM071650) for financial support of this work. M.L.L. was
supported by the Michigan CBI Training Program (NIH
5T32GM008597-12). Additional support was provided by the
Camille and Henry Dreyfus Foundation (Camille Dreyfus
Teacher Scholar Award), GlaxoSmithKline, Eli Lilly, Amgen,
and 3M.
Supporting Information Available: Experimental proce-
dures, spectroscopic data, and copies of 1H and 13C NMR spectra
for all new compounds reported in the text. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) IPr ) 1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene. Although this
electron-rich ligand is also sterically bulky, it appears that ligand electronic
properties play a larger role than steric properties in this particular reaction. For
further discussion on the steric and electronic properties of NHC ligands, see:
Diez-Gonzalez, S.; Nolan, S. P. Coord. Chem. ReV. 2007, 251, 874.
JO9007223
5110 J. Org. Chem. Vol. 74, No. 14, 2009