Palladium-catalyzed vicinal amino alcohols synthesis from allyl amines by in situ tether formation and carboetherification

Article abstract of DOI:10.1002/anie.201500636

Vicinal amino alcohols are important structural motifs of bioactive compounds. Reported herein is an efficient method for their synthesis based on the palladium-catalyzed oxy-alkynylation, oxy-arylation, or oxy-vinylation of allylic amines. High regio- and stereoselectivity were ensured through the in situ formation of a hemiaminal tether using the cheap commercially available trifluoroacetaldehyde in its hemiacetal form. The obtained compounds are important building blocks, which can be orthogonally deprotected to give either free alcohols, amines, or terminal alkynes.

Full text of DOI:10.1002/anie.201500636

Angewandte
Chemie
DOI: 10.1002/anie.201500636
Synthetic Methods
Palladium-Catalyzed Vicinal Amino Alcohols Synthesis from Allyl
Amines by in Situ Tether Formation and Carboetherification**
Ugo Orcel and Jerome Waser*
Abstract: Vicinal amino alcohols are important structural
motifs of bioactive compounds. Reported herein is an efficient
method for their synthesis based on the palladium-catalyzed
oxy-alkynylation, oxy-arylation, or oxy-vinylation of allylic
amines. High regio- and stereoselectivity were ensured through
the in situ formation of a hemiaminal tether using the cheap
commercially available trifluoroacetaldehyde in its hemiacetal
form. The obtained compounds are important building blocks,
which can be orthogonally deprotected to give either free
alcohols, amines, or terminal alkynes.
me 1b).[2] Although straightforward, these methods are often
plagued by regioselectivity issues.[2b] The use of tethers has
emerged as a viable strategy to achieve better selectivity and
reactivity in organic synthesis.[3] However, this method often
lacks efficiency as extra steps are required for tether
introduction and removal. Regarding the synthesis of vicinal
amino alcohols, allyl amines are particularly attractive start-
ing materials: numerous methods are available for their
synthesis and the high nucleophilicity of nitrogen atom should
allow the in situ formation of a hemiaminal tether by reaction
with an aldehyde. Amino alcohol synthesis could be accom-
panied by the introduction of a second functional group onto
the alkene, thus allowing a maximal increase in molecular
V
icinal amino alcohols are highly important structural motifs
found in bioactive compounds such as the drug Tamiflu (1) or
the natural product AI-77-B (2;[1] Scheme 1a). They have also
been broadly applied as chiral ligands and auxiliaries. There-
fore, there is a strong interest in the development of new
methods to access them. Two of the most common synthetic
approaches are the ring-opening of epoxides or aziridines and
the metal-catalyzed aminohydroxylation of alkenes (Sche-
À
complexity (Scheme 1b). The formation of a valuable C C
bond would be especially interesting, yet more challenging
than the introduction of a second heteroatom.[4] Concerning
the multifunctionalization of unactivated olefins, palladium
catalysis has been highly successful in the last decades,[5] but
has not yet been applied to the outlined strategy.[6]
Precedence for the projected in situ formation of a hemi-
aminal tether using allyl amines and aldehydes can be found
in the elegant metal-free approach developed by Beauchemin
and co-workers for the Cope-type hydroamination of allylic
amines (Scheme 2a).[7] However, the use of an aldehyde as
Scheme 1. Importance and synthesis of vicinal amino alcohols.
Scheme 2. The tether strategy for allyl amine functionalization.
[*] U. Orcel, Prof. Dr. J. Waser
Laboratory of Catalysis and Organic Synthesis
Ecole Polytechnique Fꢀdꢀrale de Lausanne, EPFL SB ISIC LCSO
BCH 4306, 1015 Lausanne (Switzerland)
E-mail: jerome.waser@epfl.ch
a tether has never been reported for the palladium-catalyzed
multifunctionalization of olefins. Even in the broader field of
palladium catalysis, the potential of this approach has only
been scarcely explored. Menche and co-workers developed
an elegant synthesis of 1,3-diols through a domino acetal-
formation/Tsuji–Trost reaction starting from homoallylic
alcohols.[8] Hiemstra and co-workers, and more recently
Stahl and co-workers, reported the use of hemiaminals for
the Wacker cyclization reaction starting from allyl amines and
Homepage: http://lcso.epfl.ch/
[**] EPFL and F. Hoffmann-La Roche Ltd are acknowledged for financial
support. We thank Dr. Tanguy Saget from the Laboratory of
Asymmetric Catalysis and Synthesis at EPFL for helpful discussions
and Alfa Aesar and Johnson Matthey for a gift of PdCl2.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201500636.
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Table 1: Optimization of the tethered oxyalkynylation.[a]
alcohols, but the diastereoselectivity was low for the former
and an additional step was needed to install the tether for
both methods.[9]
Based on this precedence and our interest in olefin oxy-
and aminoalkynylation,[10] we demonstrate herein that tri-
fluoroacetaldehyde, used as its cheap hemiacetal form 3,
enables the palladium-catalyzed carbo-oxygenation of allyl
amines through a one-pot tethered process (Scheme 2b). In
this transformation, amino alcohols are successfully formed
with the concomitant introduction of alkynyl, aryl, and vinyl
groups. This versatile strategy combines key advantages of
both intramolecular and intermolecular reactions: high
reactivity, stereo-, regio-, and diastereoselectivity, as well as
the use of simple starting materials.
Entry
Tether (equiv)
Ligand
Base
Yield [%][b]
1
2
3
4
5
6
7
8
8a (5.0)
8b (5.0)
8c (5.0)
8d (5.0)
8e (5.0)
3 (5.0)
3 (1.0)
3 (5.0)
3 (5.0)
3 (5.0)
3 (1.5)
3 (5.0)
3 (5.0)
3 (1.5)
3 (1.5)
3 (1.5)
DPEPhos (7a)
DPEPhos (7a)
DPEPhos (7a)
DPEPhos (7a)
DPEPhos (7a)
DPEPhos (7a)
DPEPhos (7a)
DPEPhos (7a)
DPEPhos (7a)
XantPhos (7b)
XantPhos (7b)
binap (7c)
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
NaOtBu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
<1
<1
5
5
25
92[c]
71
76
8
8
59
6
<5
93
82
40
To develop a one-pot tethered synthesis of amino alcohols
starting from allyl amines, it is first important to analyze the
key parameters for success of this challenging process
(Scheme 3). First, the allyl amine starting materials could
9
10
11
12
13[d]
14[d]
15[d]
16[e]
PPh3 (7d)
(2-Furyl)3P (7e)
(4-CF3C6H4)3P (7 f)
SPhos (7g)
[a] Reactions were carried out on a 0.10 mmol scale. [b] Yields were
calculated from 1H NMR spectra by using trimethoxybenzene as internal
standard. [c] Yield of isolated product on 0.30 mmol scale. [d] 12 mol%
of ligand was used. [e] 8 mol% of ligand was used. Cp=cyclopenta-
dienyl.
Scheme 3. Speculative analysis for the tether-formation step.
react directly with palladium, thus leading to catalyst
deactivation or side reactions such as Heck coupling and
À
Buchwald–Hartwig type C N bond formation. To avoid these
pitfalls, formation of the hemiaminal intermediate A should
be both fast and thermodynamically favored. Second, for-
mation of a reactive iminium intermediate B should be
avoided, as it can lead to unproductive aminal formation with
the allyl amine. Basic conditions should be better suited in this
respect, as formation of the iminium is usually acid catalyzed.
This would furthermore facilitate olefin functionalization by
a faster syn oxypalladation on intermediate C. Indeed, we had
shown in our previous work that basic conditions were
necessary for the oxyalkynylation of olefins using a palla-
dium(0) catalyst.[10c,d] However, hemiaminal formation is
usually performed under slightly acidic conditions.
With these challenges in mind, we started our studies by
examining the reaction of benzyl allyl amine (4a) with
triisopropylsilylethynyl bromide (5a) in the presence of
different bases and aldehydes (8) under the reaction con-
ditions optimized for the intramolecular oxyalkynylation
reaction [Pd0 catalyst,[11] DPE-Phos (7a) as ligand, toluene,
608C; Table 1].[10c] No product could be observed when using
reported tether precursors such as acetaldehyde (8a) or
formaldehyde (8b; entries 1 and 2).[8,9] A small amount
(about 5% yield) of the desired product 9 could be obtained
only with benzaldehyde (8c; entry 3). We speculated that this
failure was due to the inefficient formation of the hemiaminal
under the basic reaction conditions. To accelerate the
formation of this key intermediate, more-electron-deficient
aldehydes were then examined (entries 4–6). With chloral
(8d) and para-trifluoromethylbenzaldehyde (8e), 9 could
indeed be obtained in 5 and 25% yield, respectively (entries 4
and 5). Finally, the best result was obtained with the
commercial hemiacetal form 3 of trifluoroacetaldehyde,[12]
and the oxyalkynylation product 9aa could be isolated in
92% yield after optimization of the reaction conditions
(entry 6).[13] The best results were obtained using five
equivalents of 3. Nevertheless, 9aa could still be isolated in
71% yield when only 1.1 equivalents of 3 were used (entry 7).
The base played also a critical role in the success of the
reaction, as both potassium carbonate (entry 8) and sodium
tert-butoxide (entry 9) gave inferior results. The product 9aa
was obtained with low diastereoselectivity (< 2:1 d.r.) under
all the reaction conditions tested, but this is inconsequential
when considering that the trifluoromethyl stereocenter is not
present in the final amino alcohol product.[14]
The phosphine ligand had also a strong effect on the
outcome of the reaction. Other biphosphine ligands gave 9aa
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in lower yields (Table 1, entries 10–12). Interestingly, with
XantPhos (7b) a better yield was obtained when only
1.5 equivalents of 3 were used (entry 11). Finally, the results
obtained with monophosphine ligands were highly dependent
of their structure. Whereas nearly no product formation was
observed with triphenylphosphine (7d; entry 13), good results
were obtained with less electron-rich aryl phosphines
(entries 14 and 15). In particular tris(2-furyl)phosphine (7e)
gave 9aa in 93% yield (entry 14). The more sterically
hindered electron-rich SPhos ligand (7g) led to the formation
of 9aa in only 40% yield (entry 16). From the screening of
ligands, two optimum conditions emerged with either DPE-
Phos (7a) or tris(2-furyl)phosphine (7e) as ligands (entries 6
and 14). As more reproducible results were obtained on
preparative scale using 7a as the ligand, it was used to
examine the scope of the reaction (Scheme 4).[15]
We started by investigating the functional-group tolerance
of the oxyalkynylation by modifying the benzyl group on the
allyl amine (Scheme 4a). The reaction was successful in the
presence of an ether, trifluoromethyl, bromo, and nitro group,
as well as an aldehyde (9ba–fa). It is particularly interesting to
see that an aryl bromide group can be tolerated. This
tolerance clearly indicated a higher reactivity of the alkynyl
bromide towards oxidative addition. Oxazolines bearing an
ortho-chlorobenzyl group or
a furan heterocycle were
obtained in 87 and 92% yield, respectively (9ga and 9ha).
Finally, the reaction was also successful for a simple methyl
(9ia) or allyl (9ja) substituent. In contrast, only traces of
product were observed when anilines or amides/carbamates
were used as starting materials.[13]
We then turned to the use of amines bearing a substituent
at the allylic position (Scheme 4b). This class of starting
materials is especially interesting, as the existing stereocenter
À
could be expected to control the formation of the C O bond
and more functionalized products are obtained. Unfortu-
nately, only very low yields were observed when using
diphosphines as ligands. In this case, 7e was the ligand of
choice, and the oxazoline 9ka, derived from the methyl-
substituted allyl amine 9k, was obtained in 81% yield as
a major diastereoisomer. With larger alkyl substituents,
a nearly perfect diastereoselectivity was observed (9la and
9ma). Aryl substituents could also be used: the phenyl-
substituted oxazoline 9na was obtained in 90% and more
than 12:1 d.r., whereas the heterocycle-substituted products
9oa and 9pa were formed in good yields but lower
diastereoselectivity.
Substitution of the olefin of the allyl amine was examined
next (Scheme 4c). 1,2-disubstituted olefins could not be used
in the reaction. In contrast, the formation of tertiary ethers
was possible when using 7b as the ligand. The reaction was
successful in the case of a simple methyl group (9qa) and also
for more functionalized alkyl chains (9ra and 9sa).
Up to now, only triisopropylsilylethynylbromide (5a) had
been used as a partner for the multifunctionalization reaction.
This choice was based on the excellent properties of this
substrate in oxyalkynylation reactions[10c] and also its syn-
thetic versatility as a precursor of terminal alkynes. Never-
theless, the use of functionalized alkynes would give a more
convergent access into molecular complexity. Good yields
could also be obtained with alkynes derived from tertiary or
secondary propargylic alcohols (9ab and 9qc) and diynes
(9qd) (Scheme 5a).
We finally extended the developed strategy to oxyaryla-
tion (Scheme 5b).[16] The reaction was successful provided
that aryl bromides slightly activated by an electron-with-
drawing group were used. Benzene bromides bearing either
a trifluoromethyl, fluoro, trifluoromethoxy, or chlorine group
gave the oxyarylation products 9ae–h in 55–69% yield. The
oxazoline 9ai bearing a pyridine heterocycle could be
obtained in 93% yield. Finally, oxyalkenylation was also
successful and gave the trifluormethyl-substituted alkene 9aj
in 69% yield.
Scheme 4. Scope of allylamines in the tethered-oxyalkynylation reac-
tion. [a] Reactions were carried out on a 0.30 mmol scale. Yield of
isolated products. [b] The d.r. value was lower than 2:1. [c] With 8
mol% 6 and 24 mol% P(2-furyl)3 (7e). [d] The d.r. value was enriched
from 4:1 to 12:1 during column chromatography.
The obtained building blocks are highly useful, as they
contain three orthogonally protected functional groups (an
alcohol, an amine, and an alkyne). To demonstrate this
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In conclusion, we have developed the first palladium-
catalyzed, tethered carbo-etherification of allylamines for the
synthesis of vicinal amino alcohols. The use of the hemiacetal
of trifluoroacetaldehyde for in situ tether formation was key
to enable high yield, and regio- and diastereoselectivity under
mild reaction conditions. The reaction proceeded with broad
scope and high functional-group tolerance. The versatility of
our method was highlighted by the possibility to introduce
alkynyl, aryl, and vinyl groups onto the alkene. Free alcohols,
amines, or terminal alkynes could be obtained orthogonally in
one step from the synthesized products. Future work will
focus on the development of an asymmetric version of the
transformation and the extension to other classes of tethers.
Received: January 22, 2015
Published online: && &&, &&&&
Keywords: alcohols · alkenes · heterocycles · palladium ·
.
synthetic methods
[1] Y. Shimojima, H. Hayashi, J. Med. Chem. 1983, 26, 1370.
[2] a) S. C. Bergmeier, Tetrahedron 2000, 56, 2561; b) T. J. Donohoe,
C. K. A. Callens, A. Flores, A. R. Lacy, A. H. Rathi, Chem. Eur.
J. 2011, 17, 58.
[3] F. Diederich, P. J. Stang, Templated Organic Synthesis, Wiley-
VCH, Chichester, UK, 2000.
Scheme 5. Scope of electrophiles in the tethered-oxyfunctionalization
reaction. [a] Reactions were carried out on a 0.30 mmol scale. Yield of
isolated products. The d.r. value was lower than 3:1, unless otherwise
noted.
[4] Selected examples for metal-catalyzed methods using removable
tethers with further introduction of a heteroatom: a) T. J.
Donohoe, P. D. Johnson, A. Cowley, M. Keenan, J. Am. Chem.
Soc. 2002, 124, 12934; b) T. J. Donohoe, M. J. Chughtai, D. J.
Klauber, D. Griffin, A. D. Campbell, J. Am. Chem. Soc. 2006,
128, 2514; c) E. J. Alexanian, C. Lee, E. J. Sorensen, J. Am.
Chem. Soc. 2005, 127, 7690; d) G.-S. Liu, Y.-Q. Zhang, Y.-A.
Yuan, H. Xu, J. Am. Chem. Soc. 2013, 135, 3343, and references
therein.
[5] Selected reviews: a) M. Beller, J. Seayad, A. Tillack, H. Jiao,
Angew. Chem. Int. Ed. 2004, 43, 3368; Angew. Chem. 2004, 116,
3448; b) K. H. Jensen, M. S. Sigman, Org. Biomol. Chem. 2008,
6, 4083; c) K. MuÇiz, Angew. Chem. Int. Ed. 2009, 48, 9412;
Angew. Chem. 2009, 121, 9576; d) R. I. McDonald, G. S. Liu, S. S.
Stahl, Chem. Rev. 2011, 111, 2981.
[6] For rare examples of tethered aminocarbonylation, see: a) Y.
Tamaru, H. Tanigawa, S. Itoh, M. Kimura, S. Tanaka, K. Fugami,
T. Sekiyama, Z. I. Yoshida, Tetrahedron Lett. 1992, 33, 631; b) H.
Harayama, A. Abe, T. Sakado, M. Kimura, K. Fugami, S.
Tanaka, Y. Tamaru, J. Org. Chem. 1997, 62, 2113; for an example
of oxyarylation of allenes using carbon dioxide for tether
formation, see: c) S. Li, J. Ye, W. Yuan, S. Ma, Tetrahedron
2013, 69, 10450.
synthetic potential, 9ba was synthesized on gram scale
(2.51 mmol, 1.15 g, 84%) and subjected to selective depro-
tection (Scheme 6). The hemiaminal tether could be readily
removed, thus affording the aminoalcohol 10 in 87% yield.
Access to the amine 11 was possible by DDQ-promoted PMB
cleavage. Reductive opening of the hemiaminal yielded the
trifluoroethylamine 12 in excellent yield, while TIPS removal
afforded the terminal alkyne 13, which could be additionally
functionalized.
[7] a) M. J. MacDonald, D. J. Schipper, P. J. Ng, J. Moran, A. M.
Beauchemin, J. Am. Chem. Soc. 2011, 133, 20100; b) N.
Guimond, M. J. MacDonald, V. Lemieux, A. M. Beauchemin,
J. Am. Chem. Soc. 2012, 134, 16571; c) M. J. MacDonald, C. R.
Hesp, D. J. Schipper, M. Pesant, A. M. Beauchemin, Chem. Eur.
J. 2013, 19, 2597.
[8] a) L. Wang, D. Menche, Angew. Chem. Int. Ed. 2012, 51, 9425;
Angew. Chem. 2012, 124, 9559; b) B. Tang, L. Wang, D. Menche,
Synlett 2013, 625.
[9] a) R. A. T. M. Van Benthem, H. Hiemstra, W. N. Speckamp, J.
Org. Chem. 1992, 57, 6082; b) R. A. T. M. van Benthem, H.
Hiemstra, G. R. Longarela, W. N. Speckamp, Tetrahedron Lett.
1994, 35, 9281; c) A. B. Weinstein, D. P. Schuman, Z. X. Tan, S. S.
Stahl, Angew. Chem. Int. Ed. 2013, 52, 11867; Angew. Chem.
2013, 125, 12083.
Scheme 6. Scale-up and orthogonal deprotections. Reaction condi-
tions: a) 4.5 equiv 3, 1.3 equiv 5a, 4 mol% 6, 6 mol% 7a, 1.3 equiv
Cs2CO3 in toluene at 608C; b) p-toluenesulfonic acid, THF/MeOH
(9:1), 608C; c) DDQ, CH2Cl2/H2O (24:1); d) DIBAL-H, toluene, À78 to
À258C; e) TBAF, THF. DIBAL-H=diisobutylaluminum hyride,
DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, PMB=para-meth-
oxybenzyl, TBAF=tetra-n-butylammonium fluoride, THF=tetrahydro-
furan.
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[10] a) S. Nicolai, S. Erard, D. Fernandez Gonzalez, J. Waser, Org.
Lett. 2010, 12, 384; b) S. Nicolai, C. Piemontesi, J. Waser, Angew.
Chem. Int. Ed. 2011, 50, 4680; Angew. Chem. 2011, 123, 4776;
c) S. Nicolai, J. Waser, Org. Lett. 2011, 13, 6324; d) S. Nicolai, R.
Sedigh-Zadeh, J. Waser, J. Org. Chem. 2013, 78, 3783.
[11] [Pd(Cinnamyl)Cp] was used instead of [Pd2dba3] in our previous
work, as it is a cleaner source of Pd0. See: a) A. W. Fraser, J. E.
Besaw, L. E. Hull, M. C. Baird, Organometallics 2012, 31, 2470;
b) M. V. Vita, J. Waser, Org. Lett. 2014, 16, 5768.
Org. Lett. 2001, 3, 3707; b) F. Ghelfi, A. F. Parsons, D.
Tommasini, A. Mucci, Eur. J. Org. Chem. 2001, 1845; c) G. D.
Joly, E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126, 4102; d) A.
Leitner, C. Shu„ J. F. Hartwig, Org. Lett. 2005, 7, 1093; e) A.
Aponick, A. L. Dietz, W. H. Pearson, Eur. J. Org. Chem. 2008,
4264; f) F. Russo, F. Wangsell, J. Saevmarker, M. Jacobsson, M.
Larhed, Tetrahedron 2009, 65, 10047; g) D. Solꢂ, O. Serrano, J.
Org. Chem. 2010, 75, 6267; h) A. M. C. H. Van den Nieuwendijk,
M. Ruben, S. E. Engelsma, M. D. P. Risseeuw, R. J. B. H. N.
van den Berg, R. G. Boot, J. M. Aerts, J. Brussee, G. A. van der
Marel, H. S. Overkleeft, Org. Lett. 2010, 12, 3957; i) E. Bene-
detti, M. Lomazzi, F. Tibiletti, J.-P. Goddard, L. Fensterbank, M.
Malacria, G. Palmisano, A. Penoni, Synthesis 2012, 3523; j) S.-B.
Zhao, E. Bilodeau, V. Lemieux, A. M. Beauchemin, Org. Lett.
2012, 14, 5082.
[12] Cheap technical grade 3 could be used directly without further
purification.
[13] See the Supporting Information for further details.
[14] For examples of the use and synthetic transformations of
trifluoromethylated oxazolidines, see: a) A. Ishii, K. Higa-
shiyama, K. Mikami, Synlett 1997, 1381; b) N. Lebouvier, C.
Laroche, F. Huguenot, T. Brigaud, Tetrahedron Lett. 2002, 43,
2827; c) F. Gosselin, A. Roy, P. D. OꢀShea, C.-Y. Chen, R. P.
Volante, Org. Lett. 2004, 6, 641; d) A. Tessier, J. Pytkowicz, T.
Brigaud, Angew. Chem. Int. Ed. 2006, 45, 3677; Angew. Chem.
2006, 118, 3759; e) G. Chaume, O. Barbeau, P. Lesot, T. Brigaud,
J. Org. Chem. 2010, 75, 4135; f) G. Chaume, J. Simon, C.
Caupꢁne, N. Lensen, E. Miclet, T. Brigaud, J. Org. Chem. 2013,
78, 10144.
[16] Selected examples of palladium-catalyzed oxy-arylation and
oxy-vinylation reactions: a) M. F. Semmelhack, W. R. Epa,
Tetrahedron Lett. 1993, 34, 7205; b) J. P. Wolfe, M. A. Rossi, J.
Am. Chem. Soc. 2004, 126, 1620; c) M. B. Hay, J. P. Wolfe, J. Am.
Chem. Soc. 2005, 127, 16468; d) J. S. Nakhla, J. W. Kampf, J. P.
Wolfe, J. Am. Chem. Soc. 2006, 128, 2893; e) S. Hayashi, H.
Yorimitsu, K. Oshima, J. Am. Chem. Soc. 2009, 131, 2052;
Review: f) D. M. Schultz, J. P. Wolfe, Synthesis 2012, 351.
[15] The allyl amines used in this study were commercially available
or prepared using reported procedures: a) A. Lee, J. A. Ellman,
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Communications
Synthetic Methods
U. Orcel, J. Waser*
&&& — &&&
Palladium-Catalyzed Vicinal Amino
Alcohols Synthesis from Allyl Amines by
in Situ Tether Formation and
Carboetherification
Just tether it! Vicinal amino alcohols are
important structural motifs of bioactive
compounds. Reported herein is an effi-
cient method for their synthesis based on
the palladium-catalyzed oxy-alkynylation,
oxy-arylation, or oxy-vinylation of allyl
amines. High regio- and stereoselectivity
were ensured through the in situ forma-
tion of a hemiaminal tether using the
commercially available trifluoroacetalde-
hyde in its hemiacetal form.
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