Tandem catalytic allylic amination and [2,3]-stevens rearrangement of tertiary amines

Article abstract of DOI:10.1021/ja204717b

We have developed a catalytic allylic amination involving tertiary aminoesters and allylcarbonates, which is the first example of the use of tertiary amines as intermolecular nucleophiles in metal-catalyzed allylic substitution chemistry. This process is

Full text of DOI:10.1021/ja204717b

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pubs.acs.org/JACS
Tandem Catalytic Allylic Amination and [2,3]-Stevens Rearrangement
of Tertiary Amines
Arash Soheili and Uttam K. Tambar*
Department of Biochemistry, Division of Chemistry, The University of Texas Southwestern Medical Center at Dallas,
5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States
S Supporting Information
b
in metal-catalyzed allylic substitution chemistry.6 Our discovery
ABSTRACT: We have developed a catalytic allylic amina-
tion involving tertiary aminoesters and allylcarbonates,
which is the first example of the use of tertiary amines as
intermolecular nucleophiles in metal-catalyzed allylic sub-
stitution chemistry. This process is employed in a tandem
ammonium ylide generation/[2,3]-rearrangement reaction,
which formally represents a palladium-catalyzed Stevens
rearrangement. Low catalyst loadings and mild reaction
conditions are compatible with an unprecedented substrate
scope for the ammonium ylide functionality, and products
are generated in high yields and diastereoselectivities. Me-
chanistic studies suggested the reversible formation of an
ammonium intermediate.
that tertiary amines participate in this mode of reactivity may
provide a general strategy for synthesizing complex molecules, as
highlighted by the development of a tandem ammonium ylide
generation/[2,3]-rearrangement reaction. This transformation
formally represents a palladium-catalyzed Stevens rearrangement
with an unprecedented substrate scope for the ammonium ylide
functionality and high diastereoselectivity for products having
two stereocenters.
Initially, we focused on establishing tertiary aminoesters as
intermolecular nucleophiles for allylic amination. With Pd2dba3
3
CHCl3 as a catalyst and Cs2CO3 as an external base, we
attempted to couple aminoester 1a with cinnamyl carbonate 2
(Table 1). While we did not observe appreciable amounts of
product in the absence of ligand (entry 1) or in the presence of
several phosphine ligands (entries 2À5), we obtained the [2,3]-
Stevens rearrangement product 4 in 90% yield, albeit as a modest
2:1 mixture of diastereomers, when PPh3 was used (entry 6).
To increase the diastereoselectivity of this process, we em-
ployed tert-butyl aminoester 1b (entry 7). Although the diaster-
eomeric ratio increased to 9:1, the product yield decreased
dramatically to 39%. We examined a series of electronically
distinct ligands to optimize the efficiency of this reaction with
the less reactive tert-butyl aminoester 1b (entries 8À11). Once
we realized that electron-deficient ligands led to greater yields of
product, we employed the electron-deficient and sterically un-
encumbered P(2-furyl)3 ligand (entry 11), which generates a
π-acidic palladium complex that is more susceptible to nucleophilic
attack by tert-butyl aminoester 1b.7 Interestingly, the electronic
characteristics of the ligand had no effect on the diastereoselec-
tivity of the tandem process, and we isolated the desired product
4 in 95% yield with a diastereomeric ratio of 9:1.8 The rearranged
product 4 was formed in diminished yield even in the absence of
Cs2CO3, which suggests that the ethoxide byproduct from the
ethyl carbonate is basic enough to convert the ammonium salt
into ammonium ylide 3 (entry 12).
he synthetic utility of ammonium ylides is exemplified by their
T
selective sigmatropic rearrangements into complex nitrogen-
containing products. For example, allylic ammonium enolates
undergo [2,3]-Stevens rearrangements to produce unnatural ami-
no acid derivatives with multiple stereocenters (Scheme 1).1
Unfortunately, the broad application of these rearrangements has
not been fully realized because of the difficulties associated with
synthesizing and isolating many ammonium salt precursors.2,3 The
development of a mild and general metal-catalyzed tandem
ammonium ylide generation/[2,3]-rearrangement would obviate
the need to synthesize and isolate these reactive intermediates.
While metal carbenoid-mediated couplings between tertiary allylic
amines and diazoesters represent the most successful catalytic
strategy for generating ammonium ylides, the challenge of synthe-
sizing diazoesters with diverse functionalities reduces the potential
scope of this approach.4
To address the need for a more general catalytic method of
synthesizing allylic ammonium ylides for [2,3]-rearrangements,
we turned our attention to allylic substitution chemistry. Metal-
catalyzed allylic amination involving primary or secondary
amines and allylic electrophiles has become one of the most
versatile methods for synthesizing nitrogen-containing com-
pounds.5 As an intriguing extension of these protocols, the
coupling of tertiary aminoesters with allylic electrophiles would
generate synthetically useful ammonium ylides (Scheme 1).
Unfortunately, tertiary amines are not generally appreciated as
nucleophiles in allylic amination processes. In this communica-
tion, we describe the catalytic allylic amination reaction of tertiary
aminoesters and allylcarbonates, which constitutes the first
example of the use of tertiary amines as intermolecular nucleophiles
With our optimized reaction conditions in hand, we explored
the scope of allylcarbonates that can participate in this transfor-
mation (Table 2). In addition to using linear allylcarbonates such
as 2 (Table 1), we successfully coupled aminoester 1b with
branched carbonates 5, which are often more synthetically acces-
sible than their linear counterparts. Allylcarbonates with electro-
nically diverse aryl rings were well-behaved in this process
(entries 1À7). For example, both halogen-substituted and
Received: May 23, 2011
Published: July 27, 2011
r
2011 American Chemical Society
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Scheme 1
Table 2. Substrate Scope of Allylcarbonatesa
Table 1. Optimization of Reaction Conditionsa
a Reaction conditions: 1.5 equiv of aminoester 1b, 1 equiv of allylcarbo-
nate 5, 1 mol % Pd2dba3 CHCl3, and 4 mol % ligand. b Isolated yields.
3
c Diastereomeric ratios as determined by NMR analysis. d With slow
addition of carbonate.
esters (Table 3). In view of the accessibility of the starting
materials and the mildness of the reaction conditions, our
method provides an efficient alternative to traditional protocols
for generating ammonium ylides and metal carbenoid-mediated
couplings between tertiary allylic amines and diazoesters.
We observed reasonable reactivity with aminoester derivatives
containing various nitrogen functionalities (entries 1 and 2). We
also extended the metal-catalyzed process to R-amino ketones,
which resulted in the stereoselective synthesis of complex cyclic
and acyclic products (entries 3À6). For example, a piperidone
was coupled with allylcarbonate 5a to generate a cyclic product
with two contiguous stereocenters (entry 3). The diastereoselec-
tivity of the [2,3]-rearrangement of acyclic ketone-derived
ammonium ylides was affected by the steric bulk of the ketone
substituent (entries 4À6). We were also interested in applying
our tandem methodology to the assembly of fully substituted unnatural
R-amino acids with multiple stereocenters, which are not easily
accessible by known protocols. Gratifyingly, aminoester deriva-
tives with R-substituents furnished the desired [2,3]-Stevens
rearrangement products containing fully substituted carbons
with good levels of diastereoselectivity (entries 7À8). On the
basis of the seminal work by Sweeney and co-workers on chiral
auxiliary-based ammonium ylide rearrangements,2d we success-
fully incorporated Oppolzer’s camphorsultam into our tertiary
amine substrates, highlighting the potential of our metal-cata-
lyzed ammonium ylide generation for use in the stereoselective
synthesis of enantioenriched unnatural amino acid derivatives
(entries 9À11).
a Reaction conditions: 1.5 equiv of aminoester 1, 1 equiv of allylcarbo-
nate 2, 1 mol % Pd2dba3 CHCl3, 4 mol % ligand, 3 equiv of Cs2CO3, 0.2
3
M in MeCN. b GC yields. c Diastereomeric ratios as determined by GC.
d No Cs2CO3 was used.
methoxy-substituted phenyl derivatives were synthesized in good
yields with high diastereomeric ratios. The reaction conditions
also tolerated heterocycles with a Lewis basic pyridine function-
ality (entry 7), which may be especially problematic for protocols
mediated by Lewis acids3 or metal carbenoids.4 Since aliphatic
substituents did not impact the reaction efficiency (entry 8), this
method may provide access to a diverse array of unnatural amino
acid derivatives. The relative stereochemistry of the major
diastereomer of the products was confirmed by X-ray crystal-
lography and is consistent with an exo-selective transition state
that is evoked in traditional ammonium ylide [2,3]-rearrange-
ments (see below).3e
After demonstrating the wide range of allylcarbonates that
can participate in the tandem ammonium ylide generation/
[2,3]-rearrangement, we expanded the utility of the reaction by
employing tertiary amine nucleophiles other than N,N-dimethylglycine
We devised a series of experiments to gain mechanistic insight
into our palladium-catalyzed Stevens rearrangement. Although
we did not observe the coupled ammonium salts formed by allylic
amination of tertiary amines, we designed an internal crossover
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Table 3. Substrate Scope of Tertiary Amine Nucleophilesa
Scheme 2
Scheme 3
aPd(II)Àπ-allyl complex such as 16 (Scheme2b).10 An unfavorable
equilibrium for the palladium-catalyzed ammonium salt forma-
tion, in conjunction with the facile conversion of ammonium salts
into the [2,3]-rearrangement products, could account for the
difficulty of observing any ammonium intermediates. We believe
that these studies also explain why catalytic intermolecular allylic
amination with tertiary amines has not been reported previously.
On the basis of these experiments, we propose a mechanism
wherein aminoester 1b and Pd(II)Àπ-allyl complex 18 establish
an unfavorable equilibrium with Pd(0) and ammonium salt 19
(Scheme 3). As soon as this unstable ammonium intermediate is
formed, it undergoes rapid deprotonation to generate ammo-
nium ylide 20, which is transformed into the observed [2,3]-
rearrangement product 6 through exo transition state 21.
In conclusion, we have developed a palladium-catalyzed allylic
amination involving tertiary amines and allylcarbonates that
generates ammonium ylides, which rearrange under the reaction
conditions to give unnatural amino acid derivatives and complex
R-amino ketones with unprecedented levels of stereocontrol.
The mild reaction conditions enable the use of a wide range of
tertiary amine nucleophiles and allylcarbonates. Mechanistic
studies support the formation of a fleeting ammonium salt
intermediate that is formed by allylic amination with a tertiary
amine substrate. We also believe that the palladium-catalyzed
a Reaction conditions: 1.5 equiv of tertiary amine 7, 1 equiv of
allylcarbonate 5, 1 mol % Pd2dba3 CHCl3, and 4 mol % ligand.
3
b Isolated yields. c Diastereomeric ratios as determined by NMR analysis.
d Reaction time was 16 h. e Reaction conditions: 1 equiv of 7, 2 equiv of 5,
2 mol % Pd2dba3 CHCl3, and 8 mol % ligand. f 1.2 equiv of 7 was used.
3
substrate 9 that suggested the formation of these fleeting inter-
mediates (Scheme 2a). Subjection of aminoester 9 to the reaction
conditions yielded two allylation products, 10 and 11, which is
most easily explained by an allylic amination mechanism in which
both the allyl and cinnamyl appendages of ammonium ylide 13
participated in the [2,3]-rearrangement.9 We attributed the
difficulty of observing an ammonium intermediate to the ex-
ceedingly high rate of ammonium salt deprotonation to yield an
ammonium ylide and subsequent [2,3]-rearrangement (12 f 13
f 10 + 11). In addition, we suspected that aminoester 9 formed
an unfavorable equilibrium with the initially formed ammonium
salt 12. This hypothesis was confirmed by our observation that
morpholine ammonium salt 14 exchanged its cinnamyl substi-
tuent with aminoester 1b under the reaction conditions to
yield Stevens rearrangement product 4b, presumably through
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allyl exchange of ammonium salts may have broader synthetic
utility as a new strategy for allyl transfer. We are currently
exploring a catalytic enantioselective version of this process
and its application to the synthesis of stereochemically complex
natural produdcts.
(5) (a) Johannsen, M.; Jørgensen, K. A. Chem. Rev. 1998,
98, 1689–1708. (b) Hartwig, J. F.; Stanley, L. M. Acc. Chem. Res.
2010, 43, 1461–1475. (c) Trost, B. M.; Zhang, T.; Sieber, J. D. Chem.
Sci. 2010, 1, 427–440.
(6) For seminal examples of intramolecular allylic amination with
tertiary amines, see: (a) Grellier, M.; Pfeffer, M.; van Koten, G.
Tetrahedron Lett. 1994, 35, 2877–2880. (b) van der Schaaf, P. A.; Sutter,
J.-P.; Grellier, M.; van Mier, G. P. M.; Spek, A. L.; van Koten, G.; Pfeffer,
M. J. Am. Chem. Soc. 1994, 116, 5134–5144.
’ ASSOCIATED CONTENT
(7) (a) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585–9595.
(b) Amatore, C.; Jutand, A.; Meyer, G.; Atmani, H.; Khalil, F.; Chahdi, F. O.
Organometallics 1998, 17, 2958–2964.
(8) When we resubjected the major diastereomer of the rearranged
product to the reaction conditions, we did not observe any epimeriza-
tion, indicating that the dr in this tandem process reflects the high
diastereoselectivity of the [2,3]-rearrangement via a well-ordered
transition state.
(9) Direct allylic alkylation of the aminoester was ruled out as a
mechanistic possibility for several reasons, including the ligand-inde-
pendent regioselecitivity and diastereoselectivity of product formation
(Table 1) as well as the inability of Cs2CO3 to deprotonate an
aminoester directly (on the basis of pKa values).
(10) Murahashi, S.-I.; Imada, Y. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-I., Ed.; Wiley-Interscience:
New York, 2002; pp 1817À1825.
S
Supporting Information. Complete experimental proce-
b
dures and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
uttam.tambar@utsouthwestern.edu
’ ACKNOWLEDGMENT
Financial support was provided by the Robert A. Welch
Foundation (Grant I-1748) and the W. W. Caruth, Jr., Endowed
Scholarship.
’ REFERENCES
(1) (a) Stevens, T. S.; Creigton, E. M.; Gordon, A. B.; MacNicol, M.
J. Chem. Soc. 1928, 3193–3197.(b) Markꢀo, I. E. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York,
1991; Vol. 3, pp 913À974. (c) Br€uckner, R. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York,
1991; Vol. 6, pp 873À908. (d) Honda, K.; Inoue, S.; Sato, K. J. Am.
Chem. Soc. 1990, 112, 1999–2001. (e) Arborꢀe, A. P. A.; Cane-Honeysett,
D. J.; Coldham, I.; Middleton, M. L. Synlett 2000, 236–238. (f) Vanecko,
J. A.; Wan, H.; West, F. G. Tetrahedron 2006, 62, 1043–1062. (g)
Sweeney, J. B. Chem. Soc. Rev. 2009, 38, 1027–1038.
(2) (a) Coldham, I.; Middleton, M. L.; Taylor, P. L. J. Chem. Soc.,
Perkin Trans. 1 1997, 2951–2952. (b) Coldham, I.; Middleton, M. L.;
Taylor, P. L. J. Chem. Soc., Perkin Trans. 1 1998, 2817–2821. (c) Honda,
K.; Tabuchi, M.; Kurokawa, H.; Asami, M.; Inoue, S. J. Chem. Soc., Perkin
Trans. 1 2002, 1387–1396. (d) Workman, J. A.; Garrido, N. P.; Sanc€uon,
J.; Roberts, E.; Wessel, H. P.; Sweeney, J. B. J. Am. Chem. Soc. 2005,
127, 1066–1067. (e) Gawley, R. E.; Moon, K. Org. Lett. 2007, 9
3093–3096.
(3) Lewis acids have been shown to mediate aza-Wittig-type re-
arrangements of aminoesters and aminoamides via the generation of
allylic ammonium ylides and subsequent [2,3]-rearrangement. See: (a)
Murata, Y.; Nakai, T. Chem. Lett. 1990, 2069–2072. (b) Kessar, S. V.;
Singh, P.; Singh, K. N.; Kaul, V. K.; Kumar, G. Tetrahedron Lett. 1995,
36, 8481–8484. (c) Blid, J.; Somfai, P. Tetrahedron Lett. 2003,
44, 3159–3162. (d) Blid, J.; Brandt, P.; Somfai, P. J. Org. Chem. 2004,
69, 3043–3049. (e) Blid, J.; Panknin, O.; Somfai, P. J. Am. Chem. Soc.
2005, 127, 9352–9353. (f) Blid, J.; Panknin, O.; Tuzina, P.; Somfai, P.
J. Org. Chem. 2007, 72, 1294–1300. (g) Somfai, P.; Panknin, O. Synlett
2007, 1190–1202.
(4) (a) Doyle, M. P.; Tamblyn, W. H.; Bagheri, V. J. Org. Chem.
1981, 46, 5094–5102. (b) Del Zotto, A.; Baratta, W.; Miani, F.; Verardo,
G.; Rigo, P. Eur. J. Org. Chem. 2000, 3731–3735. (c) Padwa, A.; Beall,
L. S.; Eidell, C. K.; Worsencroft, K. J. J. Org. Chem. 2001, 66, 2414–2421.
(d) Clark, J. S.; Middleton, M. D. Tetrahedron Lett. 2003,
44, 7031–7034. (e) Glaeske, K. W.; Naidu, B. N.; West, F. G. Tetra-
hedron: Asymmetry 2003, 14, 917–920. (f) Zhou, C.-Y.; Yu, W.-Y.; Chan,
P. W. H.; Che, C.-M. J. Org. Chem. 2004, 69, 7072–7082. (g) Roberts, E.;
Sanc€uon, J. P.; Sweeney, J. B. Org. Lett. 2005, 7, 2075–2078. (h) Honda,
K.; Shibuya, H.; Yasui, H.; Hoshino, Y.; Inoue, S. Bull. Chem. Soc. Jpn.
2008, 81, 142–147.
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