Unlocking ylide reactivity in the metal-catalyzed allylic substitution reaction: Stereospecific construction of primary allylic amines with aza-ylides

Article abstract of DOI:10.1021/ja9041302

(Chemical Equation Presented) The transition metal catalyzed allylic amination represents a powerful and versatile cross-coupling for the asymmetric construction of stereogenic C-N bonds that are present in secondary metabolites and medicinally important

Full text of DOI:10.1021/ja9041302

Published on Web 06/05/2009
Unlocking Ylide Reactivity in the Metal-Catalyzed Allylic Substitution
Reaction: Stereospecific Construction of Primary Allylic Amines with
Aza-Ylides
P. Andrew Evans* and Elizabeth A. Clizbe
Department of Chemistry, The UniVersity of LiVerpool, LiVerpool, L69 7ZD, U.K.
Received January 10, 2009; E-mail: Andrew.Evans@liverpool.ac.uk
The transition metal catalyzed allylic amination reaction represents
a powerful method for the asymmetric construction of stereogenic C-N
bonds that are present in secondary metabolites and medicinally
important agents.1,2 Nonetheless, the development of this process into
a general cross-coupling reaction has been impeded by the ability to
control regioselectivity in the union of unsymmetrical acyclic allylic
alcohol derivatives with the requisite nitrogen pronucleophiles.1,2
Although a variety of transition metal complexes now provide
enantiomerically enriched acyclic secondary allylic amines in a highly
regioselective manner with more conventional nitrogen pronucleo-
philes, the examination of charge-separated derivatives has not been
forthcoming.1-6 We envisioned that ylides would provide ideal partners
for this transformation given their low basicity and would thus provide
a new class of nucleophiles for this venerable process. Herein, we now
describe the regio- and enantiospecific rhodium-catalyzed allylic
amination of chiral nonracemic secondary allylic carbonates 1, using
the aza-ylide derived from 1-aminopyridinium iodide, for the construc-
tion of secondary allylic pyridinium salts 2 (eq 1).
Ph(CH2)2) with the aza-ylide derived from 1-aminopyridinium iodide
in the presence of Wilkinson’s catalyst modified with trimethyl
phosphite furnished secondary allylic pyridinium iodide rac-2a in 71%
yield, with g19:1 regioselectivity (entry 1). This contrasts the results
with the phosphonium and sulfonium aza-ylides, which proved
completely unreactive under analogous conditions (entries 2/3). As
anticipated, the nature of the alkali metal does not affect the selectivity;
however, the sodium and potassium derivatives provide some recovered
allylic carbonate rac-1a (entry 1 vs 4/5). Further studies examined
the effect of inorganic and tertiary amine bases, in which potassium
carbonate9 afforded a similar yield of rac-2a, whereas 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) was less efficient, albeit with
complete conversion (entry 6/7). The lower yield for the reactions that
consume all the allylic carbonate was ascribed to the formation of
methoxide from the fragmentation of the methyl carbonate-leaving
group, which can presumable generate the aza-ylide of rac-2a.
Gratifyingly, quenching the reaction with acetic acid and lithium iodide
furnished the secondary allylic amino pyridinium salt rac-2a in an
improved 89% yield with analogous selectivity (entry 8).10
Table 1. Optimization of the Regioselective Rhodium-Catalyzed
Allylic Amination Reaction using Aza-ylides (eq 1; rac-1a R )
Ph(CH2)2)a
H2N-X+Y-
A critical feature with the metal-catalyzed allylic substitution reaction
is the mechanistic dichotomy created by the nucleophile, which can
significantly alter the regio- and stereochemical outcome of this
process.2 With this detail in mind, we elected to examine the merit of
aza-ylides as stabilized nitrogen nucleophiles for the regio- and
stereospecific rhodium-catalyzed allylic amination, since it was
envisioned that the nucleophilicity of the ylide could be tailored through
the judicious choice of the stabilizing group (Figure 1).7,8 For example,
phosphonium and sulfonium ylides are field and resonance stabilized,
whereas the ammonium and pyridinium derivatives are only field
stabilized.8 Hence, the latter should be considerably more reactive in
this process since they are less stabilized and therefore more nucleo-
philic.
ratio of
rac-2a/3ab c
yield
(%)d
,
entry
X )
Y )
base
additive
1
2
3
4
5
6
7
8
NC5H5
PPh3
SPh2
NC5H5
“
I
LiHMDS
“
-
-
-
-
-
-
-
g19: 1
-
-
g19: 1
“
“
“
71
Br
Cl
“
NR
NR
“
e
NaHMDS
KHMDS
K2CO3
DBU
68
65
e
“
e
“
“
“
“
68
39
89
NC5H5
I
LiHMDS
LiI/AcOH
g19: 1
a All reactions were carried out on a 0.25 mmol reaction scale using 10
mol% RhCl(PPh3)3 modified with 40 mol% P(OMe)3 and 1.1 equiv of the
anion of the pyridinium salt in MeCN/THF (1.5:1) at room temperature.
b Regioselectivity was determined by 500 MHz 1H NMR on the crude
reaction mixtures. c The linear product 3a was prepared independently
Via Pd(0) catalysis. d Isolated yields. e Recovered rac-1a (5-10%).
Table 2 summarizes the application of the optimized reaction
conditions (Table 1, entry 8) to a variety of racemic secondary allylic
carbonates (Vide infra). The regioselectivity in the allylic alkylation is
tolerant of a wide array of allylic alcohol derivatives. For example,
linear and branched alkyl substituents afford excellent regiocontrol
(Table 2, entries 1-5 and 6-9), in which the branching is inconse-
quential in terms of regioselectivity contrary to our previous work with
N-alkyl sulfonamides.3 Additional studies demonstrated that benzyl
and tert-butyldimethylsilyl protected hydroxymethyl and ethyl deriva-
tives also provide excellent selectivity (entries 10-13), as did the aryl
substituents (entries 14 and 15).
Figure 1. Relative stability of various ylides based on field and resonance
stabilization.
Table 1 outlines the preliminary evaluation of the proposed allylic
amination with an aza-ylide. We envisioned that the stabilizing group
would be the most important contributing factor for the ylide contrary
to our previous studies, which demonstrated that the alkali metal salt
of the pronucleophile was critical for attaining high yield and
regioselectivity.3,8 Treatment of the allylic carbonate rac-1a (R )
9
8722 J. AM. CHEM. SOC. 2009, 131, 8722–8723
10.1021/ja9041302 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Regioselective Rhodium-Catalyzed Allylic
Amination Reaction with the 1-Aminopyridinium Ylide (eq 1; rac-1
X ) NC5H5, Y ) I)a
available ammonia equivalent, which serves to illustrate the synthetic
potential of this nucleophile for the preparation of primary allylic
amines. Overall, this work provides an opportunity to investigate the
utility of this new class of nucleophiles in related metal-catalyzed
reactions.
allylic carbonate
rac-1 R2
ratio of
rac-2/3b c
,
entry
)
yield (%)d
1
2
3
4
5
6
7
8
Ph(CH2)2
a
b
c
d
e
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
89
76
87
87
73
79
75
86
78
88
84
84
86
81
89
Me
Acknowledgment. Dedicated to Prof. Philip D. Magnus, FRS on
the occasion of his 65th birthday. We sincerely thank the NIH
(GM58877) for generous financial support. We also thank Prof. Jeffrey
N. Johnston for helpful discussions pertaining to the isolation of
primary amines. Finally we would like to acknowledge the Royal
Society for a Wolfson Research Merit Award (P.A.E.) and the
University of Liverpool for a Postgraduate Research Studentship
(E.A.C.).
nPr
nBu
CH2dCH(CH2)2
iPr
f
cHex
g
h
i
j
k
l
m
n
o
iBu
9
PhCH2
BnOCH2
BnO(CH2)2
TBSOCH2
TBSO(CH2)2
Ph
10
11
12
13
14
15
Supporting Information Available: Experimental procedures and
spectral data for rac-2a-o, (S)-4, and rac-5 (PDF). X-ray crystal-
lographic file in CIF format for rac-2o. This material is available free
of charge via the Internet at http://pubs.acs.org.
Npth
a All reactions were carried out on a 0.25 mmol reaction scale.
b Regioselectivities were determined by 500 MHz 1H NMR analysis of
the crude reaction mixtures. c The linear products 3 were prepared
independently Via Pd(0) catalysis. d Isolated yields.
References
(1) For a recent review on allylic amination, see: Jørgensen, K. A. in Modern
Amination Methods; Ricci, A., Ed.; Wiley-VCH: Weinheim, Germany,
2000; Chapter 1, pp 1-35.
Additional studies examined the mechanistic course of the allylic
amination in the context of the stereospecificity. Treatment of the allylic
carbonate (S)-1j (98% ee) with the aza-ylide under the optimized
reaction conditions furnished the chiral nonracemic secondary allylic
pyridinium salt (S)-2j in 88% yield, with retention of absolute
configuration in accord with our previous studies with soft nucleophiles
(b/l g 19:1, 98% cee).11 Reductive cleavage of the pyridinium salt
(S)-2j with samarium diiodide furnished the enantiomerically enriched
primary allylic amine (S)-4 in 88% yield.12
(2) For recent reviews on metal-catalyzed allylic substitution, see: (a) Trost,
B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921. (b) Leahy, D. K.;
Evans, P. A. In Modern Rhodium-Catalyzed Organic Reactions; Evans,
P. A., Ed.; Wiley-VCH: Weinheim, Germany, 2005; Chapter 10, pp 191-
214. (c) Helmchen, G.; Dahnz, A.; Du¨bon, P.; Schelwies, M.; Weihofen,
R. Chem. Commun. 2007, 675 and pertinent references cited therein.
(3) For examples of the stereospecific intermolecular rhodium-catalyzed allylic
amination reactions, see: (a) Evans, P. A.; Robinson, J. E.; Nelson, J. D.
J. Am. Chem. Soc. 1999, 121, 6761; 12214. (b) Evans, P. A.; Robinson,
J. E. Org. Lett. 1999, 1, 1929. (c) Evans, P. A.; Robinson, J. E.; Moffett,
K. K. Org. Lett. 2001, 3, 3269. (d) Evans, P. A.; Lai, K. W.; Zhang, H.-
R.; Huffman, J. C. Chem. Commun. 2006, 844. (e) Evans, P. A.; Qin, J.;
Robinson, J. E.; Bazin, B. Angew. Chem., Int. Ed. 2007, 46, 7417.
(4) For related examples of stereospecific metal-catalyzed allylic amination
reactions, see: (a) Fe: Plietker, B. Angew. Chem., Int. Ed. 2006, 45, 6053.
(b) Ir: Singh, O. V.; Han, H. Org. Lett. 2007, 9, 4801.
Scheme 1. Stereospecific Allylic Amination and N-N Bond
Cleavage
(5) For leading examples of intermolecular enantioselective metal-catalyzed
allylic amination reactions with various nitrogen pronucleophiles, see: (a)
Hayashi, T.; Kishi, K.; Yamamoto, A.; Ito, Y. Tetrahedron Lett. 1990, 31,
1743. (b) You, S.-L.; Zhu, X.-Z.; Luo, Y.-M.; Hou, X.-L.; Dai, L.-X. J. Am.
Chem. Soc. 2001, 123, 7471. (c) Ohmura, T.; Hartwig, J. F. J. Am. Chem.
Soc. 2002, 124, 15164. (d) Lipowsky, G.; Helmchen, G. Chem. Commun.
2004, 116. (e) Tissot-Croset, K.; Polet, D.; Alexakis, A. Angew. Chem.,
Int. Ed. 2004, 43, 2426. (f) Miyabe, H.; Matsumura, A.; Moriyama, K.;
Takemoto, Y. Org. Lett. 2004, 6, 4631. (g) Yamashita, Y.; Gopalarathnam,
A.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7508. (h) Miyabe, K;
Yoshida, K.; Reddy, V. K.; Takemoto, Y. J. Org. Chem. 2009, 74, 305
and pertinent references cited therein.
(6) For examples of the regioselective allylic amination with hydrazine
derivatives, see: (a) Matunas, R.; Lai, A. J.; Lee, C. Tetrahedron 2005, 61,
6298. (b) Johns, A. M.; Liu, Z.; Hartwig, J. F. Angew. Chem., Int. Ed.
2007, 46, 7259.
(7) (a) Nitrogen, Oxygen and Sulfur Ylide Chemistry: A Practical Approach
to Chemistry; Clark, J. S., Ed.; Oxford University Press: Oxford, 2002. (b)
Phosphorus Ylides; Chemistry and Application in Organic Synthesis;
Kolodiazhnyi, O. I.; Wiley-VCH: Weinheim, 1999.
Finally, the synthetic utility of this process was further illustrated
with the development of a novel one-pot protocol using 1-aminopy-
ridinium iodide as a novel ammonia equivalent.13 Based on our
preliminary work with weak inorganic bases we envisioned that the
allylic amination could be promoted with catalytic base, which would
provide an opportunity to affect the in situ reductive cleavage to the
primary amine. Gratifyingly, treatment of the allylic carbonate rac-1a
under the analogous reaction conditions, albeit using catalytic potas-
sium carbonate at 30 °C, followed by the in situ reductive cleavage
using Zn/NH4Cl, furnished the allylic amine hydrochloride salt rac-5
in 74% overall yield (b/l g 19:1).14
(8) For the discussion of the stability of various ylides, see: (a) Naito, T.;
Nagase, S.; Yamataka, H. J. Am. Chem. Soc. 1994, 116, 10080. (b) Cheng,
J.-P.; Liu, B.; Zhao, Y.; Sun, Y.; Zhang, X.-M.; Lu, Y. J. Org. Chem.
1999, 64, 604. (c) Aggarwal, V. K.; Harvey, J. N.; Robiette, R. Angew.
Chem., Int. Ed. 2005, 44, 5468.
(9) Although potassium carbonate is a more convenient and cheaper base, the
reaction is not stereospecific (74% cee) and is less reliable with the
R-branched and hydroxymethyl substituents.
(10) Quenching the reaction with LiI/AcOH was more convenient than HI, which
afforded the pyridinium salt rac-2a in a reduced 74% yield.
(11) Rama Rao, A. V.; Bose, D. S.; Gurjar, M. K.; Ravindranathan, T.
Tetrahedron 1989, 45, 7031.
(12) Souppe, J.; Danon, L.; Namy, J. L.; Kagan, H. B. J. Organomet. Chem.
1983, 250, 227.
(13) For recent examples of the regio- and enantioselective metal-catalyzed allylic
amination with ammonia equivalents, see: (a) Weihofen, R.; Tverskoy, O.;
Helmchen, G. Angew. Chem., Int. Ed. 2006, 45, 5546. (b) Defieber, C.;
Ariger, M. A.; Moriel, P.; Carreira, E. M. Angew. Chem., Int. Ed. 2007,
46, 3139. (c) Pouy, M. J.; Leitner, A.; Weix, D. J.; Ueno, S.; Hartwig,
J. F. Org. Lett. 2007, 9, 3949.
In conclusion, we have developed a regio- and enantiospecific
rhodium-catalyzed allylic amination reaction using the aza-ylide derived
from 1-aminopyridinium iodide. This investigation demonstrates the
importance of the ylide-stabilizing group for obtaining the desired
nucleophilicity and the ability to utilize the aza-ylide as a commercially
(14) Shapiro, D.; Abramovitch, R. A. J. Am. Chem. Soc. 1955, 77, 6690.
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