Enantioselective organocatalytic allylic amination

Article abstract of DOI:10.1021/ja0539847

A new strategy for catalytic enantioselective allylic amination based on organocatalysis has been developed. Using a commercially available organocatalyst we demonstrate a direct highly enantioselective allylic electrophilic functionalization of alkyliden

Full text of DOI:10.1021/ja0539847

Published on Web 08/02/2005
Enantioselective Organocatalytic Allylic Amination
Thomas B. Poulsen, Carlos Alemparte, and Karl Anker Jørgensen*
The Danish National Research Foundation: Center for Catalysis, Department of Chemistry, Aarhus UniVersity,
DK-8000 Aarhus C, Denmark
Received June 16, 2005; E-mail: kaj@chem.au.dk
Table 1. Screening Results for the Enantioselective
The enantioselective functionalization of allylic positions is a
major goal in organic chemistry due to the broad synthetic potential
of the enantioenriched alkenes obtained for the preparation of
complex molecules.1 The most widely used and developed approach
to this challenge has been the transition metal-catalyzed allylic
substitution,2,3 which can now be considered one of the most firmly
established methodologies in asymmetric catalysis and has therefore
been frequently utilized in total synthesis.1 This strategy relies on
the oxidative addition of the metal to a substrate having a leaving
group (Lg) on the allylic position, enabling it to undergo a
nucleophilic addition reaction (Scheme 1, eq 1).
We envisioned the possibility of developing a new concept in
catalytic asymmetric allylation chemistry by performing enanti-
oselective electrophilic additions to allylic C-H bonds activated
by a chiral base (Scheme 1, eq 2). Recently, we have documented
the catalytic generation of chiral nucleophiles using cinchona
alkaloid derivatives as the catalysts.4 In this communication we
introduce this novel strategy by reporting the first enantioselective
metal-free allylic amination.5
Organocatalytic Allylic Amination Reactiona
entry
R
catalyst
solvent
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
Bn (1a)
Bn (1a)
Bn (1a)
(DHQD)2PHALd
(DHQD)2AQNd
(DHQD)2PYR
(DHQ)2PYR
(DHQ)2PYR
(DHQ)2PYR
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
Et2O
EtOAc
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
2a - nd
2a - nd
2a - 83
2b - 90
2b - 20
2b - 19
2b - 61
2c - 90
2d - 71
2b - 90
2e - 62
2f - 21
75
75
94
97
95
94
96
90
90
93
93
91
allyl (1b)
allyl (1b)
allyl (1b)
allyl (1b)
Me (1c)
Et (1d)
allyl (1b)
i-Pr (1e)
t-Bu (1f)
(DHQ)2PYR
(DHQD)2PYR
(DHQD)2PYR
(DHQD)2PYR
(DHQD)2PYR
(DHQD)2PYR
9
10
11
12
a Reactions performed with 1 (0.2 mmol), (NBoc)2 (0.24 mmol), and
catalyst (0.02 mmol) in 1 mL of solvent for 41-47 h. b Isolated yield. c Ee
determined by HPLC. d 20 mol % of the catalyst was used. nd: not
determined. For catalyst structures, see Supporting Information.
Scheme 1. Equation 1 Shows the Nucleophilic Allylic Substitution
Catalyzed by Metal Complexes, while Equation 2 Presents the
Electrophilic Organocatalytic Approach to Allylic Substitution
lectivity (entries 4-7), and excellent enantiomeric excesses are
obtained, even in highly polar media, such as EtOAc (entry 7), a
very unusual solvent for chiral ion-pair-based reactions. Low
solubility of the reactants accounts for the diminished reaction rate
observed in solvents other than CH2Cl2. The nature of the ester
group (R) also has a scarce influence on the stereochemical outcome
(entries 3, 4, 8-12) of the process but a significant impact on the
yield of the reaction (entry 8 vs 12).6 Thus, benzyl (1a), allyl (1b),
methyl (1c), ethyl (1d), and isopropyl (1e) are tolerated as ester
substituents giving both high yields and enantioselectivities.7
Finally, both pseudoenantiomers of the catalyst gave consistent
results (compare entries 4 and 10).
The tolerance of this organocatalytic enantioselective allylic
amination reaction to the presence of different substituents in R,
â, and γ positions was then evaluated (eq 4, Table 2). Long chain
(1g, entry 2), branched (1h, entry 3), functionalized (1i,j, entries
4, 5), and heteroatom-containing (1k, entry 6) substituents in the
allylic position (R3) consistently gave good yields and very high
enantioselectivities. The alkoxycarbonyl group is not essential for
a successful reaction, and satisfactory results were also achieved
with dicyano compounds (1l-n, entries 7-9). Furthermore, tetra-
substituted alkenes (1m,n, entries 8, 9) can smoothly be converted
to the desired γ-amination products under the same reaction
conditions with similar efficiency and enantioselectivities up to 88%
ee. The reaction is amenable to scale-up; thus, 5 mmol of the cyano
ester 1i was transformed to the corresponding amination product
2i, without any decrease in the yield (89%) or the enantioselectivity
(98% ee).
In relation to the organocatalytic reaction shown in eq 2, several
obstacles need to be overcome: the regioselectivity issue (R- vs
γ-amination) and two possible drawbacks arising from the presence
of another acidic proton in the γ-aminated compound: (i) the
formation of double amination products and (ii) the racemization
of the tertiary stereocenter created under the basic reaction
conditions. Hence, the right combination of substrate pKa and
catalyst activity that addresses these difficulties must be found.
We have studied the reaction of alkylidene cyanoacetates (1)
with dialkyl azodicarboxylates catalyzed by cinchona alkaloids and
derivatives (eq 3). When a monomeric catalyst (e.g., quinine) was
employed at ambient temperature, mixtures of R-, γ-, and double
amination products were formed. Gratifyingly, the use of dimeric
catalysts at lower temperatures (-24 °C) gave rise to the γ-ami-
nation product only, along with traces of the byproducts.
A survey of some reaction parameters was then performed, and
some representative results are presented in Table 1. First, com-
mercially available cinchona alkaloid derivative (DHQD)2PYR was
identified as the optimal catalyst affording 2a with 94% ee (entry
3). Surprisingly, the solvent polarity does not affect the enantiose-
9
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10.1021/ja0539847 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Organocatalytic Enantioselective Allylic Amination of
Compounds 1c,g-n with Di-tert-butyl Azodicarboxylatea
Alder reaction with 2,3-dimethyl-1,3-butadiene. Pleasingly, the
cycloadduct 4 was obtained in good yield (86%) and with high
diastereoselectivity (>15:1). The structure of 4 was confirmed by
X-ray analysis (see Supporting Information). Finally, we devised
an effective protocol for obtaining chiral γ-amino nitrilessa class
of chiral building blocks which could be further elaborated to give
the 1,4-diamino motif found in various important bioactive
compounds such as quinacrine, chloroquine, and analogues thereof.8
Under the standard catalytic conditions, compound 2o carrying a
Bn-ester was prepared with 98% ee. Treatment with H2 and Pd/C
effectively both reduces the double bond and cleaves the Bn ester.
Simply heating the compound in DMF after filtration of the Pd
catalyst brings about decarboxylation to give 5 (76% yield over
two steps). To cleave the N-N bond, the reductive power of SmI2
was relied upon.9 Some experimentation revealed that just an
acetylation was sufficient to activate the bond toward reduction,
and under optimized conditions Boc-protected γ-amino nitrile 6
could be obtained in 93% yield.
entry
substrate
R1
R2
R3
yield (%)b
ee (%)c
1
2
1c
1g
1h
1i
1j
1k
1l
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CN
H
H
H
H
H
H
H
Ph
Ph
Et
n-hexyl
i-Pr
Bn
allyl
(CH2)3OTBS
Et
Me
Bn
2c - 84
2g - 90
2h - 87
2i - 89
2j - 85
2k - 80
2l - 65
2m - 85
2n - 84
98
99
90g
98
96
97
91
86
88
3d
4e
5
6
7f
8
1m
1n
CN
CN
9
a Reactions performed with 1 (0.2 mmol), (NBoc)2 (0.24 mmol), and 2d
(0.02 mmol) in 1 mL of CH2Cl2 for 41-47 h. b Isolated yield. c Ee
determined by HPLC. d Reaction performed at 4 °C. e 96% ee and 53%
yield are obtained when the reaction is performed at -24 °C. f Reaction
performed on a 5 mmol scale. g Reaction time was 15 h.
In conclusion, we have presented the first example of a highly
enantioselective direct allylic electrophilic functionalization by
addition of dialkyl azodicarboxylates to alkylidene cyanoacetates
and malononitriles using commercially available organocatalysts.
It is our belief, that the concept introduced herein can be applied
to other electrophilic addition reactions, and studies toward this
aim are already well underway in our laboratories.
Scheme 2. Synthetic Utility of the Products (2)a
Acknowledgment. This work was made possible by a grant
from The Danish National Research Foundation. We are grateful
to Dr. Jacob Overgaard for X-ray crystallographic analysis of 4.
Supporting Information Available: Experimental procedures,
structure of the catalysts, characterization data for all new compounds
and stereochemical proof. This material is available free of charge via
the Internet at http://pubs.acs.org.
References
(1) See e.g.: (a) Trost, B. M. J. Org. Chem. 2004, 69, 5813. (b) Trost, B.
M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921.
(2) (a) Belda, O.; Moberg, C. Acc. Chem. Res. 2004, 37, 159. (b) Trost, B.
M.; Lee, C. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.;
Wiley-VCH: New York, 2000; p 593. (c) Pfaltz, A.; Lautens, M. In
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds.; Springer: New York, 1999; Vol. 2, p 833. (d)
Helmchen, G. J. Organomet. Chem. 1999, 576, 203. (e) Trost, B. M.;
Van Vranken, D. L. Chem. ReV. 1996, 96, 395.
(3) Other approaches to catalytic asymmetric allylic functionalization have
been described; see, e.g.: Oxidation: (a) Andrus, M. B.; Lashley, J. C.
Tetrahedron 2002, 58, 845. (b) Eames, J.; Watkinson, M. Angew. Chem.,
Int. Ed. 2001, 40, 3567. C-H activation: (c) Davies, H. M. L.; Beckwith,
R. E. J. J. Org. Chem. 2004, 69, 9241. (d) Omura, K.; Murakami, M.;
Uchida, T.; Irie, R.; Katsuki, T. Chem. Lett. 2003, 32, 354. (e) Kohmura,
Y.; Katsuki, T. Tetrahedron Lett. 2001, 42, 3339.
(4) (a) Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 2896. (b) Bella, M.; Kobbelgaard, S.;
Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 3670. (c) Saaby, S.; Bella,
M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120. (d) Bella, M.;
Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 5672. See also: (e) Li,
H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng,
L. Angew. Chem., Int. Ed. 2005, 44, 105. (f) Li, H.; Song, J.; Liu, X.;
Deng, L. J. Am. Chem. Soc. 2005, 127, 8948.
a Conditions: (i) H2, Pd/C, EtOH, 0 °C, 45 min, 90% (dr 1.5:1). (ii)
2,3-Dimethyl-1,3-butadiene, toluene, 80 °C, 23 h, 86%. (iii) H2, Pd/C, EtOH,
rt, 2 h. (iv) DMF, 150 °C, 2 h, 76% (over two steps). (v) Ac2O, pyridine,
DMAP, 50 °C, 48 h, 73% (+20% recovered 5). (vi) SmI2, HMPA, THF,
rt, 30 min, 93%.
The absolute configuration of the products was established to
be (S) by chemical correlation with R-hydrazino aldehydes obtained
by proline-catalyzed R-amination (see Supporting Information).
Several synthetic manipulations of the aminated products can
be envisioned (Scheme 2).
The double bond in the allylic aminated product can be reduced
in high yield to afford 3 without compromising the enantiomeric
excess. An important feature of the organocatalytic allylic amination
is the presence of a highly electron-deficient double bond in 2,
thus enabling these to react as electrophiles. Additionally, the
relative asymmetric induction from additions to the double bond
might possibly be influenced by the chiral center already present
in 2. As an example, we employed 2i as a dienophile in the Diels-
(5) For a review on allylic amination, see: Ricci, A., Ed. Modern Amination
Methods; Wiley-VCH: Weinheim, 2000.
(6) The effect of variation in the azodicarboxylate was also assessed. The
Boc group was revealed as superior to Troc, Cbz, and CO2Et in terms of
both yield and enantioselectivity.
(7) The stereochemical stability of the products might be due to A1,3-strain.
(8) Both chloroquine and quinacrine have been demonstrated to exhibit
differential activity when used in optically pure form. See e.g.: (a) Witiak,
D. T.; Grattan, D. A.; Heaslip, R. J.; Rahwan, R. G. J. Med. Chem. 1981,
24, 712. (b) Ryou, C.; Legname, G.; Peretz, D.; Craig, J. C.; Baldwin, M.
A.; Pruisner, S. B. Lab. InVest. 2003, 83, 837.
(9) See, e.g.: Sturino, C. F.; Fallis, A. G. J. Am. Chem. Soc. 1994, 116, 7447.
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