Diastereoselective and enantiospecific synthesis of γ-substituted α,β-unsaturated nitriles from O-protected allylic cyanohydrins

Article abstract of DOI:10.1021/jo060239j

γ-Functionalized α,β-unsaturated nitriles are prepared diastereoselectively and enantiospecifically from enantioenriched cyanohydrin-O-phosphates and carbonates derived from α,β-unsaturated aldehydes, either by palladium or iridium-catalyzed nucleophilic

Full text of DOI:10.1021/jo060239j

Diastereoselective and Enantiospecific Synthesis of γ-Substituted
r,â-Unsaturated Nitriles from O-Protected Allylic Cyanohydrins
Alejandro Baeza, Jes u´ s Casas, Carmen N a´ jera,* and Jos e´ M. Sansano
Departamento de Qu ´ı mica Org a´ nica, Facultad de Ciencias, and Instituto de S ´ı ntesis Org a´ nica (ISO),
UniVersidad de Alicante Apdo. 99, 03080-Alicante, Spain
cnajera@ua.es
ReceiVed February 6, 2006
γ-Functionalized R,â-unsaturated nitriles are prepared diastereoselectively and enantiospecifically from
enantioenriched cyanohydrin-O-phosphates and carbonates derived from R,â-unsaturated aldehydes, either
by palladium or iridium-catalyzed nucleophilic allylic substitution reactions with different nucleophiles.
Appropriate reaction conditions for dibenzylamine, benzylamine, sodium azide, NaOAc, tetra-n-
butylammonium acetate (TBAA), the corresponding sodium salts of phenol and N-hydroxysuccinimide
and the carbonucleophile sodium dimethyl malonate are described. Different substituted O-protected
cyanohydrins, such as carbonates and phosphates, derived from crotonaldehyde, (E)-hex-2-enal, oct-2-
enal, 2-methylbut-2-enal, and cinnamaldehyde are used as allylic substrates. The substitution takes place
with total retention of the configuration for the (E)-γ-functionalized nitriles and with inversion of the
configuration for the Z-isomers. In general, cyanohydrin-O-phosphates are the materials of choice to get
the highest E-diastereoselectivity. Dibenzylamine is the best nucleophile for the synthesis of γ-nitrogenated
R,â-unsaturated nitriles in the presence of either palladium or iridium catalysts when aliphatic compounds
and cinnamaldehyde derivative are used (up to 98% dr). For the synthesis of γ-oxygenated R,â-unsaturated
nitriles sodium or TBAA the reagents are selected to avoid epimerizations in up to 76% dr. Finally, the
Tsuji-Trost reaction with sodium malonate works only under palladium catalysis in up to 70% dr.
Introduction
carbon-carbon double bond reduction followed by oxidation
of the nitrile group gave aldehyde 8, which has been used in
the total synthesis of the (+)-allocyathin B2. The transformation
Enantiomerically enriched γ-functionalized R,â-unsaturated
nitriles 1 and 2 are very important chiral building blocks in the
total synthesis of natural products. These molecules are prone
to undergo functional group transformations at both nitrile and
γ-position substituent and classical carbon-carbon double bond
reactions including electrocyclic rearrangements and Michael-
type additions (Figure 1). γ-Hydroxy-R,â-unsaturated nitriles
and their O-substituted derivatives 1 (R ) OH) have been used
as chiral intermediates in the total synthesis of coriolic acid by
the conversion of the nitrile to the aldehyde 7 (Figure 1). The
3
of the nitrile group into a primary alcohol, followed by the
epoxidation of the double bond, afforded compound 9 as
intermediate for the synthesis of a segment of the fish poisoning
4
ciguatoxin CTX1B. The Claisen-Johnson ortho ester rear-
rangement was studied in the reaction of allylic alcohols 1 with
triethyl orthoacetate in refluxing xylene furnishing 3-cyano
3
5
esters. The Michael-type addition reactions onto the R,â-
unsaturated nitrile moiety in compounds 1 have been employed
1
6
for different synthetic purposes such as in the modified Baylis-
4
generation of the carboxylic acid 7 (R ) OH) from the nitrile
was required to perform the final macrolactonization in the
(3) (a) Trost, B. M.; Dong, L.; Schroeder, G. M. J. Am. Chem. Soc. 2005,
127, 10259-10268. (b) Trost, B. M.; Dong, L.; Schroeder, G. M. J. Am.
Chem. Soc. 2005, 127, 2844-2845.
synthesis of the (+)-patulolide C.2 A combined sequential
(4) Takemura, A.; Fujiwara, K.; Shimawaki, K.; Murai, A.; Kawai, H.;
(
(
1) Johnson, D. V.; Griengl, H. Tetrahedron 1997, 53, 617-624.
2) Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2003,
Suzuki, T. Tetrahedron 2005, 61, 7392-7419.
(5) Giardin a´ , A.; Marcantoni, E.; Mecozzi, T.; Petrini, M. Eur. J. Org.
Chem. 2001, 713-718.
5
, 3021-3024.
1
0.1021/jo060239j CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/07/2006
J. Org. Chem. 2006, 71, 3837-3848
3837

Baeza et al.
of the absolute configuration of the E/Z-mixture products
generated from preliminary palladium-catalyzed nucleophilic
allylic substitution reaction of enantiomerically enriched cy-
1
2
anocarbonates 5 (Figure 1).
Several diastereoselective synthetic sequences allow the
preparation of chiral nitriles 1, for example, the Wittig or Wittig-
type reactions using chiral aldehydes or ketones,7
,16,17
the
reaction between R-(arylsulfinyl)acetonitriles and aldehydes or
3
,5,18,19
ketones,
alkenes,
the oxyselenylation-deselenylation reaction of
8
,9,20-22
the addition of the cyanide anion to optically
2
3,24
active epoxides,
dihydroxy nitriles, and the cyanation reaction of vinyl iodides
by copper cyanide. Also, diastereoselective Wittig reactions
were used for the preparation of aminonitriles 2. The most
direct and simple synthetic approach to γ-substituted R,â-
unsaturated nitriles 1 and 2 involves cyanohydrin derivatives
the â-elimination reactions involving chiral
25
2
6
1
1
3
-5. The reduction of O-trimethylsilyl cyanohydrin 3 (Z )
4
TMS) mediated by a Lewis acid, thermal or palladium-
catalyzed [3,3]-sigmatropic rearrangements of carbonates 5 (Z
2
)
CO2R), and the palladium-mediated dynamic kinetic resolu-
FIGURE 1. Preparation and main uses of compounds 1 and 2 in
organic synthesis.
27
tion of these carbonates using a salen-palladium complex
Figure 1) have been successively employed. However, the most
(
Hillman reaction, which served to obtain a cyclic intermediate
employed in the synthesis of the illudane skeleton present in
many toxic sesquiterpenes. Intramolecular 1,4-additions onto
important and versatile strategy for the synthesis of compounds
1 and 2 is the palladium-catalyzed nucleophilic allylic substitu-
tion reaction onto derivatives 4 and 5. Racemic O-protected
7
chiral derivatives 1 have been exploited in the synthesis of
(
15) (a) Jasmin, L.; Wu, M. V.; Ohara, P. T. Curr. Drug Targets: CNS
8
9
enantiomerically enriched 1,4-dioxanes and morpholines by
the direct attack of a sodium alkoxide or a sodium carbamate,
respectively (Figure 1). Several intermediates containing the
skeleton of 1 have been proposed in the reaction of racemic
Neurol. Disord. 2004, 3, 487-505. (b) Pharmaceuticals; McGuire, J. L.,
Ed.; Wiley-VCH: Weinheim, 2000.
(
16) Marcus, J.; van Meurs, P. J.; van den Nieuwendijk, A. M. C. H.;
Porchet, M.; Brussee, J.; van der Gen, A. Tetrahedron 2000, 56, 2491-
495.
17) For racemic Wittig or Wittig-type reactions, see: (a) Gr e´ e, D.;
2
10
γ-oxo-R,â-unsaturated nitriles with Grignard reagents through
a sequential carbonyl addition-conjugated addition onto the
resulting R,â-unsaturated nitriles.
(
Vallerie, L.; Gr e´ e, R.; Toupet, L.; Washington, I.; Pelicier, J.-P.; Villacampa,
M.; P e´ rez, J. M.; Houk, K. N. J. Org. Chem. 2001, 66, 2374-2381. (b)
Cherkaoui, H.; Soufiaoui, M.; Gr e´ e, R. Tetrahedron 2001, 57, 2379-2383.
In the case of γ-nitrogenated-R,â-unsaturated nitriles 2, their
application as chiral building blocks has been directed to the
synthesis of γ-amino acids by functional group transformations
(
18) (a) Burgess, K.; Henderson, I. Tetrahedron: Asymmetry 1990, 1,
57-60. (b) Burgess, K.; Cassidy, J.; Henderson, I. J. Org. Chem. 1991,
6, 2050-2058.
19) For other uses of R-(arylsufinyl)acetonitrile in the racemic synthesis,
5
(
1
1,12
involving the cyano and carbon-carbon double bond.
R,â-
see: (a) Ono, T.; Tamaoka, T.; Yuasa, Y.; Matsuda, T.; Nokami, J.;
Wakabayashi, S. J. Am. Chem. Soc. 1984, 106, 7890-7893. (b) Nokami,
J.; Mandai, T.; Nishimura, A.; Takeda, T.; Wakabayashi, S. J. Am. Chem.
Soc. 1986, 27, 5109-5112. (c) Trost, B. M.; Tometzki, G. B. Synthesis
Unsaturated γ-amino acids are also attractive chiral building
blocks in organic synthesis12 and intriguing conformationally
restricted amino acids, especially when they are incorporated
1
2
991, 1235-1245. (d) Rodr ´ı guez-Rivero, M.; Carretero, J. C. J. Org. Chem.
003, 68, 2975-2978. (e) Adrio, J.; Rodr ´ı guez-Rivero, M.; Carretero, J.
13
into peptides as vinylogous amino acids. γ-Aminobutyric acid
(
GABA)14 is considered as an inhibitory neurotransmitter found
C. Org. Lett. 2005, 7, 431-434.
(20) (a) Tiecco, M.; Testaferri, L.; Marini, F.; Santi, C.; Bagnoli, L.;
in almost every region of the brain and spinal cord. In addition,
GABA analogues have been used for many purposes. For
example, they have been used as antineoplasic agents, as mood
Temperini, A.; Tomassini, C. Eur. J. Org. Chem. 1998, 2275-2277. (b)
Tiecco, M.; Testaferri, L.; Marini, F.; Santi, C.; Bagnoli, L.; Temperini, A.
Tetrahedron: Asymmetry 1999, 10, 747-757.
(21) For the racemic selective γ-oxyselenation-deselenylation examples,
see: (a) Tiecco, M.; Testaferri, L.; Tingoli, M.; Bagnoli, L.; Santi, C. J.
Chem. Soc., Chem. Commun. 1993, 637-638. (b) Fleming, F. F.; Wang,
Q.; Zhang, Z.; Steward, O. W. J. Org. Chem. 2002, 67, 5953-5956. (c)
Fleming, F. F.; Wang, Q.; Steward, O. W. J. Org. Chem. 2003, 68, 4235-
4238.
1
5
enhancement agents, tranquilizers, and analgesic drugs. Very
recently, a chiral nitrile 2 has been used in the determination
(
(
6) Fleming, F. F.; Wang, Q. Chem. ReV. 2003, 103, 2035-2077.
7) Tokuzaki, K.; Kanemitu, Y.; Yoshimitsu, T.; Nagaoka, H. Tetrahe-
dron Lett. 2000, 41, 5923-5926.
8) Tiecco, M.; Testaferri, L.; Marini, F.; Sternativo, S.; Santi, C.;
Bagnoli, L.; Temperini, A. Tetrahedron: Asymmetry 2003, 14, 2651-2657.
9) Tiecco, M.; Testaferri, L.; Marini, F.; Sternativo, S.; Santi, C.;
Bagnoli, L.; Temperini, A. Tetrahedron: Asymmetry 2003, 14, 1095-1102.
10) (a) Fleming, F. F.; Zhang, Z.; Wang, Q.; Steward, O. W. Angew.
(22) For different selective oxidations, see: Matsushita, Y.; Sugamoto,
K.; Nakama, T.; Sakamoto, T.; Matsui, T. Tetrahedron Lett. 1995, 36,
1879-1882.
(
(
(23) Urabe, H.; Matsuda, T.; Sato, F. Tetrahedron Lett. 1992, 33, 4179-
4182.
(
(24) For other racemic processes involving cyanomethyloxiranes, see:
(a) Larcheveque, M.; Perriot, P.; Petit, Y. Synthesis 1983, 297-299. (b)
Fleming, F. F.; Wang, Q.; Steward, O. W. J. Org. Chem. 2001, 66, 2171-
2174.
(25) (a) Tanikaga, R.; Hosoya, K.; Kaji, A. Chem. Lett. 1987, 829-
832. (b) Kang, S. K.; Lee, D. H.; Kim, Y. S. C. Synth. Commun. 1992, 22,
1109-1113.
(26) (a) Yamakawa, I.; Urabe, H.; Kobayashi, Y.; Sato, F. Tetrahedron
Lett. 1991, 32, 2045-2048. (b) Ostwald, R.; Chavant, P.-Y.; Stadtm u¨ ller,
H.; Knochel, P. J. Org. Chem. 1994, 59, 4143-415.
(27) Gais, H.-J.; Bondarev, O.; Hetzer, R. Tetrahedron Lett. 2005, 46,
6279-6283.
Chem., Int. Ed. 2004, 43, 1126-1129. (b) Fleming, F. F.; Zhang, Z.; Wei,
G.; Steward, O. W. Org. Lett. 2005, 7, 447-449.
(
11) Colson, P.-J.; Hegedus, L. S. J. Org. Chem. 1993, 58, 5918-5924.
(12) Deardorff, D. R.; Taniguchi, C. M.; Nelson, A. C.; Pace, A. P.;
Kim, A. J.; Pace, A. K.; Jones, A.; Tafti, S. A.; Nguyen, C.; O’Connor, C.;
Tang, J.; Chen, J. Tetrahedron: Asymmetry 2005, 16, 1655-1661.
(
13) (a) Hagihara, M.; Schreiber, S. L. J. Am. Chem. Soc. 1992, 114,
6
1
570-6571. (b) Kotter, T.; Klein, A.; Giannis, A. Angew. Chem., Int. Ed.
992, 31, 1391-1392.
(14) Camps, P.; Mu n˜ oz-Tornero, D.; S a´ nchez, L. Tetrahedron: Asym-
metry 2004, 15, 311-321 and references therein.
3838 J. Org. Chem., Vol. 71, No. 10, 2006

Synthesis of γ-Substituted R,â-Unsaturated Nitriles
In this article, we describe a comprehensive study of the
synthetic potential of the enantioenriched cyanohydrin-O-
carbonates 5 and cyanohydrin-O-phosphates 6 to provide the
corresponding γ-substituted R,â-unsaturated nitriles using het-
eronucleophiles and malonate as nucleophiles in the presence
of palladium or iridium complexes as catalysts. The optimal
conditions for each nucleophile and substrate, concerning the
stereoselectivity and enantioselectivity, as well as the compari-
son between the carbonate and the phosphate as leaving groups
will be evaluated.
FIGURE 2. Chiral bifunctional complex 10.
cyanohydrins 4 and 5 have been transformed into γ-function-
alized R,â-unsaturated nitriles by using NaOAc, sodium azide,
and tin alkoxides as nucleophiles.28 Enantioenriched O-acyl
cyanohydrins 4 (Z ) COR) have been used as allylic substrates
Results and Discussion
35
As part of the very attractive family of cyanohydrins, chiral
3
0
in the reactions with sodium carboxylates,1,29 and optically active
cyanocarbonates 5 and, for the first time, chiral cyanophos-
3
1
phates 6 have been prepared by our research group in very
cyanohydrin carbonates 5 (X ) CO2R) have been transformed
into products 2 by reaction with sodium azide or trimethylsilyl
high enantiomeric excess (ee) from aldehydes, in only one-step
36
1
2
process, using chiral bifunctional (R)- or (S)-BINOLAM-AlCl
complexes 10 (Figure 2) as catalysts. Certainly, the preparation
of the enantiomerically enriched cyanohydrin-O-phosphates 6
represented a synthetic task more difficult than the elaboration
azide.
We have recently described the enantioselective cyanoformy-
lation30 and cyanophosphorylation31 of aldehydes catalyzed by
the bifunctional complex BINOLAM-AlCl 10 (Figure 2), which
afforded enantiomerically enriched cyanohydrin-O-carbonates
3
7
of the racemic ones, and the chemical (non-enzymatic)
31
procedures to achieve them were recently reported by us and
5
and -phosphates 6, respectively. Preliminary studies about the
3
8
39,40
Shibasaki’s group. A priori, cyanohydrin-O-phosphates
reactivity of these chiral phosphates 6, derived from R,â-
unsaturated aldehydes, in the palladium-catalyzed nucleophilic
substitution with NaOAc and dibenzylamine allowed the dias-
tereoselective and stereospecific generation of the compounds
resemble very exciting molecules due to their high functional
density and the electrophilic character of the phosphate moiety,
which has been the choice by nature in multiple biotransfor-
mations acting as the leaving group.
3
4
31
1
(R ) Ac) and 2 (R ) n-Bu). From these studies, we could
establish that the compounds 1 and 2 with (E)-configuration
were obtained with retention (double inversion) of the config-
uration and the Z-isomer with inversion of the configuration
(35) For recent reviews of the synthesis and applications of cyanohydrins
and their derivatives, see: (a) North, M. Synlett 1993, 807-820. (b)
Effenberger, F. Angew. Chem., Int. Ed. Engl. 1994, 33, 1555-1563. (c)
Gregory, R. J. H. Chem. ReV. 1999, 99, 3649-3682. (d) North, M.
Tetrahedron: Asymmetry 2003, 14, 147-176. (e) Poechlauer, P.; Skranc,
W.; Wubbolts, M. Asymmetric Catalysis on Industrial Scale; Blaser H. U.,
Schmidt, E., Eds.; Wiley-VCH: Weinheim, 2004; pp 151-164. (f) North,
M. Science of Synthesis; Murahashi, S.-I., Ed.; Thieme: Stuttgart, 2004;
Vol. 19, pp 235-284. (g) Brunel, J.-M.; Holmes, I. P. Angew. Chem., Int.
Ed. 2004, 43, 2752-2778. (h) Synthesis and Applications of Non-Racemic
Cyanohydrins and R-Amino Acids. Tetrahedron Symposium in Print; North,
M., Ed.; 2004, 60, 10371-10568.
31
after the palladium-catalyzed nucleophilic substitution. Usually
allylic acetates 4 and, especially, carbonates 5 are used instead
of the unknown (and not easily accessible) enantioenriched
phosphates 6.3
2,33
The oxidative addition involved in this process
onto allylic electrophiles to give allyl-substituted palladium(II)
species is faster for allylic carbonates, while allylic phosphates
and the analogous carboxylates possess a similar chemical
34
behavior in this type of reaction.
(36) For reviews about bifunctional catalysis, see: (a) Gr o¨ ger, H. Chem.-
Eur. J. 2001, 7, 5246-5251. (b) Rowlands, G. J. Tetrahedron 2001, 57,
1865-1882. (c) Shibasaki, M.; Kanai, M.; Funabashi, K. Chem. Commun.
2002, 1189-1199. (d) Matsunaga, S.; Ohshima, T.; Shibasaki, M. AdV.
Synth. Catal. 2002, 344, 3-15. (e) Kanai, M.; Kato, N.; Ichikawa, E.;
Shibasaki, M. Synlett 2005, 1491-1508.
(37) (a) Mic o´ , I.; N a´ jera, C. Tetrahedron 1993, 49, 4327-4322. (b)
Baeza, A.; N a´ jera, C.; Sansano, J. M. ARKIVOC 2005, ix, 353-363.
(38) Abiko, Y.; Yamahiwa, N.; Sugita, M.; Tian, J.; Matsunaga, S.;
Shibasaki, M. Synlett 2004, 2434-2436.
(39) For some examples of synthetic applications of the racemic
cyanohydrin-O-phosphates, see: (Preparation of other nitriles) (a) Haru-
sawa, S.; Yoneda, R.; Kurihara, T.; Hamada, Y.; Shiori, T. Tetrahedron
Lett. 1984, 25, 427-428. (b) Yoneda, R.; Harusawa, S.; Kurihara, T. J.
Chem. Soc., Perkin Trans. 1 1988, 3163-3168. (c) Yoneda, R.; Osaki, H.;
Harusawa, S.; Kurihara, T. J. Chem. Soc., Perkin Trans. 1 1990, 607-610.
(d) Yoneda, R.; Harusawa, S.; Kurihara, T. J. Org. Chem. 1991, 56, 1827-
1832. (In Friedel-Crafts acylations and [3,3]-sigmatropic rearrange-
ments): (e) Kurihara, T.; Harusawa, S.; Hirai, J.; Yoneda, R. J. Chem. Soc.,
Perkin Trans. 1 1987, 1771-1776. (f) Kurihara, T.; Miki, M.; Santo, K.;
Harusawa, S.; Yoneda, R. Chem. Pharm. Bull. 1986, 34, 4620-4628. (g)
Kurihara, T.; Miki, M.; Yoneda, R.; Harusawa, S. Chem. Pharm. Bull. 1986,
34, 2747-2753. (h) Kurihara, T.; Santo, K.; Harusawa, S.; Yoneda, R.
Chem. Pharm. Bull. 1987, 35, 4777-4788. (i) Yoneda, R.; Santo, K.;
Harusawa, S.; Kurihara, T. Synth. Commun. 1987, 17, 921-92. (In
heterocyclic synthesis): (j) Kurihara, T.; Hanakawa, M.; Harusawa, S.;
Yoneda, R. Chem. Pharm. Bull. 1983, 31, 2932-2935.
(
28) For other racemic procedures catalyzed by palladium complexes,
see: (a) Tsuji, J.; Ueno, H.; Kobayashi, Y.; Okumoto, H. Tetrahedron Lett.
1
1
3
981, 22, 2573-2574. (b) Keinan, E.; Roth, Z. J. Org. Chem. 1983, 48,
769-1772. (c) Keinan, E.; Sahai, M.; Roth, Z. J. Org. Chem. 1985, 50,
558-3566. (d) Tsuji, J.; Shimizu, I.; Minami, I.; Ohashi, Y.; Sugiura, T.;
Takahashi, K. J. Org. Chem. 1985, 50, 1523-1529. (e) Deardorff, D. R.;
Taniguchi, C. M.; Tafti, S. A.; Kim, H. Y.; Choi, S. Y.; Downey, K. J.;
Nguyen, T. V. J. Org. Chem. 2001, 66, 7191-7194.
(
29) Abe, H.; Nitta, H.; Mori, A.; Inoue, S. Chem. Lett. 1992, 2443-
2
446.
30) (a) Casas, J.; Baeza, A.; Sansano, J. M.; N a´ jera, C.; Sa a´ , J. M.
(
Tetrahedron: Asymmetry 2003, 14, 197-200. (b) Casas, J.; Baeza, A.;
N a´ jera, C.; Sansano, J. M.; Sa a´ , J. M. Eur. J. Org. Chem. 2006, 1949-
1
958.
(31) (a) Baeza A.; Casas J.; N a´ jera, C.; Sansano, J. M.; Sa a´ , J. M. Angew.
Chem., Int. Ed. 2003, 42, 3143-3146. (b) Baeza, A.; N a´ jera, C.; Sansano,
J. M.; Sa a´ , J. M. Chem.-Eur. J. 2005, 11, 3849-386.
(32) (a) Handbook of Organopalladium Chemistry for Organic Systems;
Negishi, E., Ed.; Wiley: New York, 2002; Vol. II, Chapter V.2, p 1669.
(
(
b) Tsuji, J. Palladium Reagents and Catalysis; Wiley: Chichester, 2004.
c) Paquin, J.-F.; Lautens, M. ComprehensiVe Asymmetric Catalysis,
Supplement 2; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
Heidelberg, 2004; pp 73-95.
(33) For recent reviews of asymmetric palladium-catalyzed allylic
substitutions, see: (a) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103,
921-2943. (b) Trost, B. M. J. Org. Chem. 2004, 69, 5813-5837. (c)
Miyabe, H.; Takemoto, Y. Synlett 2005, 1641-1655.
34) Tsuji, J. Palladium Reagents and Catalysts: InnoVations in Organic
Synthesis; Wiley: Chichester, 1995; p 22.
2
(40) The reactivity as R-acyl anion synthon of a cyanohydrin-O-chiral-
cyclic-amidophosphate has been reported: (a) Schrader, T. Angew. Chem.,
Int. Ed. 1995, 34, 917-919. (b) Schrader, T. Chem.-Eur. J. 1997, 3, 1273-
1282.
(
J. Org. Chem, Vol. 71, No. 10, 2006 3839

Baeza et al.
SCHEME 1. Enantioselective Synthesis of Cyanohydrin
Derivatives 5 and 6
analyzed, clearly indicating that the mixture Pd(OAc)2/dppe gave
the best (E)-2aa/(Z)-2aa ratio (Table 1 entries 2-8). The
introduction of lower amounts of palladium produced lower
chemical yields in uncompleted reactions. The influence of the
solvent was studied with the mentioned catalytic mixture (Table
1
, entries 2, 9-11) obtaining the highest selectivity in shorter
reaction times in the reaction run in toluene (Table 1, entry 11).
Other solvents as dichloromethane or THF gave the same
chemical yields, affording (E)-2/(Z)-2 ratios (94:6) lower than
that of the reaction performed in the presence of toluene (Table
1
, entries 9-11). The couple Pd(OAc)2/tris(o-tolyl)phosphine
was also tested and achieved a faster reaction with a lower (E)-
aa/(Z)-2aa ratio (Table 1, compare entries 11 and 12). For
2
carbonate 5a, a lower loading of Pd(OAc)2 (3 mol %) was used,
giving Ph3P and dppe the same results in acetonitrile, although
dppe showed cleaner reaction products (Table 1, entries 13 and
14). A noticeable reaction acceleration was observed in toluene
that afforded a slightly better (E)-2aa/(Z)-2aa ratio and 5% of
the R-substitution product (Table 1, entry 15). Despite lowering
the reaction temperature at 0 and -10 °C, it was not possible
to direct the reaction to give pure R-substitution product,
achieving its maximum percentage when the reaction was
performed at 0 °C (Table 1, entries 15-17). In any case, these
R-substitution products were isolated and characterized because
their separation from the (E)-2/(Z)-2 mixtures was not possible.
It can be concluded that the cyanohydrin-O-phosphate 6a gave
the highest E/Z-diastereomeric ratio of compound 2aa using Pd-
(OAc)2/dppe as catalyst and toluene as solvent. Although the
analogous carbonate 5a needed lower catalyst loading, competi-
tive R-substitution occurred for this type of substrate.
By employing these reaction conditions, different cyanohy-
drin-protected carbonates 5 and phosphates 6 reacted with
dibenzylamine or benzylamine, affording mixtures of (E)-2a/
Unsaturated cyanohydrin-O-carbonates 5 and phosphates 6,
derived from R,â-unsaturated aldehydes, with (R)-configuration
were the selected starting materials to run the allylic displace-
ment of the carbonate and phosphate groups. They were obtained
from the corresponding aldehydes employing a 10 mol % of
(Z)-2a (Table 2). Carbonate 5d, derived from cinnamaldehyde,
3
0
gave much better E/Z-diastereoselectivity than the crotonalde-
hyde derivative 5a (Table 2, entries 1 and 2). Cyanophosphates
6a,d,e derived from crotonaldehyde, cinnamaldehyde, and
the catalyst (S)-10 and 3 equiv of methyl cyanoformate and
.1 equiv of diethyl cyanophosphonate, respectively, at room
1
31
temperature under anhydrous conditions (Scheme 1). The
additional treatment of the reaction mixture in acidic media was
made with the aim to recover the chiral ligand (S)-3,3′-bis-
2
-methylbut-2-en-al, respectively, furnished good yields and
high diastereomeric ratios (Table 2, entries 3-5). The less
nucleophilic benzylamine reacted with cyanohydrin-O-phosphate
6a under the optimized nucleophilic allylic substitution condi-
tions, achieving diastereoselectivity similar to that exhibited by
dibenzylamine, and the pure compound (E,R)-2ba was isolated
after selective solubilization in hexanes with an overall retention
of the configuration (Table 2, entry 6). On the other side, very
high (E)-diastereoselection was detected in the reaction involv-
ing the cinnamaldehyde derivative (R)-6d, but surprisingly,
(
diethylaminomethyl)-1,1′-bi(2-naphthol) [(S)-BINOLAM] al-
30,31
most quantitatively (up to 91%).
Particularly, the ee of the
cyanohydrin-O-phosphate 6a was very sensitive to the humidity
present in the freshly distilled crotonaldehyde, the enantiomeric
excesses being achieved in the range of 88-92%.
Nitrogenated Nucleophiles. Initially, the allylic phosphate
6a, derived from crotonaldehyde, was selected for the optimiza-
tion of the reaction conditions of each tested nucleophile, and
dibenzylamine was chosen as the heteronucleophile in the model
reaction, which will serve as a general pattern to be extended
to other nitrogenated nucleophiles. The reactions were performed
at room temperature employing a catalyst charge of 5 mol %
of a palladium source and 10 mol % of the corresponding
phosphine. To establish the best chemical yield and the best
E/Z-ratio, palladium(II) acetate was first tested in acetonitrile
as solvent and using several phosphines (Table 1, entries 1-3).
The best E/Z ratio corresponded to the catalytic mixture
composed of palladium(II) acetate (5 mol %)/1,2-bis(diphe-
nylphosphino)ethane (dppe, 10 mol %), (Table 1, entry 2). Next,
the effects of the different palladium sources such as palladium-
(
E,R)-2bd was isolated with a very significant loss of optical
activity (Table 2, entry 7). Both reactions were completed in
2
5
as nucleophile [Pd(OAc)2 (3 mol %)/dppe (6 mol %), toluene,
room temperature], the reaction did not occur as expected. While
5
including a low proportion of 2ba, carbonate 5d gave N-benzyl
O-methyl carbamate 11 and the corresponding cyanohydrin 12d
as major reaction products as a consequence of the direct attack
of the amine onto the carbonyl group (Scheme 2).
.5 h as revealed GC analysis. When cyanocarbonates 5a and
d were submitted to the reaction conditions using benzylamine
a afforded a very complex mixture of unidentified products,
Iridium complexes also catalyzed this type of nucleophilic
3
3c,41
(II) acetate, tetrakis(triphenylphosphine)palladium(0), tris(diben-
allylic substitutions.
In this context, the catalyst [Ir(COD)-
zylideneacetone)dipalladium(0), and π-allylpalladium(II) chlo-
Cl]2 (2.5 mol %) promoted the nucleophilic substitution reaction
ride dimer, with or without addition of phosphine, were
of benzylamine onto chiral phosphate 6a, in toluene, giving the
3840 J. Org. Chem., Vol. 71, No. 10, 2006

Synthesis of γ-Substituted R,â-Unsaturated Nitriles
TABLE 1. Optimization of the Palladium-Catalyzed Allylic Substitution Reactions Using Dibenzylamine
5a or 6a
entry
(% ee)
Z
Pd source
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
phosphine
Ph3P
solvent
time (h)
(E)-2aa/(Z)-2aaa
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
6a (88)
6a (88)
6a (88)
6a (88)
6a (88)
6a (88)
6a (88)
6a (88)
6a (88)
6a (88)
6a (90)
6a (90)
5a (74)
5a (74)
5a (74)
5a (74)
5a (74)
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
CO2Me
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
CH2Cl2
THF
12
18
> 24
20
12
18
17
15
12
12
6
(77)/(23)
(86)/(14)
(78)/(22)
(73)/(27)
(70)/(30)
(76)/(24)
(75)/(25)
(78)/(22)
(75)/(25)
(87)/(23)
(94)/(6)
(83)/(17)
(72)/(27)
(72)/(27)
(75)/(25)
(87)/(13)
(75)/(25)
85
91
<25
91
92
90
90
87
91
90
89
90
88
88
nd
88
88
88
88
88
88
88
90
90
74
74
74
74
74
d
dppe
dpppe
-
Pd(Ph3P)4
(PdCl-π-allyl)2
Pd(Ph3P)4
(PdCl-π-allyl)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
-
-
dpped
d
dppe
dpped
f
d
10
11
12
13
14
15
16
17
dppe
dpped
PhMe
PhMe
MeCN
MeCN
PhMe
(o-Tol)3P
Ph3P
1
g
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
20
20
1
9
20
80
g
d
CO2Me
CO2Me
CO2Me
CO2Me
dppe
80
94
80
94
g
dpped
dpped
dpped
h
g
i
j
PhMe
g
PhMek
l
Pd(OAc)2
a
1
b
c
Determined by H NMR spectroscopy. Isolated yield of the (E)-2aa/(Z)-2aa mixture after flash chromatography. Enantiomeric excesses for both E-
d
e
and Z-isomers, determined by chiral HPLC (Chiralcel OD-H). dppe ) 1,2-bis(diphenylphosphino)ethane. dppp ) 1,3-bis(diphenylphosphino)propane.
f
1
g
1
0% of the corresponding R-substitution product was observed by H NMR spectroscopy in the crude reaction mixture. A 3 mol % charge of palladium(II)
h
1
i
j
acetate and a 6 mol % of the phosphine were used. 5% of the R-substitution product was identified by H NMR. Performed at 0 °C. A 1:1 ratio of R-
1
k
l
1
and γ-substitution products was identified by H NMR. Performed at -10 °C. A 1:4 ratio of R- and γ-substitution products was identified by H NMR.
TABLE 2. Palladium-Catalyzed Allylic Substitution Reactions onto 5 and 6 Using Dibenzylamine and Benzylamine
5/6
1
2
(E)-2/(Z)-2a
yield (%)b
ee (%)c
entry
(% ee)
R , R
Z
amine
time (h)
1
2
3
4
5
6
7
5a (74)d
5d (68)
6a (90)
6d (95)
6e (82)
6a (92)
6d (95)
Me, H
Ph, H
Me, H
Ph, H
Me, Me
Me, H
Ph, H
CO2Me
CO2Me
Bn2NH
Bn2NH
Bn2NH
Bn2NH
Bn2NH
BnNH2
BnNH2
1
20
1
10
24
2.5
2.5
(E)-2aa (75)/(Z)-2aa (25)
(E)-2ad (99)/(Z)-2ad (1)
(E)-2aa (94)/(Z)-2aa (6)
(E)-2ad (95)/(Z)-2ad (5)
(E)-2ae (90)/(Z)-2ae (10)
(E)-2ba (93)/(Z)-2ba (7)
(E)-2bd (99)/(Z)-2bd (1)
94e
94
90
86
70
86
91
74
68f
90
d
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
f
95
82f
g
92
31
g
a
Determined by H NMR spectroscopy. Isolated yield of the (E)-2/(Z)-2 mixtures after flash chromatography. c Identical enantiomeric excesses for both
1
b
d
E- and Z-isomers, determined by chiral HPLC (Chiralcel OD-H). A 3 mol % charge of palladium(II) acetate and a 6 mol % of the phosphine were added.
e
% of the R-substitution product was identified by H NMR. Chiralpak AS. g Chiralpak AD.
1
f
5
SCHEME 2. Side Reaction of Compound 5d with
Benzylamine
SCHEME 3. Iridium-Catalyzed Dibenzylamine Substitution
onto 6a
times (12 h) than with Pd(OAc)2 (Scheme 3). Unfortunately,
no reaction occurred with carbonates 5 under identical reaction
conditions. In the palladium-catalyzed addition of sodium azide
onto carbonates, we observed a noticeable amount of the product
resulting from the a-attack; however, this product was not
observed when the reaction was performed with iridium. It has
highest (E)-2aa/(Z)-2aa ratio (98:2) in very good chemical yields
with total retention of the configuration but in longer reaction
(
41) (a) Miyabe, H.; Matsumura, A.; Moriyama, K.; Takemoto, Y. Org.
Lett. 2004, 6, 4631-4634. (b) Lipowski, G.; Helmchem, G. Chem. Commun.
004, 116-117. (c) Miyabe, H.; Yoshida, K.; Yamauchi, M.; Takemoto,
Y. J. Org. Chem. 2005, 70, 2148-2153.
4
2
43
44
been reported that rhodium, ruthenium, and molybdenum
complexes also promoted the nucleophilic allylic substitution
2
J. Org. Chem, Vol. 71, No. 10, 2006 3841

Baeza et al.
TABLE 3. Palladium-Catalyzed Allylic Substitution Reactions Using Sodium Azide
5/6
entry
(% ee)
R1
Z
phosphine
solvent
time (h)
(E)-2c/(Z)-2ca
yield (%)b
ee (%)c
74
d
THF/H2Oe
1
2
3
4
5
5a (74)
5b (72)
5b (72)
6a (92)
6a (92)
Me
CO2Me
CO2Me
CO2Me
PO(OEt)2
PO(OEt)2
Ph3P
24
24
24
(E)-2ca (84)/(Z)-2ca (16)
(E)-2cb (84)/(Z)-2cb (16)
(E)-2cb (84)/(Z)-2cb (16)
(E)-2ca (72)/(Z)-2ca (28)
(E)-2ca (82)/(Z)-2ca (18)
85
85
85
65
85
d
e
f
C3H7
C3H7
Me
Ph3P
THF/H2O
80
d
THFg
h
80f
92
92
Ph3P
Ph3P
dppe
THF/H2Oe
THF/H2Oe
24
6
Me
a
Determined by H NMR spectroscopy. Isolated yield of (E)-2c/(Z)-2c mixtures after flash chromatography. c Enantiomeric excesses for both E- and
1
b
d
Z-isomers, determined by chiral HPLC (Chiralpak AD). The reaction was performed with 3 mol % of palladium(II) acetate and 6 mol % of the corresponding
phosphine. 1:1 mixture (in volume). f Enantiomeric excesses for both E- and Z-isomers, determined by chiral HPLC (Chiralpak AS). Anhydrous.
e
g
h
Trimethylsilyl azide (1.5 equiv) was used instead of sodium azide.
reactions with different regioselectivity, but in these title
transformations neither carbonates 5 nor phosphates 6 gave any
noticeable result. Thus, the iridium-catalyzed allylic substitution
reaction represented a valuable alternative to prepare γ-diben-
zylamino R,â-unsaturated nitriles only from chiral cyanohydrin-
O-phosphates.
FIGURE 3. Compound E/Z-13.
SCHEME 4. Iridium-Catalyzed Substitution onto 6a with
Sodium Azide
Sodium azide proved to be a very useful nucleophile in the
palladium-catalyzed allylic substitution reaction onto racemic
cyanoallylic carbonates, such as those described previously,
employing mixtures of THF/water as solvent, (Ph3P)4Pd as
catalyst, and working at room temperature.2 In trying the same
reaction conditions for chiral allylic carbonates 5 and phosphates
8e
6
, we observed that the mixture Pd(OAc)2/dppe or Ph3P gave
furnishing, such as occurred in the precedent reactions with
dibenzylamine, the highest (E)-2ca/(Z)-2ca ratios (95:5) in a
better results and cleaner reaction products. Thus, sodium azide
reacted slowly with carbonate 5a in approximately 1 d,
employing Pd(OAc)2 (3 mol %)/triphenylphosphine (6 mol %)
and giving a 84:16 mixture of (E)-2ca/(Z)-2ca (Table 3, entry
1:1 mixture of THF/water (12 h) in good chemical yields (76%)
(Scheme 4). Under these reaction conditions employing sodium
azide, cyanophosphate 6d yielded, basically, isomerized product
13, and carbonate 5a did not react at all.
All these results revealed that cyanohydrin-O-phosphates
1
). Analogously, 5b gave the same diastereoselectivity in both
1
2
examples run with sodium azide or with trimethylsilyl azide
in anhydrous THF (Table 3, entries 2 and 3). Compound 5c
derived from (E)-oct-2-enal] was inert under the described
reaction conditions. Starting material (R)-6a afforded compounds
E)-2ca and (Z)-2ca in ratios dependent on the phosphine used;
6
a-e satisfactorily underwent both economical and chemical
[
nucleophilic allylic substitution reactions with nitrogenated
nucleophiles employing Pd(OAc)2 (5 mol %)/dppe (10 mol %)
as catalyst. Meanwhile, the [Ir(COD)Cl]2 complex was a good
alternative method to obtain and characterize almost pure (E,R)-
(
for example, the reaction involving dppe (10 mol %) as additive
provided both yields (85%) and diastereomeric ratios (82:18)
higher than those of the reaction performed with triphenylphos-
phine (10 mol %) (Table 3, compare entries 4 and 5). Unlike
the reaction with carbonate 5a with trimethylsilyl azide,
cyanohydrin-O-phosphate 6a did not afford the desired molecule
2
ca product from phosphate 6a. Normally, the reactions of
cyanohydrin-O-phosphates 6 were faster, or run in the same
reaction times, than the corresponding reactions of carbonates
5
. On the other side, phosphates 6 and more versatile reagents
than carbonates 5 (in terms of reactivity) were independent of
the nucleophile used or structural backbone.
(
E)-2ca. Disappointingly, it was not possible to generate
cinnamaldehyde derivatives (E)-2cd and (Z)-2cd in more than
0% yield, and instead the isomerized compound E/Z-13 was
In general, the obtained compounds (E)-2c and (Z)-2c are
very interesting R,â-unsaturated γ-amino nitriles. Usually,
conventional functional group transformation operating under
mild conditions is required to access enantiomerically enriched
1
generated in quantitative yield, as occurred in the reaction with
the iridium complex (Figure 3). In the examples run with
carbonates 5, the use of dppe as ligand afforded very low
conversions of the allylic substitution product.
The phosphine-free iridium-catalyzed allylic substitution was
also tested with [Ir(COD)Cl]2 (2.5 mol %) in the allylic
substitution reaction of sodium azide (2 equiv) onto alkene 6a
1
3
15
R,â-unsaturated γ-amino acids or γ-amino acids (GABA).
The already mentioned opposite configuration observed for
(E)-1 or -2 versus (Z)-1 or -2 was clearly identified by the
exhaustive HPLC analysis of each derivatized enantiomeric
mixture of the diamine 14, which was obtained in a parallel
manner from enantiomerically enriched carbonate 5a and
phosphate 6a. The simultaneous reduction of the carbon-carbon
double bond and the nitrile group of (E)- and (Z)-2aa using
lithium aluminum hydride, followed by protection of the
resulting primary amine with benzoyl chloride in the presence
of pyridine, led to N-benzoyl-1,4-diamine 14 (Scheme 5). The
(
42) Leahy, D. K.; Evans, P. A. Modern Rhodium-Catalyzed Organic
Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005; pp 191-214.
43) Kondo, T.; Mitsudo, T. Ruthenium in Organic Synthesis; Wiley
VCH: Weinheim, 2004; pp 129-151.
44) (a) Belda, P. A.; Moberg, C. Acc. Chem. Res. 2004, 37, 159-167.
b) Krska, S. W.; Hughes, D.; Reamer, R. A.; Mathre, D. J.; Palucki, M.;
Yasuda, N.; Sun, Y.; Trost, B. M. Pure Appl. Chem. 2004, 76, 625-633.
(
(
(
3842 J. Org. Chem., Vol. 71, No. 10, 2006

Synthesis of γ-Substituted R,â-Unsaturated Nitriles
SCHEME 5. Determination of the Opposite Configuration of (E)- and (Z)-2aa
TABLE 4. Optimization of the Palladium-Catalyzed Allylic Substitution Reactions onto 6a and 5a Using NaOAc and TBAA
5
a or 6a
product (E)-1ba
yield (%)b ee (%)c
entry
(% ee)
Z
XOAc (equiv)
phosphine
solvent
MeCN
time (h)
(E)-1aa/(Z)-1aaa
d
1
2
3
4
5
6
7
8
9
6a (88)
6a (88)
6a (88)
6a (88)
6a (88)
6a (92)
6a (88)
6a (88)
5a (74)
5a (74)
5a (74)
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
CO2Me
NaOAc(4)
NaOAc(4)
NaOAc(4)
Ph3P
dppe
dppe
dppe
dppe
Ph3P
Ph3P
(o-Tol)3P
Ph3P
20
20
24
0.4
1
0.8
1
0.5
20
24
0.8
(83)/(17)
(78)/(22)
(72)/(28)
(70)/(30)
(78)/(22)
(81)/(19)
(83)/(17)
(78)/(22)
(83)/(17)
(75)/(25)
(82)/(18)
78
63
50
60
70
77
78
70
77
70
75
88
88
88
88
88
92
88
88
74
74
74
d
MeCN
THF/H2Oe
THF
d
TBAA (1.5)
TBAA (1.5)
TBAA (1.5)
TBAA (1.5)
TBAA (1.5)
f
THF
THF
THF
f
THF
d
NaOAc (4)
MeCN
MeCN
THF
d
1
1
0
1
CO2Me
CO2Me
NaOAc (4)
(o-Tol)3P
Ph3P
TBAA (1.5)
a
Determined by H NMR spectroscopy. Isolated yield of allylic alcohols (E)-1ba after flash chromatography. c Identical enantiomeric excesses for both
1
b
E- and Z-isomers of the compounds (E)-1aa and (Z)-1aa [determined by chiral HPLC (Chiralcel OD-H)] and (E)-1ba (determined by comparison between
their optical rotations and the values reported in the literature). d AcOH (4 equiv) was added. e 1:1 mixture in volume. Reaction run at 0 °C.
f
final ee obtained for the unknown compound 14 was determined
by chiral HPLC analysis (Daicel Chiralpak AD).31
better ligand than (o-tolyl)3P and dppe (Table 4, entries 4-6
and 8), giving the highest (E)-1aa/(Z)-1aa ratio by lowering
the temperature to 0 °C (Table 4, entries 5 and 7). The same
pattern of reactivity was observed in the reactions performed
with cyanocarbonate 5a, where acetonitrile was the selected
solvent and triphenylphosphine was preferred over tris(o-tolyl)-
phosphine (Table 4, entries 9 and 10). Surprisingly, with dppe
the reaction did not work at all. The expected acceleration
occurred when the reaction was run with TBAA, obtaining
slightly lower (E)-1aa/(Z)-1aa ratios than the analogous reaction
carried out with NaOAc (Table 4, entry 11). In this occasion,
all the tests onto carbonates 5 were run with 5 mol % of
palladium(II) acetate because uncompleted reactions were
observed after 1 d when 3 mol % of the metal salt was added.
To summarize, the best reaction conditions for both reagents
were Pd(OAc)2 (5 mol %)/Ph3P (10 mol %) as catalytic mixture,
room temperature, and acetonitrile (when using NaOAc) and
THF (when using TBAA) as solvents.
With these optimized reaction conditions in hand, several
chiral carbonates (5a, 5b, and 5c) were allowed to react with
both NaOAc (Table 5 entries 1, 3, and 5) and TBAA (Table 5,
entries 2, 4, and 6). At room temperature, both acetates gave
an identical (E)-1a/(Z)-1a ratio and chemical yield for each
particular chiral carbonate but required different reaction times,
while NaOAc took 24 h to complete the reaction that TBAA
just needed 1 h to complete. No reaction was observed when
cinnamaldehyde derivative 5d was employed as starting mate-
rial. Cyanohydrin-O-phosphates 6a and 6c, together with
Oxygenated Nucleophiles. Several acetates were employed
in the palladium-catalyzed nucleophilic substitution upon allylic
electrophiles (R)-5 or (R)-6 for the preparation of γ-cyanoallylic
alcohols 1. The reaction was optimized with cyanohydrin-O-
phosphates 6a and carbonate 5a and NaOAc (4 equiv) in the
presence of AcOH (4 equiv) according to our previous experi-
ences.31 Due to high instability of the resulting unsaturated
γ-acetoxy R,â-unsaturated nitriles (E)-1a and (Z)-1a during flash
1
2
chromatography, the obtained crude products were submitted
1
to a very mild base-catalyzed hydrolysis with K2CO3 in MeOH,
3
1
affording, after purification, alcohols (E)-1b exclusively. The
optimized reaction conditions were applied to carbonate 5a and
also to another oxygenated nucleophile different from acetates.
Thus, NaOAc (4 equiv) reacted sluggishly in acetonitrile with
compound 6a in the presence of AcOH (4 equiv), Pd(OAc)2 (5
mol %), and Ph3P (10 mol %), giving an 83:17 ratio of products
3
1
(E)-1aa/(Z)-1aa in good chemical yield (Table 4, entry 1).
The substitution of the Ph3P by dppe did not have the same
positive effect as the analogous one described in the reaction
involving dibenzylamine (see above), neither in a mixture THF/
water nor in acetonitrile (Table 4, entries 2 and 3). The reaction
did not occur in toluene as solvent. More soluble tetra-n-
butylammonium acetate (TBAA) was an excellent reagent
because it took very short reaction times to complete the allylic
substitution reaction (Table 4, entries 4-8). For the particular
reaction with this source of acetate, triphenylphosphine was a
J. Org. Chem, Vol. 71, No. 10, 2006 3843

Baeza et al.
TABLE 5. Palladium-Catalyzed Allylic Substitution Reactions with Oxygenated Nucleophiles onto 5 and 6
5/6
product 1
X+ -OR3
(equiv)
time
(h)
yield
(%)
ee
(%)
b
c
entry
(% ee)
R1
Me
Z
phosphine
solvent
(E)-1/(Z)-1a
R3
No.
1
2
3
4
5
6
7
8
9
5a (74)
5a (74)
5b (72)
5b (72)
5c (80)
5c (80)
6a (88)
6a (92)
6c (94)
6c (94)
6a (90)
6a (90)
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
NaOAc (4)d
TBAA (1.5)
NaOAc (4)
TBAA (1.5)
NaOAc (4)
TBAA (1.5)
NaOAc (4)
TBAA (1.5)
NaOAc (4)
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
dppe
dppe
MeCN
THF
MeCN
THF
MeCN
THF
MeCN
THF
20
0.8
24
1
24
1
20
0.8
24
1.5
1.5
9
(E)-1aa (83)/(Z)-1aa (17)
(E)-1aa (82)/(Z)-1aa (18)
(E)-1ab (88)/(Z)-1ab (12)
(E)-1ab (88)/(Z)-1ab (12)
(E)-1ac (81)/(Z)-1ac (19)
(E)-1ac (81)/(Z)-1ac (19)
(E)-1aa (83)/(Z)-1aa (17)
(E)-1aa (81)/(Z)-1aa (19)
(E)-1ac (81)/(Z)-1ac (19)
(E)-1ac (78)/(Z)-1ac (22)
(E)-1ca (79)/(Z)-1ca (21)
(E)-1da (78)/(Z)-1da (22)
H
H
H
H
H
H
H
H
H
H
Ph
1ba
1ba
1bb
1bb
1bc
1bc
1ba
1ba
1bc
1bc
1ca
1da
77
82
80
80
83
83
78
89
73
74
74
74
72
72
80
80
88
92
94
94
Me
d
C3H7
C3H7
C5H11
C5H11
Me
d
d
Me
d
C5H11
C5H11
Me
MeCN
THF
10
11
12
TBAA (1.5)
NaOPh
e
f,g
f,h
f,h
THF
85
90
16
90
Na-NHSui
THFe
Su
j
f,g
Me
a
Determined by H NMR spectroscopy. Isolated yield of allylic alcohols (E)-1b after flash chromatography. c Identical enantiomeric excesses for both
1
b
E- and Z-isomers of the compounds (E)-1a and (Z)-1a [determined by chiral HPLC (Chiralcel OD-H)] and (E)-1b and (Z)-1b (determined by comparison
d
e
f
between their optical rotations and the values reported in the literature). AcOH (4 equiv) was added. Anhydrous. Mixture of (E)-1 and (Z)-1 compounds.
g
h
Isolated yield of compounds (E)-1c,d and (Z)-1c,d, after flash chromatography. Identical enantiomeric excesses for both E- and Z-isomers of the compounds
E)-1c,d and (Z)-1c,d [determined by chiral HPLC (Chiralpak AS)]. Sodium salt of the N-hydroxysuccinimide (Na-NHSu). Succinimide.
i
j
(
SCHEME 6. Iridium-Catalyzed Substitution onto 6a with
NaOAc and TBAA
triphenylphosphine as additive, afforded a better ratio of
compounds (E)-1ac/(Z)-1ac using NaOAc than the equivalent
reaction performed with TBAA, taking longer reaction times
(Table 5, entries 9 and 10). Once more, the cinnamaldehyde-
derived cyanohydrin-O-phosphate 6d did not afford the desired
reaction product despite modification of all of the possible
parameters, and isomerized compound (E/Z)-13 was obtained
as the major product.
If evaluating the entries and data depicted in Tables 4 and 5,
we can assume that there is not an appreciable difference
between working with phosphates 6 and carbonates 5, but
Product (E)-1bc, which is the intermediate in the synthesis
of coriolic acid, was achieved by Griengl and Johnson in a four-
step process (involving enzymatic generation of the nonracemic
cyanohydrin followed by acylation) in 55% overall yield from
1
analyzing the aspect of crude H NMR spectra, we found that
chiral phosphates 6 furnished cleaner transformations. For
oxygenated nucleophiles, it was not possible to establish a
common rule as succeeded for the nitrogenated nucleophiles.
The optimal reaction conditions with acetates required the
catalytic mixture Pd(OAc)2/Ph3P at room temperature. Never-
theless, the catalyst formed by Pd(OAc)2 and dppe was preferred
in the allylic substitution reaction involving sodium phenolate
and N-hydroxysuccinimide sodium salt.
The iridium complex [Ir(COD)Cl]2 (2.5 mol %) was also
tested in the allylic substitution reaction of cyanohydrin deriva-
tive 6a with NaOAc in acetonitrile or TBAA in THF, giving,
in both cases, poor conversions (41 and 25% after 30 h,
respectively) but in very good (E)-1aa/(Z)-1aa ratios (95:5)
(Scheme 6). Also, the iridium complex was ineffective in the
reaction of the acetates onto 6d in the presence of the standard
catalytic mixture.
1
the initial (E)-oct-2-enal. However, with our combined meth-
odology, it was possible to employ only a three-step sequence
to obtain compound (E)-1bc in a 66-67% overall yield, with
an optical purity of 80 or 94% ee for the routes involving
cynocarbonate 5c or cyanophosphate 6c.
Each enantiomeric excess of acetates (E)-1a/(Z)-1a was
determined by chiral HPLC analysis (Chiralcel OD-H), while
the optical purity of allylic alcohol was evaluated according to
the relationship between their optical rotation and the values
reported in the literature for pure original samples. Consequently,
the sign of the optical rotation of the purified allylic alcohols
3
1
29
1
(
E)-1ba, (E)-1bb, and (E)-1bc ensured the absolute con-
figuration of the newly generated stereocenters.
When other oxygenated nucleophiles such as phenol and
N-hydroxysuccinimide (previously deprotonated by reaction with
sodium hydride) were allowed to react with cyanophosphate
Sodium Dimethyl Malonate as Nucleophile. A stabilized
carbon nucleophile as sodium dimethyl malonate was chosen
for the palladium-catalyzed allylic substitution reaction (also
6a under the optimized reaction conditions discussed before [Pd-
(OAc)2 (5 mol %)/Ph3P (10 mol %)], we obtained chemical
3
2
yields and diastereomeric ratios of compounds (E)-1ca/(Z)-1ca
lower than those in the reaction run with dppe as additive (79:
called the Tsuji-Trost reaction) employing Pd(OAc)2 as
palladium source in light of the results of the experiments
performed with heteronucleophilic reagents. By using THF as
solvent, we found that dppe proved to be the more suitable
ligand for this reaction than Ph3P, obtaining the best (E)-15a/
(Z)-15a ratio in very good yield and short reaction times (Table
6, entries 1 and 2). Toluene was not so efficient a solvent as
THF, exhibiting a worse diastereomeric ratio at room temper-
2
1) (Table 5, entry 11). In this last example, almost racemized
products (E)-1ca and (Z)-1ca were obtained. However, in the
presence of dppe as ligand, the N-hydroxysuccinimide sodium
4
1c
salt proved to be a good nucleophile under these reaction
conditions giving, rather than with Ph3P, a better (E)-1da/(Z)-
1
da ratio and chemical yield (Table 5, entry 12).
3844 J. Org. Chem., Vol. 71, No. 10, 2006

Synthesis of γ-Substituted R,â-Unsaturated Nitriles
TABLE 6. Palladium-Catalyzed Allylic Substitution Reactions Using Sodium Dimethyl Malonate
5/6
entry
(% ee)
R1
Z
phosphine
solvent
time (h)
(E)-15/(Z)-15a
yield (%)b
ee (%)c
1
2
3
4
5
6
6a (88)
6a (88)
6a (88)
6d (95)
5a (74)
5a (74)
Me
Me
Me
Ph
Me
Me
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
CO2Me
Ph3P
dppe
dppe
dppe
dppe
PPh3
THF
THF
PhMe
THF
THF
THF
12
1
6
3
4
(E)-15a (58)/(Z)-15a (42)
(E)-15a (85)/(Z)-15a (15)
(E)-15a (78)/(Z)-15a (22)
(E)-15d (99)/(Z)-15d (1)
(E)-15a (80)/(Z)-15a (20)
(E)-15a (50)/(Z)-15a (50)
71
80
80
80
93
92
88
88
88
16
74
74
d
CO2Me
4
a
Determined by H NMR spectroscopy. Isolated yield after flash chromatography. c Identical enantiomeric excesses for both E- and Z-isomers, determined
1
b
d
by chiral HPLC (Chiralpak AD). Enantiomeric excesses for both E- and Z-isomers were determined by chiral HPLC (Chiralpak AS).
SCHEME 7. Opposite Absolute Configuration in (E)-1,2 and (Z)-1,2
ature (Table 6, compare entries 2 and 3). Cinnamaldehyde-
derived cyanophosphate 6d reacted with sodium dimethyl
malonate in 3 h, but the corresponding pure (E)-15d was isolated
with a notable degree of racemization (16% ee from a 95% ee
of 6d; Table 6, entry 4). The racemization could not be avoided
by lowering the temperature to 0 °C, because in this experiment
the reaction raised 10% of conversion after 8 h. Although usually
allylic carbonates reacted under neutral conditions, the reaction
of dimethyl malonate with allylic carbonates 5 did not take place
after 1 d. For this reason, sodium dimethyl malonate was used,
affording the corresponding product 15 in good yields together
with a catalyst charge of Pd(OAc)2 (5 mol %)/dppe (10 mol
expected double inversion involving intermediate 16 easily
explains why the major E-isomer of 1, 2, or 15 should possess
3
the (R)-configuration. In addition, since η -allyl palladium 17
3
3
is in equilibrium with η -allyl palladium 20 by means of a η -
1
1
3
η shift to 18, bond rotation, and η -η shift. This species
should give rise upon nucleophilic attack to the Z-isomer-1, -2,
or -15 with the opposite (S)-configuration (Scheme 7). It is also
possible that the sequence of intermediate species 17, 18, and
20, favored by affinity of the palladium atom to the nitrile group,
is responsible for the notable amounts of the Z-isomers obtained
in all of the examples described in this work. The regiochemistry
of the Pd- and Ir-catalyzed nucleophilic allylic substitution can
be justified by the apparent manifestation of the energy-lowering
effect of the olefinic conjugative overlap with the p-orbitals in
%
). The influence of the phosphine in this type of reaction is
crucial in some cases; for example, carbonate 5a afforded a high
E)-15a/(Z)-15a ratio when using dppe, while a 1:1 mixture of
2
8e
(
the cyano group as reported by Deardorff et al.
products (E)-15a and (Z)-15a was achieved with triphenylphos-
phine (Table 6, entries 5 and 6).
The observed racemization in products (E)-2bd and (Z)-2bd
(resulting from the nucleophilic attack of benzylamine; Table
2), (E)-1ca and (Z)-1ca (resulting from the nucleophilic attack
of sodium phenoxide), and (E)-15d/(Z)-15d could be due to the
The employment of the iridium complex [Ir(COD)Cl]2 (2.5
mol %) was not as advantageous as in the precedent heteronu-
cleophilic substitutions: the reaction was very slow, it was not
complete after 3 days (<40%), and its presence in the allylic
substitution reaction onto compound 6d did not avoid the almost
total racemization.
high acidity of the H proton of the cyanohydrin-O-phosphates
R
6. The normal course of the reaction should be represented by
Route A (Scheme 8), but the presence of a basic nucleophile
promoted the partial racemization just before the coordination
of the palladium atom to the alkene, such as that described in
Route B (Scheme 8). This fact was also justified by the results
obtained in the direct cyanophosphorylation reaction of enan-
Mechanistic Aspects. The already mentioned stereochemical
outcome of the cyanohydrin-O-phosphates described previ-
1
2,31
ously
performed with carbonates 5 and is consistent with the reaction
can be extended to the corresponding reactions
mechanism reported for allylic carbonates1
carbonate anion remains ligated to the palladium atom. The
2,28e
where the methyl
(45) Cantat, T.; Agenet, N.; Jutand, A.; Pleixats, R.; Moreno-Ma n˜ as, M.
4
5
Eur. J. Org. Chem. 2005, 4277-4286.
J. Org. Chem, Vol. 71, No. 10, 2006 3845

Baeza et al.
SCHEME 8. Reaction Mechanisms in Palladium-Catalyzed Allylic Substitution Reactions onto Compounds 6a,d
tiomerically enriched cyanohydrins catalyzed by bases12 and by
the studies of racemization of enantiomerically enriched cy-
anohydrin-O-phosphates in the presence of 1 equiv of amine.
According to these data, the bulkier dibenzylamine was the
unique reagent able to react cleanly with substrate (R)-6d
through Route A, avoiding undesired epimerizations and
isomerizations.
The increased extended conjugation effect underwent the
R-carbon in molecule 6d and probably caused an increment of
the acidity of its HR, unlike the acidity of HR of the molecules
expected Route A using the appropriate palladium/phosphine
catalytic system (see Tables 1, 3, and 4 and Scheme 8). Although
it was not indicated in Scheme 8, Routes B and C can be
connected because a first racemization, promoted by a basic
and weak nucleophile, followed by a further isomerization
cannot be discarded.
4
6
Conclusions
In general, enantioenriched cyanohydrin-O-phosphates, de-
rived from R,â-unsaturated aldehydes, are better substrates than
carbonates for the metal-catalyzed regiospecific nucleophilic
allylic substitution reactions affording γ-substituted R,â-unsatur-
ated nitriles with higher (E)-diastereoselectivity. From all tested
nitrogenated nucleophiles, such as dibenzylamine, benzylamine,
sodium azide, and trimethylsilyl azide, dibenzylamine was the
most efficient and diastereoselective reagent for the preparation
of enantioenriched γ-nitrogenated R,â-unsaturated nitriles under
palladium or iridium catalysis with overall retention of the
configuration. In the case of oxygenated nucleophiles, sodium
and tetra-n-tetrabutylammonium acetates, sodium phenolate and
the sodium salt of N-hydroxysuccinimide were the best reagents,
the latter being faster concerning the reaction rates. However,
these oxygenated nucleophiles failed when cinnamaldehyde-
derived O-protected cyanohydrins were used as substrates. In
addition, oxygenated nucleophiles also gave poor results under
the iridium-catalyzed reaction conditions. Finally, for sodium
dimethyl malonate Pd(OAc)2/dppe was the catalytic mixture and
THF was the selected solvent to give the optimal results onto
crotonaldehyde-derived cyanohydrins, whereas the cinnamal-
dehyde derivative did not afford the desired result.
6
a,c,e and 5. This hypothesis can support the easy and fast
34,47
palladium(0)-catalyzed isomerization of the double bond
in
6
d (Scheme 8, Route C). Presumably, compound (E/Z)-13 was
generated after the initial double bond palladium(0) coordination
intermediate C), followed by a nucleophilic attack of the
(
palladium(0) atom onto HR. The result of this step would be a
_
C H insertion of palladium to give the carbanionic intermediate
D. The hydride transfer from the palladium atom to the allylic
moiety and the regeneration of the catalytically active palladium-
3
4
(
0) species in intermediate E completed the process. Perhaps
the driving force that governs this fast abstraction of the acidic
hydrogen, rather than the attack onto phosphate unit, is the
generation of a more stable trisubstituted conjugated alkene (E/
Z)-13. We reckon essential the presence of the stable carbanion,
drawn in intermediate D, to explain the variable ratios of E/Z-
1
3 obtained in the crude reaction products. Compound 13 was
obtained as clean product in the absence of nucleophiles when
phosphate 6d was allowed to react with Pd(OAc)2 (5 mol %)/
dppe (10 mol %). However, the related carbonate 5d did not
undergo any transformation under the previous mentioned
conditions. In general, working with 6d, weaker nucleophiles
permitted the acceleration of Route C in detriment of the
The studies of palladium versus iridium catalysis revealed
that palladium catalysts accelerated the reaction in detriment
of the E/Z ratio, which is lower than that obtained by the more
expensive iridium complex although employing larger reaction
times. Iridium catalysis allowed us to obtain pure E-isomers in
the cases of dibenzylamine and sodium azide, but it give poor
conversions with acetates and no reaction occurred with sodium
dimethyl malonate.
(46) The racemization of cyanohydrin-O-phosphate derived from ben-
zaldehyde has been evaluated in the presence of 1 equiv of nitrogenated
bases at room temperature, in THF (under an inert atmosphere) during 12
h. The results of the table below clearly demonstrate a stronger basic
character of the benzylamine and triethylamine versus dibenzylamine,
N-methylimidazole (NMI), and pyridine.
Experimental Section
Synthesis of (2R,3E)-2-(Diethylphosphoryloxy)-3-methylpent-
3
1
(47) Handbook of Organopalladium Chemistry for Organic Systems;
3-enenitrile (6e). 6e was prepared as described previously in 2 h
Negishi, E., Ed.; Wiley: New York, 2002; Vol. II, Chapter VII.3, p 2783.
time. After purification by flash chromatography, a colorless oil
3846 J. Org. Chem., Vol. 71, No. 10, 2006

Synthesis of γ-Substituted R,â-Unsaturated Nitriles
was obtained in 89% yield. [R]25
-13.8 (c 1.5, CHCl
2% ee from HPLC: Daicel Chiralpak AD, λ ) 210 nm, n-hexane/
-propanol 95:5, 1 mL/min, t ) 10.8 and 14.1 min; R 0.54 (n-
, 82% ee);
(2E,4R)-4-Azidopent-2-enenitrile (2ca): Colorless oil. [R]25
12
D
3
D
, 92% ee); {lit.12 [R]
25
8
2
-14.2 (c 0.8, CHCl
3
D
3
-38.7 (c 1.870, CHCl ,
r
f
81% ee)}; 92% ee from HPLC: Daicel Chiralpak AS, λ ) 254
nm, n-hexane/2-propanol 99:1, 1 mL/min, t ) 18.8 and 17.8 min;
0.63 (n-hexane/ethyl acetate 3:2); IR (neat): ν 2225, 2113 cm ;
hexane/ethyl acetate 3:2); IR (neat): ν 2225, 1664, 1264, 1031
r
-
1
1
-1
cm
;
H NMR (300 MHz, CDCl
3
): δ 1.30-1.39 (m, 6H),
R
f
1
1
.70 (d, J ) 7.9 Hz, 3H), 1.80 (s, 3H), 4.09-4.22 (m, 4H), 5.36
3
H NMR (300 MHz, CDCl ): δ 1.39 (d, J ) 6.8 Hz, 3H), 4.19
13
(
(
d, J ) 8.4 Hz, 1H), 5.89 ppm (q, J ) 6.7 Hz, 1H); C NMR
(m, 1H), 5.60 (d, J ) 16.8 Hz, 1H), 6.60 ppm (dd, J ) 16.8, 1.8
75 MHz, CDCl ): δ 11.7, 13.5, 15.9, 64.6, 115.8, 128.2, 129.5
3
Hz, 1H); 13C NMR (75 MHz, CDCl
152.3 ppm.
3
): δ 19.1, 57.6, 101.3, 116.7,
+
ppm; MS (EI): m/z ) 247 (M , 6%), 191 (18), 155 (56), 127 (63),
+
9
9 (100); HRMS calcd for C12
H
14
N
2
(M ): 186.1157; found:
Synthesis of r,â-Unsaturated γ-Acetoxynitriles (1a). In a
round-bottomed flash was stirred, at the corresponding temperature,
186.1154.
Synthesis of r,â-Unsaturated γ-Aminonitriles (2aa, 2adb,
aea 2ba, and 2bd). In a round-bottomed flask, a solution of the
2
a mixture of compound 5 or 6 (0.4 mmol), Pd(OAc) (4.5 mg, 0.02
2
mmol, 5 mol %), and triphenylphosphine (11 mg, 0.04 mmol, 10
mol %) in acetonitrile (4 mL). Then NaOAc (131 mg, 1.6 mmol,
4 equiv) and AcOH (93 µL, 1.6 mmol, 4 equiv) were added, and
stirring was continued at the same temperature. When the reaction
was judged complete, the solvent was evaporated, water (5 mL)
was added, and it was extracted with ethyl acetate (2 × 10 mL).
compound 5 or 6 (0.40 mmol) in toluene (2 mL) was stirred at
room temperature, and then Pd(OAc) (2.7 mg, 0.012 mmol, 3 mol
or 4.5 mg, 0.02 mmol, 5 mol %) and dppe (10 mg, 0.024 mmol,
mol % or 16 mg, 0.04 mmol, 10 mol %) were added. After being
2
%
6
stirred for 10 min, the corresponding amine (1.5 equiv, 0.6 mmol)
was added, and the reaction was stirred at the same temperature.
When the reaction was judged complete, water (12 mL) and ethyl
acetate (3 × 5 mL) were added. The organic layer was dried
4
The combined organic layers were dried (MgSO ) to obtain the
crude compounds (E)-1a and (Z)-1a.
The identical procedure was employed when tetra-n-buthylam-
monium acetate (1.5 equiv) was used instead of NaOAc and AcOH
and replacing acetonitrile by THF (4 mL).
(
4
MgSO ) and evaporated to give the crude compounds, which were
purified by flash chromatography to obtain pure γ-aminonitriles.
The identical procedure was utilized when the reaction was carried
2E,4R)-4-Acetoxypent-2-enenitrile (1aa):31 Sticky pale yellow
oil. 88% ee from HPLC: Daicel Chiralcel OD-H, λ ) 210 nm,
hexane/2-propanol 97:3, 0.6 mL/min, t
(
out using [Ir(COD)Cl]
mixture.
2
(2.5 mol %) instead of the Pd(OAc)
2
/dppe
r
) 17.5, 19.6 min (Z) and
3
1
1
(
2E,4R)-4-(N,N-Dibenzylamino)pent-2-enenitrile (2aa): Pale
20.7, 27.7 (E) min; H NMR (300 MHz, CDCl ): δ 1.36 (d, J )
3
25
yellow oil. [R]
D
+154.9 (c 2.0, CHCl
3
, 90% ee E/Z 98:2); 90%
6.7 Hz, 3H), 2.09 (s, 3H), 5.39-5.49 (m, 1H), 5.54 (d, J ) 16.3
13
ee from HPLC: Daicel Chiralcel OD-H, λ ) 254 nm, n-hexane/
Hz, 1H), 6.65 ppm (dd, J ) 16.3, 4.9 Hz, 1H). C NMR δ 13.9,
2
-propanol 95:5, 1.0 mL/min, t
r
) 8.1 and 13.9 (Z), 10.3 and 11.8
35.4, 72.0, 100.5, 116.6, 152.0, 170.1.
min (E); R 0.53 (Z) and 0.60 (E) (n-hexane/ethyl acetate 4:1); IR
f
2E,4R)-4-Acetoxyhept-2-enenitrile (1ab):29 Pale yellow oil.
(
-
1 1
(
neat): ν 2222, 1636 cm ; H NMR for the E-isomer (300 MHz,
8
0% ee from HPLC, Daicel Chiralcel OD-H, λ ) 210 nm, n-hexane/
-propanol 99:1, 0.5 mL/min, t (Z-isomer) ) 17.5 and 20.2 min,
(E-isomer) ) 18.0 and 24.6 min); R 0.77 (n-hexane/ethyl acetate
:2). IR (neat): ν 2226, 1740, 1641 cm . H NMR (300 MHz,
CDCl ): δ 0.91-0.96 (t, J ) 7.1 Hz, 3H), 1.25-1.35 (m, 2H),
.56-1.65 (m, 2H), 2.10 (s, 3H), 5.37 (q, J ) 5.2 Hz, 1H), 5.50
CDCl
3
): δ 1.21 (d, J ) 6.9 Hz, 3H), 3.50 (m, 1H), 3.58 (s, 4H),
2
r
5
7
.48 (d, J ) 16.5 Hz, 1H), 6.78 (dd, J ) 16.5 and 5.3 Hz, 1H),
.22-7.37 ppm (m, 10H); 13C NMR (75 MHz, CDCl
): δ 13.1,
3.7, 54.4, 100.1, 117.4, 127.1, 128.3, 128.4, 139.2, 157.4 ppm;
t
3
r
f
3
-1 1
5
3
1
H NMR for the Z-isomer (300 MHz, CDCl ): δ 1.29 (d, J ) 6.9
3
1
Hz, 3H), 3.52 and 3.77 (2xd, J ) 14.4 Hz, 4H), 5.41 (d, J ) 11.2
13
(
d, J ) 16.4 Hz, 1H), 6.63 (dd, J ) 16.4, 5.2 Hz, 1H). C NMR
75 MHz, CDCl ): δ 13.7, 18.0, 20.7, 35.4, 72.0, 100.0, 116.5,
51.9, 169.8. MS (EI) m/z: 167 (M , 4%), 124 (45), 108 (100).
HRMS calcd for C : 167.0946; found: 167.0947.
Synthesis of γ-Hydroxynitriles 1b by Hydrolysis of r,â-
13
Hz, 1H), 6.54 (m, 1H), 7.22-7.37 ppm (m, 11H); C NMR (75
MHz, CDCl ): δ 17.4, 54.2, 55.3, 100.2, 117.4, 127.2, 128.3, 128.4,
39.3, 155.5 ppm. MS (EI): m/z 276 (M , 2%), 261 (21), 91 (100).
(
1
3
3
+
+
1
9 2
H13NO
+
HRMS calcd for C19
2E,4R)-4-(N,N-Dibenzylamino)-4-phenylbut-2-enenitrile
2ad): Colorless prisms. Mp 105 °C (from n-hexane/ethyl acetate);
20 2
H N (M ): 276.3801; found: 276.3805.
(
1,31
Unsaturated γ-Acetoxynitriles (1a).
To a solution of com-
(
[
pounds 1a (0.8 mmol) in dry methanol (5 mL) solid potassium
carbonate was added (28 mg, 0.2 mmol) and the mixture was stirred
at room temperature during 16 h. Then, silica was added, and the
mixture was stirred another 5 min, After that, the suspension was
filtered and evaporated, and the crude residue was purified by flash
2
0
R]
D
3
-2.2 (c 1.5, CHCl , 95% ee); 95% ee from HPLC: Daicel
Chiralpak AS, λ ) 254 nm, n-hexane/2-propanol 97:3, 1 mL/min,
t
r
) 7.6 and 8.3 min; R 0.76 (n-hexane/ethyl acetate 3:2); IR
f
-
1 1
(
KBr): ν 2220, 1627 cm ; H NMR (300 MHz, CDCl
3
): δ 3.51
and 3.63 (2xd, J ) 13.9, 4H), 4.43 (d, J ) 7.2 Hz, 1H), 5.60 (d, J
chromatography to obtain pure γ-hydroxynitriles 9.
)
16.4 Hz, 1H), 6.62 (dd, J ) 16.4, 7.2 Hz, 1H), 7.23-7.43 ppm
m, 15H); 13C NMR (75 MHz, CDCl
): δ 53.9, 64.4, 102.5, 117.1,
27.3, 128.1, 128.4, 128.5, 128.6, 128.9, 137.3, 138.7, 154.3 ppm;
27,31
(
2E,4R)-4-Hydroxypent-2-enenitrile (1ba):
Colorless oil;
-51.5 (c 0.9,
(
1
3
25
) 98% ee; {lit. [R]25
31
[
R]
CHCl
D
-51.5 (c 0.9, CHCl
3
D
1
3
) 98% ee}; H NMR (300 MHz, CDCl ): δ 1.33 (d, J ) 7.0
3
+
MS (EI): m/z ) 338 (M , 9%), 247 (20), 142 (25), 115 (24), 91
100); HRMS calcd for C24H N (M ): 338.1783; found: 338.1779.
22 2
Hz, 3H), 3.40 (br s, 1H, OH), 4.50 (ddq, J ) 7.0, 3.9, 0.9 Hz, 1H),
.65 (dd, J ) 16.3, 0.9 Hz, 1H), 6.75 (dd, J ) 16.3, 3.9 Hz, 1H);
13
+
(
5
CAUTION: Azido compounds may represent an explosion
hazard when concentrated under vacuum or as stored material. A
safety shield and appropriate handling procedures are recommended.
C NMR (75 MHz, CHCl
(
3
): δ 22.3, 66.8, 97.9, 117.3, 157.8.
2E,4R)-4-Hydroxyhept-2-enenitrile (1bb):29 Colorless oil.
25
[
1
R]
D
-12.2 (c 0.3; CHCl
3
, 72% ee); IR (neat): ν 3432, 2224,
CAUTION: Trimethylsilyl azide is an extremely toxic agent.
-1 1
630 cm . H NMR (300 MHz, CHCl ): δ 0.93-0.98 (m, 3H),
1.23-1.28 (m, 4H), 3.22 (br s, 1H), 4.34 (m, 1H), 5.67 (d, J )
3
Synthesis of r,â-Unsaturated γ-Azidonitriles (2c). To a
13
solution of compound 5 or 6 (0.4 mmol), Pd(OAc)
2
(2.7 mg, 0.012
16.2 Hz, 1H), 6.75 (dd, J ) 4.0, 16.2 Hz, 1H). C NMR (300
MHz, CHCl ): δ 13.8, 19.1, 39.2, 73.8, 98.2, 117.0, 156.9. MS
(EI) m/z: 96 (M - 29, 5%), 85 (11), 58 (100). HRMS calcd for
mmol, 3 mol % or 4.5 mg, 0.02 mmol, 5 mol %), and phosphine
6 mol % or 10 mol %) in a (1:1) THF/H O mixture, NaN (52
3
+
(
2
3
+
mg, 0.8 mmol, 2 equiv) was added. When the reaction was judged
complete, the THF was evaporated under vacuo, and ethyl acetate
7
C H11NO (M ): 125.1722; found: 125.1730.
2E,4R)-4-Hydroxynon-2-enenitrile (1bc): Colorless oil. [R]25
31
(
D
(
2 × 10 mL) was added. The organic layers were dried (MgSO
4
)
31
25
-
37.0 (c 1.0, CHCl
3
, 94% ee) [lit. [R]
D
-1
-37.0 (c 1.0, CHCl
3
),
and evaporated to obtain a crude unpurified product as yellow oil.
1
9
4% ee)]; IR (neat): ν 3439, 2225, 1634 cm ; H NMR (300 MHz,
The same procedure was employed using [Ir(cod)Cl]
instead of a palladium source.
2
(2.5% mol)
CDCl ): δ 0.87-0.91 (t, J ) 6.6, 3H), 1.23-1.61 (m, 8H), 4.31
3
(m, 1H), 5.67 (d, J ) 16.4 Hz, 1H), 6.75 ppm (dd, J ) 16.4, 4.0
J. Org. Chem, Vol. 71, No. 10, 2006 3847

Baeza et al.
Hz, 1H); 13C NMR (75 MHz, CDCl
6.4, 71.0, 98.7, 117.3, 156.6 ppm.
phase was dried (MgSO
15 and (Z)-15 after flash chromatography.
) and evaporated, yielding products (E)-
3
): δ 13.9, 22.4, 24.7, 31.5,
4
3
Palladium-Catalyzed Nucleophilic Substitution Reaction with
Methyl (3R,4E)-5-Cyano-3-methyl-2-(methoxycarbonyl)pent-
Sodium Phenoxide and N-Hydroxysuccinimide Sodium Salt.4
The corresponding sodium salt, previously formed by reaction of
phenol (57 mg, 0.6 mmol) or N-hydroxysuccinimide (69 mg, 0.6
mmol) with sodium hydride (24 mg, 0.6 mmol, 60% dispersion in
mineral oil) in dry THF for 1 h, was added to a solution containing
1c
4-enoate (15a): Pale yellow oil. [R]
25
D
3
+26.7 (c 1, CHCl ); 88%
ee from HPLC: Daicel Chiralpak AD, λ ) 210 nm, hexane/2-
propanol 98:2, 1.0 mL/min, t ) 11.4 and 13.3 Z-isomer and 13.9
and 15.9 min E-isomer; R 0.59 (n-hexane/ethyl acetate 3:2); IR
r
f
1
3
(neat): ν 2223, 1731, 1633. H NMR (300 MHz, CDCl ): E-isomer
compound 6a (69 mg, 0.4 mmol), Pd(OAc)
2
(4.5 mg, 0.02 mmol,
δ 1.14 (d, J ) 6.9 Hz, 3H), 3.09 (m, 1H), 3.38 (d, J ) 7.8 Hz,
5
mol %), and dppe (16 mg, 0.04 mmol, 10 mol %) in dry THF
and under inert atmosphere (argon). The mixture was stirred until
it was judged complete. Then, the solvent was evaporated, and water
1H), 3.73 (s, 6H), 5.40 (d, J ) 16.5 Hz, 1H), 6.70 (dd, J ) 16.5
1
and 8.1 Hz, 1H). H NMR (300 MHz, CDCl
3
): Z-isomer δ 1.19
(d, J ) 6.9 Hz), 3.43-3.50 (m, 2H), 3.75 (s, 3H), 5.35 (d, J )
11.2 Hz, 1H), 6.55 (m, 1H). 13C NMR (75 MHz, CDCl
): E-isomer
δ 16.8, 37.2, 52.6, 56.1, 100.9, 116.9, 155.6, 167.7. 13C NMR (75
MHz, CDCl ): Z-isomer δ 17.8, 36.4, 52.6, 56.1, 100.2, 115.2,
(
5 mL) and ethyl acetate (2 × 10 mL) were added. The organic
3
layers were dried (MgSO ) and evaporated to give the crude
4
compounds, which were purified by flash chromatography to afford
the corresponding pure compounds (E)-1ca/(Z)-1ca and (E)-1da/
Z)-1da.
3
+
154.7, 167.7. MS (EI): m/z ) 211 (M , 1%), 179 (12), 151 (54),
136 (19), 119 (100), 101 (53). HRMS calcd for C10
(
4
H13NO :
(
2E,4R)-4-(2,5-Dioxopyrrolidin-1-yloxy)pent-2-enenitrile [(E)-
211.0845; found: 211.0849.
25
1
da]: Colorless oil. [R]
from HPLC: Daicel Chiralpak AS, λ ) 215 nm, n-hexane/2-
D
+66.1 (c 1.5, CHCl
3
, 90% ee); 90% ee
Methyl (3R,4E)-5-Cyano-2-(methoxycarbonyl)-3-phenylpent-
4-enoate (15d):28 Colorless oil. [R]
ee); 16% ee from HPLC Daicel Chiralpak AS, λ ) 215 nm,
n-hexane/2-propanol 99:1, 1 mL/min, t ) 36.6 and 38.2 min; R
0.53 (n-hexane/ethyl acetate 3:2); IR (neat): ν 2221, 1738, 1633,
25
D
3
-4.3 (c 1.2, CHCl , 16%
propanol 70:30, 1 mL/min, t
hexane/ethyl acetate 3:2); IR (neat): ν 2227, 1786, 1721 cm ; H
NMR (300 MHz, CDCl ): δ 1.48 (d, J ) 6.4 Hz, 3H), 2.73 (s,
H), 4.85 (m, 1H), 5.68 (d, J ) 16.4 Hz, 1H), 6.71 ppm (dd, J )
6.4, 6.8 Hz, 1H); 13C NMR (75 MHz, CDCl
): δ 18.7, 25.3, 81.6,
02.9, 116.0, 151.2, 171.2 ppm; MS (EI): m/z 194 (M , 0.2%),
r
) 19.8 and 35.8 min; R
f
0.25 (n-
-
1 1
r
f
3
-
1 1
4
1
1
1
3
1298, 1030 cm ; H NMR (300 MHz, CDCl ): δ 3.78 (s, 6H),
3
3.87 (d, J ) 10.4 Hz, 1H), 4.24 (m, 1H), 5.34 (dd, J ) 1.2, 16.2
Hz, 1H), 6.89 (dd, J ) 16.2, 8.1 Hz), 7.18 (m, 2H), 7.29-7.38
+
+
13
79 (0.15), 96 (2), 80 (100); HRMS calcd for C
CH
H N O
8 7 2 3
(M
-
ppm (m, 3H); C NMR δ 48.6, 52.8, 56.1, 102.1, 116.7, 128.0,
+
3
): 179.0456; found: 179.0458.
128.2, 129.2, 136.6, 153.4, 167.1 ppm; MS (EI): m/z ) 273 (M ,
(2Z,4S)-4-(2,5-Dioxopyrrolidin-1-yloxy)pent-2-enenitrile [(Z)-
7.2%), 241 (22), 209 (100), 182 (28), 181 (40), 154 (34), 153 (51),
25
1
da]: Colorless oil. [R]
from HPLC: Daicel Chiralpak AS, λ ) 215 nm, n-hexane/2-
propanol 70:30, 1 mL/min, t ) 30.7 and 43.2 min; R 0.29 (n-
hexane/ethyl acetate 3:2); IR (neat): ν 2227, 1786, 1721 cm . H
NMR (300 MHz, CDCl ): δ 1.55 (d, J ) 6.5 Hz, 3H), 2.73 (s,
H), 5.15 (m, 1H), 5.49 (d, J ) 11.0 Hz, 1H), 6.71 ppm (m, 1H);
C NMR (75 MHz, CDCl
51.3, 171.1 ppm. MS (EI): m/z 194 (M , 0.2%), 179 (0.15), 96
2), 80 (100); HRMS calcd for C
found: 179.0454.
D
+10.9 (c 1.5, CHCl
3
, 90% ee); 90% ee
127 (23), 115 (26), 104 (75); HRMS calcd for C15
273.1001; found: 273.0998.
4
H15NO :
r
f
Acknowledgment. This article is dedicated to the memory
of Professor Marcial Moreno Ma n˜ as. This work has been
supported by the DGES of the Spanish Ministerio de Educaci o´ n
y Cultura (MEC) (CTQ2004-02375/BQU and CTQ 2004-00808/
BQU) and Generalitat Valenciana (CTIOIB/2002/320, GRU-
POS03/134 and GV05/144) and by the University of Alicante.
A.B. also thanks Generalitat Valenciana for a predoctoral
fellowship (CTBPRB/2002/107).
-
1 1
3
4
13
3
): δ 18.4, 25.4, 80.5, 103.1, 114.5,
+
1
(
+
H N O
8 7 2 3
3
(M - CH ): 179.0456;
Palladium-Catalyzed Allylic Substitution Reactions with
Sodium Dimethyl Malonate. General Procedure. A suspension
of Pd(OAc) (4.5 mg, 0.02 mmol, 5 mol %) and phosphine (0.1
2
Supporting Information Available: General experimental
details, physical and spectroscopic data of compounds 2ae, 2ba,
mmol) in the solvent shown in Table 5 (5 mL) was stirred at room
temperature for 15 min. Then, compound 5 or 6 (0.4 mmol) and
sodium dimethyl malonate (0.4 mmol) suspended in THF (1.5 mL)
were successively added. The reaction mixture was stirred at room
temperature for the period of time shown in Table 5. The solvent
was evaporated, water (5 mL) was added, and this aqueous phase
was extracted with ethyl acetate (2 × 10 mL). The resulting organic
1
2
bd, 2cb, 14, 1ac, 1ca, E-13, Z-13, as well as the H NMR and
1
3
C NMR spectra of new compounds 6e, 2ad, 2ae, 2ba, 2bd, 1ca,
E-1da, Z-1da, E-13, Z-13, and 15a and NOESY bidimensional
representation of compounds E-13 and Z-13. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO060239J
3848 J. Org. Chem., Vol. 71, No. 10, 2006