Enantioselective Rh-catalyzed hydrogenation of N-formyl dehydroamino esters with monodentate phosphoramidite ligands

Article abstract of DOI:10.1021/jo052451d

Enantioselectivities up to >99% ee were achieved in the rhodium-catalyzed asymmetric hydrogenation of N-formyl dehydroamino esters using monodentate phosphoramidites as chiral ligands. The substrates were synthesized by condensation of methyl isocyanoacetate with a range of aldehydes and with cyclohexanone. A highly convenient multigram scale one step synthesis of methyl 2-(formamido)acrylate was developed. This compound was used in the synthesis of methyl 2-(formamido)cinnamate via a solvent free Heck reaction. Moreover, full conversion and >99% ee were obtained in 1 h in the hydrogenation of methyl 2-(formamido)acrylate with 0.2 mol% catalyst and 2 bar hydrogen pressure. The versatility of the formyl protection was established by its removal under mild conditions.

Full text of DOI:10.1021/jo052451d

Enantioselective Rh-Catalyzed Hydrogenation of N-Formyl
Dehydroamino Esters with Monodentate Phosphoramidite Ligands
Lavinia Panella,† Alicia Marco Aleixandre,† Gerlof J. Kruidhof,† Jort Robertus,†
Ben L. Feringa,*,† Johannes G. de Vries,*,†,‡ and Adriaan J. Minnaard*,†
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, UniVersity of Groningen,
Nijenborgh 4, 9747 AG Groningen, The Netherlands, and DSM Research, Life Sciences-AdVanced
Synthesis, Catalysis and DeVelopment, P.O. Box 18, 6160 MD Geleen, The Netherlands
b.l.feringa@rug.nl; hans-jg.Vries-de@dsm.com; a.j.minnaard@rug.nl
ReceiVed NoVember 28, 2005
Enantioselectivities up to >99% ee were achieved in the rhodium-catalyzed asymmetric hydrogenation
of N-formyl dehydroamino esters using monodentate phosphoramidites as chiral ligands. The substrates
were synthesized by condensation of methyl isocyanoacetate with a range of aldehydes and with
cyclohexanone. A highly convenient multigram scale one step synthesis of methyl 2-(formamido)acrylate
was developed. This compound was used in the synthesis of methyl 2-(formamido)cinnamate via a solvent
free Heck reaction. Moreover, full conversion and >99% ee were obtained in 1 h in the hydrogenation
of methyl 2-(formamido)acrylate with 0.2 mol % catalyst and 2 bar hydrogen pressure. The versatility of
the formyl protection was established by its removal under mild conditions.
Introduction
chemocatalytic technology for the synthesis of amino acid
derivatives.5 The reaction is extremely clean and efficient, as
only substrate, solvent, hydrogen, and a small amount of catalyst
are needed. Since their introduction, an enormous number of
bidentate chiral phosphorus ligands have been prepared,6 as they
were considered to be the key to high enantioselectivity. More
recently,7 a number of monodentate phosphorus based chiral
ligands have been demonstrated to be equally effective or, in
some cases, even superior to bidentate ligands, providing easier
Enantiopure natural and unnatural amino acids play an
important role as building blocks in the preparation of many
pharmaceuticals and other biologically active compounds.1 They
are also widely used in organic chemistry as chiral auxiliaries
and as catalysts.2 Unnatural amino acids in particular have
received increasing attention in drug discovery and protein
engineering, because of novel and interesting properties they
confer to biologically relevant peptides.3 Therefore, it is not
surprising that, in industry as well as in academia, there is a
great interest in the use of catalytic asymmetric approaches for
the preparation of optically active amino acids and their
derivatives.4
(4) For a recent review, see: Ma, J.-A. Angew. Chem., Int. Ed. 2003,
42, 4290.
(5) Lennon, I. C.; Moran, P. H. Curr. Opin. Drug DiscoVery DeV. 2003,
6, 855.
(6) (a) Brown, J. M. In ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, Germany, 1999;
Vol. 1, Chapter 5.1. (b) Chaloner, P. A.; Esteruelas, M. A.; Joo´, F.; Oro, L.
A. Homogeneous Hydrogenation; Kluwer: Dordrecht, The Netherlands,
1994. (c) Brunner, H.; Zettlmeier, W. Handbook of EnantioselectiVe
Catalysis; VCH: Weinheim, Germany, 1993. (d) de Vries, J. G.; Elsevier:
C. J. Handbook of Homogeneous Hydrogenation; Wiley-VCH: Weinheim,
Germany, 2006.
Among these different approaches, rhodium-catalyzed asym-
metric hydrogenation is the most widely applied enantioselective
† University of Groningen.
‡ DSM Research, Life Sciences-Advanced Synthesis, Catalysis and Develop-
ment.
(1) Sewald, N.; Jakubke, H.-D. Peptides: Chemistry and Biology; Wiley-
VCH: Weinheim, Germany, 2002; Chapter 9.
(2) Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmetric
Synthesis; Wiley: New York, 1995.
(3) (a) Cleland, J. L.; Craik, C. S. Protein Engineering: Principals and
Practice; Wiley-Liss, New York, 1996. (b) Kazmierski, W. M. Peptido-
mimetics Protocols; Humana Press: Totowa, NJ, 1999. (c) Goodman, M.;
Felix, A. Synthesis of Peptides and Peptidomimetics; Science of Synthesis
Series; Goodman, M., Ed.; Thieme: Stuttgart, Germany, 2003; Vol. E22b.
(7) (a) Guillen, F.; Fiaud, J.-C. Tetrahedron Lett. 1999, 40, 2939. (b)
Claver, C.; Fernandez, E.; Gillon, A.; Heslop, K.; Hyett, D. J.; Martorell,
A.; Orpen, A. G.; Pringle, P. G. Chem. Commun. 2000, 961. (c) Reetz, M.
T.; Mehler, G. Angew. Chem., Int. Ed. 2000, 39, 3889. (d) van den Berg,
M.; Minnaard, A. J.; Schudde, E. P.; van Esch, J.; de Vries, A. H. M.; de
Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2000, 122, 11539. (e) Hua,
Z.; Vassar, V. C.; Ojima, I. Org. Lett. 2003, 5, 3831.
10.1021/jo052451d CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/02/2006
2026
J. Org. Chem. 2006, 71, 2026-2036

Hydrogenation of N-Formyl Dehydroamino Esters
FIGURE 1. Asymmetric hydrogenation of R-dehydroamino esters with
monodentate chiral phosphoramidite ligands.
FIGURE 2. Coordination provided by the acyl moiety, as stereodi-
recting functionality.
access to new catalysts.8 Thus, Rh-catalyzed asymmetric
hydrogenation is a well-established, though still evolving,9
technology on both laboratory and industrial scale.10
In our laboratories, BINOL-derived monodentate phosphor-
amidites have been successfully used in the Rh-catalyzed
hydrogenation of a range of olefinic substrates, including the
benchmark substrates methyl 2-(acetamido)acrylate (1) and
methyl (Z)-2-(acetamido)cinnamate (2) (Figure 1).11
It is generally accepted that, to achieve excellent enantio-
selectivities in the Rh-catalyzed asymmetric hydrogenation of
dehydroamino esters, the presence of the R-acetamido group
coordinating to the rhodium is essential (Figure 2).12
In an early study conducted by Glaser and co-workers, the
influence of the nature of the stereodirecting group has been
studied in relation to the reactivity and enantioselectivity
obtained. Using DIOP as a chiral bis-phosphine ligand the
superiority of the acetamido substituent was clearly established
in terms of both reactivity and enantioselectivity.13 More
recently, also carbamate stereodirecting groups (Boc and Z) have
been shown to be effective.14
FIGURE 3. Synthesis of dehydroamino esters via (A) Erlenmeyer
azlactone synthesis, (B) the Horner-Emmons method with Schmidt’s
phosphorylglycine esters, (C) Suzuki cross-coupling, (D) Heck arylation,
and (E) acetamide R-ketoester condensation.
There is extensive literature on the preparation of dehy-
droamino acid derivatives and frequently used methods are
depicted in Figure 3.15The Erlenmeyer synthesis via azlactone16
(Figure 3, method A) and the condensation of aldehydes with
phosphorylglycine esters (method B) are the most frequently
used.17 The main limitation of the azlactone approach lies in
the harsh reaction conditions, which limits its use to aromatic
aldehydes devoid of acid-sensitive groups.18 In addition, sub-
strates with carbamate protecting groups cannot be prepared.
The use of phosphorylglycine esters is instead more versatile
and the synthesis milder. This method is complementary to the
Erlenmeyer synthesis as it allows access to â-alkyl-R-enamides.
Nevertheless, although ketones also can be used, reaction times
in this case are long.19 Moreover, the preparation of the Horner-
Emmons reagent requires several steps.
(8) For reviews, see: (a) Jerphagnon, T.; Renaud, J.-L.; Bruneau, C.
Tetrahedron: Asymmetry 2004, 15, 2101. (b) Komarov, I. V.; Bo¨rner, A.
Angew. Chem., Int. Ed. 2001, 40, 1197. (c) Lagasse, F.; Kagan, H. B. Chem.
Pharm. Bull. 2000, 48, 315. (d) de Vries, J. G. In Handbook of Chiral
Chemicals; Ager, D. J., Ed.; CRC: Boca Raton, FL, 2005. (e) van den
Berg, M.; Feringa, B. L.; Minnaard, A. J. In Handbook of Homogeneous
Hydrogenation; Wiley-VCH: Weinheim, Germany, 2006.
(9) (a) Chi, Y.; Tang, W.; Zhang, X. In Modern Rhodium-Catalyzed
Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, Germany,
2005; Chapter 1. (b) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029.
(10) For reviews, see: (a) Lennon, I. C.; Pilkington, C. J. Synthesis
(Stuttg.) 2003, 11, 1639. (b) Blaser, H. U.; Malan, C.; Pugin, B.; Spindler,
F.; Steiner, H.; Studer, M. AdV. Synth. Catal. 2003, 345, 103. (c) Ager, D.
J. Curr. Opin. Drug DiscoVery DeV. 2002, 5, 892. (d) de Vries, J. G. In
Encyclopedia of Catalysis; Horvath, I. T., Ed.; John Wiley & Sons: New
York, 2003; Vol. 3, p 295.
(11) (a) Pen˜a, D.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. J. Am.
Chem. Soc. 2002, 124, 14552. (b) van den Berg, M.; Minnaard, A. J.; Haak
R. M.; Leeman, M.; Schudde, E. P.; Meetsma, A.; Feringa, B. L.; de Vries,
A. H. M.; Maljaars, C. E. P.; Willans, C. E.; Hyett, D.; Boogers, J. A. F.;
Henderickx, H. J. W.; de Vries, J. G. AdV. Synth. Catal. 2003, 345, 308.
(c) Pen˜a, D.; Minnaard, A. J.; de Vries, A. H. M.; de Vries, J. G.; Feringa,
B. L. Org. Lett. 2003, 5, 475. (d) Hoen, R.; van den Berg, M.; Bernsmann,
H.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. Org. Lett. 2004, 6,
1433. (e) Bernsmann, H.; van den Berg, M.; Hoen, R.; Minnaard, A. J.;
Mehler, G.; Reetz, M. T.; de Vries, J. G.; Feringa, B. L. J. Org. Chem.
2005, 70, 943. (f) Hoen, R.; Boogers, J. A. F.; Bernsmann, H.; Minnaard,
A. J.; Meetsma, A.; Tiemersma-Wegman, T. D.; de Vries, A. H. M.; de
Vries, J. G.; Feringa, B. L. Angew. Chem., Int. Ed. 2005, 44, 4209. (g)
Panella, L.; Feringa, B. L.; de Vries, J. G.; Minnaard, A. J. Org. Lett. 2005,
7, 4177.
Both â-aryl- and â-alkenyl-substituted enamides can be
conveniently obtained through Suzuki coupling (method C).20
(14) (a) Burk, M. J.; Bienewald, F. In Transition Metals for Organic
Chemistry; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, Germany,
1998; Vol. 2, Chapter 1.1.2. (b) Burk, M. J.; Feaster, J. E.; Nugent, W. A.;
Harlow, R. L. J. Am. Chem. Soc. 1993, 115, 10125.
(15) For an overview, see: (a) Schmidt, U.; Lieberknecht, A.; Wild, J.
Synthesis (Stuttg.) 1988, 3, 159. (b) Reference 14a. For the sole example
of a Knoevenagel condensation, followed by selective deprotection of the
resulting diester and subsequent Curtius rearrangement leading to the desired
substrate, see: (c) Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am. Chem. Soc.
1996, 118, 9202. (d) Nitz, T. J.; Holt, E. M.; Rubin, B.; Stammer, C. H. J.
Org. Chem. 1981, 46, 2671.
(16) (a) Herbst, R. M.; Shemin, D. Organic Syntheses; Wiley: New York,
1943; Collect. Vol. II, p 1. (b) Vogel, A. I. Practical Organic Chemistry,
3rd ed.; Longman: Harlow: UK, 1956; p 907.
(17) Schmidt, U.; Lieberknecht, A.; Schanbacher, U.; Beuttler, T.; Wild,
J. Angew. Chem., Int. Ed. Engl. 1982, 10, 776.
(12) Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J. J. Mol. Catal.
1983, 19, 159 and references therein.
(13) (a) Glaser, R.; Geresh, S. Tetrahedron 1979, 35, 2381. (b) Glaser,
R.; Geresh, S. Tetrahedron Lett. 1977, 29, 2527.
(18) The use of Pb(OAc)4 extended somewhat the scope of the reaction:
Baltazzi, E.; Robinson, R. Chem. Ind. 1954, 7, 191.
(19) Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberknecht, A.;
Mangold, R.; Meyer, R.; Riedl, B. Synthesis (Stuttg.) 1992, 5, 487.
J. Org. Chem, Vol. 71, No. 5, 2006 2027

Panella et al.
Nevertheless, also in this case the preparation of the starting
methyl â-bromo(acetamido)acrylate is quite laborious and low
yielding. Arylation of methyl 2-(acetamido)acrylate is achieved
by using the Heck reaction (method D).21 This method, despite
its potential, is somewhat neglected, once more because of the
problematic synthesis of the starting material, especially on large
scale.22 The condensation of R-ketoesters and acetamide (method
E) allows, in principle, the preparation of a large variety of
R-enamides. However, also in this case, its use is limited by
the harsh reaction conditions and low yields.15
FIGURE 4. Synthesis of N-formyl protected dehydroamino esters via
the Scho¨llkopf 2-oxazoline.
Although the acyl moiety is the most employed stereodirect-
ing group, strongly acidic conditions are needed for its
removal.23,24 This might cause degradation of sensitive func-
tionalities or loss of optical purity. Deprotection with basic
conditions is precluded because of competing azlactone forma-
tion with subsequent racemization.25 To overcome this problem,
Burk and co-workers achieved a milder deprotection by first
converting the acylamide in its Boc derivative, followed by
deacetylation and Boc removal, respectively.26 Nevertheless, this
implies an extra transformation. Mild deprotection is also
provided by enzymatic hydrolysis with acylases, but D-selective
amino acid acylases are not commercially available.27
During our studies on amino acid synthesis, we realized that
while the asymmetric hydrogenation step has been developed
very well, both the synthesis of the substrates and the removal
of the directing group on the amine after hydrogenation limit
the scope and applicability of this strategy. Clearly, there is a
need for (1) a more general, mild and easily applicable synthetic
method for the preparation of the required dehydroamino esters,
(2) a directing group that can be removed under mild conditions,
and (3) a suitable protecting group that can be used directly for
other transformations, such as, for example, peptide synthesis.
We propose that all these requirements can be met by using
a formyl group as a stereodirecting functionality. The formyl
moiety, as protective group, is considered a desirable choice
due to its low cost of preparation, introduction, removal, and
improved water solubility.28 For the synthesis of the required
2-(formamido)acrylate derivatives, we adopted the Scho¨llkopf
method involving the condensation of aldehydes and ketones
with methyl isocyanoacetate.29 The ring opening by elimination
FIGURE 5. Use of the formyl moiety in metal-catalyzed asymmetric
hydrogenation.
of the 2-oxazolines yields the desired N-formyl dehydroamino
esters (Figure 4).
To our surprise, the formyl group as the stereodirecting group
is not used in Rh-catalyzed enantioselective hydrogenation.
Cyclic N-formyl enamides (Figure 5A) have been hydroge-
nated with Ru-BINAP and Ru-BIPHEMP yielding key inter-
mediates in the synthesis of morphine analogues, with high
enantioselectivities.30 Reetz and co-workers reported diastereo-
selective Rh-catalyzed asymmetric hydrogenation of enantiopure
γ-amino N-formyl dehydroamino esters (Figure 5B) employing
DIOP, DIPAMP, CHIRAPHOS, and BINAP as chiral ligands.31
An isolated case is the Rh-catalyzed enantioselective hydroge-
nation of an N-formyl, N-Boc protected tetrahydropyrazine
(Figure 5C).32 However, in this case it is unclear whether the
directing group was the formyl or the Boc moiety.
The main reason the formyl group is not used in asymmetric
hydrogenation seems directly connected to the results obtained
by Glaser and co-workers.13 The direct comparison between the
Rh-catalyzed asymmetric hydrogenation of N-acyl and N-formyl
cinnamic acid methyl ester with DIOP as the chiral ligand
showed a considerable decrease in enantioselectivity in the latter
case (69% and 58% ee, respectively). Not surprisingly, the
conclusion drawn from these studies was that an acyl group
coordinates stronger to the metal center than a formyl group.
In addition, from a synthetic point of view, N-formyl dehy-
droamino esters cannot be prepared by using the Erlenmeyer
azlactone synthesis.33
(20) (a) Miossec, B.; Danion-Bougot, R.; Danion, D. Synthesis (Stuttg.)
1994, 11, 1171. (b) Burk, M. J.; Allen, J. G.; Kiesman, W. F.; Stoffan, K.
M. Tetrahedron Lett. 1997, 38, 1309.
(21) Cutolo, M.; Fiandanese, V.; Naso, F.; Sciacovelli, O. Tetrahedron
Lett. 1983, 24, 4603.
(22) For some early approaches, see: (a) Srinivasan, A.; Stephenson,
R. W.; Olsen, R. K. J. Org. Chem. 1977, 42, 2253. (b) Wojciechowska,
H.; Pawlowicz, R.; Audruszkiewicz, R.; Grzybowska, J. Tetrahedron Lett.
1978, 19, 4063. (c) Reference 15a.
(23) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Chemistry, 3rd ed.; Wiley: New York, 1999; Chapter 7.
(24) Dilbeck, G. A.; Field, L.; Gallo, A. A.; Gargiuolo, R. J. J. Org.
Chem. 1978, 43, 4593. The acyl protection can be removed under acid
conditions. 1.2 N HCl, reflux, 9 h.
(25) Sewald, N.; Jakubke, H.-D. Peptides: Chemistry and Biology; Wiley-
VCH: Weinheim, Germany, 2002; Chapter 4.4.
In view of the fact that catalysts have evolved tremendously
since the introduction of DIOP, we felt the use of formyl as a
stereodirecting group should be reconsidered. Herein we report
the practical preparation of N-formyl dehydroamino esters and
their enantioselective hydrogenation, using Rh-phosphoramidites
catalysts.
Results and Discussion
Synthesis of N-Formyl Dehydroamino Esters. N-Formyl
(26) Burk, M. J.; Allen, J. G. J. Org. Chem. 1997, 62, 7054.
(27) (a) Duthaler, R. O. Tetrahedron 1994, 50, 1539. (b) Waldmann,
H.; Sebastian, D. Chem. ReV. 1994, 94, 911. (c) Chenault, H. K.; Dahmer,
J.; Whitesides, G. M. J. Am. Chem. Soc. 1989, 111, 6354.
(28) For examples of the use of formyl protection in peptide synthesis,
see: (a) Sheehan, J. C.; Yang, D.-D. H. J. Am. Chem. Soc. 1958, 80, 1154.
(b) Flo¨rsheimer, A.; Kula, M.-R. Monatsh. Chem. 1988, 119, 1323. (c)
Murakami, Y.; Yoshida, T.; Hayashi, S.; Hirata, A. Biotechnol. Bioeng.
2000, 69, 57. (d) Kotha, S.; Behera, M.; Khedkar, P. Tetrahedron Lett.
2004, 45, 7589. (e) Sonke, T.; Kaptein, B.; Wagner, A. F. V.; Quaedflieg,
P. J. L. M.; Schultz, S.; Ernste, S.; Schepers, A.; Mommers, J. H. M.;
Broxterman, Q. B. J. Mol. Catal. B: Enzym. 2004, 29, 265.
dehydroamino esters can be obtained by mild aldol condensation
(29) Scho¨llkopf, U.; Gerhart, F.; Schro¨der, R.; Hoppe, D. Liebigs Ann.
Chem. 1972, 766, 116.
(30) (a) Noyori, R.; Ohta, M.; Hsiao, Y.; Kitamura, M.; Ohta, T.; Takaya,
H. J. Am. Chem. Soc. 1986, 108, 7117. (b) Kitamura, M.; Hsiao, Y.; Noyori,
R. Tetrahedron Lett. 1987, 28, 4829. (c) Heiser, B.; Broger, E. A.; Crameri,
Y. Tetrahedron: Asymmetry 1991, 2, 51.
(31) Reetz, M. T.; Kayser, F. Tetrahedron: Asymmetry 1992, 3, 1377.
(32) Rossen, K.; Pye, P. J.; DiMichele, L. M.; Volante, R. P.; Reider, P.
J. Tetrahedron Lett. 1998, 39, 6823.
2028 J. Org. Chem., Vol. 71, No. 5, 2006

Hydrogenation of N-Formyl Dehydroamino Esters
TABLE 1. Synthesis of N-Formyl Dehydroamino Esters with
SCHEME 1
Methyl Isocyanoacetatea
entry
product
method
Z:E
yield (%)
1
2
3
4
5
6
7
8
9
3
4
4
5
5
5
6
7
7
D
A
B
A
B
D
B
C
D
2.9:1
5.7:1
1.9:1
1.2:1
1.5:1
1.6:1
1.5:1
83
30
79
29
63
65
58
35
82
SCHEME 2
a Method A: (a) 1 equiv of t-BuOK, THF, -60 °C; (b) 1 equiv of AcOH,
CH2Cl2, 0 °C. Method B: (a) CuCl/NEt3 (5%), THF, rt; (b) 1 equiv of
t-BuOK THF, 0 °C; (c) 1 equiv of AcOH, CH2Cl2, 0 °C. Method C: 1
equiv of ZnCl2, THF, rt; (b) 1 equiv of t-BuOK THF, 0 °C; (c) 1 equiv of
AcOH, CH2Cl2, 0 °C. Method D: (a) Cu2O (5%), Et2O, rt; (b) 1 equiv of
t-BuOK THF, 0 °C; (c) 1 equiv of AcOH, CH2Cl2, 0 °C.
Method A proved to be less efficient (Table 1, entries 2 and
4) as the products 4 and 5 were obtained in 30% and 29% yield,
respectively, from complex crude mixtures. On the other hand,
the same products could be obtained in good yields by using
the stepwise approach of method B (entries 3 and 5). The
reactions were run overnight at room temperature in the presence
of a catalytic amount of CuCl and NEt3 (5%). In most cases,
1H NMR of the crude mixtures showed complete conversion to
the 2-oxazoline intermediate.40 In all cases with Cu(I) or Zn-
(II) the 2-oxazolines were converted in situ to the desired
N-formyl protected dehydroamino esters by adding t-BuOK in
THF to the reaction mixture, followed by acetic acid in CH2-
Cl2. The use of Cu(I) also allowed a satisfactory synthesis of
the more delicate substrate 6 (entry 7).41 Aldol condensation
with methyl isocyanoacetate using ketones as electrophiles has
not been frequently described in the literature. Ito reported the
use of ZnCl2 in combination with 2-cyclohexenone yielding the
corresponding 2-oxazoline in 29% yield.37 Applying the same
methodology, dehydroamino ester 7 was obtained in 35% yield
(entry 8).42 However, a very good 82% yield was obtained with
use of catalytic Cu2O (entry 9).43 The same procedure was
adopted by using benzaldehyde for the synthesis of 3, which
was obtained in 83% yield (entry 1).44 Furthermore, Cu2O was
also used for the preparation of 5 and the result was similar to
that obtained when using CuCl (entry 6). As a general
of methyl isocyanoacetate with a variety of alkyl, aryl, or
heterocyclic aldehydes and ketones.15a Methyl isocyanoacetate
is commercially available and can be conveniently prepared, in
good yields and on a multigram scale, via N-formylation of
glycine methyl ester followed by subsequent dehydration with
POCl3.34 The dehydroamino esters can be prepared either in a
single step, by performing the condensation in the presence of
t-BuOK (Scheme 1, method A),35 or via the isolation and
subsequent ring opening of the corresponding 2-oxazolines.36
Ito et al. introduced the use of the Lewis acids CuCl and ZnCl2
for the synthesis of 2-oxazolines (methods B and C).37 The use
of Cu2O proved to be beneficial when using ketones in the
condensation reaction instead of aldehydes (method D).38
Subsequent treatment of the 2-oxazolines with t-BuOK leads
to the dehydroamino esters.39 It was decided to compare the
various methods present in the literature for the preparation of
2-oxazolines and develop a one-pot synthesis that would avoid
their isolation.
The substrates shown in Scheme 2 were prepared adopting
the different methods described in Scheme 1 and the results
are shown in Table 1.
(33) When N-formyl glycine was used in the Erlenmeyer azlactone
synthesis with benzaldehyde, the corresponding methyl-substituted azlactone
was isolated in 70% yield, due to the in situ acylation-deformylation of
the substrate.
(34) A slight modification of a literature procedure was used: Park, W.
K. C.; Auer, M.; Jaksche, H.; Wong, C.-H. J. Am. Chem. Soc. 1996, 118,
10150.
(35) See for example: (a) Hoppe, D.; Schmincke, H.; Kleemann, H.-W.
Tetrahedron 1989, 45, 687. For the use of NaH, see: (b) Numani, K.-I.;
Hiramatsu, K.; Hayashi, K.; Matsumoto, K. Tetrahedron 1988, 44, 5467.
(36) For a review, see: Scho¨llkopf, U. Angew. Chem., Int. Ed. Engl.
1977, 16, 339.
(40) The coordination of methyl isocyanoacetate with transition metals
such as Cu or Zn increases the acidity of the R-protons.
(41) The aldehyde 5-(1,3-dioxolan-2-yl)-1-pentanal, used as starting
material for the synthesis of substrate 6, was obtained by monodeprotection
of the corresponding bis-1,3-dioxolane, following a modified literature
procedure: Takacs, J. M.; Myoung, Y.-C.; Anderson, L. G. J. Org. Chem.
1994, 59, 6928.
(37) Ito, Y.; Matsuura, T.; Saegusa, T. Tetrahedron Lett. 1985, 26, 5781.
(38) (a) Saegusa, T.; Ito, Y.; Kinoshita, H.; Tomita, S. J. Org. Chem.
1971, 36, 3316. (b) Soloshonok, V. A.; Hayashi, T.; Ishikawa, K.;
Nagashima, N. Tetrahedron Lett. 1994, 35, 1055. (c) Arnone, A.; Gestmann,
D.; Meille, S. V.; Resnati, G.; Sidoti, G. Chem. Commun. 1996, 22, 2569.
(39) For an example with NaCN in the condensation step, see: Hoppe,
I.; Scho¨llkopf, U. Synthesis (Stuttg.) 1982, 2, 129.
(42) The same compound was obtained in 59% yield, using NaH: Yim,
N. C. F.; Bryan, H.; Huffman, W. F.; Moore, M. L. J. Org. Chem. 1988,
53, 4605.
(43) Adapted synthesis from a literature procedure (ref 38c) with the
Cu2O content reduced to 5%.
(44) This substrate could also be prepared by using NaH (ref 35b) or
ZnCl2 (ref 37).
J. Org. Chem, Vol. 71, No. 5, 2006 2029

Panella et al.
SCHEME 3. Z and E Isomers and Trans and cis Rotamers
Observed for N-Formyl Dehydroamino Methyl Esters45
SCHEME 4. Synthesis of Methyl 2-(Formamido)acrylate (8)
able starting material, providing the possibility of establishing
a cheap, practical and efficient preparation.49 The approach
adopted is shown in Scheme 4.
Product 8 is obtained by formylation and dehydration of
inexpensive and readily available racemic serine methyl ester
hydrochloric salt, in one step on a multigram scale with methyl
formate as solvent. The use of K2CO3 turned out to be essential
as the salts formed are not soluble in the reaction mixture and,
next to driving the reaction to completion, could be easily
removed by filtration.50 Quick flash chromatography of the crude
mixture, after removal of volatiles, afforded 8 in one step and
high yield (Scheme 4), making this a highly competitive
alternative to the existing synthesis of the N-acyl equivalent.49
Having achieved an efficient protocol for the preparation of 8,
methyl (Z)-2-(formamido)cinnamate (3) was prepared by react-
ing 8 under Heck reaction conditions (Table 2).
Initially, the conditions used by RajanBabu et al. with methyl
2-(acetamido)acrylate were applied (11.5% palladium acetate).51
Product 3 was obtained in higher yield with use of phenyl iodide
(Table 2, entry 2) than when the less reactive phenyl bromide
was used (entry 1). Upon lowering the amount of palladium
acetate to 5% and 2%, the yields slightly increased when phenyl
iodide was used (entries 4 and 6 vs entry 2). Good regioselec-
tivities were obtained, with the Z isomer being the major product
in all cases.
conclusion, the most versatile procedures involve the use of
catalytic Cu(I), with the subsequent in situ ring opening of the
2-oxazolines formed to yield the desired N-formyl dehydroamino
esters.
In all cases a mixture of Z and E isomers was obtained (entries
1-7). The isomers were separated by flash chromatography,
as we were interested in the influence of the double bond
configuration on the activity and enantioselectivity in the Rh-
catalyzed hydrogenation. In addition, every isomer consisted
of a mixture of trans and cis rotamers corresponding to slow
isomerization of the formamide bond (Scheme 3).
Identification of the different isomers and rotamers was
1
achieved by H NMR based on previous studies.46 To identify
the Z and E isomers, the position of the vinylic Hâ and of the
proton on the nitrogen is very diagnostic. In the case of the Z
isomer both signals appear at higher field compared to the
corresponding E isomer (Scheme 3). In both Z and E isomers,
the proton on the formyl group appears as a singlet for the trans
rotamer and as a doublet for the cis rotamer. Not only the
position of the formyl and the amido protons differs between
trans and cis rotamers, but also the Hâ vinylic proton. This
facilitates further identification of the Z and E isomers, as the
trans and cis Hâ vinylic protons of the E isomer appear at clearly
different chemical shifts. For both Z and E isomers the trans
rotamer is generally present in major amount. The ratio
decreases with the increasing bulkiness of the â-substituent.47
As a second versatile method for the preparation of N-formyl
dehydroamino esters, the Heck reaction between aryl halides
and methyl 2-(formamido)acrylate (8) was explored. This
approach is analogous to the one reported, among others, by
RajanBabu and co-workers for the N-acyl substrate (Figure 3,
method D).48 This methodology gives access in two steps to
numerous substrates for asymmetric hydrogenation. Thus,
methyl 2-(formamido)acrylate would appear as extremely valu-
Asymmetric Hydrogenation of N-Formyl Dehydroamino
Esters. The substrates prepared (Scheme 2) were used in the
(47) The difference in chemical shift between the signals of trans and
cis rotamers allowed via variable-temperature 1H NMR the determination,
for methyl 2-(formamido)cinnamate, of a coalescence temperature of Tc )
45 °C. From this value, the free energy of activation, which corresponds to
the rotational barrier, was calculated to be ∆G# ) 63.3 kJ/mol. Once the
rotational barrier was known, a frequency of rotation at room temperature
of 50 s-1 (180 000 h-1) was calculated, using the Eyring equation. Due to
this fast rotation, no influence was expected on the hydrogenation reactions
outcome. (a) Hesse, M.; Meier, H.; Zeeh, B. Spectroscopic Methods in
Organic Synthesis; Thieme: New York, 1997; p 95. (b) Ohki, M. In Topics
in Stereochemistry; Allinger, N. L., Eliel, E. L., Wilen, S. H., Eds.; Wiley:
New York, 1983; Vol. 14, Chapter 1.
(48) For examples of Heck reactions employed in the synthesis of
2-(acetamido)cinnamic methyl ester derivatives, see: (a) Reference 21. (b)
Harrington, P. H.; Hegedus, L. S. J. Org. Chem. 1984, 49, 2657. (c) Bozell,
J. J.; Vogt, C. E.; Gozum, J. J. Org. Chem. 1991, 56, 2584. (d) Gallou-
Dagommer, I.; Gastaud, P.; RajanBabu, T. V. Org. Lett. 2001, 3, 2053. (e)
Willans, C. E.; Mulders, J. M. C. A.; de Vries, J. G.; de Vries, A. H. M. J.
Organomet. Chem. 2003, 687, 494.
(45) Sewald, N.; Jakubke, H.-D. Peptides: Chemistry and Biology; Wiley-
VCH: Weinheim, Germany, 2002; Chapter 2.1. The definition of trans and
cis conformers adopts the definition of the conformation of the amide bond
in the peptide backbone:
(49) For a multigram scale synthesis of methyl 2-(acetamido)acrylate,
see: (a) Nugent, W. A.; Feaster, J. E. Synth. Commun. 1998, 28, 1617. (b)
Nugent, W. A. U. S. Patent 5,559,268, 1996. This protocol provides a 1:1
mixture of mono- and diacetylated product. In a later report (ref 48d) the
same protocol was applied and methyl 2-(acetamido)acrylate was isolated
in 38% yield.
(50) The use of a catalytic amount of NEt3 (100 µL on a 10 g scale), in
addition to K2CO3, ensured enough base in solution to keep the reaction
going. When only NEt3 was used, the reaction was much slower and
eventually stopped. The use of Cs2CO3, under the same reaction conditions,
resulted in a slightly faster reaction, but the product was obtained in lower
yield as a polymerization process started to take place. The product 8 was
obtained in 92% isolated yield starting from 1 g of racemic serine
hydrochloric acid methyl ester and in 89% starting from 10 g.
(51) According to literature procedure (ref 48d), see the Supporting
Information.
(46) (a) Glaser, R.; Geresh, S.; Scho¨llkopf, U.; Meyer, R. J. Chem. Soc.,
Perkin Trans. 1 1979, 1, 1746. (b) Mazurkiewicz, R.; Kuz´nik, A.; Grymel,
M.; Kuz´nik, N. Magn. Reson. Chem. 2005, 43, 36.
2030 J. Org. Chem., Vol. 71, No. 5, 2006

Hydrogenation of N-Formyl Dehydroamino Esters
TABLE 2. Reaction of Methyl 2-(Formamido)acrylate under Heck
Reaction Conditions
TABLE 3. Asymmetric Hydrogenation of N-Formyl
Dehydroamino Methyl Estersa
ee (%)b,c
entry
Pd (%)a
PhX
Z:Eb
yieldc (%)
entry
substrate
product
ligand
1
2
3
4
5
6
11.5
11.5
5.0
PhBr
PhI
PhBr
PhI
PhBr
PhI
28:1
12:1
12:1
11:1
13:1
13:1
59
68
64
73
45
73
1
2
3
4
5
6
7
8
9
10
11
12
13
14
3 (Z)
3 (E)
4 (Z)
4 (Z)
4 (Z)
4 (E)
5 (Z)
5 (Z)
5 (E)
6 (Z)
6 (E)
7
9
9
A4
A4
A4
A1
A5
A4
A4
A1
A4
A4
A4
A4
A4
A1
99 (R)
46 (R)
94 (R)
75 (R)
88 (R)
64 (R)
>99 (R)
98 (R)
96 (R)
>99 (R)
97 (R)
61 (R)
>99 (R)
97 (R)
10
10
10
10
11
11
11
12
12
13
14
14
5.0
2.0
2.0
a Reactions performed in a sealed tube at 80 °C for 22 h. b Z:E ratio
determined by H NMR. c Isolated yields, not optimized.
1
SCHEME 5. Phosphoramidites Used in This Study
8
8
a Reactions performed in 4 mL of solvent with 0.2 mmol of substrate
for 16 h. Conversions determined by 1H NMR and GC. b ee values
determined by chiral GC. c In all cases, the (S)-enantiomer of the ligand
was used.
esters.54 Excellent results (>99% ee in both cases) were obtained
for substrates 5 (Z) and 6 (Z) with use of A4 (entries 7 and
10).55
In contrast to the high enantioselectivity achieved with the Z
isomers, with use of bidentate phosphine ligands the hydrogena-
tion of the E isomers usually proceeds at much lower rates and
gives poor enantioselectivities.56,57 The results of the hydrogena-
tion of the E isomer of substrates 3 and 4 seem to confirm this
trend also for monodentate phosphoramidites (entries 2 and 6).
Products 9 and 10 were obtained with enantioselectivities of
46% and 64%, respectively, without a change in the configu-
ration. Remarkably, the hydrogenation of the E isomer of
substrates 5 and 6 proceeded with much higher enantioselec-
tivities (96% and 97% ee, entries 9 and 11).58 These results are
particularly important as alkyl dehydroamino acid derivatives
are difficult to prepare in geometrically pure form. The excellent
results obtained for product 12 are very interesting as this
compound bears an additional functionality, which could be used
for further transformations.59
asymmetric Rh-catalyzed hydrogenation reaction employing
chiral phosphoramidites as ligands (Scheme 5).
For screening purposes, a catalyst loading of 5% was
employed. Dichloromethane was used as solvent, as it previously
has proven to be the solvent of choice.11b PipPhos (A4) was
selected as it showed superior performance in terms of reactivity
and enantioselectivity with many other substrates.11e,g Both Z
and E isomers of substrates 3-6 were hydrogenated. All
reactions went to full conversion and the results are listed in
Table 3.
We were pleased to see that both N-formyl phenylalanine
methyl ester (9) and N-formyl alanine methyl ester (14) were
obtained with excellent enantioselectivity (>99% ee). This
proved our hypothesis that the formyl group is comparable to
the acyl group in directing the enantioselectivity, at least for
this catalyst.52 A high 94% ee (Table 3, entry 3) was obtained
for heterocyclic substrate 4 (Z). When A1 (MonoPhos) and A5
were used, the same product 10 was obtained in only 75% and
88% ee, respectively (entries 4 and 5).53 A class of substrates
that has not been used before in Rh-catalyzed hydrogenation
using monodentate ligands are â-alkyl substituted dehydroamino
Due to the excellent results obtained with substrates 3-6 and
8, it was decided to test the activity of the system by lowering
the catalyst loading with A4 as ligand (Table 4).
(54) For the only exception, see: Fu, Y.; Xie, J.-H.; Hu, A.-G.; Zhou,
H.; Wang, L.-X.; Zhou, Q.-L. Chem. Commun. 2002, 480.
(55) The same selectivity was obtained by using DuPHOS on the N-acyl
derivative of 5: (a) Reference 14b. For more recent examples of asymmetric
hydrogenation of the N-acyl lower homologue of 5 (with enantioselectivities
between 91% and 96%) see: (b) Qiao, S.; Fu, G. C. J. Org. Chem. 1998,
63, 4168. (c) Kuwano, R.; Sawamura, M.; Ito, Y. Bull. Chem. Soc. Jpn.
2000, 73, 2571. (d) Evans, D. A.; Michael, F. E.; Tedrow, J. S.; Campos,
K. R. J. Am. Chem. Soc. 2003, 125, 3534.
(56) For some studies see: (a) Vineyard, B. D.; Knowles, W. S.; Sabacky,
M. J.; Bachman, G. L.; Weinkauff, D. J. J. Am. Chem. Soc. 1977, 99, 5946.
(b) Scott, J. W.; Kieth, D. D.; Nix, G., Jr.; Parrish, D. R.; Remington, S.;
Roth, G. P.; Townsend, J. M.; Valentine, D., Jr.; Yang, R. J. Org. Chem.
1981, 46, 5086. In this study the N-acyl derivative of 5 was also considered,
the Z isomer gave 96% ee and the E isomer 95% ee, using DIPAMP.
(57) With Rh-Binap, hydrogenation of the Z and E isomeric substrates
generates even products with opposite configurations: Miyashita, A.;
Takaya, H.; Souchi, T.; Noyori, R. Tetrahedron 1984, 40, 1245.
(58) Very high enantioselectivities have been reported also by using Rh-
DuPHOS on alkyl-substituted enamides: ref 14a.
(52) On methyl 2-(acetamido)acrylate, Rh-A4 gave 99% ee and Rh-A1
gave 97% ee. On 2-(acetamido)cinnamic methyl ester Rh-A4 gave 99% ee
(ref 11e).
(53) A similar substrate, (Z)-2-acetamido-3-(2-furfuryl)acrylic acid methyl
ester, has been used previously; see: (a) Chan, A. S. C.; Hu, W.; Pai, C.-
C.; Lau, C.-P.; Jiang, Y.; Mi, A.; Yan, M.; Sun, J.; Lou, R.; Deng, J. J.
Am. Chem. Soc. 1997, 119, 9570. (b) Li, X.; Lou, R.; Yeung, C.-H.; Chan,
A. S. C.; Wong, W. K. Tetrahedron: Asymmetry 2000, 11, 2077. (c) Zhang,
F.-Y.; Kwok, W. H.; Chan, A. S. C. Tetrahedron: Asymmetry 2001, 12,
2337. (d) Guo, R.; Li, X.; Wu, J.; Kwok, W. H.; Chen, J.; Choi, M. C. K.;
Chan, A. S. C. Tetrahedron Lett. 2002, 43, 6803. (e) Lin, C. W.; Lin, C.-
C.; Lam, L. F.-L.; Au-Yeung, T. T.-L.; Chan, A. S. C. Tetrahedron Lett.
2004, 45, 7379.
J. Org. Chem, Vol. 71, No. 5, 2006 2031

Panella et al.
TABLE 4. Asymmetric Hydrogenation of N-Formyl
Dehydroamino Methyl Esters: Optimization of the Catalyst
Loadinga
TABLE 5. Asymmetric Hydrogenation of Methyl
2-(Formamido)-3,3-cyclohexylidene Acetate (7)a
ee (%)b,c
entry
ligand
conv (%)
ee (%)b,c
entry
substrate
catalyst (mol %)
conv (%)
1
2
3
4
5
A4
A1
A5
B4
C4
100
93
54
100
35
61 (R)
25 (R)
42 (R)
41 (R)
62d (S)
1
2
3
4
5
6
7
8
3 (Z)
4 (Z)
5 (Z)
5 (E)
5 (E)
6 (Z)
6 (E)
8
1
2
1
2
1
1
2
1
100
>99
100
100
65
100
100
100
98 (R)
93 (R)
>99 (R)
93 (R)
90 (R)
>99 (R)
96 (R)
a Reactions performed in 4 mL of solvent with 0.2 mmol of substrate
for 16 h. Conversions determined by 1H NMR and GC. b ee values
determined by chiral GC. c Unless otherwise stated, the (S)-enantiomer of
the ligand was used. d In this case, the (R)-enantiomer of the ligand was
used.
>99 (R)
a Reactions performed in 4 mL of solvent with 0.2 mmol of substrate
for 16 h. Conversions determined by 1H NMR and GC. b ee values
determined by chiral GC. c In all cases, the (S)-enantiomer of the ligand
was used.
be problematic substrates.10b The first example of selective
hydrogenation of the N-acyl equivalent of 7 was reported by
Burk et al., using DuPHOS and BPE-type ligands. Enantio-
selectivities of 96% and 99%, respectively, were obtained.62a
The sole report of a monodentate ligand describes the use of a
chiral secondary phosphine oxide (85% ee).62g Due to the
moderate enantioselectivity obtained it was decided to test a
few more phosphoramidite ligands maintaining the same condi-
tions. The results are listed in Table 5.
The catalyst loading could be lowered to 1 mol % for most
Z isomers and 2-(formamido)acrylic acid methyl ester (Table
4, entries 1, 3, 6, and 8) without compromising reactivity and
enantioselectivity. Under these conditions, the hydrogenations
of 2-(formamido)acrylic acid methyl ester (8) and of the
corresponding alkyl-substituted derivatives 5 (Z) and 6 (Z) were
finished within 15 min, according to the hydrogen uptake.60
Moreover, upon reducing the catalyst loading to 0.2 mol % and
the hydrogen pressure to 2 bar in the hydrogenation of 8, full
conversion and >99% ee were still obtained in less than 1 h.
On the other hand, for substrates 5 (E) and 6 (E) the catalyst
loading could be lowered to 2 mol % maintaining good
enantioselectivities (entries 4 and 8). When 5 (E) was hydro-
genated with 1 mol % of catalyst a decrease in enantioselectivity
was observed together with an incomplete conversion (entry 4
vs 5). This means that the use of 2 mol % of catalyst allows
the hydrogenation of mixtures of Z and E isomers of alkyl-
substituted dehydroamino esters affording full conversion and
excellent ee values.61 According to Scott et al., the superior
results obtained with the E isomers of alkyl substrates compared
to the E isomers of aryl substrates suggest less interference in
the coordination to the metal center.56b Moreover, no influence
of the presence of trans and cis rotamers of the formamido group
was noticed.
It turned out that PipPhos (A4) was the best ligand in terms
of both reactivity and enantioselectivity (Table 5, entry 1) among
the ligands tested. Full conversion was achieved also by using
B4 but with considerable loss in enantioselectivity (entry 4).
Comparable enantioselectivity (62% ee) was obtained with C4,
but the ligand was clearly too bulky as only 35% conversion
was reached (entry 5).
To improve the results obtained in the hydrogenation of 7,
combinations of ligands were applied.63 The potential of forming
new highly selective chiral catalysts by mixing chiral mono-
dentate ligands with other chiral,64 achiral,65a,11f or fluxionally
chiral65b,c monodentate ligands has been recently described by
the groups of Reetz and Piarulli/Gennari as well as by our
group.66 The method has been applied not only in Rh-catalyzed
hydrogenation and hydroformylation reactions,64-65,11f but also
in Rh-catalyzed boronic acid addition.67
The hydrogenation of methyl 2-(formamido)-3,3-cyclohex-
ylidene acetate (7) turned out to be more challenging. With use
of PipPhos (A4) as ligand, the reaction went to completion but
afforded 13 with only 61% ee (Table 3, entry 12). â,â-
Disubstituted R-dehydroamino acid derivatives are known to
(62) (a) Burk, M. J.; Gross, M. F.; Martinez, J. P. J. Am. Chem. Soc.
1995, 117, 9375. For other examples, see: (b) Reference 55b. (c) Yamanoi,
Y.; Imamoto, T. J. Org. Chem. 1999, 64, 2988. (d) Gridnev, I. D.; Yamanoi,
Y.; Higashi, N.; Tsuruta, H.; Yasutake, M.; Imamoto, T. AdV. Synth. Catal.
2001, 343, 118. (e) Ohashi, A.; Imamoto, T. Tetrahedron Lett. 2001, 42,
1099. (f) Reference 55d. (g) Jiang, X.-B.; van den Berg, M.; Minnaard, A.
J.; Feringa, B. L.; de Vries, J. G. Tetrahedron: Asymmetry 2004, 15, 2223.
(63) For an early example of the influence of added phosphines in 1,4-
addition reactions, see: Gomez-Bengoa, E.; Heron, N. M.; Didiuk, M. T.;
Luchaco, C. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 7649.
(64) (a) Reetz, M. T.; Sell, T.; Meiswinkel, A.; Mehler, G. Angew. Chem.,
Int. Ed. 2003, 42, 790. (b) Pen˜a, D.; Minnaard, A. J.; Boogers, J. A. F.; de
Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. Org. Biomol. Chem. 2003,
1, 1087. (c) Reetz, M. T.; Mehler, G.; Meiswinkel, A. Tetrahedron:
Asymmetry 2004, 15, 2165.
(59) For an example of further transformation of a homologous compound
into a tetrahydropyridine derivative, see: (a) Botman, P. N. M.; Dommerholt,
F. J.; de Gelder, R.; Broxterman, Q. B.; Schoemaker, H. E.; Rutjes, F. P.
J. T.; Blaauw, R. H. Org. Lett. 2004, 6, 4941. (b) Wijdeven, M. A.; Botman,
P. N. M.; Wijtmans, R.; Schoemaker, H. E.; Rutjes, F. P. J. T.; Blaauw, R.
H. Org. Lett. 2005, 7, 4005.
(60) An identical result was obtained for the Boc protected version of
this substrate, using MonoPhos (A1) under the same conditions (DSM
private communication).
(65) For combinations of chiral and achiral ligands, see: (a) Reetz, M.
T.; Mehler, G. Tetrahedron Lett. 2003, 44, 4593. For combinations of chiral
and fluxionally chiral ligands see: (b) Monti, C.; Gennari, C.; Piarulli, U.
Tetrahedron Lett. 2004, 45, 6859. (c) Reetz, M. T.; Li, X. Angew. Chem.,
Int. Ed. 2005, 44, 2959. For combinations of different achiral ligands applied
in hydroformylation, see: (d) Reetz, M. T.; Li, X. Angew. Chem., Int. Ed.
2005, 44, 2962.
(61) E isomers of substrates 3 and 4 have not been tested at lower catalyst
loading, due to the lower enantioselectivities previously obtained (see Table
3).
(66) Hartwig, J. Nature 2005, 437, 487.
2032 J. Org. Chem., Vol. 71, No. 5, 2006

Hydrogenation of N-Formyl Dehydroamino Esters
TABLE 6. Asymmetric Hydrogenation of Methyl 2-(Formamido)-3,3-cyclohexylidene Acetate (7) with Heterocombinations of Ligandsa
a Reactions performed in 4 mL of solvent with 0.2 mmol of substrate, 0.01 mmol of Rh(COD)2BF4, 0.02 mmol of chiral phosphoramidite, and 0.01 mmol
of achiral phosphine (if present). Reactions were run for 16 h. b ee values were determined by chiral GC.
Due to the recent successful application in our laboratories
of this concept in the hydrogenation of cinnamic acids,11f it was
decided to employ a combination of chiral phosphoramidites
and achiral phosphines (with a ratio of 2:1). The phosphor-
amidites used were also tested without addition of phosphine.
The results are shown in Tables 6 and 7.
First, PipPhos (A4) was tried in combination with tri-o-
tolylphosphine (Table 6, entry 2). Pleasingly, an increase in
enantioselectivity was observed compared to the homocombi-
nation (entry 1), although the reaction was slightly slower. The
same increase in enantioselectivity but decrease in activity was
observed for MonoPhos (A1) (entries 5 and 6). On the contrary,
when the 3,3′-dimethyl-BINOL version of PipPhos (C4) was
used, an increase in terms of both reactivity and enantioselec-
tivity was observed (entries 3 vs 4). A very exciting result was
that the heterocombination of C4 and tri-o-tolylphosphine
provided full conversion to the product and a remarkable 85%
ee, as the best result so far. The influence of the phosphine was
less dramatic in the case of the 3,3′-dimethyl-BINOL version
of MonoPhos (C1) (entries 7 vs 8), where only a slight increase
in enantioselectivity was achieved. When another 3,3′-dimethyl-
substituted phosphoramidite ligand was used (C6), a somewhat
higher conversion to the product was observed for the hetero-
combination, but with the same degree of enantioselectivity
(entries 9 and 10). It should be noted that the homocombinations
of C1 and C6 showed better enantioselectivity than PipPhos
(A4) although the catalyst is slower (entries 7 and 9 vs 1). In
view of the good results obtained with C4 and tri-o-tolylphos-
phine as ligands, it was decided to test additional achiral
phosphines. The outcome of this investigation is shown in Table
7.
(67) (a) Duursma, A.; Hoen, R.; Schuppan, J.; Hulst, R.; Minnaard, A.
J.; Feringa, B. L Org. Lett. 2003, 5, 3111. (b) Duursma, A.; Boiteau, J. G.;
Lefort, L.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries, J. G.; Minnaard,
A. J.; Feringa, B. L. J. Org. Chem. 2004, 69, 8045. (c) Duursma, A.; Pen˜a,
D.; Minnaard, A. J.; Feringa, B. L. Tetrahedron: Asymmetry 2005, 16, 1901.
Complete conversion was achieved in almost all cases.
Interestingly, with tricyclohexylphosphine the opposite config-
uration of the product was obtained. The influence of the
presence and position of the methyl group on the enantioselec-
J. Org. Chem, Vol. 71, No. 5, 2006 2033

Panella et al.
TABLE 7. Asymmetric Hydrogenation of Methyl 2-(Formamido)-3,3-cyclohexylidene Acetate (7) with Heterocombination of Ligand C4 and
Different Phosphinesa
a Reactions performed in 4 mL of solvent with 0.2 mmol of substrate, 0.01 mmol of Rh(COD)2BF4, 0.02 mmol of chiral phosphoramidite, and 0.01 mmol
of achiral phosphine. Reactions were run for 16 h. b ee values were determined by chiral GC.
tivity was tested by comparing triphenylphosphine, tri-o-, tri-
m-, tri-p-tolylphosphine, and tri-3,5-dimethylphenylphosphine
(entries 2-6). The enantioselectivity obtained with tri-o-
tolylphosphine remained the highest. Poorer and comparable
results were achieved with or without methyl substituent in the
other positions. Only by using tri-p-tolylphosphine was a
consistent decrease in ee observed. Moreover, the hydrogen
uptake showed an opposite trend between reactivity and
enantioselectivity, with the catalyst based on tri-o-tolylphosphine
being the slowest (85% ee, 16 h) and the use of tri-p-
tolylphosphine as ligand provided the fastest reaction (59% ee,
approximately 4 h). Electron-donating or -withdrawing substit-
uents seemed to have little influence (entries 9-11) on the
enantioselectivity, compared to triphenylphosphine. In all three
cases the reaction rate appeared to be comparable to the one
observed with tri-p-tolylphosphine, with the p-methoxy-
substituted triphenylphosphine slightly faster than p-fluoro and
p-chloro, respectively. In conclusion, the results suggest that
the steric effect of the phosphine substituents plays a larger role
than their electronic properties.
2034 J. Org. Chem., Vol. 71, No. 5, 2006

Hydrogenation of N-Formyl Dehydroamino Esters
TABLE 8. Asymmetric Hydrogenation of 2-(Formamido)acrylic
Acida
SCHEME 6. Transformations of N-Formylamino Esters
entry
solvent
ligand
conv (%)b
ee (%)c
1
2
3
4
5
DCM
(S)-A1
(S)-A1
(S)-A1
(S,R)-A2
(S)-A3
100
70
85
21
96
92 (R)
89 (R)
53 (R)
54 (R)
86 (R)
EtOAc
i-PrOH
DCM
DCM
a Reactions performed in 4 mL of solvent with 0.2 mmol of substrate
overnight. b Conversions determined by 1H NMR and GC. c ee values were
determined by chiral GC after conversion to methyl ester.
formyl group was removed with use of recently reported
conditions for Boc deprotection, with the weaker acid H3PO4
(entry 3).72 In all cases no racemization was observed.73
Moreover, the formyl group is remarkably resistant toward basic
hydrolysis and azlactone formation. The orthogonal removal of
formyl and ester groups makes a stepwise approach toward the
synthesis of peptides possible.28a Another interesting feature
connected with the use of N-formyl protection is their convenient
transformation, in one step via borane reduction, into N-
methylamino acid derivatives.74 The properties exhibited by
various natural products, in which N-methylamino acids are
present, make them of great interest from a medicinal and
synthetic point of view.75
TABLE 9. Removal of N-Formyl Protection
entry
conditions
yield (%)
ee (%)a
1
2
3
HCl (1 equiv), MeOH reflux, 1 h
HCl (1 equiv), MeOH rt, 8 h
H3PO4 (1.5 equiv), THF, reflux, 9 h
>99
>99
89
>99
>99
>99
a ee values were determined by chiral GC after N-formyl protection of
the product.
Conclusions
Thus, by using a combination of a chiral phosphoramidite
and an achiral phosphine, full conversion and high enantio-
selectivities are obtained in the hydrogenation of â,â-dialkyl
dehydroamino ester 7. Moreover, this investigation showed that
heterocombinations of ligands lead to better results.
To show that not only esters but also N-formyl dehydroamino
acids can be successfully hydrogenated, hydrogenation of
2-(formamido)acrylic acid (15)68 was studied with MonoPhos
(A1)69 as the chiral ligand. Dichloromethane turned out to be
the best solvent and an enantioselectivity of 92% was obtained.
In the same solvent the corresponding methyl ester 8 was
hydrogenated providing 97% ee (Table 3, entry 15). Lower
conversion and enantioselectivity were obtained in EtOAc (Table
8, entry 2), which, however, was the best solvent with
2-(acetamido)acrylic acid (99% ee).7d
To establish the utility of the formyl moiety as a protecting
group, it is necessary to prove its superiority compared to the
acyl functionality during the deprotection step. As the final part
of our investigation, the removal of the formyl group was
studied. N-formyl phenylalanine methyl ester70 was converted
into the corresponding amino ester under mild acidic conditions.
Interestingly, the formyl group is removed at room temper-
ature in the presence of 1 equiv of hydrochloric acid (Table 9,
entry 2).71 These conditions are even milder than those previ-
ously reported by Sheehan and Yang.28a Alternatively, the
We have demonstrated that N-formyl-protected dehydroamino
esters are excellent substrates for Rh-catalyzed asymmetric
hydrogenation in combination with monodentate phosphor-
amidites as ligands. Excellent enantioselectivities (up to >99%
ee) were obtained for the Z isomers. An important finding is
that very high enantioselectivities can also be achieved (up to
97% ee) for the E isomers of substrates with alkyl substituents
(5, 6). Good results were obtained for a â,â-disubstituted
substrate (7, up to 85% ee) by using combinations of phos-
phoramidites and achiral phosphines. Moreover, the use of
N-formyl protection allows an efficient one-pot synthesis of a
large variety of substrates, in terms of both possible function-
alities tolerated and ease of preparation. An inexpensive,
efficient, and multigram scale protocol for the synthesis of
methyl 2-(formamido)acrylate (8) was developed. This makes
the Heck reaction even more interesting as methodology for
the preparation of aromatic dehydroamino esters. Finally, the
protecting group can be easily removed under very mild reaction
conditions.
(72) For the use of H3PO4 in the removal of tert-butoxycarbonyl groups,
see: (a) Li, B.; Bemish, R.; Buzon, R. A.; Chiu, C. K.-F.; Colgan, S. T.;
Kissel, W.; Le, T.; Leeman, K. R.; Newell, L.; Roth, J. Tetrahedron Lett.
2003, 44, 8113. For the use of H3PO4 in the removal of N-sulfinylimida-
zolidines, see: (b) Viso, A.; de la Predilla, R. F.; Lo´pez-Rodr´ıguez, M.;
Grac´ıa, A.; Flores, A.; Alonso, M. J. Org. Chem. 2004, 69, 1542.
(73) Examples of racemization occurring during deprotection in acidic
conditions of N-benzoyl functionalized products have been reported: (a)
Krause, H.-W.; Kreuzfeld, H. J.; Do¨bler, C.; Taudien, S. Tetrahedron:
Asymmetry 1992, 3, 555. (b) Taudien, S.; Schinkowski, K.; Krause, H.-W.
Tetrahedron: Asymmetry 1993, 4, 73.
(68) Prepared with pyruvic acid and formamide in 16% yield according
to a literature procedure: Frankel, M.; Reichmann, M. E. J. Chem. Soc.
1952, 105, 289.
(69) This allowed comparison with results previously obtained for
2-acetamidoacrylic acid (ref 11b).
(70) Prepared from commercially available (L)-phenylalanine methyl ester
hydrochloric salt (ref 28a).
(74) (a) Krishnamurthy, S. Tetrahedron Lett. 1982, 23, 3315. (b)
Konopelski, J. P.; Chu, K. S.; Negrete, G. R. J. Org. Chem. 1991, 56, 1355.
(c) Hall, D. G.; Laplante, C.; Manku, S.; Nagendran, J. J. Org. Chem. 1999,
64, 698.
(71) No reaction was observed applying the same conditions to the N-acyl
protected amino ester.
(75) For a review, see: Aurelio, L.; Brownlee, R. T. C.; Hughes, A. B.
Chem. ReV. 2004, 104, 5823.
J. Org. Chem, Vol. 71, No. 5, 2006 2035

Panella et al.
(EI+) for C11H11NO3, calcd 205.0739, found 205.0734. Z isomer:
white solid, Rf 0.46 (heptanes-ethyl acetate 1:1), trans:cis ) 47:
53. Mp 92.4-93.0 °C (lit.28a mp 88-89 °C). 1H NMR (400 MHz,
CDCl3) δ 8.10 (s, 1H, trans), 8.06 (d, J ) 11.2 Hz, 1H, cis), 7.92
(br, 1H, trans), 7.58 (d, J ) 8.0 Hz, 1H, cis), 7.50-7.18 (m, 6H),
3.77 (s, 3H, cis), 3.71 (s, 3H, trans). 13C NMR (100 MHz, CDCl3)
δ 165.3 (s, trans), 164.9 (s, cis), 163.8 (d, cis), 159.3 (d, trans),
133.4 (s, trans), 132.9 (d, trans), 132.6 (s, cis), 129.8 (d, cis), 129.6
(d), 129.5 (d), 129.1 (d), 129.0 (d, trans), 128.5 (d, cis), 123.9 (s,
cis), 122.3 (s, trans), 52.9 (q, cis), 52.7 (q, trans). MS, m/z (%) 205
(M+, 31.0%); HRMS (EI+) for C11H11NO3, calcd 205.0739, found
205.0735.
On the basis of our results, it is evident that the N-formyl
protection is a very versatile, useful, and underestimated
synthetic tool and provides a link between preparation and
asymmetric hydrogenation of optically active amino acids.
Experimental Section
General Method D (Scheme 1): Synthesis of 2-(Formamido)-
hex-2-enoic Acid Methyl Ester (5). To a solution containing
methyl isocyanoacetate (1.0 mL, 11.0 mmol) and butyraldehyde
(1.2 mL, 13.2 mmol, 1.2 equiv) in dry ether (10 mL) was added
Cu2O (79 mg, 0.55 mmol, 5 mol %) in one portion causing an
exothermic reaction. The mixture was stirred for 3 h at room
temperature, until TLC (heptanes-ethyl acetate 1:1) showed
complete conversion of the starting material. At that point the
temperature was lowered to 0 °C and a solution of potassium tert-
butoxide (1.28 g, 11.0 mmol) in THF (10 mL) was added. After
the solution was stirred for 30 min, acetic acid (0.65 mL, 11.0
mmol) in CH2Cl2 (27 mL) was added, and the reaction mixture
was allowed to reach room temperature and extracted with water.
The organic layer was dried over Na2SO4 and the solvent removed
under reduced pressure. The crude mixture was purified by flash
column chromatography on silica gel (heptanes-ethyl acetate 2:1)
affording the desired compounds 5 (Z/E 1.6:1, 1.22 g, 65%). E
isomer: colorless oil, Rf 0.22 (heptanes-ethyl acetate 2:1), trans:
Synthesis of 2-(Formamido)acrylic Acid Methyl Ester (8).77
A mixture of serine methyl ester hydrochloric salt (1 g, 6.4 mmol),
K2CO3 (3.5 g, 4 equiv), and a catalytic amount of NEt3 (10 µL) in
methyl formate (20 mL) was stirred overnight at room temperature.
The salts were filtered and the solvent removed under reduced
pressure. Quick purification by column chromatography (heptanes-
ethyl acetate 1:1) afforded the desired product (0.76 g, 92%). White
solid, Rf 0.56 (heptanes-ethyl acetate 1:1), trans:cis 88:12. Mp
56.9-57.2 °C (lit. mp 53-56 °C). 1H NMR (300 MHz, CDCl3) δ
8.56 (d, J ) 11.4 Hz, 1H, cis), 8.41 (s, 1H, trans), 7.87 (br, 1H,
trans), 7.60 (br, 1H, cis), 6.63 (s, 1H, trans), 5.95 (s, 1H, trans),
5.69 (s, 1H, cis), 5.44 (s, 1H, cis), 3.85 (s, 3H). 13C NMR (50 MHz,
CDCl3) δ 164.1 (s), 160.9 (d, cis), 159.4 (d, trans), 130.1 (s), 110.37
(t, trans), 104.5 (t, cis), 53.1 (q). MS, m/z (%) 129 (M+, 100%);
HRMS (EI+) for C5H7NO3, calcd 129.0426, found 129.0434.
Elemental Anal.: calcd C 46.51, H 5.46, N 10.85; found C 46.60,
H 5.51, N 10.77.
Hydrogenation General Procedure. Hydrogenations were
performed in an Endeavor, an autoclave with eight reactors equipped
with glass reaction vessels. In a typical run each glass liner was
charged open to air with Rh(COD)2BF4 (2 µmol), monodentate
phosphoramidite (4 µmol), and substrate (0.2 mmol). Solvent was
added (4 mL), the glass liners were placed in the reactors, and the
system was closed. After repetitive purging with N2 (3 × 2.5 bar)
the system was pressurized with hydrogen and the reactions were
stirred at room temperature with 750 rpm. The conversion of the
reactions was monitored by following H2 consumption. The
reactions were stopped via release of H2 pressure. The resulting
mixture was filtered over a short silica column and subjected to
conversion (1H NMR and GC) and enantiomeric excess determi-
nation (capillary chiral GC).
1
cis ) 80:20. H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H, trans),
8.24 (d, J ) 11.1 Hz, 1H, cis), 7.52 (br s, 1H), 7.29 (t, J ) 7.5 Hz,
1H, trans), 6.04 (t, J ) 7.5 Hz, 1H, cis), 3.85 (s, 3H, trans), 3.83
(s, 3H, cis), 2.63-2.50 (m, 2H), 1.58-1.40 (m, 2H), 0.95 (dt, J )
7.2, 2.4 Hz, 3H). 13C NMR (50 MHz, CDCl3) δ 164.6 (s, trans),
163.8 (s, cis), 162.3 (d, cis), 159.2 (d, trans), 134.5 (d, trans), 134.1
(d, cis), 124.8 (s, cis), 123.9 (s, trans), 52.4 (q, trans), 52.3 (q, cis),
30.4 (t, trans), 30.0 (t, cis), 22.7 (t, trans), 22.6 (t, cis), 13.8 (q,
trans), 13.7 (q, cis). MS, m/z (%) 171 (M+, 41.9%); HRMS (EI+)
for C8H13NO3, calcd 171.0895, found 171.0908. Z isomer: colorless
oil, Rf 0.19 (heptanes-ethyl acetate 2:1), trans:cis ) 58:42. 1H NMR
(300 MHz, CDCl3) δ 8.24 (s, 1H, trans), 8.17 (d, J ) 11.1 Hz, 1H,
cis), 7.20-7.00 (br, 1H), 6.75 (m, 1H, trans), 6.64 (m, 1H, cis),
3.80 (s, trans), 3.78 (s, cis), 2.32-2.08 (m, 2H), 1.60-142 (m, 2H),
1.04-0.88 (m, 3H). 13C NMR (50 MHz, CDCl3) δ 164.8 (s, trans),
164.4 (s, cis), 163.9 (d, cis), 158.9 (d, trans), 139.6 (d, trans), 135.2
(d, cis), 125.4 (s, cis), 123.2 (s, trans), 52.6 (q, cis), 52.5 (q, trans),
31.2 (t, trans), 29.9 (t, cis), 22.1 (t, cis), 21.4 (t, trans), 13.9 (q,
trans), 13.7 (q, cis). MS, m/z (%) 171 (M+, 26.9%); HRMS (EI+)
for C8H13NO3, calcd 171.0895, found 171.0904.
N-Formyl Deprotection of 2-(Formamido)-3-phenylpropionic
Acid Methyl Ester (9) with Hydrochloric Acid.78 Hydrochloric
acid (10 mmol) in methanol (6 mL) was added to a solution of
N-formyl-(L)-phenylalanine methyl ester (2.0 g, 10 mmol) in
methanol (4 mL). The reaction mixture was stirred at reflux for 1
h or at room temperature for 8 h. The reaction mixture was
concentrated under reduced pressure. (L)-Phenylalanine methyl ester
hydrochloric salt was isolated after recrystallization from methanol
(99%).
Synthesis of 2-(Formamido)cinnamic Acid Methyl Ester (3)
under Heck Reaction Conditions.76 A mixture of iodobenzene
(365 mg, 1.79 mmol), 2-(formamido)acrylic acid methyl ester 8
(305 mg, 2.13 mmol, 1.2 equiv), Pd(OAc)2 (8.0 mg, 0.036 mmol,
2%), tetra-n-butylammonium chloride (599 mg, 2.16 mmol, 1.2
equiv), and NaHCO3 (407 mg, 4.84 mmol, 2.7 equiv) was flushed
with nitrogen and heated in a sealed tube at 80 °C for 22 h.
Subsequently, the reaction mixture was cooled to room temperature
and a mixture of CH2Cl2/H2O (1:1, 100 mL) was added. The organic
layer was washed with H2O (25 mL) and the combined aqueous
layers were extracted with CH2Cl2 (25 mL). The combined organic
layers were washed with brine and dried over Na2SO4 and the
solvent was removed under reduced pressure. Purification by flash
column chromatography on silica gel (heptanes-ethyl acetate 2:1)
afforded the desired product 3 (Z/E 13:1, 268 mg, 73%). E
isomer: colorless oil, Rf 0.50 (heptanes-ethyl acetate 1:1), trans:
cis ) 75:25. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J ) 14.4 Hz,
1H, cis), 8.41 (s, 1H, trans), 8.23 (s, 1H, trans), 7.61 (br, 1H, trans),
7.52 (br, 1H, cis), 7.42-7.22 (m, 5H), 6.92 (s, 1H, cis), 3.70 (s,
3H, cis), 3.65 (s, 3H, trans). 13C NMR (50 MHz, CDCl3) δ 164.7
(s), 159.2 (d), 135.1 (s), 129.3 (d), 128.7 (s), 128.8 (d, 2C), 128.1
(d), 127.8 (d, 2C), 52.4 (q). MS, m/z (%) 205 (M+, 28.6%); HRMS
Acknowledgment. We thank T. D. Tiemersma-Wegman and
E. P. Schudde for technical support and A. Kiewiet for mass
spectrometry measurements. This work was supported by the
Dutch Organization for Scientific Research (NWO-STW).
Supporting Information Available: Experimental procedures,
spectral data for substrates and products, and methods for enan-
tiomeric excess determination. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO052451D
(77) Data in agreement with literature: Roos, E. C.; Lopez, M. C.; Brook,
M. A.; Hiemstra, H.; Speckamp, W. N.; Kaptein, B.; Kamphuis J.;
Schoemaker H. E. J. Org. Chem. 1993, 58, 3259.
(78) According to a slightly modified procedure, data in agreement with
the literature: Sheehan, J. C.; Yang, D.-D. H. J. Am. Chem. Soc. 1958, 80,
1154.
(76) Data in agreement with literature: ref 46a.
2036 J. Org. Chem., Vol. 71, No. 5, 2006