Addition of azomethine ylides to aldehydes: Mechanistic dichotomy of differentially substituted α-imino esters

Article abstract of DOI:10.1002/ejoc.201000377

The formal 1,3-dipolar cycloaddition of azomethine ylides and aldehydes is explored, as hydrolysis of the resulting oxazolidine product gives facile access to valuable syn-β-arylβ-hydroxy-α-amino esters. The use of using benzaldehydederived imines as the ylide precursor results in 1,3-dipolar cycloaddition with high conversions but low diastereoselec-tivity. In contrast, the employment of benzophenone-derived imines as the ylide precursor results in an aldol reaction, which gives the intermediate oxazolidine in high diastereoselectivity and requires a weak acid catalyst to achieve higher conversions.

Full text of DOI:10.1002/ejoc.201000377

FULL PAPER
DOI: 10.1002/ejoc.201000377
Addition of Azomethine Ylides to Aldehydes: Mechanistic Dichotomy of
Differentially Substituted α-Imino Esters
Brinton Seashore-Ludlow,[a] Staffan Torssell,[a] and Peter Somfai*[a,b]
Keywords: Amino alcohols / Azomethine ylides / Aldol reaction / Cycloaddition
The formal 1,3-dipolar cycloaddition of azomethine ylides
and aldehydes is explored, as hydrolysis of the resulting ox-
azolidine product gives facile access to valuable syn-β-aryl-
β-hydroxy-α-amino esters. The use of using benzaldehyde-
derived imines as the ylide precursor results in 1,3-dipolar
cycloaddition with high conversions but low diastereoselec-
tivity. In contrast, the employment of benzophenone-derived
imines as the ylide precursor results in an aldol reaction,
which gives the intermediate oxazolidine in high diastereo-
selectivity and requires a weak acid catalyst to achieve
higher conversions.
Introduction
Due to their prevalence in natural products, including
antibiotics and enzyme inhibitors, and their value as chiral
building blocks, β-hydroxy-α-amino acids have become in-
creasingly important synthetic targets.[1] Not only is this
structural motif present in vancomycin, sphingofungin, and
lactacystin to name but a few natural products, but this
scaffold can also be rapidly converted into 2-amino-1,3-di-
ols, β-lactams,[2] aziridines,[3] and β-haloamino acids.[4–6]
Thus, numerous methods have been developed to access
these compounds.[1]
Scheme 1. Retrosynthetic analysis of α-hydroxy-β-amino esters and
β-hydroxy-α-amino esters.
One of the most efficient strategies to construct these
valuable building blocks is the direct addition of a glycine
equivalent to an aldehyde. Recently, we disclosed a technol-
ogy to generate regioisomeric α-hydroxy-β-amino esters 1
from hydrolysis of oxazolidine 2a, which is the product of
a 1,3-dipolar cycloaddition of carbonyl ylide 3 and aldimine
4 (Scheme 1, pathway A).[7,8] Consequently, we envisaged
that an analogous retrosynthetic disconnection of oxazolid-
ine 2b would allow the synthesis of β-hydroxy-α-amino es-
ters through the reaction of azomethine ylide 6, serving as
a glycine equivalent, and aldehyde 7 (Scheme 1, path-
way B).[9–15] Interestingly, in the course of this study we un-
covered a mechanistic dichotomy between benzophenone-
derived imines and benzaldehyde-derived imines. The for-
mer undergo aldol reactions with aryl aldehydes, whereas
the latter participate in 1,3-dipolar cycloadditions.
Results and Discussion
Azomethine ylides have been studied extensively, as they
offer an effective method for the construction of nitrogen-
containing heterocycles.[16] We began our investigations by
using Vedejs’ oxazole methodology for mild, low-tempera-
ture azomethine ylide generation (Scheme 2).[17,18] Reaction
of oxazolium salt 8 with benzaldehyde 7a under reducing
conditions yielded oxazolidine 11a[19] in 58% yield via ylide
10. The resulting product was hydrolyzed to β-hydroxy-α-
amino ester 12a as a 2.3:1 mixture of syn/anti diastereomers
in 89% yield.[20]
Pleased with these initial results, we attempted to opti-
mize the reaction, both to improve the diastereoselectivity
and the yield (Table 1). A major byproduct was tertiary
amine 13, resulting from reduction of intermediate 10
(Scheme 2). Thus, we tried to alter the solvent (Table 1, En-
try 3), reduce the equivalents of PhSiH3 (Table 1, Entry 4),
reduce the temperature (Entry 5), and decrease the rate of
addition of the reducing agent (Table 1, Entry 5). However,
we were unable to preclude the formation of 13 and little
improvement of the yield was achieved.
[a] Organic Chemistry, KTH Chemical Science and Engineering,
Royal Institute of Technology,
10044 Stockholm, Sweden
Fax: +46-8-791 23 33
E-mail: somfai@kth.se
[b] Institute of Technology, University of Tartu,
Nooruse 1, 50441 Tartu, Estonia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000377.
Eur. J. Org. Chem. 2010, 3927–3933
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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B. Seashore-Ludlow, S. Torssell, P. Somfai
FULL PAPER
Scheme 2. Azomethine ylide generation from N-methyl oxazolium salt 8, reaction with benzaldehyde (7a), and subsequent hydrolysis of
oxazolidine 11a.
Table 1. Optimization of 1,3-dipolar cycloaddition of oxazolium ties were achieved with imines 14d and 14e (Table 2, En-
salt 8 and benzaldehyde (7a).[a]
tries 5 and 8). Unfortunately, neither cooling the reaction
nor changing the solvent enhanced the diastereoselectivity
(Table 2, Entries 6–9).
Table 2. Optimization of the 1,3-dipolar cycloaddition of α-imino
ester derived azomethine ylide with benzaldehyde.[a]
PhSiH3
[equiv.]
Yield[c]
[%]
Entry
Conditions
In situ formation of 8
CH2Cl2
dr[b]
1
2
3
4
5
6
1.5
1.5
1.5
1.05
1.05
1.05
2.3:1
2.3:1
n.d.
58
60
7
n.d. 53[d]
–40 °C
PhSiH3 added over 10 h
n.d.
36
n.d. 63[d]
Conv.[b]
[%]
[a] The reaction was carried out overnight with 1 equiv. of pre-
formed oxazolium salt 8. [b] Diastereoselectivity determined after
hydrolysis to amino alcohol 12 with PTSA and MeOH/H2O (95:5).
n.d. = not determined. [c] Isolated yield of all diastereomers of 11.
[d] Conversion of the reaction to the product based on integration
Entry
14
R, R2
Solvent
16
dr 16[c]
1
2
3
4
a
b
b
c
d
c
d
e
e
H, Me
F, Et
F, Et
CN, Et
CF3, Et
CN, Et
CF3, Et
CF3,Me
CF3, Me
THF
THF
THF
THF
THF
THF
DCM
THF
56
63
82
90
a
b
b
c
d
c
d
e
e
1.6:1
1.7:1
1.7:1
2.3:1
2.3:1
1.8:1
2.0:1
2.5:1
2.0:1
1
of the signals in the H NMR spectrum.
5
96[e]
6[d]
7
80
93
To circumvent over-reduction of azomethine ylide 10 to
amine 13, we reconsidered our strategy. An attractive route
to the desired species is the generation of a N-metallated
azomethine ylide.[21–23] A AgI/PPh3 catalyst has been re-
ported to activate α-imino ester 14, which can lead to
metalloazomethine ylide 15 in the presence of a mild
base.[24–26] We postulated that this intermediate could then
be intercepted by benzaldehyde to produce oxazolidine 16.
To our delight, treatment of glycine-derived imine 14a and
benzaldehyde with AgOAc/PPh3 catalyst (5 mol-%) in the
presence of catalytic amounts of iPr2NEt yielded desired
oxazolidine 16a in 56% conversion and a 1.6:1 mixture of
4,5-trans to 4,5-cis diastereomers (Table 2, Entry 1).[27] To
improve the conversion, a variety of imine derivatives were
8
9
84[e]
PhMe 78[e]
[a] Reaction conditions: imine 14 (1.0 equiv.), aldehyde 7a
(2.0 equiv.), iPr2NEt (0.2 equiv.), AgOAc (10 mol-%), and PPh3
(20 mol-%) in solvent (c = 0.1 ) at room temperature. In Entries 1
and 2, 5 mol-% of AgOAc and 10 mol-% of PPh3 were used.
1
[b] Conversion of 14 determined by analysis of the H NMR spec-
trum of the crude mixture before hydrolysis. [c] The 4,5-trans to
4,5-cis ratio of oxazolidine 16 was determined by hydrolysis to the
1
corresponding amino alcohol, and analysis of the H NMR spec-
trum of this mixture yielded the dr. Hydrolysis was performed with
HCl (1 ) in MeOH/H2O (95:5). [d] Reaction run at –20 °C. [e] 1-
Methyl-naphthalene was used as an internal standard.
To improve the outcome of the reaction, benzophenone-
examined. The more electron-withdrawing 4-fluoro-substi- derived imine 17 was examined. This reagent has previously
tuted imine improved the yield and diastereoselectivity been used in several direct aldol reactions under phase-
slightly (Table 2, Entry 2), as did increasing the catalyst transfer conditions to access anti-β-alkyl-β-hydroxy-α-
loading to 10 mol-% (Table 2, Entry 3). We explored two amino esters.[28–32] Oxazolidine 18a was obtained as a 3.8:1
other electron-deficient imines (Table 2, Entries 4 and 5) mixture of 4,5-trans to 4,5-cis diastereomers (Table 3, En-
and determined that the best yields and diastereoselectivi- try 1).[32,33] A further screen revealed toluene to be the opti-
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Addition of Azomethine Ylides to Aldehydes
Table 3. Reaction of benzophenone-derived imines with benzaldehyde.[a]
Entry
AgX
PPh3 [mol-%]
Solvent
DIEA [mol-%] Acid[b] [mol-%] Conv. 17[c] [%]
dr[d] 18
1
2
3
4
5
6
7
8
AgOAc
AgOAc
AgOAc
AgOAc
AgOTf
20
20
20
10
10
10
10
10
10
10
10
THF
DCM
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
20
20
20
20
20
20
20
10
10
20
–
–
–
–
–
–
–
–
10
5
5
64
48
3.8:1
7.3:1
10:1
30:1
36:1
24:1
9:1
17:1
36:1
58:1
–
61
75[e]
78[f]
80
Ag(MeCN)4BF4
AgOTf
30
89
72
83
AgOTf
AgOTf
AgOTf
AgOTf
9
10
11
10
–
[a] Reaction conditions: imine 17 (1.0 equiv.), aldehyde 7a (2.0 equiv.), iPr2NEt (20 mol-%), PPh3, and AgX (10 mol-%) in solvent (c =
0.1 ) at room temperature. [b] Benzoic acid was used. In these cases the benzaldehyde was distilled. [c] Determined by analysis of the
1
1H NMR spectrum of the crude mixture. [d] The 4,5-trans to 4,5-cis ratio of the oxazolidine was determined by analysis of the H NMR
spectrum of the crude reaction mixture. [e] The syn diastereomer of the amino alcohol was isolated in 70% yield after hydrolysis. [f] The
syn diastereomer of the amino alcohol was isolated in 72% yield after hydrolysis.
mal solvent, significantly increasing the diastereoselectivity; resulted in an increased yield and diastereoselectivity
although this occurred at the price of the conversion (Table 3, Entry 8). Decreasing the amount of benzoic acid
(Table 3, Entries 2 and 3). Interestingly, decreasing the increased the diastereoselectivity (Table 3, Entry 9). The op-
amount of PPh3 as compared to AgI increased the yield and timal combination proved to be 20 mol-% of iPr2NEt and
diastereoselectivity (Table 3, Entries 3–5). Examining AgI 5 mol-% benzoic acid (Table 3, Entry 10).[36]
salts, AgOTf was revealed to induce the highest yields and
Intrigued by the increased yield and diastereoselectivity
in the presence of a proton source, we probed the mecha-
diastereoselectivities (Table 3, Entries 3–6).[34]
At this point we encountered an interesting setback; in nism of the reaction. Two potential reaction manifolds from
our use of freshly distilled benzaldehyde, both the yield and the α-imino ester to the corresponding oxazolidine can be
diastereoselectivity were drastically decreased (Table 3, En- envisioned (Scheme 3). In the first, a straightforward 1,3-
try 7).[35] Knowing the major impurity in the benzaldehyde dipolar cycloaddition of metalloazomethine ylide interme-
to be benzoic acid, we tried using a 1:1 mixture (10 mol-% diate B to aldehyde would lead directly to oxazolidine prod-
each) of N,N-diisopropylethylammonium benzoate, which uct C (pathway A). Alternatively, ylide B could participate
Scheme 3. Proposed mechanisms for the reaction of azomethine ylides with aryl aldehydes.
Eur. J. Org. Chem. 2010, 3927–3933
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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B. Seashore-Ludlow, S. Torssell, P. Somfai
FULL PAPER
Table 4. Scope of silver-catalyzed direct aldol.[a]
7/18/21
R
Conv.[b] [%]
89
89
83
Ͻ10
95
78
dr 18 (trans/cis)[b]
Yield[c] [%]
dr 21 (syn/anti)[d]
1
2
3
4
5
6
7
8
a
b
c
d
e
f
Ph
58:1
26:1
18:1
–
18:1
46:1
36:1
1.5:1
68 (79)[e]
18:1
16:1
3:1
4-FC6H4
4-BrC6H4
4-MeOC6H4
3-BrC6H4
3-MeOC6H4
2-MeC6H4
furyl
62 (77)[e]
52
–
48
76
49
91[f]
–
11:1
13:1
3:1
g
h
51
94
1.3:1
[a] Reaction conditions: imine 17 (1.0 equiv.), aldehyde 7 (2.0 equiv.), iPr2NEt (20 mol-%), benzoic acid (5 mol-%), and AgOTf/PPh3 (1:1)
in THF (c = 0.1 ) at room temperature. [b] Determined by analysis of the 1H NMR spectrum of the crude reaction mixture before
hydrolysis. [c] Isolated yield of syn diastereomer. [d] Determined by analysis of the 1H NMR spectrum of the crude mixture after hydroly-
sis. [e] Yield in parenthesis is the yield of both diastereomers. [f] Isolated as a 1.3:1 mixture of diastereomers.
in an aldol-type reaction to produce intermediate 19, which a direct aldol reaction, especially because these products are
could then cyclize to oxazolidine product
C
(path- not available under phase-transfer conditions.[30] Notable
way B).[37–41] Imine 14 (R1 = H) is believed to participate exceptions are p-anisaldehyde (7d), which reduced the silver
in a 1,3-dipolar cycloaddition with the aryl aldehyde. How- catalyst to Ag0, and hindered 2-tolualdehyde (7g). 2-Fural-
ever, we cannot exclude a fast stepwise formation of the dehyde (7h) gave an excellent yield, but the diastereoselec-
oxazoline. In contrast, imine 17 (R1 = Ph) appears to react tivity was poor.
through an aldol-type pathway. The main indications for
The hydrolysis of oxazolidines 18a–h, which was reported
this are: (i) The dr improved with the use of the 1:1 Ag/ for the analogous alkyl derivatives,[32] did not proceed as
PPh3 catalyst (Table 3, Entry 4), which forms a coordina- anticipated. It was quickly discovered that both epimeri-
tively unsaturated silver salt.[42] This can then coordinate to zation (Table 4, dr 18 vs. 21) and decomposition of sub-
both the azomethine ylide, as well as to the aldehyde, re- strates 18a–h occurred. Interestingly, in other reports of ac-
sulting in an increased reactivity and a more ordered transi- cess to β-aryl-β-hydroxy-α-amino esters, the deprotection of
tion state (structure D). (ii) The observation of side product the benzophenone-derived oxazolidine results in 50% yield,
20,[43] which could result from protonation of intermediate or is not disclosed.[38,39,44] In our case, we believe that pro-
19, which was not observed when using imine 14. In line tonation of the oxygen atom in 18 can lead to a retro-aldol
with this, re-exposure of the minor diastereomer of 20 (anti) reaction, resulting in either epimerization to the thermo-
to the reaction conditions resulted in both cis- and trans- dynamic product[45,38] or to further breakdown to the origi-
18, as well as aldehyde 7a and imine 17. However, if cis-18, nal starting materials.[9,12,46] Several weaker acids and reac-
the minor stereoisomer formed in the reaction, is re-ex- tion conditions were screened, resulting in incomplete con-
posed to the reaction there is no change in the dia- version to the desired amino ester, epimerization, or decom-
stereomeric ratio. Taken together, this indicates that the for- position. Thus, it seems that the aldol product is poised to
mation of intermediate 19, or the equivalent, and alcohol undergo epimerization even under mild conditions.
20 is reversible, whereas the cyclization to form oxazolidine
18 appears to be irreversible under the reaction conditions.
In this scenario, the beneficial effect of catalytic amounts
of an ammonium salt can be rationalized by its protonation
Conclusions
of compound 19 at the imine or the alkoxy moiety, assisting
In conclusion, an unusual mechanistic dichotomy in the
reaction of azomethine ylides with aldehydes has been dis-
in regeneration of the AgI catalyst.
Armed with both mechanistic insight and optimized con- closed. Depending on the imine substituents, the reaction
ditions, this protocol was then applied to the preparation can proceed through a 1,3-dipolar cycloaddition, affording
of oxazolidines 18a–h. Good to excellent diastereoselectivi- the corresponding oxazolidines in modest selectivity, or al-
ties and conversions were obtained for many aryl aldehydes, ternatively, the reaction can proceed through an aldol-type
including heteroatom-substituted aryl aldehydes and elec- mechanism, giving good to excellent diastereoselectivities
tron-withdrawing aryl aldehydes (Table 4, Entries 1–3, 5, and conversions with aryl aldehydes. The latter reaction
and 6). To the best of our knowledge, this represents a sig- provides mild access to oxazolidines at room temperature
nificant increase in diastereoselectivity for aryl substrates in and is acid catalyzed. However, manipulation of this pro-
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Addition of Azomethine Ylides to Aldehydes
(d, J = 7.6 Hz, 1 H), 2.38 (s, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 173.5, 140.1, 128.3, 128.0, 126.3, 74.2, 70.6, 51.8,
tected amino ester into the deprotected syn-β-hydroxy-α-
amino ester proved difficult. As the formation of the N,O-
acetal is the driving force in the direct aldol reaction, this
highlights the need for creative access to this class of mole-
cules circumventing this motif.
35.2 ppm. IR (film): ν = 3430 (br.), 2925, 2854, 1729, 1643 cm–1.
˜
HRMS (ESI+): calcd. for C11H15NO3 [M + H]+ 210.11247; found
210.11240. Data for the anti isomer: 1H NMR (500 MHz, CDCl3):
δ = 7.35–7.20 (m, 5 H), 4.98 (d, J = 5.4 Hz, 1 H), 3.65 (s, 3 H),
3.54 (d, J = 5.4 Hz, 1 H), 2.41 (s, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 172.6, 140.0, 128.3, 127.9, 125.9, 72.8, 68.6, 51.7,
35.3 ppm.
Experimental Section
Imines 14a–e: Prepared by using the method described by Long-
1
General Methods: H and 13C NMR spectra were recorded at 500
mire.[25,26]
and 125 MHz, respectively, in CDCl3 by using the residual peak of
CHCl3 (1H NMR δ = 7.26 ppm) and CDCl3 (13C NMR δ =
77.0 ppm) as internal standard. Chemical shifts are reported in the
δ-scale with multiplicity (br. = broad, s = singlet, d = doublet, t =
triplet, q = quartet, and m = multiplet), coupling constant (Hz),
and integration. Dichloromethane (CH2Cl2) and tetrahydrofuran
(THF) were dried by passing through a solvent column composed
of activated alumina. Anhydrous acetonitrile (MeCN) was bought
from Sigma–Aldrich Co and stored over activated 4 Å molecular
sieves under an atmosphere of N2. Air- and moisture-sensitive reac-
tions were carried out in flame-dried, septum-capped flasks under
an atmospheric pressure of nitrogen. All liquid reagents were trans-
ferred by oven-dried syringes. Commercially available compounds
were used without further purification unless otherwise indicated.
TLC analyses were run on Merck TLC alumina sheets (Silica gel
60 F254) and were visualized by using UV and a solution of phos-
phomolybdic acid in ethanol (5 wt.-%), KMNO4 stain, or p-anisal-
dehyde stain. Flash chromatography was performed by using silica
gel 60 (35–63 µm). Melting points were measured with a Stuart
Scientific melting point apparatus (SMP3). IR was recorded with
an ATI Mattson Infinity 60 Mi Plus.
Ethyl 2-(4-cyanobenzylideneamino)ethanoate (14c): The resulting
imine was used crude and was a white powder (quantitative yield).
1
M.p. 81.6–82.7 °C. H NMR (500 MHz, CDCl3): δ = 8.38 (s, 1 H),
7.89 (d, J = 8.4 Hz, 2 H), 7.72 (d, J = 8.4 Hz, 2 H), 4.49 (d, J =
1.3 Hz, 2 H), 4.30 (q, J = 7.1 Hz, 2 H), 1.36 (t, J = 7.1 Hz, 3
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 169.6, 163.4, 139.3,
132.4, 128.9, 118.4, 114.5, 61.9, 61.3, 14.2 ppm. IR (film): ν = 3430,
˜
2227, 1731, 1651, 1209 cm–1. HRMS (ESI+): calcd. for
C12H12N2O2 [M + H]+ 217.09715; found 217.09712.
Ethyl 2-[4-(Trifluoromethyl)benzylideneamino]ethanoate (14d): The
resulting imine was used crude and was an off white powder
(890 mg, 94% yield). M.p. 58.2–58.6 °C. 1H NMR (500 MHz,
CDCl3): δ = 8.35 (s, 1 H), 7.90 (d, J = 8.1 Hz, 2 H), 7.69 (d, J =
8.2 Hz, 2 H), 4.44 (d, J = 1.2 Hz, 2 H), 4.25 (q, J = 7.1 Hz, 2 H),
1.31 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
169.8, 163.9, 138.7 (d, JC,F = 1 Hz), 132.8 (q, JC,F = 32.5 Hz),
128.7, 125.6 (q, JC,F = 3.8 Hz), 123.9 (d, JC,F = 272 Hz), 62.0, 61.3,
14.2 ppm. IR (film): ν = 3438, 2989, 1749, 1648, 1164, 1124 cm–1.
˜
HRMS (ESI+): calcd. for C12H12F3NO2 [M + H]+ 260.08929;
found 260.08929.
3,5-Dimethyl-2-phenyloxazol-3-ium (8): To a solution of 5-methoxy-
2-phenyloxazole[47] (169.5 mg, 0.97 mmol) in CH2Cl2 (10 mL) was
added methyl triflate (159.0 µL, 1.45 mmol), and the resulting solu-
tion was stirred at room temperature for 2 h. The mixture was con-
centrated under reduced pressure to give analytically pure 8
(327.1 mg, 99.6%) as a white solid. M.p. 74.5–75.3 °C. 1H NMR
(500 MHz, CDCl3): δ = 7.87 (d, J = 7.5 Hz, 2 H), 7.77 (t, J =
7.5 Hz, 1 H), 7.68 (t, J = 7.8 Hz, 2 H), 7.54 (s, 1 H, NCH=), 4.20
(s, 6 H, NCH3, OCH3) ppm. 13C NMR (125 MHz, CDCl3): δ =
159.8, 152.7, 134.5, 130.1, 129.8, 119.3, 99.2, 60.9, 37.7 ppm. IR
Methyl 2-[4-(Trifluoromethyl)benzylideneamino]ethanoate (14e):
The resulting imine (0.500 mg, 3.6 mmol) was an off white powder
and was obtained in quantitative yield. M.p. 81.6–82.7 °C. 1H
NMR (500 MHz, CDCl3): δ = 8.35 (s, 1 H), 7.90 (d, J = 8.1 Hz, 2
H), 7.68 (d, J = 8.2 Hz, 2 H), 4.46 (d, J = 0.7 Hz, 2 H), 3.79 (s, 3
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 170.3, 164.0, 138.6 (q,
JC,F = 1.1 Hz), 132.8 (q, JC,F = 32.5 Hz), 128.7, 125.6 (q, JC,F
=
3.8 Hz), 123.9 (q, JC,F = 272 Hz), 61.9, 52.3 ppm. IR (film): ν =
˜
3473, 2998, 2956, 1740, 1651 cm–1. HRMS (ESI+): calcd. for
C11H10F3NO2 [M + H]+ 246.07346; found 246.07365.
(film): ν = 3496 (br.), 3129, 1666, 1457, 1297, 1151, 1037 cm–1.
˜
General Procedure A (Silver-Catalyzed Reaction): A solution of
AgOAc (AgI salt) (2.8 mg, 0.017 mmol) and PPh3 (4.5 mg,
0.017 mmol) in the indicated solvent (0.5 mL) was stirred for
45 min, after which time imine 14 (50.2 mg, 0.17 mmol) in the indi-
cated solvent (1.2 mL) and the aldehyde (0.34 mmol) was added.
iPr2NEt (5.9 µL, 0.034 mmol) was added, and the resulting mixture
was wrapped in aluminum foil and stirred at room temperature
overnight. The reaction mixture was filtered through basic alumina
(pipette) and concentrated under reduced pressure. The conversion
of the 1,3-dipolar cycloaddition was determined by analysis of the
1H NMR spectrum of the crude reaction mixture (integration of
the tert-butyl ester signals in remaining 14 and oxazoline 16). The
residue was dissolved in MeOH/H2O (2 mL, 95:5), and to the solu-
tion was added PTSA (65 mg, 0.34 mmol). The resulting mixture
Methyl (2S*,3R*)-3-Hydroxy-2-(methylamino)-3-phenylpropanoate
(12a): To a suspension of anhydrous cesium fluoride (34.6 mg,
0.228 mmol) in dry acetonitrile (1.5 mL) was added a mixture of 8
(38.7 mg, 0.114 mmol), benzaldehyde (38.2 µL, 0.376 mmol), and
phenylsilane (21.3 µL, 0.171 mmol) in dry acetonitrile (2 mL) at
room temperature. The resulting suspension was stirred at room
temperature overnight and then concentrated under reduced pres-
sure. The ratio of 11a/8 was determined by analysis of the 1H NMR
spectrum of the crude reaction mixture. The residue was filtered
through silica gel to give crude oxazole 11a.[48] The residue was
then dissolved in MeOH/H2O (2 mL, 95:5), and to this solution
was added PTSA (1.5  in MeOH, 88 µL, 0.133 mmol). The re-
sulting mixture was stirred until no 11a remained (TLC; heptane/
EtOAc, 4:1). The reaction mixture was concentrated under reduced was stirred until no 16 remained (TLC; heptane/EtOAc, 4:1). The
pressure, neutralized with a solution of saturated NaHCO3, and
the residue was extracted with CH2Cl2 (5ϫ), dried (MgSO4), and
concentrated under reduced pressure. Flash chromatography (hep-
tane/EtOAc, 1:2) of the residue gave 12a (13.8 mg, 58%) as a clear
oil. Data for the syn isomer: 1H NMR (500 MHz, CDCl3): δ =
reaction mixture was quenched by the addition of saturated solu-
tion of NaHCO3 and concentrated under reduced pressure. The
residue was extracted with CH2Cl2 (5ϫ), dried (MgSO4), and con-
centrated under reduced pressure. The diastereomeric ratio was de-
1
termined by analysis of the H NMR spectrum of the crude reac-
7.35–7.20 (m, 5 H), 4.59 (d, J = 7.6 Hz, 1 H), 3.55 (s, 3 H), 3.22 tion mixture.
Eur. J. Org. Chem. 2010, 3927–3933
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3931

B. Seashore-Ludlow, S. Torssell, P. Somfai
FULL PAPER
General Procedure B (Benzoic Acid/DIEA Salt): To a solution of
AgOTf (4.4 mg, 0.017 mmol) in toluene (0.5 mL) (flask was cov-
ered with aluminum foil) was added freshly prepared PPh3/toluene
(0.17  solution, 100 µL), and the resulting mixture was stirred for
20 to 30 min. Subsequently, imine 17 (50 mg, 0.17 mmol) was
added in toluene by cannula (0.5 mL + 0.5 mL rinse) followed by
the aldehyde (0.34 mmol). iPr2NEt (5.9 µL, 0.034 mmol) and benz-
oic acid (1.03 mg, 0.0085 mmol) were combined in a separate flask
and toluene was added to make a standard solution (0.34 
iPr2NEt and 0.085  benzoic acid). The salt solution (100 µL) was
added, and the resulting mixture was stirred at room temperature
overnight. The reaction was concentrated, and the conversion of
the aldol addition was determined by analysis of the 1H NMR
spectrum of the crude reaction mixture (integration of the tert-
butyl ester signals in remaining 17 and oxazolidine 18). The reac-
tion mixture was filtered through basic alumina (pipette) and con-
centrated under reduced pressure. The residue was dissolved in
MeOH (4 mL) and water (0.4 mL), and to the solution was added
0.5  HCl (0.2 mL). The resulting mixture was stirred until no 18
remained (TLC; heptane/EtOAc, 1:1). The reaction mixture was
quenched by the addition of a saturated solution of NaHCO3 and
concentrated under reduced pressure. The residue was extracted
with CH2Cl2 (5ϫ), dried (MgSO4), and concentrated under re-
duced pressure. The diastereomeric ratio was determined by analy-
CDCl3): δ = 172.4, 162.4 (d, JC,F = 245 Hz), 136.6 (d, JC,F
3.1 Hz), 128.2 (d, JC,F = 8.1 Hz), 115.1 (d, JC,F = 21 Hz), 81.9,
=
74.1, 61.2, 27.9 ppm. IR (film): ν = 3386 (br.), 2960, 2931, 1728,
˜
1509, 1286, 1155 cm–1. HRMS (ESI+): calcd. for C13H18FNO3 [M
+ H]+ 256.13435; found 256.13440.
tert-Butyl
(2S*,3R*)-2-Amino-3-(4-bromophenyl)-3-hydroxyprop-
anoate (21c): Prepared according to general procedure b by using
aldehyde 7c (31.3 mg, 0.17 mmol). For the diastereomeric ratio, see
Table 4 (analysis of the 1H NMR spectrum of the crude reaction
mixture). Flash chromatography (heptane/EtOAc, 1:1 Ǟ 1:2) of the
residue gave syn-21c (26.2 mg, 52%) as a clear oil. Data for the syn
1
isomer: H NMR (500 MHz, CDCl3): δ = 7.48 (m, 2 H), 7.24 (m,
2 H), 4.70 (d, J = 5.5 Hz, 1 H), 3.46 (d, J = 5.5 Hz, 1 H), 1.36 (s,
9 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 172.3, 140.1, 131.4,
128.3, 121.7, 82.1, 73.9, 60.9, 27.9 ppm. IR (film): ν = 3496 (br.),
˜
3305, 2977, 2927, 1727, 1155 cm–1. HRMS (ESI+): calcd. for
C13H18BrNO3 [M + H]+ 316.05428; found 316.05420.
tert-Butyl
(2S*,3R*)-2-Amino-3-(3-bromophenyl)-3-hydroxyprop-
anoate (21e): Prepared according to general procedure b by using
aldehyde 7e (19.8 µL, 0.17 mmol). For the diastereomeric ratio, see
Table 4 (analysis of the 1H NMR spectrum of the crude reaction
mixture). Flash chromatography (heptane/EtOAc, 1:1 Ǟ 1:2) of the
residue gave syn-21e (25.8 mg, 48%) as a clear oil. Data for the syn
isomer: 1H NMR (500 MHz, CDCl3): δ = 7.51 (t, J = 1.7 Hz, 1
H), 7.42 (ddd, J = 7.9, 1.9, 1.1 Hz, 1 H), 7.30 (m, 1 H), 7.22 (t, J
= 7.8 Hz, 1 H), 4.68 (d, J = 5.5 Hz, 1 H), 3.47 (d, J = 5.6 Hz, 1
H), 1.37 (s, 9 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 172.2,
143.5, 130.8, 129.9, 129.7, 125.2, 122.4, 82.1, 73.8, 60.9, 27.9 ppm.
1
sis of the H NMR spectrum of the crude reaction mixture.
tert-Butyl
(4R*,5S*)-2,2,5-Triphenyloxazolidine-4-carboxylate
(18a): Prepared according to general procedure by using AgOTf
(2.2 mg, 0.0085 mmol), imine 17 (25 mg, 0.085 mmol), and alde-
hyde 7a (31.3 mg, 0.17 mmol). Flash chromatography (heptane/
EtOAc, 24:1) of the residue gave trans-18a as a white solid. Data
for the trans isomer: m.p. 113.0–114.3 °C. 1H NMR (500 MHz,
CDCl3): δ = 7.80–7.70 (m, 2 H), 7.62–7.57 (m, 2 H), 7.39–7.23 (m,
8 H), 7.15 (dd, J = 7.0, 2.4 Hz, 2 H), 4.88 (d, J = 8.4 Hz, 1 H),
3.73 (d, J = 8.4 Hz, 1 H), 3.43 (s, 1 H), 1.36 (s, 9 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 169.6, 144.9, 144.4, 139.4, 128.3,
128.3, 128.1, 128.0, 127.8, 127.5, 127.3, 127.0, 126.4, 126.2, 125.6,
IR (film): ν = 3363 (br.), 3303, 2977, 2931, 1727, 1369, 1155 cm–1.
˜
HRMS (ESI+): calcd. for C13H18BrNO3 [M + H]+ 316.05428;
found 316.05423.
tert-Butyl (2S*,3R*)-2-Amino-3-(3-methoxyphenyl)-3-hydroxyprop-
anoate (21f): Prepared according to general procedure b by using
7f (31.3 mg, 0.17 mmol). For the diastereomeric ratio, see Table 4
(analysis of the 1H NMR spectrum of the crude reaction mixture).
Flash chromatography (heptane/EtOAc, 1:1 Ǟ 1:2) of the residue
gave syn-21f (33.1 mg, 76%) as a clear oil. Data for the syn isomer:
1H NMR (500 MHz, CDCl3): δ = 7.26 (t, J = 8.1 Hz, 1 H), 6.94–
6.93 (dd, J = 4.6, J = 2.7 Hz, 2 H), 6.82 (ddd, J = 8.1, J = 2.5, J
= 1.0 Hz, 1 H), 4.75 (d, J = 5.2 Hz, 1 H), 3.18 (s, 3 H), 3.54 (d, J
= 5.2 Hz, 1 H), 1.37 (s, 9 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 172.4, 159.7 142.7, 129.4, 129.4, 118.8, 113.3, 112.0, 81.9, 74.3,
101.1, 84.4, 82.3, 69.3, 27.9 ppm. IR (film): ν = 3313, 3062, 3031,
˜
2979, 1730, 1450, 1157, 700 cm–1. HRMS (ESI+): calcd. for
C14H21NO4 [M + H]+ 402.20637; found 402.20639.
tert-Butyl (2S*,3R*)-2-Amino-3-hydroxy-3-phenylpropanoate (21a):
Prepared according to general procedure b by using aldehyde 7a
(34.6 µL, 0.34 mmol) in PhMe. For the diastereomeric ratio, see
Table 4 (analysis of the 1H NMR spectrum of the crude reaction
mixture). Flash chromatography (heptane/EtOAc, 1:1 Ǟ 1:2) of the
residue gave syn-21a (27.9 mg, 68%) as a clear oil. Data for the syn
isomer: 1H NMR (500 MHz, CDCl3): δ = 7.37–7.26 (m, 5 H), 4.73
(d, J = 5.5 Hz, 1 H), 3.51 (d, J = 5.5 Hz, 1 H), 1.34 (s, 9 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 172.5, 140.9, 128.3, 127.8, 126.5,
60.9, 55.3, 27.9 ppm. IR (film): ν = 3379 (br.), 2978, 2931, 1728,
˜
1257, 1155 cm–1. HRMS (ESI+): calcd. for C14H21NO4 [M + H]+
268.15433; found 268.15439.
tert-Butyl (2S*,3R*)-2-Amino-3-(2-methylphenyl)-3-hydroxyprop-
anoate (21g): Prepared according to general procedure b by using
aldehyde 7g (31.3 mg, 0.17 mmol). For the diastereomeric ratio, see
Table 4 (analysis of the 1H NMR spectrum of the crude reaction
mixture). Flash chromatography (heptane/EtOAc, 1:1 Ǟ 1:2) of the
residue gave syn-21g (19.6 mg, 49%) as a clear oil. Data for the syn
isomer: 1H NMR (500 MHz, CDCl3): δ = 7.42 (dd, J = 7.5, 1.2 Hz,
1 H), 7.21 (dt, J = 7.5, 1.8 Hz, 1 H), 7.17 (dt, J = 7.5, 1.5 Hz, 1
H), 7.12 (d, J = 7.0 Hz, 1 H), 5.05 (d, J = 4.5 Hz, 1 H), 3.54 (d, J =
4.5 Hz, 1 H), 2.34 (s, 3 H), 1.36 (s, 9 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 170.7, 137.5, 138.0, 128.7, 125.8, 124.6, 124.3, 80.0,
81.7, 74.6, 61.0, 27.8 ppm. IR (film): ν = 3370 (br.), 3305, 2980,
˜
2933, 1727, 1369, 1155 cm–1. HRMS (ESI+): calcd. for C13H19NO3
[M + H]+ 238.14377; found 238.14363. Data for the anti isomer:
1H NMR (500 MHz, CDCl3): δ = 7.36–7.24 (m, 5 H), 4.93 (d, J =
5.5 Hz, 1 H), 3.72 (d, J = 5.5 Hz, 1 H), 1.38 (s, 9 H) ppm.
tert-Butyl
(2S*,3R*)-2-Amino-3-(4-fluorophenyl)-3-hydroxyprop-
anoate (21b): Prepared according to general procedure b by using
aldehyde 7b (31.3 mg, 0.17 mmol). for the diastereomeric ratio, see
Table 4 (analysis of the 1H NMR spectrum of the crude reaction
mixture). Flash chromatography (heptane/EtOAc, 1:1 Ǟ 1:2) of the
residue gave syn-21b (25.2 mg, 62%) as a white solid. Data for the
69.3, 57.4, 26.1, 17.4 ppm. IR (film): ν = 3370 (br.), 2977, 2931,
˜
1728, 1367, 1155 cm–1. HRMS (ESI+): calcd. for C14H21NO3 [M
+ H]+ 252.15942; found 252.15961.
1
syn isomer: M.p. 68.2–70.3 °C. H NMR (500 MHz, CDCl3): δ =
tert-Butyl (2S*,3R*)-2-Amino-3-(furan-2-yl)-3-hydroxypropanoate
7.40–7.31 (m, 2 H), 7.09–6.96 (m, 2 H), 4.67 (d, J = 6.0 Hz, 1 H), (21h): Prepared according to general procedure b by using aldehyde
3.45 (d, J = 6.0 Hz, 1 H), 1.34 (s, 9 H) ppm. 13C NMR (125 MHz,
7h (28.2 µL, 0.34 mmol). For the diastereomeric ratio, see Table 4
3932
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3927–3933

Addition of Azomethine Ylides to Aldehydes
(analysis of the 1H NMR spectrum of the crude reaction mixture).
Flash chromatography (heptane/EtOAc, 1:1 Ǟ 1:2) of the residue
gave an inseparable mixture of syn/anti-21h (34.5 mg, 91%) as a
4536; b) A. G. M. Barrett, M. A. Seefeld, J. P. White, D. J. Wil-
liams, J. Org. Chem. 1996, 61, 2677–2685; c) U. M. Lindström,
P. Somfai, Synthesis 1998, 109–117.
[21] L. M. Harwood, R. J. Vickers, Synthetic Applications of 1,3-
Dipolar Cycloaddition Chemistry Towards Heterocycles and
Natural Products, John Wiley & Sons, New York, 2002.
[22] G. Pandey, P. Banerjee, S. R. Gadre, Chem. Rev. 2006, 106,
4484–4517.
1
clear oil. Data for the syn isomer: H NMR (500 MHz, CDCl3): δ
= 7.38 (dd, J = 1.7, 0.8 Hz, 1 H), 6.33 (dd, J = 3.2, 1.8 Hz, 1 H),
6.31 (d, J = 3.3 Hz, 1 H), 4.77 (d, J = 5.1 Hz, 1 H), 3.76 (d, J =
5.1 Hz, 1 H), 1.40 (s, 9 H) ppm. 13C NMR (125 MHz, CDCl3): δ
= 172.0, 153.9, 142.1, 110.2, 107.7, 81.9, 68.7, 58.1, 27.9 ppm. Data
[23] H. Pellisier, Tetrahedron 2007, 63, 3235–3238.
1
for the anti isomer: H NMR (500 MHz, CDCl3): δ = 7.32 (dd, J [24] R. Grigg, M. I. Lansdell, M. Thorton-Pett, Tetrahedron 1999,
55, 2025–2044.
= 1.7, 0.7 Hz, 1 H), 6.31 (m, 1 H), 6.27 (d, J = 3.2 Hz, 1 H), 4.95
(d, J = 5.2 Hz, 1 H), 3.74 (d, J = 5.2 Hz, 1 H), 1.39 (s, 9 H) ppm.13C
NMR (125 MHz, CDCl3): δ = 171.8, 153.6, 142.0, 110.1, 107.6,
[25] J. M. Longmire, B. Wang, X. Zhang, J. Am. Chem. Soc. 2002,
124, 13400–13401.
[26] C. Chen, X. Li, S. L. Schreiber, J. Am. Chem. Soc. 2003, 125,
10174–10175.
[27] For other Lewis acids examined please see the Supporting In-
formation.
82.0, 68.0, 58.6, 27.9 ppm. Data for the major isomer: IR (film): ν
˜
= 3434 (br.), 2929, 1729, 1641, 1155 cm–1. HRMS (ESI+): calcd.
for C11H17NO4 [M + H]+ 228.12303; found 228.12299.
[28] M. J. O’Donnell, W. D. Bennet, S. Wu, J. Am. Chem. Soc. 1989,
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of 8, 11a, 12a, 14c, 14d, 14e, 21a–
111, 2353–2355.
[29] M. Horikawa, J. Busch-Petersen, E. J. Corey, Tetrahedron Lett.
1999, 40, 3843–3846.
h.
[30] T. Ooi, M. Taniguchi, M. Kameda, K. Maruoka, Angew.
Chem. Int. Ed. 2002, 41, 4542–4544.
[31] N. Yoshikawa, M. Shibasaki, Tetrahedron 2002, 58, 8289–8298.
[32] T. Ooi, M. Kameda, M. Taniguchi, K. Maruoka, J. Am. Chem.
Soc. 2004, 126, 9685–9694.
[33] J. B. MacMillan, T. F. Molinski, Org. Lett. 2002, 4, 1883–1886.
[34] For 4-fluorobenzaldehyde, AgOTf gave 15:1dr, and Ag-
(MeCN)4BF4 gave 10:1dr with similar yields.
[35] W. L. F. Armarego, D. D. Perrin, Purification of Laboratory
Chemicals, 4th ed., Reed Educational and Professional Publish-
ing Ltd., Woburn, MA, 1996.
[36] To achieve consistent results, the benzoic acid/iPr2NEt salt
should be preformed as a standard solution.
[37] Y. Ito, M. Sawamura, T. Hayashi, J. Am. Chem. Soc. 1986, 108,
6405–6406.
Acknowledgments
The authors would like to thank the Knut and Alice Wallenberg
Foundation, as well as the Swedish Research Council for funding.
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Received: March 18, 2010
Published Online: May 25, 2010
Eur. J. Org. Chem. 2010, 3927–3933
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3933