N-monoalkylation of α-amino acid esters under solid-liquid PTC conditions

Article abstract of DOI:10.1002/(sici)1099-0690(200004)2000:8<1443::aid-ejoc1443>3.0.co;2-5

N-(2-Nitrophenylsulfonyl)- (o-NBS-AA-OMe, 4) and N-(4- Nitrophenylsulfonyl)-α-amino acid methyl esters (p-NBSAA-OMe, 5) were N- alkylated with a variety of alkyl halides 6 under solid-liquid phase-transfer catalysis (SL-PTC) conditions, affording the alkylated products o-NBS-N-R²- AA-OMe 7 and p-NBS-N-R²-AA-OMe 8 in excellent yields without any detectable racemization.

Full text of DOI:10.1002/(sici)1099-0690(200004)2000:8<1443::aid-ejoc1443>3.0.co;2-5

FULL PAPER
N-Monoalkylation of α-Amino Acid Esters under Solid-Liquid PTC Conditions
Domenico Albanese,[a] Dario Landini,*[a] Vittoria Lupi,[a] and Michele Penso[a]
Keywords: Amino acids / Alkylations / Phase-transfer catalysis / Asymmetric synthesis
N-(2-Nitrophenylsulfonyl)- (o-NBS-AA-OMe, 4) and N-(4-
Nitrophenylsulfonyl)-α-amino acid methyl esters (p-NBS-
AA-OMe, 5) were N-alkylated with a variety of alkyl halides
6 under solid-liquid phase-transfer catalysis (SL-PTC) condi-
tions, affording the alkylated products o-NBS-N-R2-AA-OMe
7 and p-NBS-N-R2-AA-OMe 8 in excellent yields without
any detectable racemization.
Introduction
by reaction of N-(nitrophenylsulfonyl)-α-amino acid methyl
esters (e.g. -isomers 4a and 5a) with an alkyl bromide 6,
using a stoichiometric amount of cesium carbonate as base
in anhydrous DMF (Scheme 1). Under these conditions the
isolated yields of the N-alkyl derivatives 7 and 8 reached
72–87%, whereas they were lower with acetonitrile as solv-
ent and/or potassium carbonate as base.
Here we report that N-(2-nitrophenylsulfonyl)- and N-(4-
nitrophenylsulfonyl)-α-amino acid esters 4 and 5 are ad-
vantageously N-alkylated under solid-liquid phase-transfer
catalysis (SL–PTC) conditions[4] in the presence of anhyd-
rous potassium carbonate, which is widely used as a non-
nucleophilic base, especially in N-alkylations.[4,5] Since the
nitrophenylsulfonyl groups of sulfonamides 7 and 8 can be
easily removed,[6] this protocol represents a useful proced-
ure for the synthesis of selective N-monoalkylated α-amino
acid esters 9 (Scheme 1).
N-Monoalkylated α-amino acids and esters are very im-
portant intermediates in the synthesis of many biologically
active compounds.[1] Therefore, the interest in developing
new protocols for the selective N-monoalkylation of optic-
ally pure α-amino acid derivatives is increasing in recent
years. However, the numerous methods reported so
far[1a,1c–1e,2] are not generally applicable and most of them
deal only with N-methylation reactions.[1b–1e,2b,2c]
Recently Bowman and Coghlan[3] described a general
procedure for the N-monoalkylation of α-amino acid esters
Results and Discussion
The nitrophenylsulfonamides o-NBS-AA-OMe (4) and p-
NBS-AA-OMe (5) were obtained in 74–90% yields as en-
antiopure compounds (Table 1)[6] by reacting the corres-
ponding sulfonyl chloride o-NBS–Cl (2) or p-NBS-Cl (3)
with the optically pure α-amino ester hydrochlorides AA-
OMe HCl (1) in the presence of TEA, according to a previ-
ously described procedure (Scheme 1).[6]
Table 1. Preparation of N-(nitrophenylsulfonyl)-α-amino acid
methyl esters 4,5 from the corresponding hydrochlorides of α-am-
ino acid methyl esters (AA-OMe HCl) 1
1,4,5R1
AA
t [h]Product
Yield [%]
a
b
c
d
e
f
i-Pr
CH2OH
-Val 18 o-NBS--Val-OMe 4a86 (93)[a]
-Ser 1.5 o-NBS--Ser-OMe 4b77
Scheme 1. Preparation of N-alkylated α-amino acids 9 by al-
kylation under SL-PTC of N-(nitrophenylsulfonyl)-α-amino acid
methyl esters 4,5
CH2CH2SMe -Met
R-CH(OH)Me-Thr
3
2
1
o-NBS--Met-OMe 4c74
o-NBS--Thr-OMe 4d86
H
Gly
o-NBS-Gly-OMe
4e90
PhCH2
Ph
-Phe 24 o-NBS--Phe-OMe 4f 83
-PhGly24 o-NBS--PhGly-OMe4g88
-Val 12 p-NBS--Val-OMe 5a80
[a]
g
a
Centro CNR and Dipartimento di Chimica Organica e
i-Pr
`
Industriale dell’Universita
Via Golgi, 19, I-20133 Milano, Italy
Fax: (internat.) ϩ 39–02/236–4369
E-mail: dario.landini@unimi.it
[a] In parentheses isolated yield of 4a (purity Ն 98%) without chro-
matographic purification.
Eur. J. Org. Chem. 2000, 1443Ϫ1449
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0408Ϫ1443 $ 17.50ϩ.50/0
1443

D. Albanese, D. Landini, V. Lupi, M. Penso
FULL PAPER
The N-alkylation reactions of the sulfonamides 4,5 were zylammonium cation.[4a,4d,7,8] Only a small excess of al-
performed by stirring a heterogeneous mixture of anhyd- kylating agent 6 (1.05 mol equiv.) was required for the com-
rous potassium carbonate and an acetonitrile or dioxane plete conversion of the substrates 4,5. However, as shown
solution of 4 or 5, alkylating agent 6 and triethylbenzylam- for 4a (Table 2, entries 3 and 4), a 100% excess of 6 in-
monium chloride (TEBA) as phase-transfer catalyst at 25 creased the reaction rate without causing bisalkylation and
or 80 °C. The reaction between the -valine derivative o- represents the best compromise between reaction time and
NBS-Val-OMe (4a) and allyl bromide (6a) was chosen for amount of alkylating agent in the case of the non-activated
the process optimisation (Table 2).
electrophiles 6b,d (Table 3, entries 2, 4, 14 and 19).
The alkylation was shown to be very sensitive to steric
hindrance, e.g. o-NBS--Val-OMe (4a), p-NBS--Val-OMe
(5a) and o-NBS-Gly-OMe (4e) were recovered unchanged
after 24 h from the crude of the reaction with 3-bromopen-
tane or 1-bromo-3,3-dimethylpropane. Both non-anhydrous
analar grade acetonitrile or dioxane can be used as pur-
chased, even if the reaction times were shorter under anhyd-
rous conditions (Table 2, entries 4, 6 and 7).
Under the best reaction conditions (Table 3) the sulfona-
mides 4,5,21 reacted with various electrophiles 6 affording
the corresponding N-alkylated products 7,8,22 in excellent
yields (86–96%).
In contrary to that found by Bowman and Coghlan,[3]
under SL–PTC conditions we did not observe decomposi-
Table 2. N-Alkylation of o-NBS--Val-OMe (4a) with allyl bromide
(6a) under SL–PTC conditions
Entry[a]
6a [mol equiv]
T [°C]
t [h]
7a, Yield [%][b]
1
2
3
4
5
6
7
8
9
2
25
25
80
80
80
80
80
80
80
7
88
2
46
1
91[c]
90
2
1.05
1.05
1.05
1.05
1.05
1.05
2
93
8
94[d]
95[e]
97[f]
93[g]
97[f,g]
3
3.5
1.5
1
[a]
Substrate 4a (10 mmol), 6a (10.5–20 mmol), K2CO3 (15 mmol),
[b]
TEBA (1 mmol), anhydrous CH3CN (100 mL). – 7a: o-NBS-N-
[c]
[d]
allyl--Val-OMe. –
Without TEBA. –
In the presence of
0.1 mmol of TEBA. – [e] Commercial non-anhydrous acetonitrile. – tion or rearrangement of the products 7a-e,g,h,j-m and 8a,d,
[f]
[g]
In dioxane (100 mL). – In the presence of 1 mmol of tetrabu-
tylammonium bromide (TBAB) as catalyst.
even in the presence of a molar excess of potassium carbon-
ate (1.5 mol equiv.). However, the alkylation of o-NBS--
The alkylation reactions were complete in 1–8 h and, as Ser-OMe (4b) with allyl bromide (6a) in acetonitrile at 80
expected for a PTC process,[4] the reaction time increased °C (Table 3, entry 6) afforded only 12% of the expected o-
by decreasing the amount of the catalyst (Table 2, entries 4 NBS-N-allyl--Ser-OMe (7f) and major amounts (35%) of
and 5). In the absence of TEBA (Table 2, entry 2) the reac- o-NBS-N-allyl-∆Ala-OMe (11). When the reaction was per-
tion was much slower than the catalysed alkylation (Table 2, formed at 25 °C the yields of 7f and 11 became 46% and
entry 1), the yields remaining high. The catalytic efficiency 19%, respectively, although the reaction rate was much
of tetrabutylammonium bromide (TBAB) was found to be lower (120 h) (Table 3, entry 7). A further yield increase of
superior to that of TEBA (Table 2, entries 4, 8 and 7, 9). 7f (76%) in an acceptable reaction time (7 h) was obtained
This behaviour can be likely explained assuming that the by using anhydrous DMF instead of MeCN, at room tem-
ion pair formed by the anion derived from the sulfonamide perature (Table 3, entry 8). The ester 11 probably derives
and the tetrabutylammonium cation has higher solubility from the intermediate o-NBS-N,O-diallyl--Ser-OMe (9)
and reactivity than the ion pair containing the triethylben- through a base-catalysed β-elimination of a molecule of
Table 3. Alkylation of o-NBS-AA-OMe 4,21 and p-NBS-AA-OMe 5 with alkyl halides 6 under SL-PTC conditions
Entry[a]
R2X
mol equiv.
t [h]
Product
Yield [%]
1
4a
4a
4a
4a
4a
4b
4b
4b
4c
4c
4d
4d
21
4e
4f
6a
6b
6c
6d
6e
6a
6a
6a
6a
6c
6f
1.05
2
2
o-NBS-N-allyl--Val-OMe (7a)
o-NBS-N-C4H9--Val-OMe (7b)
o-NBS-N-Bn--Val-OMe (7c)
91
2
12
1
89
3
1.05
2
96
4
8
o-NBS-N-(4-pentenyl)--Val-OMe (7d)
o-NBS-N-Me--Val-OMe (7e)
o-NBS-N-allyl--Ser-OMe (7f)
o-NBS-N-allyl--Ser-OMe (7f)
o-NBS-N-allyl--Ser-OMe (7f)
o-NBS-N-allyl--Met-OMe (7g)
o-NBS-N-Bn--Met-OMe (7h)
o-NBS-N-propargyl--Thr-OMe (7i)
o-NBS-N-propargyl--Thr-OMe (7i)
o-NBS-N-propargyl--allo-Thr-OMe (22)
o-NBS-N- C4H9-Gly-OMe (7j)
o-NBS-N-allyl--Phe-OMe (7k)
o-NBS-N-Me--Phe-OMe (7l)
o-NBS-N-Me--PhGly-OMe (7m)
p-NBS-N-allyl--Val-OMe (8a)
p-NBS-N-(4-pentenyl)--Val-OMe (8d)
96
5
1.05
1.05
1.05
1.05
1.05
1.05
1.05
1.05
1.05
2
1.05
1.05
2
1.05
2
1.5
4
87
6
12[b]
46[c] [d]
76[e]
94
7
120
7
8
9
1
10
11
12
13
14
15
16
17
18
19
0.25
6
91
66
6f
10
2.5
1.5
0.5
0.15
15
2
84[e]
86[e]
80
6f
6b
6a
6e
6e
6a
6d
88
4f
86
4g
5a
5a
91[c]
91
6
91
[a]
[b]
Reaction conditions: K2CO3 (1.5 mol equiv), TEBA (0.1 mol equiv.), MeCN (0.1 ), 80 °C. – Together with 35% of o-NBS-N-allyl-
[c]
[d]
[e]
∆Ala-OMe (11). – At 25 °C in anhydrous MeCN. – Together with 15% of 11. – At 25 °C in anhydrous DMF.
1444 Eur. J. Org. Chem. 2000, 1443Ϫ1449

N--Monoalkylation of α-Amino Acid Esters
FULL PAPER
Scheme 2. Synthesis of o-NBS-N-allyl--Ser-OMe (7f) and o-NBS-N-propargyl--Thr-OMe (7i) and mechanism of the elimination to the
corresponding acrylic derivatives 11 and 12
allyl alcohol (13) (Scheme 2).[2c,9] A similar behaviour was
found in the alkylation of o-NBS--Thr-OMe (4d) with pro-
pargyl alcohol (6f) (Scheme 2 and Table 3, entries 11 and
12), even if, in this case, the yields of the expected product
7i in both MeCN and DMF were higher (66 and 84%, re-
spectively). These results indicate that both temperature and
solvent are crucial factors for the outcome of the N-al-
kylation reaction. Clearly, at higher temperature (80 °C) the
bisalkylation process favourably competes with N-monoalk-
ylation, affording the unstable N,O-dialkylated products 11
or 12. In contrast, at 25 °C N-monoalkylation is the fa-
voured process, especially in anhydrous DMF. This behavi-
our is probably due to the higher solubility of the sulfonam-
ide onium salt in DMF than in MeCN or dioxane. The
lower acidity and higher steric requirements of the hydroxy
group of 4d with respect to that of 4b account for the good
yield of N-monoalkylated product 7i obtained. The -allo-
threonine derivative 21 (Scheme 3), possessing a less-
hindered nitrogen, is more reactive than the diasteroisom-
eric -threonine derivative 7i and its alkylation with propar-
gyl bromide (6f) is complete in 2.5 h, producing o-NBS-N-
propargyl--allo-Thr-OMe (22) in 86% yield (Table 3,
entry 13).
The products 7a,e,k and 8a were chosen to check the de-
protection procedure to the corresponding amino esters 9.
The substrates 7,8 were reacted at 50 °C with excess PhSH
[6,3]
Scheme 3. Preparation of o-NBS-N-propargyl--allo-Thr-OMe (22)
and solid potassium carbonate in MeCN,
or at 25 °C
from -Thr (15)
with a 0.5  solution of PhS–Kϩ [1c,1d] and the deprotected
enantiopure esters 9 were isolated in 62–92%. The sulfona-
mides o-NBS-N-R2-AA-OMe (7,21) and p-NBS-N-R2-AA- tecting this latter with o-NBS–Cl. The determination of the
OMe (8) were isolated as optically pure compounds, indic- [α]D of the resulting racemized 7m allowed the calculation
ating that no racemization took place during the PTC al- of the value of the pure enantiomer and the amount of race-
kylation of the enantiopure substrates o-NBS-AA-OMe (4) mization in the alkylation (50%) and deprotection (29%)
and p-NBS-AA-OMe (5). Only in the case of o-NBS-- steps (see Experimental Section).
PhGly-OMe (4g), whose benzylic α-proton has a high acid-
Whereas 7a,b,d,f are known compounds and their phys-
ity, did the alkylation with MeI proceed to o-NBS-N-Me- ical properties match those of products reported in literat-
PhGly-OMe (7m) with partial racemization. The ee of 7m ure, the optical purities of the new compounds 7c,e,g,h,k
1
was determined by deprotecting this sulfonamide to the were determined by H NMR spectroscopy in comparison
known amino ester 9m, obtained in 21% ee, and repro- with the corresponding racemized material 7-rac, by using
Eur. J. Org. Chem. 2000, 1443Ϫ1449
1445

D. Albanese, D. Landini, V. Lupi, M. Penso
FULL PAPER
°C). – [α]2D0 ϭ –103.0 (c ϭ 3.0 in MeOH) {ref.[3] [α]2D8.5 –103.5 (c ϭ
3.0 in MeOH)}.
an appropriate shift reagent (see Experimental Section).
The sulfonamides 7a and 8a were deprotected to the known
9a; similarly 7c and 7l were transformed into the corres-
ponding known α-amino esters 9c and 9l, respectively. Fi-
nally, 1H NMR analysis of the -threonine derivative 7i
o-NBS-L-Met-OMe (4c): -Met-OMe HCl (1c), o-NBS–Cl (2), 3 h,
AcOEt–PE 1:2; 4c, 2.52 g (74%); oil, [α]2D0 ϭ –176.7 (c ϭ 0.67 in
1
CHCl3). – H NMR (CDCl3): δ ϭ 1.92–2.17 (m, 2 H, CH2CH2S),
shows minor amounts (Յ 3%) of the α-racemized product 2.05 (s, 3 H, SCH3), 2.50–2.66 (m, 2 H, CH2S), 3.47 (s, 3 H, OCH3),
4.29–4.36 (m, 1 H, CHCOOR), 6.22 (d, 3J ϭ 8.9 Hz, 1 H, NH),
derived from -allo-threonine 22 (and vice versa), which in
turn is synthesised starting from -threonine (15)[10] by se-
lective inversion of the C-3 stereogenic centre via the oxazo-
line 18 and subsequent alkylation of the sulfonamide 21
7.70–7.73 (m, 2 H, Ar), 7.89–7.91 (m, 1 H, Ar), 8.04–8.07 (m, 1 H,
Ar). – C12H16N2O6S2 (348.40): calcd. C 41.37, H 4.63, N 8.04;
found C 41.48, H 4.57, N 8.00.
(Scheme 3).
o-NBS-L-Thr-OMe (4d): -Thr-OMe HCl (1d), o-NBS–Cl (2), 2 h,
AcOEt–PE 1:1; 4d, 2.74 g (86%); m.p. 80–81 °C. – [α]2D0 ϭ –97.1
(c ϭ 0.82 in MeOH). – 1H NMR (CDCl3): δ ϭ 1.32 (d, 3J ϭ
3
6.4 Hz, 3 H, CH3CH), 2.11 (bd, J ϭ 4.9 Hz, 1 H, OH), 3.50 (s, 3
Conclusion
3
H, OCH3), 4.13 (dd, J ϭ 9.4, 2.7 Hz, 1 H, CHCOOR), 4.27–4.38
3
(m, 1 H, CHOH), 6.34 (d, J ϭ 9.4 Hz, 1 H, NH), 7.70–7.74 (m, 2
In conclusion, the results indicate that SL-PTC is an ef-
fective procedure for the N-alkylation of (nitrophenyl)sul-
fonamides of α-amino acid esters. The procedure is particu-
larly suitable for the scale-up of the process since it involves
the use of cheap and environmentally friendly reagents. The
enantiopure compounds 7,8 can be isolated with excellent
yields and purities after an aqueous workup.
H, Ar), 7.91–7.94 (m, 1 H, Ar), 8.00–8.07 (m, 1 H, Ar). –
C11H14N2O7S (318.30): calcd. C 41.51, H 4.43, N 8.80; found C
41.40, H 4.36, N 8.77.
o-NBS-allo-D
-Thr-OMe (21): -allo-Thr-OMe HCl (20),[10]
{[α]2D0 ϭ –22.8 (c ϭ 5.0 in MeOH; ref.[10] [α]2D3 ϭ –23.1 (c ϭ 5.0 in
MeOH)}, o-NBS–Cl (2), 3.5 h, AcOEt–PE 5:4; 21, 2.26 g (71%); oil,
[α]2D0 ϭ ϩ202.7 (c ϭ 2.96 in CHCl3). – 1H NMR (CDCl3),: δ ϭ
1.24 (d, 3J ϭ 6.3 Hz, 3 H, CH3CH), 2.18 (bd, 3J ϭ 4.8 Hz, 1 H,
OH), 3.52 (s, 3 H, OCH3), 4.12–4.17 (m, 1 H, CHOH), 4.19 (dd,
3J ϭ 9.2, 4.2 Hz, 1 H, CHCOOR), 6.39 (d, 3J ϭ 9.2 Hz, 1 H, NH),
7.73–7.76 (m, 2 H, Ar), 7.92–7.95 (m, 1 H, Ar), 8.07–8.10 (m, 1 H,
Ar). – C11H14N2O7S (318.30): calcd. C 41.51, H 4.43, N 8.80; found
C 41.38, H 4.40, N 8.72.
Experimental Section
General Remarks: Melting points were determined on a Büchi 535
apparatus and are corrected. [α]D’s were measured at 589 nm on a
Perkin–Elmer 241 polarimeter using a 10 cm ϫ 5 mL cell and c is
1
in g/100 mL. H NMR spectra were recorded on a Bruker AC 300
o-NBS-Gly-OMe (4e): Gly-OMe HCl (1e), o-NBS–Cl (2), 1 h,
AcOEt–PE 3:4; 4e, 2.43 g (90%), m.p. 112–113 °C. – 1H NMR
(CDCl3): δ ϭ 3.60 (s, 3 H, OCH3), 4.01 (d, 3J ϭ 5.7 Hz, 2 H,
CH2COOR), 6.05 (t, 3J ϭ 5.7 Hz, 1 H, NH), 7.72–7.75 (m, 2 H,
Ar), 7.91–7.94 (m, 1 H, Ar), 8.07–8.10 (m, 1 H, Ar). – C9H10N2O6S
(274.25): calcd. C 39.42, H 3.68, N 10.21; found C 39.53, H 3.60,
N 10.15.
spectrometer operating at 300.133 MHz; TMS was used as external
reference; δ are in ppm and J are in Hz. IR spectra were recorded
on a Perkin–Elmer FT-IR 1725 spectrometer and frequency values
are in cm–1. Reagent-grade commercially available reagents and
solvents were used and dried, when required, before use. Petroleum
ether (PE) having boiling range 40–60 °C was used in the chroma-
tographic purifications. Amino esters AA-OMe HCl (1) are com-
mercially available products, whereas 20 was prepared by a
known procedure.[10]
o-NBS-L-Phe-OMe (4f): -Phe-OMe HCl (1f), o-NBS–Cl (2), 24 h,
AcOEt–PE 2:3; 4f, 3.03 g (83%), m.p. 81–82 °C. – [α]2D0 ϭ –93.7
(c ϭ 1.0 in CHCl3). – 1H NMR (CDCl3): δ ϭ 3.06 (dd, 2J ϭ
General Method for the Preparation of Sulfonamides 4, 5, 21:[6] In a
well-dried round bottomed flask was dissolved AA-OMe HCl (1)
(10 mmol) in anhydrous dichloromethane (80 mL). This solution
was cooled to 0 °C and anhydrous TEA (2.3 g, 22.7 mmol) was
added under stirring in 5 min. The corresponding (nitrophenyl)sul-
fonyl chloride 2 or 3 (10 mmol) was added in portions in 10 min
and the stirring was continued at 25 °C until no starting material
was detectable (TLC). The reaction mixture was washed with water
(3 ϫ 20 mL) and the organic phase was dried over sodium sulfate,
evaporated to dryness under vacuum and purified by flash column
chromatography on silica gel (230–400 mesh). Starting amino ester
hydrochloride and (nitrophenyl)sulfonyl chloride, reaction time,
chromatographic eluent, yield and physical, spectroscopic and ana-
lytical data of 4a–g,5a,21 are as follows:
3
3
13.9 Hz, J ϭ 5.7 Hz, 1 H, HCHPh), 3.15 (dd,2J ϭ 13.9 Hz, J ϭ
7.0 Hz, 1 H, HCHPh), 3.51 (s, 3 H, OCH3), 4.42–4.48 (m, 1 H,
CHCOOR), 6.01 (d, 3J ϭ 7.9 Hz, 1 H, NH), 7.09–7.11 (m, 2 H,
Ar), 7.16–7.22 (m, 3 H, Ar), 7.64–7.69 (m, 2 H, Ar), 7.81–7.84 (m,
1 H, Ar), 7.93–7.96 (m, 1 H, Ar). – C16H16N2O6S (364.37): calcd.
C 52.74, H 4.43, N 7.69; found C 52.81, H 4.32, N 7.60.
o-NBS-L-PhGly-OMe (4g): -PhGly-OMe HCl (1g), o-NBS–Cl (2),
24 h, AcOEt–PE 1:1; 4g, 3.02 g (88%), m.p. 97–98 °C. – [α]2D0
ϩ87.4 (c ϭ 1.0 in CHCl3). – H NMR (CDCl3): δ ϭ 3.61 (s, 3 H,
OCH3), 5.26 (d, 3J ϭ 8.0 Hz, 1 H, CHCOOR), 6.64 (d, 3J ϭ
8.0 Hz, 1 H, NH), 7.15–7.19 (m, 3 H, Ar), 7.22–7.25 (m, 2 H, Ar),
ϭ
1
3
3
7.45 (dd, J ϭ 7.9, 7.9 Hz, 1 H, Ar), 7.59 (dd, J ϭ 7.9, 7.9 Hz, 1
3
3
H, Ar), 7.68 (d, J ϭ 7.9 Hz, 1 H, Ar), 7.79 (d, J ϭ 7.9 Hz, 1 H,
Ar). – C15H14N2O6S (350.35): calcd. C 51.42, H 4.03, N 8.00; found
C 51.37, H 4.12, N 7.89.
o-NBS-L-Val-OMe (4a): -Val-OMe HCl (1a), o-NBS–Cl (2), 18 h,
AcOEt–PE 1:3; 4a, 2.71 g (86%). Ester 4a with a sufficient purity
(Ն 98%) for the alkylation step can be obtained in 93% yield with-
out chromatographic purification; oil, [α]2D0 ϭ –213.9 (c ϭ 3.8 in
CHCl3) {ref.[3] [α]2D8.5 ϭ –214.5 (c ϭ 3.8 in CHCl3)}.
p-NBS-L-Val-OMe (5a): -Val-OMe HCl (1a), p-NBS-Cl (3), 20 h,
AcOEt–PE 1:2; 5a, 2.52 g (80%), m.p. 102 °C. – [α]2D0 ϭ ϩ33.2 (c ϭ
0.9 in CHCl3) {ref.[3] [α]2D6 ϭ ϩ36.4 (c ϭ 3.1 in CHCl3)}.
o-NBS-
L
-Ser-OMe (4b): -Ser-OMe HCl (1b), o-NBSCl (2), 1.5 h,
General Method for the Alkylation of Sulfonamides 4,5,21: In a
AcOEt–PE 2:3; 4b, 2.34 g (77%), m.p. 109–110 °C (ref.[3] 110.5–112 dried flask connected to a CaCl2 tube, anhydrous potassium car-
1446
Eur. J. Org. Chem. 2000, 1443Ϫ1449

N--Monoalkylation of α-Amino Acid Esters
FULL PAPER
bonate (2.07 g, 15 mmol) was added to an acetonitrile (or DMF)
o-NBS-N-Bn-
L
-Met-OMe (7h): o-NBS--Met-OMe (4c), benzyl
solution (50 mL) of sulfonamide 4,5 (10 mmol), alkyl halide 6 bromide (6c), 0.25 h; 7h, 3.98 g (91%); oil, [α]2D0 ϭ –12.9 (c ϭ 0.68
(10.5–20 mmol) and TEBA (0.23 g, 1 mmol). The heterogeneous
mixture was magnetically stirred at 25–80 °C until no starting 4,5 HCHCH2S), 1.90 (s, 3 H, SCH3), 2.05–2.17 (m, 1 H, HCHCH2S),
in CHCl3). – 1H NMR (CDCl3): δ ϭ 1.76–1.93 (m, 1 H,
was detectable (TLC analysis, AcOEt–PE 1:1) and then cooled to
room temperature, diluted with water (50 mL) and extracted with
Et2O or CH2Cl2 (3 ϫ 20 mL). The organic layer was washed with
water (2 ϫ 20 mL), dried over Na2SO4 and evaporated under va-
cuum to give pure N-alkyl sulfonamides 7,8,22. Starting sulfonam-
ide and alkyl halide, reaction time, yield and physical, spectroscopic
and analytical data of 7a–m,8a,8d,22 are as follows:
2.31–2.51 (m, 2 H, CH2S), 3.51 (s, 3 H, OCH3), 4.34 (d, 2J ϭ
15.7 Hz, 1 H, HCHPh), 4.81 (m, 1 H, CHCOOR), 4.82 (d, 2J ϭ
15.7 Hz, 1 H, HCHPh), 7.22–7.24 (m, 3 H, Ar), 7.37–7.39 (m, 2
H, Ar), 7.53–7.64 (m, 3 H, Ar), 7.82 (d, 1 H, J ϭ 7.9 Hz, Ar). –
C19H22N2O6S2 (438.52): calcd. C 52.04, H 5.06, N 6.39; found C
52.00, H 5.17, N 6.37.
o-NBS-N-propargyl-L-Thr-OMe (7i): (using anhydrous DMF in-
o-NBS-N-allyl-L-Val-OMe (7a): o-NBS--Val-OMe (4a), allyl
stead of MeCN, Table 3, entry 12) o-NBS--Thr-OMe (4d), propar-
gyl bromide (6f), 6 h; purified by flash column chromatography
using AcOEt-EP 5:6; 7i, 2.98 g (84%); oil, [α]2D0 ϭ ϩ12.8 (c ϭ 1.6
in CHCl3). – 1H NMR (CDCl3): δ ϭ 1.38 (d, 3J ϭ 6.2 Hz, 3 H,
bromide (6a), 2 h; 7a, 3.24 g (91%); oil, [α]2D0 ϭ –61.8 (c ϭ 3.5 in
CHCl3) {ref.[3] [α]2D9 ϭ –62.4 (c ϭ 3.6 in CHCl3)}.
o-NBS-N-C4H9-L-Val-OMe (7b): o-NBS--Val-OMe (4a), butyl
4
3
CH3CH), 2.33 (t, J ϭ 2.4 Hz, 1 H, CHϵ), 2.43 (d, J ϭ 5.4 Hz,
bromide (6b), 12 h; 7b, 3.30 g (89%); oil, [α]2D0 ϭ –70.1 (c ϭ 5.0 in
CHCl3) {ref.[3] [α]2D9 ϭ –70.0 (c ϭ 4.7 in CHCl3)}.
1 H, OH), 3.62 (s, 3 H, OCH3), 4.45 (dd, 4J ϭ 2.4, 1.5 Hz, 2 H,
3
4
CH2N), 4.46–4.56 (m, 1 H, CHOH), 4.57 (dd, J ϭ 5.0 Hz, J ϭ
1.5 Hz, 1 H, CHCOOR), 7.59–7.62 (m, 1 H, Ar), 7.66–7.71 (m, 2
H, Ar), 8.14–8.17 (m, 1 H, Ar). – C14H16N2O7S (356.35): calcd. C
47.19, H 4.53, N 7.86; found C 47.06, H 4.44, N 7.96.
o-NBS-N-Bn-
L-Val-OMe (7c): o-NBS--Val-OMe (4a), benzyl
bromide (6c), 1 h; 7c, 3.93 g (96%), 76–77 °C. – [α]2D0 ϭ –17.4 (c ϭ
1
3
0.66 in CHCl3). – H NMR (CDCl3): δ ϭ 0.88 (d, J ϭ 6.7 Hz, 3
H, CHCH3), 0.91 (d, J ϭ 6.6 Hz, 3 H, CHCH3), 2.07–2.19 (m, 1
3
o-NBS-N-propargyl-D- allo-Thr-OMe (22): (using anhydrous DMF
H, CHCH3), 3.55 (s, 3 H, OCH3), 4.31 (d, 3J ϭ 10.2 Hz, 1 H,
CHCOOR), 4.54 (d, 2J ϭ 15.2 Hz, 1 H, HCHPh), 4.91 (d, 2J ϭ
15.2 Hz, 1 H, HCHPh), 7.15–7.25 (m, 3 H, Ar), 7.34–7.43 (m, 3 H,
Ar), 7.55–7.65 (m, 3 H, Ar). – C19H22N2O6S (406.45): calcd. C
56.14, H 5.46, N 6.89; found C 56.00, H 5.35, N 6.81.
instead of MeCN, Table 3, entry 13) o-NBS--allo-Thr-OMe (21),
propargyl bromide (6f), 2.5 h; purified by flash column chromato-
graphy using AcOEt-EP 4:5; 7i, 3.05 g (86%); oil, [α]2D0 ϭ ϩ96.6
(c ϭ 1.64 in CHCl3). – 1H NMR (CDCl3): δ ϭ 1.43 (d, 3J ϭ 6.2 Hz,
4
3 H, CH3CH), 2.20 (t, J ϭ 2.5 Hz, 1 H, CHϵ), 2.48 (br. s, 1 H,
OH), 3.61 (s, 3 H, OCH3), 4.39 (dd, 4J ϭ 2.5, 0.8 Hz, 2 H, CH2N),
4.46 (q, 3J ϭ 6.2 Hz, 1 H, CHOH), 4.50 (d, 3J ϭ 5.5 Hz, 1 H,
CHCOOR), 7.63–7.69 (m, 1 H, Ar), 7.70–7.75 (m, 2 H, Ar), 8.14–
8.17 (m, 1 H, Ar). – C14H16N2O7S (356.35): calcd. C 47.19, H 4.53,
N 7.86; found C 47.06, H 4.44, N 7.96.
o-NBS-N-(4-pentenyl)-L-Val-OMe (7d): o-NBS--Val-OMe (4a), 4-
pentenyl bromide (6d), 8 h; 7d, 3.68 g (96%); oil, [α]2D0 ϭ –65.7 (c ϭ
3.0 in CHCl3) {ref.[3] [α]2D6 ϭ –63.8 (c ϭ 3.0 in CHCl3)}.
o-NBS-N-Me-
L-Val-OMe (7e): o-NBS--Val-OMe (4a), methyl iod-
ide (6e), 1.5 h; 7e, 2.88 g (87%), m.p. 66–67 °C. – [α]2D0 ϭ –13.5 (c ϭ
1
3
o-NBS-N-C4H9-Gly-OMe (7j): o-NBS-Gly-OMe (4e), butyl brom-
0.78 in CHCl3). – H NMR (CDCl3): δ ϭ 0.93 (d, J ϭ 6.7 Hz, 3
H, CHCH3), 0.96 (d, J ϭ 6.6 Hz, 3 H, CH3CH), 2.11–2.23 (m, 1
1
3
ide (6b), 1.5 h; 7j, 2.65 g (80%); oil. – H NMR (CDCl3): δ ϭ 0.86
(t, 3J ϭ 7.3 Hz, 3 H, CH3 aliph), 1.19–1.32 (m, 2 H, CH2 aliph), 1.45–
H, CHCH3), 3.03 (s, 3 H, NCH3), 3.54 (s, 3 H, OCH3), 4.11 (d,
3J ϭ 10.2 Hz, 1 H, CHCOOR), 7.61–7.69 (m, 3 H, Ar), 7.98–8.01
(m, 1 H, Ar). – C13H18N2O6S (330.36): calcd. C 47.26, H 5.49, N
8.48; found C 47.11, H 5.37, N 8.44.
3
1.55 (m, 2 H, CH2 aliph), 3.37 (t, J ϭ 7.6 Hz, 2 H, CH2N), 3.64 (s,
3 H, OCH3), 4.16 (s, 2 H, CH2COOR), 7.58–7.61 (m, 1 H, Ar),
7.65–7.69 (m, 2 H, Ar), 8.05–8.08 (m, 1 H, Ar). – C13H18N2O6S
(330.36): calcd. C 47.26, H 5.49, N 8.48, O 29.06, S 9.71; found C
47.11, H 5.47, N 8.55.
o-NBS-N-allyl-L-Ser-OMe (7f): (using anhydrous DMF instead of
MeCN, Table 3, entry 8) o-NBS--Ser-OMe (4b), allyl bromide
(6a),; 7 h; purified by flash column chromatography: 7f, 2.62 g
(76%); oil, [α]2D0 ϭ –11.4 (c ϭ 0.59 in CHCl3) {ref.[3] [α]2D3 ϭ –12.2
(c ϭ 2.4 in CHCl3)}. Compound 11 was also obtained as an oil
o-NBS-N-allyl-
L-Phe-OMe (7k): o-NBS--Phe-OMe (4f), allyl
bromide (6a), 0.5 h; 7k, 3.54 g (88%); oil, [α]2D0 ϭ –24.6 (c ϭ 0.56
1
2
3
in CHCl3). – H NMR (CDCl3): δ ϭ 3.04 (dd, J ϭ 14.1 Hz, J ϭ
2
3
1
7.5 Hz, 1 H, HCHPh), 3.35 (dd, J ϭ 14.1 Hz, J ϭ 7.7 Hz, 1 H,
(0.49 g, 15%). – H NMR (CDCl3): δ ϭ 3.63 (s, 3 H, OCH3), 4.20
HCHPh), 3.56 (s, 3 H, OCH3), 3.80 (dd, 2J ϭ 16.5 Hz, 3J ϭ 6.5 Hz,
(d, 3J ϭ 6.7 Hz, 2 H, CH2N), 5.12–5.19 (m, 2 H, CH2ϭ), 5.71–
5.84 (m, 2 H, CH2ϭ), 5.95 (s, 1 H, CHϭ), 6.55 (s, 1 H, NH), 7.58–
7.69 (m, 3 H, Ar), 7.97–8.00 (m, 1 H, Ar). – C13H14N2O6S (326.33):
calcd. C 47.85, H 4.32, N 8.58; found C 47.92, H 4.22, N 8.49.
2
3
1 H, HCHN), 4.11 (dd, J ϭ 16.5 Hz, J ϭ 6.3 Hz, 1 H, HCHN),
4.91 (t, 3J ϭ 7.6 Hz, 1 H, CHCOOR), 5.11 (dd, Jcis ϭ 10.8 Hz,
3
2J ϭ 0.8 Hz, 1 H, HCHϭ), 5.22 (dd, 3Jtrans ϭ 17.2 Hz, 2J ϭ 0.8 Hz,
3
1 H, HCHϭ), 5.72–5.86 (dm, J ϭ 6.7 Hz, 1 H, CHϭ), 7.20–7.29
o-NBS-N-allyl-L-Met-OMe (7g): o-NBS--Met-OMe (4c), allyl
(m, 5 H, Ar), 7.53–7.68 (m, 3 H, Ar), 7.82–7.85 (m, 1 H, Ar). –
C19H20N2OS (404.44): calcd. C 56.42, H 4.98, N 6.93; found 56.31,
H 4.80, N 6.99.
bromide (6a), 1 h; 7g, 3.66 g (94%); oil, [α]2D0 ϭ ϩ9.4 (c ϭ 0.63 in
CHCl3). – 1H NMR (CDCl3): δ ϭ 1.95–2.11 (m, 1 H, HCHCH2S),
2.11 (s, 3 H, SCH3), 2.24–2.38 (m, 1 H, HCHCH2S), 2.53–2.67 (m,
2 H, CH2S), 3.59 (s, 3 H, OCH3), 3.88 (dd, 2J ϭ 16.5 Hz, 3J ϭ o-NBS-N-Me-
L-Phe-OMe (7l): o-NBS--Phe-OMe (4f), methyl
7.3 Hz, 1 H, HCHN), 4.14 (dd, 2J ϭ 16.5 Hz, 3J ϭ 5.6 Hz, 1 H,
iodide (6e), 0.15 h; 7l, 3.25 g (86%); oil, [α]2D0 ϭ ϩ55.2 (c ϭ 1.45 in
HCHN), 4.79 (dd, 3J ϭ 9.1, 5.5 Hz, 1 H, CHCOOR), 5.14 (d, CHCl3). – 1H NMR (CDCl3): δ ϭ 2.98 (dd, 2J ϭ 14.3 Hz, 3J ϭ
3
3Jcis ϭ 10.1 Hz, 1 H, HCHϭ), 5.24 (d, Jtrans ϭ 17.2 Hz, 1 H,
9.5 Hz, 1 H, HCHPh), 3.04 (s, 3 H, NCH3), 3.36 (dd, 2J ϭ 14.3 Hz,
HCHϭ), 5.86–5.97 (m, 1 H, CHϭ), 7.61–7.64 (m, 1 H, Ar), 7.69– 3J ϭ 6.2 Hz, 1 H, HCHPh), 3.65 (s, 3 H, OCH3), 4.94 (dd, J ϭ
3
7.74 (m, 2 H, Ar), 8.07–8.11 (m, 1 H, Ar). – C15H20N2O6S2 6.2, 9.5 Hz, 1 H, CHCOOR), 7.20–7.28 (m, 5 H, Ar), 7.54–7.74
(388.46): calcd. C 46.38, H 5.19, N 7.21; found C 46.46, H 5.25,
N 7.26.
(m, 3 H, Ar), 7.74–7.77 (m, 1 H, Ar). – C17H18N2O6S (378.40):
calcd. C 53.96, H 4.79, N 7.40; found C 53.78, H 4.71, N 7.33.
Eur. J. Org. Chem. 2000, 1443Ϫ1449
1447

D. Albanese, D. Landini, V. Lupi, M. Penso
FULL PAPER
o-NBS-N-Me-
L
-PhGly-OMe (7m): o-NBS--PhGly-OMe (4g),
H, CHϭ), 7.15–7.31 (m, 5 H, Ar). – C13H17NO2 (219.28): calcd. C
71.21, H 7.81, N 6.39; found C 71.10, H 7.69, N 6.33.
methyl iodide (6e), 15 h; 7m, 3.32 g (91%); oil, [α]2D0 ϭ ϩ56.0 (c ϭ
1
1.1 in CHCl3). – H NMR (CDCl3): δ ϭ 2.84 (s, 3 H, NCH3), 3.70
N-Me-L
-PhGly-OMe (9m): 63 mg (88%); oil, [α]2D0 ϭ ϩ27.5 (c ϭ
(s, 3 H, OCH3), 5.98 (s, 1 H, CHCOOR), 7.24–7.28 (m, 2 H, Ar),
7.35–7.38 (m, 3 H, Ar), 7.64–7.72 (m, 3 H, Ar), 8.05–8.08 (m, 1 H,
Ar). – C16H16N2O6S (364.37): calcd. C 52.74, H 4.43, N 7.69; found
C 52.61, H 4.36, N 7.61.
1.0 in CHCl3) {ref.[11] [α]2D8 ϭ ϩ131.3, c not reported, in CHCl3
solution}, 21% ee. Compound 9m was reprotected as previously
described in this section. 7m, [α]2D0 ϭ ϩ23.3 (c ϭ 1.0 in CHCl3)
corresponding to 21% ee. Theoretical value of the pure enantiomer
7m: [α]2D0 ϭ ϩ111.0. The measured [α]2D0 ϭ ϩ55.5 of the starting
7m corresponds to 50% ee.
p-NBS-N-allyl-L-Val-OMe (8a): p-NBS--Val-OMe (5a), allyl
bromide (6a), 2 h; 8a, 3.24 g (91%); oil, [α]2D0 ϭ –124.2 (c ϭ 0.65 in
CHCl3). – 1H NMR (CDCl3): δ ϭ 0.93 (d, 3J ϭ 6.6 Hz, 3 H,
Method B:[1c][1d] sulfonamide 7 (0.4 mmol) in 0.8 mL of a 0.5 
solution of PhS–Kϩ in DMF was left to stand at 25 °C until no
starting 7 was detectable by TLC. After usual workup, the follow-
ing esters 9 were isolated:
3
CH3CH), 1.02 (d, J ϭ 6.6 Hz, 3 H, CH3CH), 2.14–2.21 (m, 1 H,
CHCH3), 3.46 (s, 3 H, OCH3), 3.88 (ddt, 2J ϭ 16.4 Hz, 3J ϭ
4
2
3
5.3 Hz, J ϭ 1.4 Hz, 1 H, HCHN), 4.06 (dd, J ϭ 16.4 Hz, J ϭ
7.8 Hz, 1 H, HCHN), 4.16 (d, 3J ϭ 10.5 Hz, 1 H, CHCOOR), 5.09
3
(dd, Jcis ϭ 10.1 Hz, 2J ϭ 0.9 Hz, 1 H, HCHϭ), 5.19 (dd, 3Jtrans
ϭ
N-Me-L
-Phe-OMe (9l): 71 mg (92%); oil, [α]2D0 ϭ ϩ28.0 (c ϭ 0.95
17.2 Hz, 2J ϭ 0.9 Hz, 1 H, HCHϭ), 5.65–5.79 (m, 1 H, CHϭ),
in CHCl3) {ref.[10] [α]2D8 ϭ ϩ28.6, c not reported, in CHCl3
8.00 (dd, 2 H, J ϭ 6.9 Hz, J ϭ 2.1 Hz, Ar), 8.31 (dd, 2 H,3J ϭ
3
4
solution}.
4
6.9 Hz, J ϭ 2.1 Hz, Ar). – C15H20N2O6S (356.40): calcd. C 50.55,
N-Me-L
-PhGly-OMe (9m): 49 mg (68%); oil, [α]2D0 ϭ ϩ15.0 (c ϭ
1.1 in CHCl3), 11% ee.
H 5.66, N 7.86; found C 50.45, H 5.52, N 7.93.
p-NBS-N-(4-pentenyl)-L-Val-OMe (8d): p-NBS--Val-OMe (5a), 4-
pentenyl bromide (6d), 6 h; 8d, 3.49 g (91%); oil, [α]2D0 ϭ –77.7 (c ϭ
0.6 in CHCl3) {ref.[3] [α]2D5 ϭ –82.3 (c ϭ 2.5 in CHCl3)}.
Acknowledgments
1
This work was supported by MURST and the National Project
‘‘Stereoselezione in Sintesi Organica. Metodologie e Applicazioni’’.
Determination of Optical Purities: H NMR analyses to determine
the optical purities of new compounds were made by recording the
spectrum of a solution of 7 (2.6 mg) in CDCl3 (0.5 mL) after the
addition of an appropriate amount of a CDCl3 solution of Eu(hfc)3
(100 mg/mL CDCl3) or Eu(tfc)3 (75 mg/mL CDCl3) as shift re-
agents. The same procedure was applied to the corresponding ra-
cemized sulfonamide 7-rac, obtained by reacting the enantiopure 7
(0.2 mmol) with sodium methylate (1 mmol) in anhydrous meth-
anol (1 mL) at 25–65 °C. The starting enantiopure 7, temperature
and time for the racemization, ee of the racemized 7-rac, type and
amount of the solution of the shift reagent and signals involved in
the shift are as follows.
[1]
[1a]
See, inter alia:
B. M. Trost, T. L. Calkins, C. Oertelt, J.
Zambrano, Tetrahedron Lett. 1998, 39, 1713–1716 and refer-
ences therein. – [1b] U. Bhatt, N. Mohamed, G. Just, E. Roberts,
[1c]
Tetrahedron Lett. 1997, 38, 3679–3682. –
S. C. Miller, T. S.
[1d]
Scanlan, J. Am. Chem. Soc. 1997, 119, 2301–2302. –
Miller, T. S. Scanlan, J. Am. Chem. Soc. 1998, 120, 2690–
S. C.
[1e]
2691. –
P. Manavalan, F. A. Momany, Biopolymers 1980,
19, 1943–1973.
[2]
[2a] D. Papaioannou, C. Athanassopoulos, V. Magafa, N. Kara-
manos, G. Stavropoulos, A. Napoli, G. Sindona, D. W. Aksnes,
[2b]
G. W. Francis, Acta Chem. Scand. 1994, 48, 324–333. –
R.
L. Dorow, D. E. Gingrich, J. Org. Chem. 1995, 60, 4986–4987
and references therein. – [2c] S. T. Cheung, N. L. Benoiton, Can.
J. Chem. 1977, 55, 906–910. – [2d] D. H. Rich, J. Tam, P. Mathi-
aparanam, J. Grant, Synthesis 1975, 402–404. – [2e] A. A. Patch-
ett, E. Harris, E. W. Tristram, M. J. Wyvratt, M. T. Wu, D.
Taub, E. R. Peterson, T. J. Ikeler, J. ten Broeke, L. G. Payne,
D. L. Ondeyka, E. D. Thorsett, W. J. Greenlee, N. S. Lohr, R.
D. Hoffsommer, H. Joshua, W. V. Ruyle, J. W. Rothrock, S. D.
Aster, A. L. Maycock, F. M. Robinson, R. Hirschmann, C. S.
7c: 25 °C, 8 h, 7c-rac ee ϭ 55%; Eu(hfc)3, 60 µL; δ ϭ 4.31, 4.54,
4.91.
7e: 65 °C, 4 h, 7e-rac ee ϭ 0%; Eu(hfc)3, 80 µL; δ ϭ 4.11.
7g: 25 °C, 30 h, 7g-rac ee ϭ 0%; Eu(hfc)3, 60 µL; δ ϭ 3.88.
7h: 25 °C, 25 h, 7h-rac ee ϭ 0%; Eu(hfc)3, 60 µL; δ ϭ 4.34.
7k: 25 °C, 3 h, 7k-rac ee ϭ 45%; Eu(tfc)3, 200 µL; δ ϭ 4.91.
Sweet, E. H. Ulm, D. M. Gross, T. C. Vassil, C. A. Stone,
[2f]
Nature 1980, 288, 280–283. –
Y. Ohfune, N. Kurokawa, N.
Higuchi, M. Saito, M. Hashimoto, T. Tanaka, Chem. Lett.
1984, 441–444.
W. R. Bowman, D. R. Coghlan, Tetrahedron 1997, 53, 15787–
Deprotection of Sulfonamides 7,8:
[3]
[4]
Method A:[3,6] Sulfonamide 7 or 8 (0.4 mmol), PhSH (1.2 mmol),
acetonitrile (10 mL) and anhydrous potassium carbonate
(1.6 mmol), were stirred at 50 °C for 1 h. Under these reaction con-
ditions the following esters 9 were obtained:
15798.
[4a]
For monographs and reviews see, inter alia:
F. Montanari,
D. Landini, F. Rolla, Top. Curr. Chem. 1982, 101, 147–200. –
[4b]
M. Makosza, M. Fedorynki, Adv. Catal. 1988, 35, 375–
422. – [4c] E. V. Dehmlow, S. Dehmlow, in Phase Transfer Cata-
[4d]
lysis, 3rd ed., VCH, Weinheim, 1993. –
C. M. Starks, C.
N-Allyl-L-Val-OMe (9a): 43 mg (62%) from 7a, 40 mg (58%) from
Liotta, M. Halpern, in Phase Transfer Catalysis. Fundamentals,
Applications and Industrial Perspectives, Chapman and Hall,
New York, 1994.
8a; oil, [α]2D0 ϭ –21.8 (c ϭ 1.6 in CHCl3) {ref.[3] [α]2D5 ϭ –21.8 (c ϭ
1.6 in CHCl3)}.
[5] [5a]
D. Landini, M. Penso, J. Org. Chem. 1991, 56, 420–423. –
N-Bn-
CHCl3) {ref.[3] [α]2D4 ϭ –51.5 (c ϭ 2.1 in CHCl3)}.
L
-Val-OMe (9c): 74 mg (83%); oil, [α]2D0 ϭ –51.1 (c ϭ 2.1 in
[5b] D. Albanese, D. Landini, M. Penso, J. Org. Chem. 1992, 57,
1603–1605. – [5c] D. Albanese, D. Landini, A. Maia, M. Penso,
J. Mol. Catal. 1999, 150, 113–131. – [5d] P. Tundo, G. Moraglio,
F. Trotta, Ind. Chem. Res. 1989, 28, 881–890 and references
therein.
N-Allyl-
L
-Phe-OMe (9k): 62 mg (72%); oil, [α]2D0 ϭ ϩ16.8 (c ϭ 1.2
1
in CHCl3). – H NMR (CDCl3): δ ϭ 1.65 (br. s, 1 H, NH), 2.95
[6]
[7]
[8]
T. Fukuyama, C.-K. Jow, M. Cheung, Tetrahedron Lett. 1995,
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D. Landini, A. Maia, Gazz. Chim. It. 1993, 123, 19–24.
(d, 3J ϭ 6.8 Hz, 2 H, CH2Ph), 3.10 (ddt, 2J ϭ 13.0 Hz, 3J ϭ 6.1 Hz,
4J ϭ 1.3 Hz, 1 H, HCHN), 3.25 (ddt, J ϭ 13.0 Hz, J ϭ 5.9 Hz,
2
3
4J ϭ 1.3 Hz, 1 H, HCHN), 3.55 (t, J ϭ 6.8 Hz, 1 H, CHCOOR),
3
3.63 (s, 3 H, OCH3), 5.03–5.14 (m, 2 H, CH2ϭ), 5.73–5.86 (m, 1
1448
Eur. J. Org. Chem. 2000, 1443Ϫ1449

N--Monoalkylation of α-Amino Acid Esters
FULL PAPER
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[11]
R. K. Olsen, J. Org. Chem. 1970, 35, 1912–1915.
P. A. Grieco, A. Bahsas, J. Org. Chem. 1987, 52, 5746–5749.
Received September 10, 1999
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42, 355–356. –
D. F. Elliot, J. Chem. Soc. 1950, 62–68.
[O99524]
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1449