LiOH-mediated N-monoalkylation of α-amino acid esters and a dipeptide ester using activated alkyl bromides

Article abstract of DOI:10.1016/S0040-4039(01)02394-2

Selective N-monoalkylation of α-amino esters with activated alkyl bromides was studied using various alkali or alkali earth metal bases. In the production of N-monoalkylated amino ester derivatives and suppression of N,N-dialkylation, lithium hydroxide wa

Full text of DOI:10.1016/S0040-4039(01)02394-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1273–1276
LiOH-mediated N-monoalkylation of a-amino acid esters and a
dipeptide ester using activated alkyl bromides
Jong Hyun Cho and B. Moon Kim*
Center for Molecular Catalysis, School of Chemistry and Molecular Engineering, Seoul National University, Seoul 151-747,
South Korea
Received 4 October 2001; revised 13 December 2001; accepted 21 December 2001
Abstract—Selective N-monoalkylation of a-amino esters with activated alkyl bromides was studied using various alkali or alkali
earth metal bases. In the production of N-monoalkylated amino ester derivatives and suppression of N,N-dialkylation, lithium
hydroxide was more effective than any other alkali or alkali earth bases examined. Using this protocol, a variety of N-alkylated
a-amino esters and even dipeptide esters have been successfully prepared using various activated alkyl bromides. © 2002 Elsevier
Science Ltd. All rights reserved.
N-Alkylated amino acids are often key components of
peptide turn structures1 and small cyclic peptide mimet-
ics.2 Most of these secondary amino acids form tertiary
amide bonds in bioactive peptides and peptidomimetics.
Also, recent advances in solid-phase synthesis using
organic polymer supports in relation to the construc-
tion of combinatorial libraries often require highly
efficient N-alkylation methods for connecting an amine
functionality onto various supports or linkers.3
(PNBBr) in the presence of CsOH or Cs2CO3 following
the reported procedure4 and the results are summarized
in Table 1. In the alkylation of phenylalanine or leucine
methyl ester hydrochloride, yields of N-monoalkylated
amino esters were in the range 58–67% (entries 1–4).
N-Monoalkylation of alanine methyl ester, which is less
hindered than the phenylalanine or leucine derivative,
proceeded in about 10% higher yields either with CsOH
or Cs2CO3 (entries 5–8). The reaction of glycine methyl
ester gave about 50% of mono-alkylated amino esters
and 10–20% of N,N-dialkylated products (entries 9–12).
The low reactivity of a-substituted amino ester deriva-
Recently, a new N-monoalkylation protocol employing
cesium hydroxide as a base has been reported by Jung
et al.4 to remedy shortcomings of common preparatory
methods for secondary amines from primary amines,
including reductive amination and direct nucleophilic
N-alkylation.5 In the course of our study employing
biologically active peptides and peptide mimics, we
needed an efficient method for N-monoalkylation of
a-amino esters. However, when the cesium hydroxide
protocol was employed for the alkylation of various
a-amino acid esters, the desired N-monoalkylated prod-
ucts were obtained only in moderate yields. Therefore,
we screened a variety of alkali and alkali earth metal
hydroxides and carbonates to find that lithium hydrox-
ide performs far better than any other metal bases
examined for our purposes. Herein we wish to report
this LiOH-promoted, selective N-monoalkylation of a-
amino ester derivatives.
Table 1. Direct N-monoalkylation of a-amino esters using
cesium bases
Entry
Amino ester
R
Base
Yield (%)a
1
2
3
4
5
6
7
8
PheOMe
PheOMe
LeuOMe
LeuOMe
AlaOMe
AlaOMe
AlaOMe
AlaOMe
GlyOMe
GlyOMe
GlyOMe
GlyOMe
Allyl
PNB
Allyl
PNB
Allyl
PNB
Allyl
PNB
Allyl
PNB
Allyl
PNB
Cs2CO3
Cs2CO3
CsOH·H2O
CsOH·H2O
Cs2CO3
67
64
58
61
78
74
65
70
Cs2CO3
CsOH·H2O
CsOH·H2O
Cs2CO3
Cs2CO3
CsOH·H2O
CsOH·H2O
9
48b
52b
54b
47b
10
11
12
First we examined alkylation of several a-amino esters
with either allyl bromide or p-nitrobenzyl bromide
a Isolated yields from silica gel chromatography.
b The N,N-dialkylated product was obtained in 10–20% yields.
* Corresponding author. E-mail: kimbm@snu.ac.kr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02394-2

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J. H. Cho, B. M. Kim / Tetrahedron Letters 43 (2002) 1273–1276
Table 2. Direct N-monoalkylation of phenylalanine methyl
ester hydrochloride using various alkali and alkali earth
metal bases
tives in the presence of cesium bases may be due to
increased steric hindrance at the amine nucleophile
through chelated cesium complex involving both the
nitrogen and the carbonyl oxygen of the amino acid
ester.
p-Nitrobenzyl bromide
H2N
HCl
CO2CH3
Ph
PNBHN
CO2CH3
Ph
o
4 A MS, LiOH.H2O,
Then we decided to screen various alkali and alkali
earth metal bases. For this purpose, we chose the
DMF, rt, 12-24 h
reaction between
L-phenylalanine and p-nitrobenzyl
Entry
Base
Reaction time (h)
Yield (%)a
,
bromide in the presence of activated 4 A molecular
sieves in anhydrous N,N-dimethylformamide (DMF) as
a control set4 and tested various metal hydroxides and
carbonates. As documented in Table 2, when alkyla-
tions employing 2.15–2.20 equiv. of each metal bases
were screened, reactions employing rubidium hydrox-
ide, cesium hydroxide, and calcium hydroxide provided
reasonable yields of alkylation products (entries 7, 10,
and 13, respectively). However, lithium hydroxide and
lithium carbonate proved to be superior to all other
metal bases in furnishing the desired N-monoalkylation
product (entries 1 and 2). In fact the reaction involving
lithium hydroxide provided the highest yield (95%)
(entry 1). It is quite intriguing to note that LiOH was
rather ineffective in selective N-monoalkylation of sim-
ple primary amines.6 This appears to be due to the fact
that, compared to other metals, lithium metal is smaller
and possesses strong covalent character to bind the
nitrogen and oxygen atoms of a-amino esters.7
1
2
3
4
5
6
7
8
LiOH·H2O
Li2CO3
NaOH
Na2CO3
KOH
K2CO3
RbOH·xH2O
Rb2CO3
CsOH·H2O
Cs2CO3
Mg(OH)2
MgCO3
Ca(OH)2
CaCO3
Sr(OH)2
SrCO3
Ba(OH)2·H2O
BaCO3
12
12
12
24
12
24
12
24
12
12
12
24
12
24
12
24
12
24
95
87
55
50
60
31
71
25
70
64
36
63
75
52
68
42
60
21
9
10
11
12
13
14
15
16
17
18
b
a Isolated yields after silica gel chromatography.
b (MgCO3)4·Mg(OH)2·5H2O was employed.
With the LiOH protocol in hand, we examined alkyla-
tion of various a-amino esters with p-nitrobenzyl bro-
mide as depicted in Table 3.8 Alkylation of alanine,
phenylalanine and leucine methyl esters all went
through smoothly under the LiOH conditions (entries
1–6). Even with valine methyl ester, a highly hindered
amino ester, the reaction involving LiOH ensured clean
conversion to N-monoalkylated derivative in 85% yield
(entry 7). Several multifunctional amino acid deriva-
tives such as serine, aspartic acid, arginine, tyrosine and
ornithine derivatives have also been examined under
the same reaction conditions and in all cases respectable
yields of the desired N-monoalkylated products were
obtained (entries 8–12). Alkylation of the most unhin-
dered amino acid, glycine methyl ester gave mono-alkyl-
ated products in 61 and 54% yields from the reaction
with allyl bromide and p-nitrobenzyl bromide, respec-
tively (entries 14 and 15). In these cases, N,N-dialkyl-
ated side products were obtained in 10–15% yields.
Table 3. Direct N-monoalkylation of representative a-amino
esters using LiOH
H
N
RBr,LiOH.H2O
H2N
HCl
CO2CH3
CO2CH3
R
o
R'
R'
4 A MS, DMF, rt
2
1
Entry
Amino ester
R
[h]2D5 a
Yield (%)c
1
2
3
4
5
6
7
8
AlaOMe
AlaOMe
PheOMe
PheOMe
LeuOMe
LeuOMe
ValOMe
Ser(OtBu)OMe
Asp(OtBu)OMe
Arg(Cbz)2OMe
Tyr(OtBu)OMe
PNB
Allyl
PNB
Allyl
PNB
Allyl
PNB
PNB
Bn
−52.7
−45.5
−25.9
+23.0
−19.5
−7.4
−64.5
−18.7
−26.0
−2.6
+22.7
−18.8b
+18.6
–
86
82
95
90
88
94
85
In order to investigate the stereochemical integrity at
the a-carbon center of amino esters in the course of
alkylation under the conditions employing LiOH, we
87
9
75d
80
10
11
12
13
14
15
Allyl
Allyl
have examined the enantiomeric purity of the L-phenyl-
76
alanine methyl ester derivative upon reaction with p-
nitrobenzyl bromide and compared it with a racemic
derivative. Chiral HPLC analyses of both derivatives
(Daicel Chiracel OD-H column; eluent: n-hexane/iso-
propanol 90:10; 1.0 mL/min) clearly indicated that no
enantiomerization of the amino acid derivative has
occurred. As for other side reactions, hydrolysis of the
ester moiety followed by subsequent alkylation was not
observed to a detectable extent, which was similar to
the previously reported case involving cesium bases.4
Orn(NHBoc)OMe Bn
73d
74d
61e
54e
AsnOtBu
GlyOMe
GlyOMe
Bn
Allyl
PNB
–
a [h]2D5 (c 1.0, MeOH).
b [h]2D5 (c 0.5, MeOH).
c Isolated yields after silica gel chromatography.
d The dialkylated product was obtained in 4–5% yields, respectively.
e The dialkylated product was obtained in 10–15% yields, respectively.

J. H. Cho, B. M. Kim / Tetrahedron Letters 43 (2002) 1273–1276
1275
However, an acid salt form (e.g. HCl salt) of the
N-alkylated amino esters is recommended for a longer
period of storage.
reaction proceeded with sterically hindered isopropyl
bromide even for 48 h and unreacted starting material
was recovered (entry 7).
With the efficient N-alkylating protocol for a-amino
esters in hand, we investigated the possibility of extend-
ing this methodology to the alkylation of a dipeptide
ester derivative. As shown in Table 5, when we exam-
ined the alkylation of PheLeuOMe using 2-nitrobenzyl
bromide or allyl bromide, we were pleased to find that
selective N-monoalkylation went smoothly to provide
82 and 70% yields, respectively, of the desired N-
monoalkylated products (entries 1 and 2).
We then screened a variety of activated and unactivated
alkyl halides under the LiOH-promoted alkylation con-
ditions. As depicted in Table 4, when alkylation with
iodomethane, propargyl bromide, benzyl bromide, 2-
nitrobenzyl bromide and methyl bromoacetate were
examined, all but one provided high yields of the
monoalkylated products (entries 2–5). In the case of
alkylation with iodomethane, a very low yield of the
desired N-monoalkylated product was obtained, exten-
sive dialkylation (30%) being a major side reaction
(entry 1). Reactions with unactivated alkyl bromides
such as 3-butenyl bromide and isopropyl bromide were
examined and a modest yield of desired product was
obtained in the former case (entry 6). However, no
In summary, an efficient and economical protocol has
been developed for chemoselective N-alkylation of a-
amino esters with activated alkyl bromides except for
methyl iodide employing lithium hydroxide as a base.
Various a-amino esters could be selectively monoalkyl-
ated under the reaction conditions. A variety of acti-
vated alkyl groups including propargyl, benzyl, 2-
nitrobenzyl and methoxycarbomethyl groups could be
alkylated to the amino groups of a-amino esters in high
yields. Alkylation with unactivated alkyl bromides has
not been as successful. Selective N-monoalkylation of a
representative dipeptide ester was also successful with
allyl bromide and 2-nitrobenzyl bromide. Further stud-
ies on the scope of this reaction both in solution and
solid phase are in progress and will be reported in due
course.
Table 4. Alkylation of phenylalanine methyl ester hydro-
chloride with various alkyl halides
H
N
RX, LiOH.H2O
H2N
HCl
CO2CH3
Ph
CO2CH3
Ph
R
o
4 A MS, DMF, rt
Entry
RX
Reaction time [h]D25 a
Yield (%)c
(h)
1
2
Iodomethane 36
+27.9b
22d
80
Propargyl
bromide
Benzyl
24
+9.3
−6.1
+14.5
+6.5
+12.2b
–
Acknowledgements
3
4
5
6
7
12
87
90
86
52e
0
bromide
2-Nitrobenzyl 12
bromide
The authors would like to thank both the Korea Sci-
ence and Engineering Foundation through the Center
for Molecular Catalysis at Seoul National University
and the LGCI Life Science Research Institute for gen-
erous financial support. J.H.C. would also like to thank
the Ministry of Education, Korea for the BK21
fellowship.
Methyl
24
24
48
bromoacetate
3-Butenyl
bromide
Isobutyl
bromide
a [h]2D5 (c 1.0, MeOH).
b [h]2D5 (c 0.5, MeOH).
References
c Isolated yields after silica gel chromatography.
d The dimethylated product was obtained in 30% yield.
e The dimethylated product was obtained in 10% yield.
1. (a) Yang, J.; Gellman, S. H. J. Am. Chem. Soc. 1998, 120,
9090; (b) Feng, Y.; Wang, Z.; Jin, S.; Burgess, K. J. Am.
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hedron Lett. 1999, 40, 8193.
Table 5. Alkylation of PheLeuOMe using activated alkyl
bromides
Ph
Ph
O
O
H
N
H
N
RX, LiOH.H2O
RHN
OMe
H2N
OMe
o
4 A MS, DMF, rt
O
O
3. (a) Combinatorial Peptide and Nonpeptide Libraries; Jung,
G., Ed.; VCH: New York, 1996; (b) Combinatorial Chem-
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Liss: Singapore, 1998; (d) Solid-Phase Synthesis; Kates, S.
A.; Albericio, F., Eds.; Marcel Dekker: New York, 2000.
Entry
R
Reaction time (h)
Yield (%)a
1
2
2-Nitrobenzyl
Allyl
24
24
82
70
a Isolated yields after silica gel column chromatography.

1276
J. H. Cho, B. M. Kim / Tetrahedron Letters 43 (2002) 1273–1276
4. Salvatore, R. N.; Nagle, A. S.; Schmidt, S. E.; Jung, K. W.
Org. Lett. 1999, 1, 1893.
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amines and their salts. Elsevier: New York, 1995; Vol. 2,
pp. 297–332.
6. A 3:1 mixture of mono- versus dialkylated products were
obtained in the alkylation of 2-phenylethylamine accord-
ing to Ref. 4.
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allowed to stir for 12 h at room temperature. After filtra-
tion through a sintered glass filter to remove insoluble
inorganic salts and washing the residue several times with
EtOAc, the combined filtrate was washed with water (3×20
mL), dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure. The residue was
purified on silica gel column (hexane:EtOAc, from 6:1 to
4:1 v/v) to give the secondary amino ester derivative (0.52
g, 1.67 mmol, 95% yield) as a pale yellow oil. Rf=0.20
1
(hexane:EtOAc=4:1 v/v); H NMR (300 MHz, CDCl3) l
8.08 (d, 2H, J=8.8 Hz), 7.33 (d, 2H, J=8.8 Hz), 7.29 (m,
3H), 7.17 (m, 2H), 3.94 (d, 1H, J=14.7 Hz), 3.70 (d, 1H,
J=14.7 Hz), 3.69 (s, 3H), 3.46 (dd, 1H, J=5.8, 7.7 Hz),
3.02 (dd, 1H, J=5.8, 13.5 Hz), 2.91 (dd, 1H, J=7.7, 13.5
Hz), 1.95 (s, 1H); 13C NMR (75 MHz, CDCl3) l 175.17,
147.92, 147.44, 137.61, 129.68, 128.93, 128.84, 127.24,
,
8. General experimental procedure: To activated 4 A molecu-
lar sieve powder (1.0 g) in DMF (10.0 mL) was added
lithium hydroxide monohydrate (0.16 g, 3.79 mmol) and
then the suspension was vigorously stirred for 20 min.
123.89, 62.48, 52.25, 51.53, 40.18; IR (KBr, neat, cm−1
)
L
-Phenylalanine methyl ester hydrochloride (0.38 g, 1.76
3343, 3062, 3028, 2949, 2849, 1735, 1602, 1519, 1453, 1346,
1202, 1173, 853, 741, 701; HRMS (FAB) calcd for
C17H19N2O4 (M+H+) 315.1346, found 315.1349.
mmol) was added and the mixture was additionally stirred
for 45 min. To the white suspension was added p-nitroben-
zyl bromide (0.46 g, 2.13 mmol) and then the mixture was