BEMP-promoted C(4)-alkylation of 4-alkyloxazol-5(4 H)-ones: A rapid and efficient route to α,α-dialkyl-α-amino acids

Article abstract of DOI:10.1055/s-0032-1317801

Rapid and efficient C(4)-alkylation of 4-alkyloxazol-5(4H)-ones has been achieved by the utilization of BEMP as base. 4,4-Dialkyloxazol-5(4H)-ones, which can easily be hydrolyzed into free α,α-dialkyl-α-amino acids, were obtained in high yields (up to 99%

Full text of DOI:10.1055/s-0032-1317801

LETTER
▌701
letter
BEMP-Promoted C(4)-Alkylation of 4-Alkyloxazol-5(4H)-ones: A Rapid and
Efficient Route to α,α-Dialkyl-α-amino Acids
Rapid and Efficient Route to α,α-Dialkyl-α-amino Acids
Yeon-Ju Lee,a Jeyoung Seo,b Dong-Guk Kim,c Hyeung-geun Park,b Byeong-Seon Jeong*c
a
Natural Product Chemistry Laboratory, Korea Institute of Ocean Science and Technology, Ansan 426-744, South Korea
b
Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 151-742, South Korea
Fax +82(2)8729129; E-mail: hgpk@snu.ac.kr
c
Institute for Drug Research and College of Pharmacy, Yeungnam University, Gyeongsan 712-749, South Korea
Fax +82(53)8104654; E-mail: jeongb@ynu.ac.kr
Received: 21.01.2013; Accepted after revision: 20.02.2013
oxazolone
formation
O
O
Abstract: Rapid and efficient C(4)-alkylation of 4-alkyloxazol-
5(4H)-ones has been achieved by the utilization of BEMP as base.
4,4-Dialkyloxazol-5(4H)-ones, which can easily be hydrolyzed into
free α,α-dialkyl-α-amino acids, were obtained in high yields (up to
99%) within a few minutes (1–18 min). BEMP, a sterically hindered
strong base with low nucleophilicity facilitated the desired reaction,
while decreasing the rate of side reactions such as O-alkylation,
C(2)-alkylation and the breakage of oxazolone.
H
H2N
G
N
OH
OH
R1
O
R1
α-alkyl-α-amino acid
N-acyl-α-alkyl-α-amino acid
R1
R1
4
N
O
C(4)-substitution
4
N
G
G
2
2
O–
O
O
Key words: α,α-dialkyl-α-amino acid, oxazol-5(4H)-one, C(4)-
alkylation, BEMP, protecting group, chemoselectivity
4-alkyl-oxazol-5(4H)-one
pKa ≅ 9
4-alkyl-oxazol-5-olate
R1
O
R2
N
α,α-Dialkyl-α-amino acids (ααAAs), as either free amino
acids or components of bioactive peptides, have attracted
substantial interest in the field of medicinal and biological
chemistry owing to their pharmacological and conforma-
tional properties:1 (1) they show high stability because
most of the common metabolic pathways of amino acids,
such as transamination, oxidative deamination, and α,β-
elimination reactions, require the presence of an α-hydro-
gen atom;2 (2) they impart well-defined conformational
constraints to a peptide backbone because of severe re-
striction of the rotational freedom around their N–Cα and
Cα–C=O bonds.3 Furthermore, ααAAs are present in
many biologically active synthetic compounds or natural
products such as altemicidin.4 Accordingly, considerable
research has been focused on the development of new
methods for the synthesis of ααAAs, through which
several valid strategies have been established.5
ring-opening
H2N
R1 R2
OH
G
O
O
4,4-dialkyl-oxazol-5(4H)-one
α,α-dialkyl-α-amino acid
Scheme 1 Synthesis of α,α-dialkyl-α-amino acids via oxazol-5(4H)-
ones
Since the development of the Steglich rearrangement by
Steglich and Höfle in 1969,9a considerable effort has been
devoted to find efficient strategies for the synthesis of
ααAAs via C(4)-substitution of 4-alkyloxazol-5(4H)-ones
(Scheme 2).6–9 Significant progress was achieved by
Trost,10 who developed a palladium complex catalyzed
asymmetric allylic alkylation of 4-alkyloxazolone. Re-
cently, there has been a marked increase in research on the
conjugate addition of 4-alkyloxazolones to the electro-
philic π-bond of α,β-unsaturated aldehydes through
organocatalysis.11
One of the efficient synthetic strategies for ααAAs in-
volves substitution at the C(4)-position of oxazol-5(4H)-
ones (Scheme 1).6–12 The oxazolone moiety acts as an ex-
cellent protecting group because it can efficiently protect
both the amino and carboxylate groups of α-amino acids
under basic conditions and the protection–deprotection
sequence is very simple. Besides, this moiety enhances
the acidity of the α-proton by the formation of an aromatic
oxazole after deprotonation,8 which allows for the adapta-
tion of milder substitution conditions.
However, as compared with aforementioned approaches,
C(4)-substitution of 4-alkyloxazolones with an electro-
phile that has a leaving group attached to C(sp3) has not
been studied extensively. A few methods on C(4)-alkyla-
tion with alkyl halides are reported in the literature,12 but
most of them suffer from disadvantages such as the occur-
rence of side reactions or require harsh reaction condi-
tions. The Steglich group, who first reported the
alkylation of this type, performed reactions using Hünig’s
base (N,N-diisopropylethylamine) in hot DMF (80 °C) for
SYNLETT 2013, 24, 0701–0704
Advanced online publication: 08.03.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317801; Art ID: ST-2013-U0067-L
© Georg Thieme Verlag Stuttgart · New York

702
Y.-J. Lee et al.
LETTER
O
O
R1
R1
O
Steglich
rearrangement
N
O
N
O
Y
Y
G
G
G
G
O
R2
OR2
R1
transition-metal-
catalyzed
allylic alkylation
R1
R1
O
intermolecular
ene reaction
4
N
O
N
O
R3
N
CH3
G
R2
O
OR2
H2C
O
O
AcO
R3
R2
R1
substitution
at C(sp3)-X σ-bond
R1
conjugate addition
to electrophilic π-bond
R2
O
EWG
N
O
N
O
G
G
R2
X
EWG
R2
O
Scheme 2 Approaches for C(4)-quaternarization of 4-alkyloxazol-5(4H)-one
about 10 hours and obtained the desired alkylated prod- proach helped in suppressing major side reactions such as
ucts in moderate yields.12a
O-alkylation and dimerization13 (30–88% yields of the de-
sired product), although excess amount (up to 5.0 equiv)
of the alkylating agent had to be used. To develop a sim-
ple, atom-economical method of C(4)-alkylation of oxa-
zolones derived from tertiary amino acids, we tried to find
a base with the adequate level of basicity, nucleophilicity
and hardness/softness.
Table 1 C(4)-Benzylation of Alanine-Derived Oxazolone 1aa
PhCH2Br (1.5 equiv)
base (1.5 equiv)
N
O
N
O
Ph
Ph
Ph
solvent, r.t.
O
O
1a
2a
To find the optimal base conditions, we chose 4-methyl-
2-phenyloxazol-5(4H)-one (1a) as the substrate, which
was readily prepared in high yield from commercially
available N-benzoyl-DL-alanine by treatment with N,N′-
dicyclohexylcarbodiimide (DCC). Benzylation was used
as the model reaction for screening the reaction condi-
tions. THF was used as the reaction medium because it is
a slightly polar solvent which can dissolve a wide range of
chemicals and is known as one of the most commonly
used solvents for the C-alkylation of enolates. We then in-
vestigated the effect of base on the reaction with some
typical inorganic and organic bases (Table 1, entries 1–9).
Entry
Base
Solvent
Time
Yield (%)b
1
NaOAc
K2CO3
K3PO4
CsOH
KOt-Bu
NaH
THF
24 h
n.r.c
64
66
55
68
8
2
THF
1 h
3
THF
1 h
4
THF
1 min
1 min
1 min
1 min
1 min
1 min
1 min
1 min
5
THF
6
THF
7
Et3N
THF
73
71
85
51
73
67
Sodium acetate, the weakest base among the used, could
not make the reaction proceed at all (entry 1). In the cases
of carbonate and phosphate, the desired product 2a was
obtained in around 65% yield, but the reaction was not
completed even after five hours in both cases (entries 2
and 3). In many of the cases examined, the starting mate-
rial 1a was consumed within a minute under the given re-
action conditions, as monitored by TLC (entries 4–9). The
difference in the isolated yields was dependent upon the
level of side reactions such as oxazolone ring-opening be-
fore/after C(4)-benzylation, O-benzylation, C(2)-ben-
zylation, and so forth. It is noteworthy that BEMP (Figure
1), a phosphazene base that is strong, organic-soluble, and
non-ionic, was highly suitable for the C(4)-alkylation of
oxazolones (entry 9). BEMP abstracts the α-proton of the
substrate to give an enolate (4-oxazol-5-olate) and a bulky
soft cation on which a positive charge is delocalized,14a
which might decrease the rate of O-alkylation. The break-
age of oxazolone ring might also be decreased in favor of
8
i-Pr2NEt
BEMPd
BEMP
BEMP
BEMP
THF
9
THF
10
11
12
CH2Cl2
toluene
THF–DMF 1 min
a Base (1.5 equiv) was added to a solution of 1a (1.0 equiv), benzyl
bromide (1.5 equiv) in anhyd solvent (1 mL per 1 mmol of 1a) at r.t.
b Isolated yield.
c No reaction was observed.
Improvements in both the yield and the scope of alkylat-
ing agents were achieved by the Obrecht group.12c The
key feature of Obrecht’s method was the inverse addition
of NaH dispersion to a solution of 4-alkyloxazol-5(4H)-
one and the electrophile in cold DMF (10 °C). This ap-
Synlett 2013, 24, 701–704
© Georg Thieme Verlag Stuttgart · New York

LETTER
Rapid and Efficient Route to α,α-Dialkyl-α-amino Acids
703
low nucleophilicity of BEMP,14b while strong basicity re-
sulted in very rapid reaction process. Examination of sev-
eral solvents indicated that the reaction efficiency was the
highest with THF (entries 9–12).15
Table 2 C(4)-Alkylation of Oxazolones Derived from Alanine,
Phenylalanine, Valine, and Leucinea (continued)
R1
R2X (1.5 equiv)
R1
O
R2
O
N
O
1
N
O
BEMP (1.5 equiv)
Ph
Ph
anhyd THF, r.t.
Me
N
2
P
N
N
Entry R1
R2X
Time
Yield (%)b
N
Me
19
20
21
22
23
24
i-Bu (1d) MeI
1 min
1 min
1 min
1 min
1 min
1 min
90
95
99
91
94
90
BEMP
EtI
Figure 1 Structure of 2-tert-butylimino-2-diethylamino-1,3-di-
methylperhydro-1,3,2-diazaphosphorine (BEMP)
CH2=CHCH2Br
BnBr
Reactions of oxazolones 1a–d, derived from alanine, phe-
nylalanine, valine, and leucine, respectively, with various
alkyl halides were examined.16 As shown in Table 2, most
reactions were completed within a few minutes, resulting
in high yields of the desired products (up to 99%), which
suggested that this reaction system is highly effective for
the synthesis of various ααAAs.
4-CF3C6H4CH2Br
4-MeOC6H4CH2Br
a BEMP (1.5 equiv) was added to a solution of 1 (1.0 equiv), benzyl
bromide (1.5 equiv) in anhyd THF (1 mL per 1 mmol of 1) at r.t.
b Isolated yield.
In summary, a rapid and highly productive C(4)-alkyla-
tion of oxazolones was developed. Problematic side reac-
tions were significantly decreased, while the desired
alkylation proceeded very rapidly when using BEMP as a
base. We believe that this reaction might serve as an effi-
cient method for the synthesis of ααAAs which are rele-
vant in biological and medicinal aspects.
Table 2 C(4)-Alkylation of Oxazolones Derived from Alanine,
Phenylalanine, Valine, and Leucinea
R1
R2X (1.5 equiv)
R1
O
R2
O
N
O
1
N
O
BEMP (1.5 equiv)
Ph
Ph
anhyd THF, r.t.
2
Entry R1
R2X
Time
Yield (%)b
Acknowledgment
This work was supported by the Yeungnam University Research
Grants in 2010 (Grant No. 210-A-380-171).
1
Me (1a)
Bn (1b)
i-Pr (1c)
MeI
5 min
10 min
1 min
1 min
1 min
1 min
5 min
13 min
1 min
1 min
1 min
1 min
5 min
18 min
1 min
1 min
1 min
1 min
85
84
74
85
71
74
90
88
99
99
98
98
94
80
90
84
93
95
2
EtI
3
CH2=CHCH2Br
BnBr
References and Notes
4
(1) (a) Di Blasip, B.; Pavone, V.; Lombardi, A.; Pedone, C.;
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1980, 77, 82. (b) Khosla, M. C.; Stachowiak, K.; Smeby, R.
R.; Bumpus, F. M.; Pirious, F.; Lintner, K.; Fermandjian, S.
Proc. Natl. Acad. Sci. U.S.A. 1981, 78, 757; and references
cited therein.
(3) (a) Karle, I. L.; Rao, R. B.; Pasad, S.; Kaul, R.; Balaram, P.
J. Am. Chem. Soc. 1994, 116, 10355. (b) Kaul, R.; Balaram,
P. Bioorg. Med. Chem. 1999, 7, 105. (c) Toniolo, C.;
Crisma, M.; Formaggio, F.; Peggion, C. Biopolymers 2001,
60, 396. (d) Venkatraman, J.; Shankaramma, S. C.; Balaram,
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Tetrahedron 1991, 47, 3621. (b) Benedetti, E.; Gavuzzo, E.;
Santini, A.; Kent, D. R.; Zhu, Y. F.; Zhu, Q.; Mahr, C.;
Goodman, M. J. Pept. Sci. 1995, 1, 349. (c) Bryant, S. D.;
Guerrini, R.; Salvadori, S.; Bianchi, C.; Tomatis, R.; Attila,
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Med. Chem. 1997, 40, 647.
5
4-CF3C6H4CH2Br
4-MeOC6H4CH2Br
MeI
6
7
8
EtI
9
CH2=CHCH2Br
BnBr
10
11
12
13
14
15
16
17
18
4-CF3C6H4CH2Br
4-MeOC6H4CH2Br
MeI
EtI
CH2=CHCH2Br
BnBr
4-CF3C6H4CH2Br
4-MeOC6H4CH2Br
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 701–704

704
Y.-J. Lee et al.
LETTER
(5) For recent reviews on the synthesis of ααAAs, see: (a) Vogt,
H.; Bräse, S. Org. Biomol. Chem. 2007, 5, 406. (b) Ohfune,
Y.; Shinada, T. Eur. J. Org. Chem. 2005, 5127. (c) Cativiela,
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11, 645. (d) Cativiela, C.; Diaz-de-Villegas, M. D.
Tetrahedron: Asymmetry 1998, 9, 3517.
(6) For a recent review on the diverse chemistry of oxazol-
5(4H)-ones, see: Fisk, J. S.; Mosey, R. A.; Tepe, J. J. Chem.
Soc. Rev. 2007, 36, 1432.
(7) For recent reviews on the use of oxazol-5(4H)-ones in amino
acid syntheses, see: (a) Alba, A.-N. R.; Rios, R. Chem.
Asian J. 2011, 6, 720. (b) Mosey, R. A.; Fisk, J. S.; Tepe, J.
J. Tetrahedron: Asymmetry 2008, 19, 2755.
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120, 11532. (d) Shaw, S. A.; Aleman, P.; Vedejs, E. J. Am.
Chem. Soc. 2003, 125, 13368. (e) Nguyen, H. V.; Butler, D.
C.; Richards, C. J. Org. Lett. 2006, 8, 769. (f) Dietz, F. R.;
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Chem. Soc. 2012, 134, 5778.
(16) Analytical data for the new compounds:
4-Methyl-2-phenyl-4-[4-(trifluoromethyl)benzyl]oxazol-
5(4H)-one (Table 2, Entry 5): 1H NMR (300 MHz, CDCl3):
δ = 7.84 (d, J = 7.1 Hz, 2 H), 7.39–7.55 (m, 5 H), 7.27–7.30
(m, 2 H), 3.20 (dd, J = 18.0, 13.6 Hz, 2 H), 1.60 (s, 3 H). 13
NMR (100 MHz, CDCl3): δ = 179.8, 160.0, 138.7, 132.8,
130.5, 129.6, 129.4, 128.8, 128.4, 127.8, 125.5, 125.1,
C
125.0, 123.0, 70.4, 43.8, 23.7. IR (KBr): 2930, 1818, 1655,
1452, 1325, 1166, 1124, 1068, 1066, 944, 893, 778, 696 cm–
1. MS (FAB+): m/z = 334 [M + H]+.
4-Benzyl-2-phenyl-4-[4-(trifluoromethyl)benzyl]oxazol-
5(4H)-one (Table 2, Entry 11): 1H NMR (300 MHz, CDCl3):
δ = 7.67 (d, J = 7.8 Hz, 2 H), 7.29–7.50 (m, 7 H), 7.14–7.18
(m, 5 H), 3.33 (dd, J = 13.6, 4.0 Hz, 4 H). 13C NMR (100
MHz, CDCl3): δ = 178.4, 160.1, 138.5, 133.9, 132.6, 130.5,
130.1, 129.6, 129.3, 128.6, 128.2, 127.6, 127.3, 125.3, 125.1
(3 ×), 125.0, 75.4, 43.6, 42.9. IR (KBr): 2925, 1816, 1654,
1496, 1453, 1325, 1166, 1120, 1066, 981, 892, 698 cm–1. MS
(FAB+): m/z = 410 [M + H]+.
4-Ethyl-4-isopropyl-2-phenyloxazol-5(4H)-one (Table 2,
Entry 14): 1H NMR (300 MHz, CDCl3): δ = 8.00 (d, J = 7.0
Hz, 2 H), 7.44–7.58 (m, 3 H), 2.09–2.19 (m, 1 H), 1.53 (q, J
= 2.1 Hz, 2 H), 0.91–1.02 (m, 6 H), 0.80 (t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 180.5, 160.0, 132.5, 128.7,
127.9, 125.9, 55.7, 34.6, 25.4, 16.8, 8.2. IR (KBr): 2970,
2932, 2119, 1819, 1655, 1453, 1292, 1181, 1019, 919, 878,
780, 694 cm–1. MS (FAB+): m/z = 232 [M + H]+.
4-Isopropyl-2-phenyl-4-[4-(trifluoromethyl)-
(11) (a) Cabrera, S.; Reyes, E.; Alemán, J.; Milelli, A.;
Kobbelgaard, S.; Jørgensen, K. A. J. Am. Chem. Soc. 2008,
130, 12031. (b) Alemán, J.; Milelli, A.; Cabrera, S.; Reyes,
E.; Jørgensen, K. A. Chem. Eur. J. 2008, 14, 10958.
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(d) Hayashi, Y.; Obi, K.; Ohta, Y.; Okamura, D.; Ishikawa,
H. Chem. Asian J. 2009, 4, 246. (e) Alba, A.-N. R.;
Companyó, X.; Valero, G.; Moyano, A.; Rios, R. Chem. Eur.
J. 2010, 16, 5354.
(12) (a) Kübel, B.; Gruber, W.; Rudolf, H.; Steglich, W. Chem.
Ber. 1979, 112, 128. (b) Gelmi, M. L.; Pocar, D.; Rossi, L.
M. Synthesis 1984, 763. (c) Obrecht, D.; Bohdal, U.;
Ruffieux, R.; Müller, K. Helv. Chim. Acta 1994, 77, 1423.
(d) Hugener, M.; Heimegartner, H. Helv. Chim. Acta 1995,
78, 84. (e) Uraguchi, D.; Asai, Y.; Ooi, T. Synlett 2009, 658.
(f) Tarí, S.; Avila, A.; Chinchilla, R.; Nájera, C.
benzyl]oxazol-5(4H)-one (Table 2, Entry 17): 1H NMR (300
MHz, CDCl3): δ = 7.77 (d, J = 7.1 Hz, 2 H), 7.49–7.19 (m,
7 H), 3.21–3.15 (m, 2 H), 2.28–2.19 (m, 1 H), 1.05–1.00 (m,
6 H). 13C NMR (100 MHz, CDCl3): δ = 179.2, 160.1, 139.0,
132.6, 130.5, 129.1, 128.8, 128.6, 127.7, 125.4, 125.0, 124.9
(3 × ), 60.3, 40.8, 65.3, 17.3. IR (KBr): 2968, 1815, 1655,
1454, 1325, 1292, 1166, 1127, 1067, 1020, 970, 881, 843,
777, 695 cm–1. MS (FAB+): m/z = 362 [M+H]+.
4-Isobutyl-4-methyl-2-phenyloxazol-5(4H)-one (Table 2,
Entry 19): 1H NMR (300 MHz, CDCl3): δ = 7.98 (d, J = 6.9
Hz, 2 H), 7.37–7.58 (m, 3 H), 1.75–1.94 (m, 2 H), 1.52–1.69
(m, 1 H), 1.47 (s, 3 H), 0.85 (dd, J = 12.8, 6.6 Hz, 6 H). 13
NMR (100 MHz, CDCl3): δ = 181.5, 159.4, 132.5, 128.7,
C
127.8, 126.0, 69.1, 34.9, 25.3, 24.0, 22.9. IR (KBr): 2931,
2119, 1822, 1654, 1452, 1294, 1181, 1116, 1072, 1004, 882,
779, 698 cm–1. MS (FAB+): m/z = 232 [M + H]+.
4-Ethyl-4-isobutyl-2-phenyloxazol-5(4H)-one (Table 2,
Entry 20): 1H NMR (300 MHz, CDCl3): δ = 8.00 (d, J = 8.2
Hz, 2 H), 7.44–7.59 (m, 3 H), 1.75–1.96 (m, 4 H), 1.55–1.67
(m, 1 H), 0.77–0.94 (m, 9 H). 13C NMR (100 MHz, CDCl3):
δ = 181.0, 159.6, 132.5, 128.7, 127.8, 125.3, 73.6, 46.0, 31.9,
24.9, 24.1, 23.0, 7.8. IR (KBr): 2961, 2119, 1820, 1656,
1454, 1320, 1291, 1174, 1019, 934, 881, 779, 698 cm–1. MS
(FAB+): m/z = 246 [M + H]+.
4-Isobutyl-2-phenyl-4-[4-(trifluoromethyl)benzyl]oxazol-
5(4H)-one (Table 2, Entry 23). 1H NMR (300 MHz, CDCl3):
δ = 8.32 (d, J = 6.9 Hz, 2 H), 7.72–8.05 (m, 7 H), 3.65–3.70
(m, 2 H), 2.39–2.57 (m, 2 H), 2.09–2.20 (m, 1 H), 1.37 (dd,
J = 13.7, 6.8 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ =
179.9, 159.8, 138.2, 132.7, 130.6, 129.6, 129.3, 128.7,
127.7, 125.4, 125.0 (2 ×), 124.9 (2 ×), 74.0, 46.2, 44.4, 25.0,
24.0, 23.0. IR (KBr): 2961, 1816, 1655, 1452, 1325, 1293,
1167, 1127, 1068, 1021, 976, 883, 778, 698 cm–1. MS
(FAB+): m/z = 376 [M + H]+.
Tetrahedron: Asymmetry 2012, 23, 176.
(13) Bullerwell, R. A. F.; Lawson, A. J. Chem. Soc. 1952, 1350.
(14) (a) Mamdani, H. T.; Hartley, R. C. Tetrahedron Lett. 2000,
41, 747. (b) Kondo, Y. In Superbases for Organic Synthesis;
Ishikawa, T., Ed.; John Wiley & Sons: West Sussex, 2009,
145.
(15) Typical Procedure for the BEMP-Promoted C(4)-
Alkylation of 4-Alkyloxazol-5(4H)-one (Table 1 Entry 9):
An oven-dried round-bottom flask with magnetic stir bar
was charged with 1a (88 mg, 0.50 mmol) and anhyd THF
(0.5 mL). Benzyl bromide (89 μL, 0.75 mmol) was added in
one portion followed by the dropwise addition (1 min) of
BEMP (217 μL, 0.75 mmol) at r.t. The resulting mixture was
directly loaded onto the silica gel column and purified by
flash chromatography (5% EtOAc–n-hexane) to afford 2a
(170 mg, 0.64 mmol, 85% yield) as a colorless oil.
Synlett 2013, 24, 701–704
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