Synthesis of γ,δ-unsaturated quaternary α-alkylamino acids using umpolung reaction and Claisen rearrangement

Article abstract of DOI:10.1016/j.tetlet.2012.01.133

A new synthesis of γ,δ-unsaturated quaternary α-amino acid derivatives was developed utilizing N-alkylation and Claisen rearrangement of allyl α-iminocarboxylates.

Full text of DOI:10.1016/j.tetlet.2012.01.133

Tetrahedron Letters 53 (2012) 1847–1850
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Synthesis of c,d-unsaturated quaternary a-alkylamino acids using
umpolung reaction and Claisen rearrangement
⇑
Isao Mizota, Katsuki Tanaka, Makoto Shimizu
Department of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu, Mie 514-8507, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new synthesis of
N-alkylation and Claisen rearrangement of allyl
c
,d-unsaturated quaternary
-iminocarboxylates.
Ó 2012 Elsevier Ltd. All rights reserved.
a-amino acid derivatives was developed utilizing
Received 13 January 2012
Revised 25 January 2012
Accepted 31 January 2012
Available online 8 February 2012
a
Keywords:
c
,d-Unsaturated quaternary a-alkylamino
acids
Umpolung reaction
N-Alkylation reaction
Aluminum enolate
Claisen rearrangement
a-Amino acids containing quaternary carbons
a
to the carbonyl
lates.14,15 Although three component coupling of
a-imino esters
constitute an interesting class of nonproteinogenic acids and are
used to construct novel peptidic sequences with enhanced proper-
ties in various physiologically active peptides and proteins which
have become a major concern in the area of bioorganic chemistry.1
was reported using umpolung addition of organometals, there still
appears to remain an important issue regarding enhancement of
the reactivity of the intermediary enolates.13b Herein, we report a
one-pot tandem synthesis of
c,d-unsaturated amino ester using
Quaternary
and their synthesis has been achieved using several methods so
far.3 In general,
,d-unsaturated -amino acids are not always pop-
ular but can be important intermediates for complex peptides.4
The first synthesis of -allyl- -amino acids by the Claisen rear-
a
-amino acids are also powerful enzyme inhibitors,2
N-alkylation followed by a monoanion mediated enolate Claisen
rearrangement.
c
a
As an initial reaction, allyl 2-(4-methoxyphenylimino)-2-phen-
ylacetate 1a was first reacted with diethylaluminum chloride and
ethylaluminum dichloride in EtCN followed by treatment with
CH2N2 in diethyl ether at 0 °C for 10 min (Scheme 1). The reaction
proceeded as expected to give the desired rearranged product 2a in
a 56% yield.
a
a
rangement was described by Steglich who utilized an oxazole
intermediate in 1975.5,6 In 1982 the Ireland-Claisen rearrangement
of glycine allylic ester was reported by Bartlett.7 Kazmaier reported
diastereoselective synthesis of
c
,d-unsaturated amino acids using
In order to find optimum reaction conditions, we next screened
solvents, temperatures, reaction times, and additives, and the re-
sults are summarized in Table 1. As shown in Table 1, dichloro-
methane, 1,4-dioxane, and THF were not suitable for the reaction
(entries 2–4). Using diethyl ether as the solvent, the yield of 2a
was improved slightly (entry 5). When dimethoxyethane (DME)
the ester enolate Claisen rearrangement.8–10 Most of their methods
use dianion enolates mediated Claisen rearrangement, while there
are only a few examples in which monoanion species are involve-
d.11a Since application of new synthetic methods has developed the
chemistry of amino acids and related fields,11 the search for more
efficient tools is still a worthwhile goal.
An umpolung of a-imino ester is difficult to take place due to the
electronegativity of the imino functionality,12 and therefore, only
limited examples are available.13 We have studied umpolung
1. Et2AlCl (1.0 equiv.)
EtAlCl2 (1.0 equiv.)
PMP
O
Et
PMP
O
EtCN, rt, 7 h
H2O
Et
N
N
N
2.
Ph
PMP
reactions of
a-imino esters and have already reported N-alkyl-
Ph
Ph
3. CH2N2
Et2O, 0 oC, 10 min
CO2Me
ation-coupling reactions of the imines derived from glyoxy-
O
O
1a
2a 56%
3a 7%
⇑
Corresponding author. Tel./fax: +81 59 231 9413.
E-mail address: mshimizu@chem.mie-u.ac.jp (M. Shimizu).
Scheme 1. Initial examination of the umpolung reaction followed by Claisen
rearrangement.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.133

1848
I. Mizota et al. / Tetrahedron Letters 53 (2012) 1847–1850
Table 1
Table 2
Examination of the optimum conditions
Examination of the substituent
1. Et2AlCl (1.0 equiv.)
EtAlCl2 (1.0 equiv.)
1. Et2AlCl (1.0 equiv.)
EtAlCl2 (1.0 equiv.)
DME, 40 oC, 6-24 h
PMP
O
Et
PMP
O
solvent, temp.
H2O
Et
N
N
N
PMP
O
Et
N
2.
N
Ph
PMP
H2O
2.
3. CH2N2
Et2O, 0 oC, 10 min
R
PMP
Ph
Ph
3. CH2N2
Et2O, 0 oC, 10 min
CO2Me
R
O
O
CO2Me
O
2
1a
2a
3a
1
Entry Solvent
Temp. Time (h) Yield of 2a (%) Yield of 3a (%)
Entry
R
Yield (%)
1
2a
3
4
5
6
7
8
EtCN
CH2Cl2
1,4-Dioxane rt
THF
rt
rt
7
6
6
6
6
6
44
44
6
6
6
6
6
6
6
6
56
15
3
7
0
18
41
9
6
9
8
12
5
0
6
62
26
4
1
Ph
60
76
65
58
79
0
30
40
0
2a,b
3a
4c
5
3-F-C6H4
4-F-C6H4
4-Cl-C6H4
3-MeO-C6H4
4-MeO-C6H4
2-Thienyl
c-Hex
rt
rt
rt
rt
rt
rt
40 °C
40 °C
50 °C
50 °C
50 °C
60 °C
82 °C
4
Et2O
DME
DME
EtCN
DME
DME
DME
DME
DME
EtCN
DME
DME
37
52
23
42
49
60
57
58
0
6a,d
7e,f
8a
9
9b
10
11c
12
13d
14
15e
16f
t-Bu
a
b
c
d
e
f
Et2AlCl (2.0 equiv) was used.
N-Ethyl-4-methoxybenzenamine was obtained in a 23% yield.
At room temperature.
N-Ethyl-4-methoxybenzenamine was obtained in a 95% yield.
At 0 °C.
3
31
0
N-Ethyl-4-methoxybenzenamine was obtained in a 70% yield.
0
a
B
c
d
e
f
N-Ethyl-4-methoxybenzenamine was obtained in a 20% yield.
Compound 1a was added to the aluminum reagents.
Et2AlCl (2.0 equiv) was used.
In the presence of MS 4 Å.
N-Ethyl-4-methoxybenzenamine was obtained in a 30% yield.
N-Ethyl-4-methoxybenzenamine was obtained in a 34% yield.
diastereoselectivity of the product was observed (entry 1), while
that of crotyl ester gave no rearrangement product, and only
N-ethylated product was obtained in a low yield (entries 1,2 vs
3). The rearranged product was not obtained using
namyl ester, either.
a-imino cin-
Moreover, examination into other alkylating reagent revealed
that the reaction was sensitive to the bulk of the reagent (Scheme 2).
A proposed reaction mechanism is shown in Scheme 3. First,
ethylaluminum dichloride that is a stronger Lewis acid than dieth-
ylaluminum chloride coordinates with the carbonyl oxygen atom
followed by N-ethylation of diethylaluminum chloride to give an
intermediary aluminum enolate,16 Then Claisen rearrangement
takes place to give the amino acid derivative which is methylated
with diazomethane. Selectivity of the product geometry may be
explained in terms of two possible enolates. The (Z)-enolate leads
to the conformation 6a possessing the R1 group in an equatorial
arrangement to afford the (E)- alkene, while the (E)-counterpart
takes the conformation 7b, with an axial R1 substituent, which
seems to be unfavorable in the six-membered chair-like transition
state. However, the conformer with an oxygen coordinated to the
bulky organoaluminum reagent would be favored over 7b in view
of the 1,2-steric interaction between R1 and the coordinated alumi-
num moiety in 7a, leading to the preferential formation of (Z)-al-
kene.5 Regarding the substrate having a terminal methyl group,
was used, the yield was as good as in the case of EtCN (entry 6).
Extending the reaction time decreased the product yields (entries
7 and 8). Changing the order of the addition in which the imino es-
ter 1a was added to the aluminum reagents solution did not
noticeably improve the yield (entry 9). The reaction temperature
was next examined (entries 10–16). The reactions in DME at 40
or 50 °C gave the product in good yields (entries 10 and 12), while
more elevated temperatures such as 60 and 82 °C decreased the
product yields and gave N-ethyl-4-methoxybenzenamine formed
by hydrolysis of the iminium salt which was derived from oxida-
tion of the aluminum enolate (entries 15 and 16).14c Interestingly,
the presence of molecular sieves 4 Å as an additive prevented the
Claisen rearrangement to afford the initial N-ethylated product
3a solely in a good yield (entry 13). On the other hand, raising
the reaction temperature in EtCN did not afford the desired prod-
uct 2a at all (entry 14). The optimized reaction conditions were
thus found to be conducive to DME as solvent at 40 °C for 6 h.
The scope of substrates was next examined, and the results are
summarized in Table 2. Aromatic groups having either electron-
donating or electron-withdrawing meta- or para-substituents
underwent the desired reaction to give the products (entries 1-5)
except for the p-methoxyphenyl derivative (entry 6). In the case
of 4-methoxyphenyl derivative, hydrolyzed N-ethyl-4-methoxy-
benzenamine is the major by-product, which indicates that the
electron-donating para-methoxy group may decrease the reactiv-
ity of the intermediary iminium salt, whereas such an effect is
not prominent for meta-methoxy derivative due to the less effec-
tive electron-donating ability for the meta-position as compared
with the para-counterpart. The use of thienyl derivative afforded
the rearrangement product in a low yield (entry 7), while the sub-
strate substituted by a cyclohexyl group derivative gave the prod-
uct in a moderate yield (entry 8). However, the bulky tert-butyl
derivative gave no adduct (entry 9).
Table 3
Examination of allyl moiety
1. Et2AlCl (1.0 equiv.)
EtAlCl2 (1.0 equiv.)
DME, temp.
2. H2O
PMP
O
Et
N
N
R2
R2
Ph
PMP
R3
R1
Ph
3. CH2N2
Et2O, 0 oC, 10 min
CO2Me
O
R1
R3
1
2
Entry
R1
R2
R3
Temp. (Co)
Time (h)
Yield of 2 (%)
1a
2
3
Me
H
H
H
Me
H
H
H
Me
40
0
50
12
24
6
62b,c
73
—
d
a
b
c
Et2AlCl (2.0 equiv) was used.
E/Z = 59:41.
N-Ethylated product was obtained in a 9% yield.
N-Ethylated product was obtained in a 26% yield.
The allyl moiety was next examined, and the results are sum-
marized in Table 3. The reactions of methallyl and 2-butenyl esters
proceeded to give the desired products in good yields in which no
d

I. Mizota et al. / Tetrahedron Letters 53 (2012) 1847–1850
1849
1. Et2AlCl (2.0 equiv.)
EtAlCl2 (1.0 equiv.)
DME, 40 oC, 6.5 h
2. H2O
iBu2AlCl (2.0 equiv.)
DME, 70 oC, 6 h
1.
iBu
PMP
O
PMP
OMe
iBu
N
N
PMP
Et
N
2. H2O
O
N
Ph
PMP
O
D
3. CH2N2
N
PMP
3
O
O
5
Ph
D
3. CH2N2
CO2Me
Et2O, 0 oC, 10 min
Et2O, 0 oC, 10 min
CO2Me
D
D
O
D
OMe
OMe
1a-d2
2a-d2 51%
1e
4 14%
5 20%
D
D
:
= 86 : 14
:
= 82 : 18
D
D
D
H
Scheme 2. Reaction using diisobutyl aluminum chloride.
H
Scheme 4. Isotopic labeling experiment.
although it is possible that the intramolecular rearrangement also
occurs with this kind of disubstituted olefin, the rearranged prod-
uct is not obtained (Table 3, entry 3). This result suggests that an
intermolecular C–C bond formation might not be excluded.17
In order to clarify the reaction mechanism in more detail, a deu-
PMP
O
Et
N
N
Ph
PMP
D
Ph
D
CO2Me
D
D
O
D
1a-d2
2a-d2 66%
1. Et2AlCl (4.0 equiv.)
EtAlCl2 (2.0 equiv.)
terium labeling experiment was carried out (Scheme 4). The a-imi-
D
:
D
:
= 85 : 15
no ester 1a-d2 was prepared according to the reported method.18
The rearrangement gave only the product 2a-d2 (86% D incorpora-
tion at C3), and there was no deuterium scrambling at other posi-
tions. This result indicates that the present reaction most probably
= 82 : 18
DME, 40 oC, 6.5 h
H2O
D
D
D
H
H
2.
3. CH2N2
Et2O, 0 oC, 10 min
OMe
PMP
O
N
Et
N
proceeds via
product.
a [3,3]-sigmatropic rearrangement to give the
PMP
O
CO2Me
2e 60%
Moreover, a crossover experiment was carried out with two dif-
ferent imino esters 1a-d2 and 1e (Scheme 5). The intramolecular
reaction products 2a-d2 (85% D incorporation at C3) and 2e were
obtained in 66% and 60% yields, respectively, while an intermolec-
ular reaction product was not obtained at all. This result also sup-
ports the proposed [3,3]-sigmatropic rearrangement.
OMe
1e
Scheme 5. A crossover experiment.
In conclusion, we have found a new one-pot synthesis of
-amino acid derivatives having an a-quaternary carbon utilizing
a
Et
Cl Al Et
PMP
PMP
O
Et2AlCl
EtAlCl2
R2
N
R2
N
O
Ar
Ar
R1
O
R1
O
Cl Al
Et
Cl
Ph
R2
O
Et
PMP
N
R1
O
Al
Et
PMP
Cl
Et
N
Et
N
6a
OAlEtCl
R2
R2
Ph
Ph
PMP
R1
O
CO2H
R1
Ph
R2
(
Z
)-enolate
E
( )-product
Et
PMP
O
N
O
R1
Al
Et
Cl
6b
PMP
Et
R2
R1
O
N
Cl
Al Et
Ph
O
7a
Et
N
1
Et
PMP
O
R
R2
Ph
N
PMP
Ph
CO2H
R1
R2
R1
OAlEtCl
O
Cl
Al Et
Ph
Et
O
R2
(
E
)-enolate
Z
( )-product
N
PMP
7b
Scheme 3. Proposed reaction mechanism.

1850
I. Mizota et al. / Tetrahedron Letters 53 (2012) 1847–1850
13. For N-alkylation to
a-imino esters: (a) Dickstein, J. S.; Kozlowski, M. C. Chem.
a monoanion enolate Claisen rearrangement of the aluminum eno-
late prepared by umpolung reaction in moderate to good yields.
This reaction provides a useful addition to existing methods for
the synthesis of biologically active nitrogen-containing compounds
having a quaternary carbon.
Soc. Rev. 2008, 37, 1166–1173; (b) Dickstein, J. S.; Fennie, M. W.; Norman, A. L.;
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K.; Yan, F.; Hirama, S.; Katagiri, T. Tetrahedron Lett. 1996, 37, 2045–2048; (h)
Yamamoto, Y.; Ito, W. Tetrahedron 1988, 44, 5415–5423; (i) Fiaud, J.-C.; Kagan,
H. B. Tetrahedron Lett. 1971, 12, 1019–1022.
Acknowledgments
14. (a) Shimizu, M.; Hachiya, I.; Mizota, I. Chem. Commun. 2009, 7, 874–889; (b)
Shimizu, M. Pure Appl. Chem. 2006, 78, 1867–1876; (c) Shimizu, M.; Itou, H.;
Miura, M. J. Am. Chem. Soc. 2005, 127, 3296–3297; (d) Niwa, Y.; Shimizu, M. J.
Am. Chem. Soc. 2003, 125, 3720–3721; (e) Niwa, Y.; Takayama, K.; Shimizu, M.
Bull. Chem. Soc. Jpn. 2002, 75, 1819–1825; (f) Niwa, Y.; Takayama, K.; Shimizu,
M. Tetrahedron Lett. 2001, 42, 5473–5476; (g) Shimizu, M.; Niwa, Y. Tetrahedron
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This work was supported by Grants-in-Aid for Scientific
Research (B) and on Innovative Areas ‘‘Organic Synthesis Based
on Reaction Integration. Development of New Methods and
Creation of New Substances’’ from JSPS and MEXT.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.01.133.
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O
Et2AlCl (1.0 equiv.)
Et
PMP
Ph
PMP
EtAlCl2 (1.0 equiv.),
(5.0 equiv.)
H
N
Ph
N
EtCN, -78 o C to rt, 30 h
EtO2C
Ph
CO2Et
Ph
OH
O
Et
PMP
PMP
N
N
Et2AlCl (5.0 equiv.),
p
-ClC6H4
H (1.5 equiv.)
p-ClC6H4
DMI, 10-20 oC, 6 h
EtO2C
EtO2C
OH
61%
syn = 72 :28
anti
:
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Chem. Eur. J. 2003, 9, 6145–6154; (d) Cordova, A.; Notz, W.; Zhong, G.;
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