Regioselective tandem N-alkylation/ C-acylation of β,γ-alkynyl α-imino esters

Article abstract of DOI:10.1021/ol401934x

A new synthesis of α-quaternary alkynyl amino esters and allenoates was developed utilizing umpolung N-addition to β,γ-alkynyl α-imino esters followed by regioselective acylation. The reaction exhibits broad substrate generality and unique regioselectivity. Moreover, synthesis of α-quaternary alkynyl amino esters was also carried out via oxidation of the intermediary enolate followed by alkylation.

Full text of DOI:10.1021/ol401934x

ORGANIC
LETTERS
2013
Vol. 15, No. 16
4206–4209
Regioselective Tandem N‑Alkylation/
C‑Acylation of β,γ-Alkynyl R‑Imino Esters
Isao Mizota, Yuri Matsuda, Satoshi Kamimura, Hirotaka Tanaka, and Makoto Shimizu*
Department of Chemistry for Materials, Graduate School of Engineering,
Mie University, Tsu, Mie 514-8507, Japan
imizota@chem.mie-u.ac.jp; mshimizu@chem.mie-u.ac.jp
Received July 9, 2013
ABSTRACT
A new synthesis of R-quaternary alkynyl amino esters and allenoates was developed utilizing umpolung N-addition to β,γ-alkynyl R-imino esters
followed by regioselective acylation. The reaction exhibits broad substrate generality and unique regioselectivity. Moreover, synthesis of
R-quaternary alkynyl amino esters was also carried out via oxidation of the intermediary enolate followed by alkylation.
Quaternary R-amino acids are an interesting class
of nonproteinogenic acids and also powerful enzyme
inhibitors. Their synthesis is very important, and several
methods have been developed.1 In particular, β,γ-alkynyl
R-amino acids represent important optically active non-
proteinogenicR-amino acids. It isknown that introduction
of R-ethynyl substituents to certain natural amino acids
can convert their biological properties from enzyme sub-
strates to enzyme-activated irreversible inhibitors with
potential therapeutic utility.2c However, the synthesis of
β,γ-alkynyl R-amino acid derivatives is a challenging topic,
and to our knowledge only limited examples are available.2
Yet, although allenoates are also useful precursors to
important biologically active compounds,3 only a few
general synthetic methods exist.4
An umpolung of an R-imino ester is difficult due to the
electronegativity of the imino group.5 Our laboratory has
developed umpolung reactions of R-imino esters,6 and we
have recently reported a new type of CÀC bond formation
using the N-alkylation followed by the Claisen rearrange-
ment to give γ,δ-unsaturated amino esters.6e However, it is
still of interest for us to construct CÀC bonds via alkyla-
tion of the enolate formed in situ by N-alkylation. Herein,
we report a one-pot tandem synthesis of R-quaternary
(4) (a) Xu, J.; Wu, L.; Huang, X. J. Org. Chem. 2011, 76, 5598. (b)
Malhotra, D.; Liu, L.-P.; Hammond, G. B. Eur. J. Org. Chem. 2010, 6855.
(c) Hashimoto, T.; Sakata, K.; Maruoka, K. Angew. Chem., Int. Ed. 2009,
48, 5014. (d) Yang, H.; Xu, B.; Hammond, G. B. Org. Lett. 2008, 10, 5589.
(e) Miesch, L.; Rietsch, V.; Welsch, T.; Miesch, M. Tetrahedron Lett. 2008,
49, 5053. (f) Liu, L.-P.; Xu, B.; Hammond, G. B. Org. Lett. 2008, 10, 3887.
(g) Wang, W.; Xu, B.; Hammond, G. B. Org. Lett. 2008, 10, 3713. (h) Xu,
B.; Hammond, G. B. Angew. Chem., Int. Ed. 2008, 47, 689. (i) Lepore, S. D.;
He, Y. J. Org. Chem. 2005, 70, 4546. (j) Lepore, S. D.; He, Y.; Damisse, P.
J. Org. Chem. 2004, 69, 9171. (k) Denichoux, A.; Ferreira, F.; Chemla, F.
Org. Lett. 2004, 6, 3509. (l) Tsuboi, S.; Kuroda, H.; Takatsuka, S.; Fukawa,
T.; Sakai, T.; Utaka, M. J. Org. Chem. 1993, 58, 5952. (m) Tokuda, M.;
Nishio, O. J. Org. Chem. 1985, 50, 1592.
(1) For a general review of the construction of quaternary R-amino
acids: Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry
1998, 9, 3517.
(2) (a) Shao, Z.; Pu, X.; Li, X.; Fan, B.; Chan, A. S. C. Tetrahedron:
Asymmetry 2009, 20, 225. (b) Williams, R. M.; Aldous, D. J.; Aldous,
S. C. J. Org. Chem. 1990, 55, 4657. (c) Castelhano, A. L.; Horne, S.;
Taylor, G. J.; Billedeau, R.; Krantz, A. Tetrahedron 1988, 44, 5451.
(3) (a) Dudnik, A. S.; Sromek, A. W.; Rubina, M.; Kim, J. T.; Kel’in,
A. V.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 1440. (b) Sromek,
A. W.; Rubina, M.; Gevorgyan, V. J. Am. Chem. Soc. 2005, 127, 10500.
r
10.1021/ol401934x
Published on Web 08/02/2013
2013 American Chemical Society

alkynyl amino esters and allenoates using an umpoled
N-addition to a β,γ-alkynyl R-imino ester followed by
electrophilic R- or γ-addition. Moreover, we also found
an alternative R-quaternary alkynyl amino ester synthesis
utilizing the addition to the iminium salts formed by the
oxidation of the intermediary enolates.
Table 1. Optimization of N-Ethylation/R-Acetylationa
As an initial reaction, ethyl-2-((4-methoxyphenyl)imino)-
4-phenylbut-3-ynoate 1a first reacted with ethylmagne-
sium bromide and subsequently with acetyl chloride
in THF at À78 °C to rt for 24 h (Table 1, entry 1).5b
Gratifyingly, the reaction proceeded as expected to give
the desired R-addition product 2a in 64% yield. To find
optimum reaction conditions, we next screened the
amount of Grignard reagent, additives, and reaction times,
which are summarized in Table 1. First, the amount of
nucleophile was examined (entries 1À3). An excess of
Grignard reagent led to a slight improvement in the yield
of 2a (entries 2 and 3). Additives such as molecular sieves
x
time
(h)
yield
(%)b
entry equiv
additive
1
1.5
2.0
3.0
2.0
2.0
2.0
1.5
1.1
1.0
1.1
3.0
1.1
none
none
none
24
24
24
24
2
64
69
66
59
69
74
80
79
70
66
57
65
2
3
˚
4
MS 4 A (1.3 g/mmol)
5
none
6
none
0.5
0.5
0.5
0.5
0.5
24
0.5
7
none
˚
4 A, 1,10-phenanthroline, TMEDA, and TMSCl were not
8
none
effective (entries 4, 10À12), while shortening the reaction
time increased the product yields (entries 5 and 6). These
results indicated that 2a was relatively unstable under the
reaction conditions. The amount of Grignard reagent was
next reexamined (entries 7À9), and a satisfactory product
yield was obtained using 1.1 equiv of Grignard reagent in
THF at À78 °C to rt for 30 min (entry 8).
9
none
10
11
12
1,10-phenanthroline (0.7 equiv)
TMEDA (3.0 equiv)
TMSCl (1.1 equiv)
a The reaction was carried out according to the general procedure
(Supporting Information (SI)). b Isolated yield.
The scope of substrates, electrophiles, and nucleophiles
was next examined under the optimized reaction condi-
tions, and the results are summarized in Table 2. Use of
acetyl bromide was not effective in this reaction (entry 2).
Acyl chlorides having linear aliphatic groups such as acetyl
and propionyl chlorides underwent the desired reaction
to give the products 2a, 2b in high yields (entries 1 and 3),
while those having branched aliphatic groups such as
isobutyryl and pivaloyl chlorides decreased the yield or
gave no product, presumably because of the steric hin-
drance (entries 4 and 5). Aromatic and heteroaromatic
acid chlorides also afforded the desired products 2e, 2f in
moderate to high yields (entries 6 and 7). Ethyl chloroform-
ate and crotonoyl chloride gave the products 2g, 2h
in high yields (entries 8 and 9). The substrates having
aromatic substituents with electron-withdrawing groups
or an aliphatic substituent afforded the desired products
2iÀk in high yields (entries 10À12). We also found that
silyl substituents were efficient for this reaction to give the
products 2lÀp in high yields (entries 13À17). The substrate
with a thienyl group gave the product 2q in 70% yield
(entry 18), while other nucleophiles such as methyl- and
benzylmagnesium bromides gave the products in moderate
to good yields (entries 19 and 20).
Since R-addition proceeded regioselectively, we next
studied γ-addition to give allenyl enolates. Although we
examined various reaction conditions, e.g., use of various
electrophiles and addition of some ligands to weaken the
OÀMg bond of magnesium enolate, the R-adduct was
obtained in all cases. Finally we obtained the γ-product 3a
in 18% yield, when CH2Cl2 was used as a solvent (Table 3,
(5) For N-alkylation to R-imino esters: (a) Dickstein, J. S.; Kozlowski,
M. C. Chem. Soc. Rev. 2008, 37, 1166. (b) Dickstein, J. S.; Fennie, M. W.;
Norman, A. L.; Paulose, B. J.; Kozlowski, M. C. J. Am. Chem. Soc. 2008,
130, 15794. (c) Chiev, K. P.; Roland, S.; Mangeney, P. Tetrahedron:
Asymmetry 2002, 13, 2205. (d) Mae, M.; Amii, H.; Uneyama, K. Tetra-
hedron Lett. 2000, 41, 7893. (e) Bertrand, M. P.; Feray, L.; Nouguier, R.;
Perfetti, P. Synlett 1999, 1148. (f) Yoo, S. E.; Gong, Y. D. Heterocycles
1997, 45, 1251. (g) Uneyama, K.; Yan, F.; Hirama, S.; Katagiri, T.
Tetrahedron Lett. 1996, 37, 2045. (h) Yamamoto, Y.; Ito, W. Tetrahedron
1988, 44, 5415. (i) Fiaud, J.-C.; Kagan, H. B. Tetrahedron Lett. 1971, 12,
1019.
(6) (a) Sano, T.; Mizota, I.; Shimizu, M. Chem. Lett. 2013, DOI:
10.1246/cl.130396. (b) Shimizu, M.; Kurita, D.; Mizota, I. Asian J. Org.
Chem. 2013, 2, 208. (c) Shimizu, M.; Takao, Y.; Katsurayama, H.; Mizota,
I. Asian J. Org. Chem. 2013, 2, 130. (d) Nishi, T.; Mizota, I.; Shimizu, M.
Pure Appl. Chem. 2012, 84, 2609. (e) Mizota, I.; Tanaka, K.; Shimizu, M.
Tetrahedron Lett. 2012, 53, 1847. (f) Shimizu, M.; Hachiya, I.; Mizota, I.
Chem. Commun. 2009, 874. (g) Shimizu, M. Pure Appl. Chem. 2006, 78,
1867. (h) Shimizu, M.; Itou, H.; Miura, M. J. Am. Chem. Soc. 2005, 127,
3296. (i) Niwa, Y.; Shimizu, M. J. Am. Chem. Soc. 2003, 125, 3720. (j)
Niwa, Y.; Takayama, K.; Shimizu, M. Bull. Chem. Soc. Jpn. 2002, 75,
1819. (k) Niwa, Y.; Takayama, K.; Shimizu, M. Tetrahedron Lett. 2001,
42, 5473. (l) Shimizu, M.; Niwa, Y. Tetrahedron Lett. 2001, 42, 2829.
entry 1). In this context, addition of a Lewis acid, BF3 OEt2,
3
was next investigated, and the yield of γ-adduct 3a was
improved to 44% (entry 2). Although use of ZnCl2 or AlCl3
was not effective (entries 4 and 5), it was found that MgBr2
was an appropriate Lewis acid to promote γ-addition, and
the combined use of THF and MgBr2 gave the best result
(entry 8). Use of MgCl2 worked equally well (entry 9).
The scope of the reaction was next examined, and
the results are summarized in Table 4. Under the optimum
reaction conditions (Conditions A, see the equation),
aromatic and heteroaromatic acyl chlorides afforded
the desired products 3a, 3b, 3f, 3k in good to high yields
(entries 1, 3, 9, and 15). However, when aliphatic acyl
chlorides were used, the γ-products 3c, 3d were not ob-
tained at all (entries 4 and 6). As compared with the results
obtained under the conditions A, the yields of 3a, 3f, and
Org. Lett., Vol. 15, No. 16, 2013
4207

acidity of MgBr2 was suitable for the in situ formation
of an acylium ion, whereas the use of BF3 OEt2 led to
3
Table 2. Tandem N-Alkylation/R-Acylationa
decomposition of the product, perhaps due to an increased
Lewis acidity. When aliphatic acid chlorides were used,
the relatively slow formation of acylium ions by MgBr2
would reflect the results.7 It should be noted that silyl
substituted imino esters gave the R-adducts exclusively in
high yields (entries 18À20). Although the selectivity of
R- to γ-addition is not readily explained, we presume that
the γ-addition would proceed via orbital control in the
presence of a Lewis acid due to lowering the LUMO level
by forming an acylium ion to overlap the HOMO of the
γ-carbon well.8
entry
R1
R2
R3
product yield (%)b
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et Me
Et Me
Et Et
Et iPr
Et tBu
Et Ph
2a
2a
2b
2c
2d
2e
2f
79
56
78
32
0
2c
3
4
5
6
75
54
80
92
80
83
76
85
88
98
87
quant
70
73
41
Table 4. Tandem N-Alkylation/γ-Acylationa
7
Et 2-furyl
Et OEt
8
2g
2h
2i
9
Et CH3CHdCH-
Et Me
10
11
12
13
14
15
16
17
18
19
20
3-FC6H4-
4-ClC6H4-
Et Me
2j
1-cyclohexenyl Et Me
2k
2l
TIPS
TIPS
TIPS
TES
Et Me
Et Ph
2m
2n
2o
2p
2q
2r
2s
entry
R1
R2
conditions product yield (%)b
Et 2-thienyl
Et Ph
1
Ph
Ph
Ph
Ph
Ph
A
B
A
A
B
A
B
B
A
B
B
B
B
B
A
B
B
A
A
A
3a
3a
3b
3c
3c
3d
3d
3e
3f
82
54
86
0
2c
3
TES
Et 2-thienyl
Et OEt
Me Me
2-thienyl
Ph
2-thienyl
4c,d Ph
Me
Ph
Bn Me
5
Ph
Ph
Ph
Ph
Me
54
0
6
Et
a The reaction was carried out according to the general procedure
(SI). b Isolated yield. c Acetyl bromide was used instead of acetyl chloride.
7
Et
42
40
82
46
42
28
36
13
63
50
36
83
86
85
8e
9f
CH3CH=CH-
2-thienyl
Ph
10e 2-thienyl
11e 2-thienyl
12 3-FC6H4-
13g 3-FC6H4-
14 4-ClC6H4-
Ph
3f
2-thienyl
Me
3g
3h
3i
Table 3. Optimization of N-Ethylation/γ-Benzoylationa
Ph
Me
3j
15 1-cyclohexenyl Ph
16g 1-cyclohexenyl Ph
17 1-cyclohexenyl Me
3k
3k
3l
2mh
2nh
2oh
18 TES
19 TIPS
20 TIPS
Ph
Ph
2-thienyl
entry
solvent
Lewis acid
none
yield (%)b
a The reaction was carried out according to the general procedure
(SI). b Isolated yield. c Acyl chloride (5.0 equiv) was used. d Toluene was
used as a solvent. e THF was used as a solvent. f Reaction was carried out
in the absence of Lewis acid. g Acyl chloride (2.0 equiv) was used.
h R-Addition product (see Table 2).
1c
2c
3
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
EtCN
18
44
54
0
BF3 OEt2
3
BF3 OEt2
3
4
ZnCl2
AlCl3
5
0
6
MgBr2
MgBr2
MgBr2
MgCl2
61
61
82
79
In our preliminary experiment, which was a simple
N-ethylation of β,γ-alkynyl-R-imino ester 1a with Et2Zn,
we found that the N-ethylation product was unstable in the
presence of a proton source due to an isomerization to the
allene.9 When the N-ethylation reaction was carried out
with Et2Zn (3.0 equiv), after the normal workup, the
7
8
THF
9
THF
a The reaction was carried out according to the general procedure
(SI). b Isolated yield. c Acetyl chloride (5.0 equiv) was used instead of
benzoyl chloride.
(7) (a) Bender, M. L.; Chen, M. C. J. Am. Chem. Soc. 1963, 85, 37. (b)
Bender, M. L.; Chen, M. C. J. Am. Chem. Soc. 1963, 85, 30. (c) Bender,
M. L.; Ladenheim, H.; Chen, M. C. J. Am. Chem. Soc. 1961, 83, 123. (d)
Ladenheim, H.; Bender, M. L. J. Am. Chem. Soc. 1960, 82, 1895.
(8) Casiraghi, G.; Zanardi, F. Chem. Rev. 2000, 100, 1929 and
references therein.
3k decreased under the conditions B (entries 2, 10, 16),
while the γ-products 3c and 3d were obtained in moderate
yields under conditions B (entries 5 and 7). These results
indicate that when benzoyl chloride was used, the Lewis
4208
Org. Lett., Vol. 15, No. 16, 2013

ketoester 4 and N-ethyl-4-methoxyaniline 5 were obtained
instead of the N-ethylated product in moderate yields
(Scheme 1). Since introduction of a substituent into the
imino carbon in situ should inhibit the tautomerization
to an allene, we next examined a further alternative syn-
thesis of R-quatenary alkynyl amino esters utilizing se-
quential N-alkylation/oxidation/nucleophilic addition to
β,γ-alkynyl-R-imino ester 1.
Scheme 2. Tandem N,C-Diethylation via an Iminium Salt
Scheme 1. N-Ethylation to R-Alkynyl Imino Ester
As an initial reaction, ethyl-2-((4-methoxyphenyl)imino)-
4-phenylbut-3-ynoate 1a first reacted with 1.2 equiv
of EtMgBr in THF at À78 °C to rt for 20 min fol-
lowed by oxidation with DBDMH (1,3-dibromo-5,5-
dimethylhydantoin) at rt for 10 min and treatment with
another 3.0 equiv of EtMgBr at À78 °C to rt for 6 h.
Unfortunately the desired product was not obtained at
all. Therefore, a series of reaction conditions such as the
amount of Grignard reagent, oxidants, temperatures,
Lewis acids, reaction times, and substrates were examined
in detail.10 As a result, the desired products 6aÀd were
obtained in a maximum 49% yield (Scheme 2). Among the
substrates examined, the one with the terminal silyl group
gave the desired product 6e in good yield.
a PhI(OAc)2 (3.0 equiv), 6 h. b Reaction time was 22 h.
Scheme 3. Plausible Mechanism
A proposed reaction mechanism is shown in Scheme 3.
First, N-ethylation of the imino ester 1 generates the
magnesium enolate A. Under basic conditions, the enolate
reacts with an electrophile at the R-position to give the
alkynyl amino ester 2, while, under Lewis acidic condi-
tions, the enolate reacts with the acylium ion derived from
acyl chloride with a Lewis acid at the γ-position through
orbital control to provide the allenyl esters 3. In the cases
with DBDMH as an oxidant, the enolate A is oxidized to
give an iminium salt as intermediate B, which reacts with
another equivalent of EtMgBr to give the alkynyl amino
ester 6.
In summary, we have developed a one-pot synthesis of
R-quatenary alkynyl amino esters and allenoates using
umpolung N-alkylation of β,γ-alkynyl R-imino esters
followed by nucleophilic R- or γ-addition. This method
has unique regioselectivity and provides important
R-quaternary alkynyl amino acids in good yields. Moreover,
we also show the synthesis of R-quaternary alkynyl amino
esters utilizing a β,γ-alkynyl R-imino ester with a terminal
silyl group via an intermediary iminium salt formed by the
oxidation of the amino ester enolate.
Acknowledgment. This work was supported by Grants-
in-Aid for Scientific Research (B) and on Innovative Areas
“Organic Synthesis Based on Reaction Integration. Devel-
opment of New Methods and Creation of New Sub-
stances” from JSPS and MEXT.
Supporting Information Available. Experimental de-
tails and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(9) The R-addition product could not be isolated on silica gel TLC
instead of silica gel column chromatography due to decomposition
under acidic conditions. See for example: Yamamoto, Y.; Hayashi, H.
Tetrahedron 2007, 63, 10149.
The authors declare no competing financial interest.
(10) See the SI for more detailed examination of reaction conditions.
Org. Lett., Vol. 15, No. 16, 2013
4209