C-selective and diastereoselective alkyl addition to β,γ-alkynyl-α-imino esters with zinc(II)ate complexes

Article abstract of DOI:10.1002/anie.201408916

Since umpolung α-imino esters contain three electrophilic centers, regioselective alkyl addition with traditional organometallic reagents has been a serious problem in the practical synthesis of versatile chiral α-amino acid derivatives. An unusual C-alkyl addition to α-imino esters using a Grignard reagent (RMgX)-derived zinc(II)ate was developed. Zinc(II)ate complexes consist of a Lewis acidic [MgX]⁺moiety, a nucleophilic [R₃Zn]^- moiety, and 2[MgX₂]. Therefore, the ionically separated [R₃Zn]^- selectively attacks the imino carbon atom, which is most strongly activated by chelation of [MgX]⁺. In particular, chiral β,γ-alkynyl-α-imino esters can strongly promote highly regio- and diastereoselective C-alkylation because of structural considerations, and the corresponding optically active α-quaternary amino acid derivatives are obtained within 5 minutes in high to excellent yields.

Full text of DOI:10.1002/anie.201408916

Angewandte
Chemie
DOI: 10.1002/anie.201408916
Synthetic Methods
C-Selective and Diastereoselective Alkyl Addition to b,g-Alkynyl-a-
imino Esters with Zinc(II)ate Complexes**
Manabu Hatano, Kenji Yamashita, Mai Mizuno, Orie Ito, and Kazuaki Ishihara*
Abstract: Since umpolung a-imino esters contain three
electrophilic centers, regioselective alkyl addition with tradi-
tional organometallic reagents has been a serious problem in
the practical synthesis of versatile chiral a-amino acid deriv-
atives. An unusual C-alkyl addition to a-imino esters using
a Grignard reagent (RMgX)-derived zinc(II)ate was devel-
laborious, since the obtained compounds often have similar
chemical properties.
In a pioneering work, Kagan reported that Et-, Pr-, iBu-,
and PhCH MgX react at the imino nitrogen atom (path b;
2
Scheme 1), whereas tBu- and allylMgX unusually react at the
[3a,b]
imino carbon atom (path a).
Later, Yamamoto et al.
+
oped. Zinc(II)ate complexes consist of a Lewis acidic [MgX]
investigated the addition of ZnBr , Et Al, Ti(OiPr) Cl, and
2
3
3
À
moiety, a nucleophilic [R Zn] moiety, and 2[MgX ]. There-
B(OMe)3 to PhCH MgX and allylMgX to control the
3
2
2
À
[6c–e]
fore, the ionically separated [R Zn] selectively attacks the
regioselectivity of these additions (paths a and b).
More-
3
imino carbon atom ,which is most strongly activated by
chelation of [MgX] . In particular, chiral b,g-alkynyl-a-imino
esters can strongly promote highly regio- and diastereoselective
C-alkylation because of structural considerations, and the
corresponding optically active a-quaternary amino acid deriv-
atives are obtained within 5 minutes in high to excellent yields.
over, in a remarkable advance in this field, Niwa and Shimizu
reported a tandem N-ethyl addition/oxidation/C-allyl addi-
tion (path b) to deliver N-PMP-a-ketimino esters (PMP = 4-
MeOC H ) using Et AlCl/EtAlCl , benzoyl peroxide, and
+
6
4
2
2
[
7]
allylbutyltin. Later, Kozlowski and co-workers also reported
[8]
a tandem reaction system (path b) with some electrophiles.
In sharp contrast, a practical and general methodology for the
unusual C-alkyl addition to a-imino-esters (i.e., path a) has
not yet been well-established. In particular, since a variety of
Grignard reagents are commercially available or can be
readily prepared in both the laboratory and industry,
a method for the highly regioselective C-alkyl addition to
1 with Grignard reagents is desired.
A
lkyl addition to a-imino esters (1) with organometallic
reagents (RM) is one of the most straightforward method-
ologies for synthesizing versatile N-substituted a-amino-acid
[
1]
[9]
derivatives (2 and 3; Scheme 1). However, regioselective
alkyl addition to 1 is problematic, since these conjugated
umpolung compounds can react with organometallic reagents
at three possible electrophilic centers: the imino carbon atom
In this context, we envisioned that zinc(II)ate reagents
À
+
[10–12]
(
path a to give 2), imino nitrogen atom (path b to give 3), and
([R Zn] [MgX] [{MgX } ]),
which are prepared in situ
3
2 2
[2]
carbonyl carbon atom (path c to give 4). Usually, regiose-
lectivity (paths a–c) depends on both the substrates and
alkylating reagents, and the desired product is often obtained
from Grignard reagents (RMgX) and ZnCl , would be highly
2
attractive for use in a path a reaction (Scheme 2). The
selective C-alkyl addition with zinc(II)ate reagents would be
[
3–5]
as part of a complex mixture.
Moreover, purification is
expected to offer both the increased nucleophilicity of an
À
anionic [R Zn] moiety and the increased Lewis acidity of
3
+
a cationic [MgX] moiety. While a chelated Grignard reagent
with 1 would be unlikely to attack the most activated imino
carbon atom beyond the adjacent imino nitrogen atom, an
ionically separated zincate might attack the most activated
imino carbon atom. Even though two or more molecules of
the Grignard reagent compete, the hard and soft acids and
Scheme 1. Alkyl addition to a-imino esters with organometallic
reagents.
[
*] Dr. M. Hatano, K. Yamashita, M. Mizuno, O. Ito, Prof. Dr. K. Ishihara
Graduate School of Engineering, Nagoya University
Furo-cho, Chikusa, Nagoya 464-8603 (Japan)
E-mail: ishihara@cc.nagoya-u.ac.jp
Homepage: http://www.ishihara-lab.net/
Prof. Dr. K. Ishihara
Japan Science and Technology Agency (JST), CREST
Furo-cho, Chikusa, Nagoya 464-8603 (Japan)
[**] Financial support was partially provided by MEXT, KAKENHI
(
26105723, 26288046), and the Program for Leading Graduate
Schools “IGER program in Green Natural Sciences”, MEXT (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201408916.
Scheme 2. Regioselective alkyl addition at the imino nitrogen atom
(path b) versus imino carbon atom (path a).
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bases (HSAB) concept might support the assumption. After
the formation of a five-membered metallacycle resulting from
contact ion-pair reagent iPrZnCl·MgCl , was not effective
2
(entry 9).
[
12f–j]
N,O chelation with one RMgX, another molecule of soft
In general, a-ketimino esters are much less reactive than
a-aldimino esters in terms of steric and electronic factors. To
confirm the unexpectedly high reactivity of 5c, we clarified
the structural considerations for the first time by X-ray
analysis of 5a–c (Figure 1). As a result we found that, 5a and
À [12k]
RMgX or even [RMgX2]
easily attack the mismatched hard imino carbon atom.
in Schlenkꢀs equilibrium cannot
[
2]
At the beginning of this study, we examined the addition
of EtMgCl (3.3 equiv) to the a-aldimino ester 5a and a-
ketimino ester 5b in either the presence or absence of ZnCl2
(
1.1 equiv) in THF (Table 1). For highly reactive 5a, the
reaction went to completion at À788C within 5 minutes, and
the unusual ethyl (at C) adduct 6a was successfully obtained
in 94% yield in the presence of ZnCl (entry 2), while the
2
ethyl (at N) adduct 7a was obtained in 95% yield in the
[
7]
absence of ZnCl , as reported by the groups of Shimizu and
2
[
8]
Kozlowski (entry 1). However, when the much less reactive
b was used, the reaction was very sluggish even with the use
of ZnCl at 08C, and the desired 6b was obtained in 44%
5
2
[13]
yield after 20 hours (entry 4).
During the course of our
study, Shimizu and co-workers reported that N-PMP-pro-
tected b,g-alkynyl-a-imino esters were effective for tandem
N-alkyl addition/C acylation to give a-quaternary alkynyl
[14]
amino esters. Inspired by this timely report, we found that
the b,g-alkynyl-a-imino ester 5c was much more reactive than
[
15]
5
b. As a result, the desired 6c was obtained in 97% yield at
À788C within 5 minutes when EtMgCl and ZnCl were used
2
(
entry 6). Moreover, the ZnCl method was effective with the
2
less reactive iPrMgCl, and the corresponding and unusual
adduct 6d was obtained in 95% yield within 30 minutes
(
entry 8). In contrast, the reaction of 5c with iPrMgCl in the
absence of ZnCl was slow, and the regioselectivity was low
Figure 1. X-ray analysis of a-imino esters and the postulated complex-
ation with zinc(II)ate complex.
2
(
entry 7). A 3:1 ratio of a Grignard reagent and ZnCl is
2
important to give the separated ion-pair zinc(II)ate complex
À
+
[
iPr Zn] [MgCl] [{MgCl } ], and the use of iPrMgCl
3 2 2
(
3.3 equiv) and ZnCl2 (3.3 equiv), which would give the
5c prefer an E geometry, while the much less-reactive 5b
prefers a Z geometry. The minimal steric constraints imposed
by H or PhCꢀC on the imino carbon atom of either 5a or 5c
might be crucial for the E geometry, since these substituents
would avoid the steric repulsion with PMP in the E geometry.
[
a]
Table 1: Alkyl addition to a-imino esters.
1
13
Moreover, H and C NMR analyses of 5a–c in CDCl3
showed that each compound has either a pure E or
Z geometry, and that the observed geometry is quite stable;
there is no interconversion between the E and Z isomers even
at room temperature. Preliminary DFT calculations (B3LYP/
6
-31G*) also supported a difference in the energy profiles of
[
b]
the E and Z isomers, and s rotation of N=CÀC=O would be
much easier than E to Z isomerization (see the Supporting
Information). Overall, both (E)-5a and (E)-5c with s-cis- or s-
Entry
5
Reagents
T [8C] Time
6/7/8
Yield [%]
6
7
8
1
2
3
4
5
6
7
8
9
5a EtMgCl
5a EtMgCl+ZnCl2
5b EtMgCl
5b EtMgCl+ZnCl2
5c EtMgCl
5c EtMgCl+ZnCl2
5c iPrMgCl
À78
À78
0
5 min 6a:7a:8a
0
95
0
0
0
0
0
0
0
0
0
0
52
6
71
0
27
0
46
+
trans-N=CÀC=O might be suitable for [MgX] chelation, as
5 min 6a:7a:8a 94
20 h 6b:7b:8b
20 h 6b:7b:8b 44
5 min 6c:7c:8c
5 min 6c:7c:8c 97
9
we show in Figure 1a and c.
0
By taking advantage of the high reactivity and regiose-
lectivity of zinc(II)ate reagents for 5c, we next examined the
diastereoselective methyl addition to the chiral 8-phenyl-
menthyl (R*) ester 9a (Scheme 3). However, the desired
C-methyl addition to 9a did not proceed selectively. Instead,
N-methylation-derived compounds were obtained in consid-
erable yields (> 40%) along with the desired 10a (36%). To
overcome this problem, we next used more reactive mixed
À78
8
À78
À78 30 min 6d:7d:8d 35
[6]
5c iPrMgCl+ZnCl2 À78 30 min 6d:7d:8d 95
[
c]
5c iPrMgCl+ZnCl2 À78 30 min 6d:7d:8d
9
[a] Unless otherwise noted, the reaction was conducted with the use of
Grignard reagent (3.3 equiv) without ZnCl or Grignard reagent
2
(
3.3 equiv) with ZnCl (1.1 equiv) in THF. [b] Yields of isolated products.
2
À
+
zinc(II)ate complexes [R(Me SiCH ) Zn] [MgX] [{MgX } ],
which we had previously developed,
[c] iPrZnCl, which was prepared in situ from iPrMgCl (3.3 equiv) and
3
2
2
2 2
[
11c,d]
ZnCl (3.3 equiv), was used. THF=tetrahydrofuran.
and 10a was
2
2
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chlorides could be used successfully, and the corresponding
desired products (10a–j) were obtained in high to excellent
yields (80–99%) within 5 minutes. In some cases, the cation
[11c,d]
effect of lithium(I) salts
was effective for improving the
reactivity and regioselectivity (i.e., C addition versus N addi-
tion). For example, the use of nBuMgCl/Me SiCH MgCl/
3
2
Scheme 3. Diastereoselective methyl addition (R*=8-Ph-menthyl).
PMP=p-methoxyphenyl.
ZnCl gave 10e in 35% yield, while the addition of LiCl
2
[
11c,d]
(1.1 equiv) or the use of Me SiCH Li
in place of
3
2
Me SiCH MgCl greatly improved the yield (99%) of 10e.
3
2
Grignard reagents with secondary alkyl chains such as
isopropyl and cyclohexyl magnesium chlorides could be
used, and the corresponding C adducts (10k and 10l) were
obtained in good yields (54–83%). Moreover, some w-
functionalized alkyl chains with olefin, acetal, chlorine, and
trimethylsilyl could successfully transfer to 9a, and the
corresponding and unusual C adducts (10m–q) were exclu-
sively obtained. It was noted that whenever zinc(II)ate
complexes were used, perfect diastereoselectivities (> 99:1)
[
16]
were observed. The excellent diastereoselectivity of the C-
alkyl addition products can be understood in terms of the
[
6]
well-known paradigms. The bulky chiral 8-phenylmenthyl
group would shield the re-face and promote the attack of the
si-face exclusively (Figure 2).
Figure 2. Possible mechanism (R*=8-Ph-menthyl).
To demonstrate the synthetic utility of the products, 10d
was reduced under typical reaction conditions (Scheme 5).
Palladium on charcoal facilitated the selective hydrogenation
of phenylacetylene to the phenethyl compound 11 in 95%
yield. The Z-olefin 12 was selectively obtained in 95% yield
by hydrogenation with Lindlar’s catalyst, while the E-olefin 13
was selectively obtained in 92% yield with the use of sodium
bis(2-methoxyethoxy)aluminum hydride (Red-Al) in THF at
Scheme 4. Regio- and diastereoselective alkyl addition to chiral
a-ketimino esters. [a] Unless otherwise noted, the reaction was
conducted with the use of Grignard reagent (1.1 equiv), ZnCl2
[
a]
(
(
1.1 equiv), and Me SiCH MgCl (2.2 equiv) in THF at À788C for 5 min
3
2
6
08C. Moreover, the treatment of 10d with lithium aluminum
standard conditions). Yields of the isolated products are shown.
[b] Yields of the isolated product are shown within brackets for
hydride in THF at 08C gave the b-alkynyl-b-amino alcohol 14
reactions using the Grignard reagent (3.3 equiv) at À788C for 5 min.
[
[
[
c] LiCl (1.1 equiv) was added under standard reaction conditions.
d] Me SiCH Li (2.2 equiv) was used in place of Me SiCH MgCl.
e] Grignard reagent (RMgBr) was prepared from Mg turnings and
3
2
3
2
alkylbromide in advance. [f] Me SiCH MgCl (3.3 equiv) and ZnCl
2
3
2
(
1.1 equiv) were used. [g] The temperature was gradually increased
from À788C to 08C over 4 h. R*=chiral 8-phenylmenthyl, TBS=tert-
butyldimethylsilyl.
obtained in 84% yield with the use of MeMgCl,
Me SiCH MgCl, and ZnCl .
3
2
2
We next investigated the scope of Grignard reagents for
a and 9b (Scheme 4). Simple Grignard reagents with
Scheme 5. Transformation of alkyne and recovery of chiral auxiliary
R*OH, R*=8-Ph-menthyl). Reaction conditions: a) H , 10 wt% Pd/C,
9
(
2
primary alkyl chains such as methyl, ethyl, n-butyl, isobutyl,
n-octyl, benzyl, p-methoxybenzyl, and phenethyl magnesium
MeOH, RT, 1 h; b) H , Pd/CaCO /Pb(OAc) , EtOH, RT, 1 h; c) Red-Al,
2
3
2
THF, 08C to 608C, 12 h; d) LiAlH , THF, 08C, 2.5 h.
4
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in 95% yield. The chiral 8-phenylmenthol 15 (R*OH) was
recovered quantitatively with the generation of the optically
pure alcohol 13 or 14. For other useful transformations of 10c
into the optically pure oxazolidinones, see the Supporting
Information.
Since optically pure aziridines are often important inter-
mediates, particularly in pharmaceuticals, 14 was transformed
into the 2-alkynyl aziridine 16 by the Mitsunobu reaction
Hachiya, I. Mizota, Chem. Commun. 2009, 874; c) K. Koyama, I.
Mizata, M. Shimizu, Pure Appl. Chem. 2014, 86, 755.
3] With Grignard reagents: a) J.-C. Fiaud, H. B. Kagan, Tetrahe-
dron Lett. 1970, 11, 1813; b) J.-C. Fiaud, H. B. Kagan, Tetrahe-
dron Lett. 1971, 12, 1019; c) P. Mꢃnster, W. Steglich, Synthesis
[
1987, 223; d) P. Ermert, J. Meyer, C. Stucki, J. Schneebeli, J.-P.
Obrecht, Tetrahedron Lett. 1988, 29, 1265; e) L. M. Harwood,
K. J. Vines, M. G. B. Drew, Synlett 1996, 1051; f) S.-E. Yoo, Y.-D.
Gong, Heterocycles 1997, 45, 1251; g) Y. Niwa, K. Takayama, M.
Shimizu, Tetrahedron Lett. 2001, 42, 5473; h) P. Calꢁ, M. Begtrup,
Synthesis 2002, 63.
(
Scheme 6). Furthermore, we found that a stereoselective
[
4] With organozinc(II) reagents: a) M. R. P. van Vliet, J. T. B. H.
Jastrzebski, W. J. Klaver, K. Goubitz, G. van Koten, Recl. Trav.
Chim. Pays-Bas 1987, 106, 132; b) G. Courtois, L. Miginiac, J.
Organomet. Chem. 1989, 376, 235; c) M. P. Bertrand, L. Feray, R.
Nouguier, P. Perfetti, Synlett 1999, 1148; d) K. P. Chiev, S.
Roland, P. Mangeney, Tetrahedron: Asymmetry 2002, 13, 2205;
e) S. Basra, M. W. Fennie, M. C. Kozlowski, Org. Lett. 2006, 8,
2659; f) M. Mitani, Y. Tanaka, A. Sawada, A. Misu, Y.
Matsumoto, Eur. J. Org. Chem. 2008, 1383; g) L. Lin, X. Fu, X.
Ma, J. Zhang, R. Wang, Synlett 2012, 2559; h) Y. Mizutani, H.
Tanimoto, T. Morimoto, Y. Nishiyama, K. Kakiuchi, Tetrahedron
Lett. 2012, 53, 5903.
Scheme 6. Transformation of 14 into the optically active 2-alkynyl
aziridine 16 and trisubstituted allene 18.
[5] With organoaluminum(II) reagents: a) M. Shimizu, Y. Niwa,
Tetrahedron Lett. 2001, 42, 2829; b) M. Shimizu, Y. Niwa, T.
Nagai, I. Hachiya, Heterocycles 2007, 72, 127; c) M. Shimizu, H.
Itou, M. Miura, J. Am. Chem. Soc. 2005, 127, 3296; d) M.
Shimizu, H. Itou, T. Iwao, Y. Umeda, Chem. Lett. 2009, 38, 732;
e) S. Hata, H. Koyama, M. Shimizu, J. Org. Chem. 2011, 76, 9670;
f) M. Shimizu, D. Kurita, I. Mizota, Asian J. Org. Chem. 2013, 2,
allene formation proceeded by ring-opening reduction,
instead of the expected S 2’ alkyl substitution, with the use
N
17]
[
of a Gilman-type cuprate and the trisubstituted allene [H]-
8 was obtained in 83% yield with 82% ee after the
1
208.
protonation of 17. The deuterated product [D]-18, which
[
6] a) E. J. Corey, H. E. Ensley, J. Am. Chem. Soc. 1975, 97, 6908;
b) W. Oppolzer, M. Kurth, D. Reichlin, C. Chapuis, M.
Mohnhaupt, F. Moffatt, Helv. Chim. Acta 1981, 64, 2802; c) Y.
Yamamoto, W. Ito, K. Maruyama, J. Chem. Soc. Chem.
Commun. 1985, 1131; d) Y. Yamamoto, S. Nishii, K. Maruyama,
T. Komatsu, W. Ito, J. Am. Chem. Soc. 1986, 108, 7778; e) Y.
Yamamoto, W. Ito, Tetrahedron 1988, 44, 5415.
7] Y. Niwa, M. Shimizu, J. Am. Chem. Soc. 2003, 125, 3720.
8] a) J. S. Dickstein, M. W. Fennie, A. L. Norman, B. J. Paulose,
M. C. Kozlowski, J. Am. Chem. Soc. 2008, 130, 15794; b) J. M.
Curto, J. S. Dickstein, S. Berritt, M. C. Kozlowski, Org. Lett.
2014, 16, 1948; c) J. M. Curto, M. C. Kozlowski, J. Org. Chem.
was obtained by CD CO D work-up with 98% D content,
3
2
supported the mechanism proposed by Alexakis et al. for the
reductive metalation of propargylic epoxides with cuprates.
[18]
In summary, we have developed an unusual C-selective
alkyl addition to a-imino esters with Grignard-reagent-
derived zinc(II)ate reagents. In particular, with the use of
chiral (E)-b,g-alkynyl-a-imino esters (9), highly regio- and
diastereoselective C-alkyl addition successfully proceeded at
À788C within 5 minutes. Moreover, synthetically useful
optically active compounds, such as E and Z olefins, amino
alcohol, aziridine, allene, and oxazolidinones, were provided
in high yields with the full recovery of (À)-8-Ph-menthol as
a chiral auxiliary. Overall, this fundamental method will
provide access to optically pure a,a-disubstituted a-quater-
nary amino acid derivatives.
[
[
2014, 79, 5359.
[
9] Excellent textbooks for Grignard reagents: a) B. J. Wakefield,
Organomagnesium Methods in Organic Chemistry, Academic
Press, San Diego, CA, 1995; b) G. S. Silverman, P. E. Rakita,
Handbook of Grignard Reagents, Marcel Dekker, New York,
1996; c) H. G. Richey, Jr., Grignard Reagents: New Develop-
ment, Wiley, Chichester, 2000; d) P. Knochel, Handbook of
Functionalized Organometallics, Wiley-VCH, Weinheim, 2005.
Received: September 8, 2014
Revised: November 14, 2014
Published online: && &&, &&&&
[10] a) M. Uchiyama, C. Wang, Top. Organomet. Chem. 2014, 47, 159;
b) F. Mongin, A. Harrison-Marchand, Chem. Rev. 2013, 113,
7563.
[
11] We have reported the catalytic and stoichiometric use of ZnCl2
Keywords: alkylation · Grignard reagents · regioselectivity ·
synthetic methods · zinc
.
with Grignard reagents for alkyl addition to ketones: a) M.
Hatano, S. Suzuki, K. Ishihara, J. Am. Chem. Soc. 2006, 128,
9
998; b) M. Hatano, S. Suzuki, K. Ishihara, Synlett 2010, 321;
c) M. Hatano, O. Ito, S. Suzuki, K. Ishihara, Chem. Commun.
010, 46, 2674; d) M. Hatano, O. Ito, S. Suzuki, K. Ishihara, J.
Org. Chem. 2010, 75, 5008.
2
[
1] For selected reviews on a-amino acid synthesis: a) R. O.
Duthaler, Tetrahedron 1994, 50, 1539; b) C. Cativiela, M. D.
Dꢁaz-de-Villegas, Tetrahedron: Asymmetry 1998, 9, 3517; c) K.
Maruoka, T. Ooi, Chem. Rev. 2003, 103, 3013; d) C. Nꢂjera, J. M.
Sansano, Chem. Rev. 2007, 107, 4584.
[12] Zinc(II)ate reagents in recent organic synthesis reports: a) T.
Harada, T. Katsuhira, A. Osada, K. Iwazaki, K. Maejima, A.
Oku, J. Am. Chem. Soc. 1996, 118, 11377; b) M. Uchiyama, S.
Furumoto, M. Saito, Y. Kondo, T. Sakamoto, J. Am. Chem. Soc.
1997, 119, 11425; c) M. Uchiyama, M. Kameda, O. Mishima, N.
Yokoyama, M. Koike, Y. Kondo, T. Sakamoto, J. Am. Chem. Soc.
[
2] For selected reviews and accounts: a) J. S. Dickstein, M. C.
Kozlowski, Chem. Soc. Rev. 2008, 37, 1166; b) M. Shimizu, I.
4
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Angewandte
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1998, 120, 4934; d) M. Uchiyama, S. Nakamura, T. Ohwada, M.
also see: k) S. Sakamoto, T. Imamoto, K. Yamaguchi, Org. Lett.
Nakamura, E. Nakamura, J. Am. Chem. Soc. 2004, 126, 10897;
e) K. Murakami, H. Yorimitsu, K. Oshima, J. Org. Chem. 2009,
2001, 3, 1793.
[13] The expected N-alkyl adducts 7b–d were not obtained since they
are unstable under acidic workup conditions, and fully decom-
posed to 8b–d.
[14] I. Mizota, Y. Matsuda, S. Kamimura, H. Tanaka, M. Shimizu,
Org. Lett. 2013, 15, 4206.
15] Preliminary results with some nBuMX for 9a are shown in the
Supporting Information.
16] Unfortunately, the present method for alkynyl and aryl additions
gives rise to a complex mixture. Further investigation is now in
progress.
7
4, 1415; f) E. Hevia, J. Z. Chua, P. Garcꢁa-ꢄlvarez, A. R.
Kennedy, M. D. McCall, Proc. Natl. Acad. Sci. USA 2010, 107,
294; g) D. R. Armstrong, W. Clegg, P. Garcꢁa-Alvarez, M. D.
5
McCall, L. Nuttall, A. R. Kennedy, L. Russo, E. Hevia, Chem.
Eur. J. 2011, 17, 4470; h) D. R. Armstrong, W. Clegg, P. Garcꢁa-
ꢄlvarez, A. R. Kennedy, M. D. McCall, L. Russo, E. Hevia,
Chem. Eur. J. 2011, 17, 8333; i) C. Vidal, J. Garcꢁa-ꢄlvarez, A.
Hernꢂn-Gꢅmez, A. R. Kennedy, E. Hevia, Angew. Chem. Int.
Ed. 2014, 53, 5969; Angew. Chem. 2014, 126, 6079; j) T. D.
Bluemke, W. Clegg, P. Garcꢁa-Alvarez, A. R. Kennedy, K.
Koszinowski, M. D. McCall, L. Russo, E. Hevia, Chem. Sci.
[
[
[
[
17] F. Chemla, F. Ferreira, Curr. Org. Chem. 2002, 6, 539.
18] a) A. Alexakis, I. Marek, P. Mangeney, J. F. Normant, Tetrahe-
dron Lett. 1989, 30, 2391; b) A. Alexakis, I. Marek, P. Mangeney,
J. F. Normant, Tetrahedron 1991, 47, 1677.
2014, 5, 3552. For the related constitution of Grignard reagent
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Synthetic Methods
M. Hatano, K. Yamashita, M. Mizuno,
O. Ito, K. Ishihara*
&&& — &&&
C-Selective and Diastereoselective Alkyl
Addition to b,g-Alkynyl-a-imino Esters
with Zinc(II)ate Complexes
Reversing umpolung: Zinc(II)ate com-
plexes, formed in situ from a Grignard
virtue of cooperation between the high
À
nucleophilicity of [R Zn] and the high
3
+
reagent and ZnCl , promoted an unusual
Lewis acidity of [MgX] . The correspond-
2
regio- and diastereoselective alkyl addi-
ing a-quaternary C adducts were
tion to b,g-alkynyl-a-imino esters by
obtained in high to excellent yields.
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!