Development of a Simple Adjustable Zinc Acid/Base Hybrid Catalyst for C?C and C?O Bond-Forming and C?C Bond-Cleavage Reactions

Article abstract of DOI:10.1002/asia.201600682

A newly designed zinc Lewis acid/base hybrid catalyst was developed. By adjusting the Lewis acidity of the zinc center, aldol-type additions of 2-picolylamine Schiff base to aldehydes proceeded smoothly to afford syn-aldol adduct equivalents, trans-N,O-acetal adducts, in high yields with high selectivities. NMR experiments, including microchanneled cell for synthesis monitoring (MICCS) NMR analysis, revealed that anti-aldol adducts were formed at the initial stage of the reactions under kinetic control, but the final products were the trans-(syn)-N,O-acetal adducts that were produced through a retro-aldol process under thermodynamic control. In the whole reaction process, the zinc catalyst played three important roles: i) promotion of the aldol process (C?C bond formation), ii) cyclization process to the N,O-acetal product (C?O bond formation), and iii) retro-aldol process from the anti-aldol adduct to the syn-aldol adduct (C?C bond cleavage and C?C bond formation).

Full text of DOI:10.1002/asia.201600682

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Accepted Article
Title: Development of a Simple Adjustable Zinc Acid/Base Hybrid Catalyst for C-C
and C-O Bond-Formation and C-C Bond-Cleavage Reactions
Authors: Yasuhiro Yamashita; Kodai Minami; Yuki Saito; Shu Kobayashi
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Development of a Simple Adjustable Zinc Acid/Base Hybrid
Catalyst for C–C and C–O Bond-Formation and C–C Bond-
Cleavage Reactions
Yasuhiro Yamashita,[a] Kodai Minami,[a] Yuki Saito,[a] and Shū Kobayashi*[a]
Dedication ((optional))
Abstract: A newly designed zinc Lewis acid/base hybrid catalyst
was developed. By adjusting the Lewis acidity of the zinc center,
aldol-type additions of 2-picolylamine Schiff base to aldehydes
proceeded smoothly to afford syn-aldol adduct equivalents, trans-
N,O-acetal adducts, in high yields with high selectivities. NMR
experiments including microchanneled cell for synthesis monitoring
(MICCS) NMR analysis revealed that anti-aldol adducts were formed
at the initial stage of the reactions under kinetic control, but that the
final products were the trans-(syn)-N,O-acetal adducts that were
produced through a retro-aldol process under thermodynamic control.
In the whole reaction process, the zinc catalyst played three
important roles: promotion of the aldol process (C–C bond formation),
the cyclization process to the N,O-acetal product (C–O bond
formation), and the retro-aldol process from the anti-aldol adduct to
the syn-aldol adduct (C–C bond cleavage and C–C bond formation).
electrophiles), and at the same time the amide moiety
deprotonates the terminal alkynes effectively. Here, we show
another Lewis acid/metal amide hybrid based on the new
concept (Figure 1); the new Zn catalyst efficiently promotes C–C
and C–O bond-forming reactions as well as C–C bond-cleavage
reactions. [5]
R2N
R2N
EWG
Zn
high Lewis acidity
Zn
R2N
EWG: Electron-withdrawing group
Figure 1 Zinc Lewis acid/metal amide hybrid
Heteroaryl-substituted alkylamine units are often observed in
biologically active compounds; among them, 1-(2-pyridyl)-1,2-
aminoalcohols are interesting synthetic components in a number
of drug candidates.[6] Although the syntheses of these
compounds have been investigated,[7,8] efficient and versatile
methods that involve catalytic C–C bond formation have been
very limited. Enders et al. reported a catalytic stereoselective
Mannich-type reaction of an imine derived from 2-
pyridinecarboxyaldehyde with 2,2-dimethyl-1,3-dioxan-5-one by
using an organocatalyst;[8g] however, it is difficult to synthesize
2-alkyl or 2-aryl-substituted 1-(2-pyridyl)-1,2-aminoalcohols
directly by using this reaction. To provide a versatile method to
synthesize these compounds, a catalytic direct aldol reaction of
protected 2-picolylamine is promising; however, to our
knowledge, this type of catalytic aldol reaction has rarely been
reported.[7,9]
The development of well-designed, conceptually advanced
catalysts with high reactivity and selectivity that can be used to
realize efficient synthesis of organic molecules is strongly
desired. Lewis acid/Brønsted base-catalyzed carbon–carbon
(C–C) bond-forming reactions are useful, fundamental, and
atom-economical methods to construct the basic framework of
complex molecules.[1] We have been focusing on the
development of simple Lewis acid/Brønsted base catalysts and
investigating metal amides as highly reactive, simple one-
molecule acid/base catalysts.[2] In synthetic organic chemistry,
metal amides have long been mainly used as strong Brønsted
bases to deprotonate acidic hydrogen atoms stoichiometrically
to form anion species; their use as highly reactive catalysts in
C–C bond-forming reactions is very limited. We have previously
revealed that chiral silver or copper amides worked well as
highly reactive catalysts in catalytic asymmetric [3+2]
cycloadditions.[3] Furthermore, we have quite recently developed
indium Lewis acid/metal amide hybrid catalysts, In(N(SiMe3)2)2X
{In(HMDS)2X, X= Cl, OTf}, as a new type of catalyst for addition
reactions of terminal alkynes to nitrones.[4] The Lewis acidity on
the metal center is adjusted by the electron-withdrawing group,
chloride or triflate, which activates the nitrones (less reactive
First, we investigated the aldol reaction of Schiff base 2,
derived from 2-picolylamine, by using zinc amide catalysts
(Table 1; for details see Table S1 in the Supporting Information
(SI)).[10] Interestingly, the reaction of 2 with benzaldehyde (1a)
proceeded in THF in the presence of a zinc Lewis acid/metal
amide hybrid, Zn(HMDS)OTf. In contrast, the use of either
Zn(HMDS)2[11] or Zn(OTf)2 did not afford any products (entries 1–
3). This is a remarkable advantage of a Lewis acid/metal amide
hybrid system compared with a simple Lewis acid or a simple
metal amide catalyst.[12] It was also found that the major product
of the reaction was not aldol adduct 4a but N,O-acetal adduct
3a. The structure of 3a, which was determined by X-ray single-
crystal structure analysis, indicated that the configuration of 3a
was trans, corresponding to syn-aldol adduct (syn-4a).[13,14]
Screening of solvents was then conducted to improve the yield
of the N,O-acetal adduct, and 1,2-dichloroethane (DCE) was
found to give both high yield and high trans-(syn)-selectivity
(entry 4). Control of the reaction temperature was important:
conducting the reaction at 0 C led to higher selectivity (entry 5).
[*]
Dr. Y. Yamashita, K. Minami, Y. Saito, Prof. Dr. S. Kobayashi
Department of Chemistry, School of Science
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
[**]
This work was partially supported by a Grant-in-Aid for Scientific
Research from the Japan Society for the Promotion of Science
(JSPS) and, the Japan Science and Technology Agency (JST). Y.
S. thanks to MERIT program, The University of Tokyo for financial
support. We also thank Rigaku Co. for their assistance of X-ray
single crystal structure analysis of 3r.
Supporting information for this article is given via a link at the end of
the document.
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Further optimization of concentrations and ratios of substrates
improved the yield to 85% (entry 7). Under the optimal
conditions, the catalyst loading could be reduced to 5 mol% to
afford the desired product in high yield with high selectivity,
albeit in a longer reaction time (entries 8 and 9). Interestingly, it
was found that the selectivity was increased by simply extending
the reaction time (vide infra).
some substrates, especially for aliphatic aldehydes. This
observation suggested that isomerization under thermodynamic
Table 2 Substrate Scopea
Entry
R (1)
3
Total yield
(%)b
Yield of
trans-3
(%)c
trans-
3/anti-4d
1
Ph (1a)
3a
3b
3c
3d
3e
3f
87
77
73
70
77
79
61
74
80
75
68
47
81
89
85
80
91
83
72
67
66
73
72
54
69
75
71
62
47
79
86
73
69
77
95:5
94:6
92:8
94:6
95:5
91:9
88:12
93:7
94:6
94:6
91:9
>99:1
98:2
99:1
86:14
87:13
85:15
2e
o-MeC6H4 (1b)
m-MeC6H4 (1c)
p-MeC6H4 (1d)
p-MeOC6H4 (1e)
p-BrC6H4 (1f)
o-O2NC6H4 (1g)
m-O2NC6H4 (1h)
p-O2NC6H4 (1i)
2-naphthyl (1j)
2-thiophenyl (1k)
tBu (1l)
Table 1 Catalytic Aldol-Type Additions of 1a with 2a
3
4
5e
6e,f
7
3g
3h
3i
8f
Entry
Cat.
Solvent
Temp.
Total
Trans
(C)
yield (%)b
/antic
9f
1d
2d
3
Zn(OTf)2
THF
THF
THF
DCE
DCE
DCE
DCEf
DCEf
DCEf
40
40
20
20
0
trace
–
10f,g
11e
12g
13g
14e
15e
16g
17g
3j
Zn(HMDS)2
trace
–
3k
3l
Zn(HMDS)OTf
Zn(HMDS)OTf
Zn(HMDS)OTf
Zn(HMDS)OTf
Zn(HMDS)OTf
Zn(HMDS)OTf
Zn(HMDS)OTf
59 (48)
79 (69)
83 (74)
79
92:8
91:9
94:6
94:6
93:7
92:8
95:5
4
iPr (1m)
3m
3n
3o
3p
3q
5
Cyclohexyl (1n)
iBu (1o)
6e
7e
8e,g
9e,g,h
0
0
85 (77)
59
C7H15 (1p)
0
C3H7 (1q)
0
88 (83)
18f,g,h
Garner’s aldehyde
(1r)
3r
73
62i
96:4
(91:9)j
[a] The reaction of 0.3 M 1a (0.33 mmol) with 2 (0.30 mmol) was conducted for
18 h at the temperature described in the presence of Zn catalyst (10 mol%)
unless otherwise noted. Zn(HMDS)OTf was prepared in situ by mixing
Zn(OTf)2 and KHMDS (1:1) in THF just before use (see supporting
information). [b] Determined by 1H NMR analysis of the crude mixture using
durene as an internal standard. [c] Determined by 1H NMR analysis of the
crude mixture. [d] 0.4 M. [e] 1a (0.30 mmol) and 2 (0.36 mmol) were used. [f]
0.6 M. [g] 5 mol% of the Zn catalyst was used. [h] The reaction was conducted
for 48 h.
[a] The reactions of 0.6 M RCHO 1 (0.30 mmol) and 2 (0.36 mmol) were
conducted in DCE at 0 C for 48 h in the presence of Zn(HMDS)OTf (0.015
mmol, 5.0 mol%) unless otherwise noted. Zn(HMDS)OTf was prepared in situ
by mixing Zn(OTf)2 and KHMDS (1:1) in THF just before use. [b] Determined
by 1H NMR analysis of the crude mixture using durene as an internal standard.
[c] Isolated yield. [d] Determined by 1H NMR analysis of the crude mixture. [e]
At 25 C. [f] 10 mol% Zn(HMDS)OTf was used. [g] At 40 C. [h] 0.3 M. [i]
Isolated yield of major diastereomer of trans-3r. [j] Diastereomer ratio of trans-
3r.
The substrate scope of the aldol-type addition reaction was
then examined (Table 2). Tolaldehydes 1b–d were also
successfully employed in the reaction, and the desired N,O-
acetal adducts were obtained in good yields with high
selectivities (entries 2–4). Benzaldehydes bearing either
electron-donating or electron-withdrawing groups also worked
well to afford the desired products in good yields with high
selectivities, although reactivities were sometimes not very high
(entries 5–9). Other aromatic aldehydes, 1j and 1k, gave similar
good results (entries 10 and 11). Aliphatic aldehydes were also
successfully employed, and, except for pivalaldehyde (1l), the
desired products were obtained in high yields. Although primary
aliphatic aldehydes 1o–q gave slightly lower selectivities (entries
15–17), bulky aliphatic aldehydes 1l–n gave excellent
selectivities (entries 12–14). An asymmetric aldol-type reaction
with Garner’s aldehyde 1r also proceeded in good yield with
high selectivities (entry 18). It should be noted that wide
substrate scope was observed in the reaction. Simple hydrolysis
of these compounds could give potential precursors of
biologically active compounds, for example, a K+ channel
inhibitor (Scheme 1).[6]
Scheme 1 Synthesis of a K+ channel inhibitor
control might occur to change the selectivity. To clarify the
detailed reaction profile, we followed the progress of reaction by
using 1H NMR analysis (details are provided in the SI). The
reaction of 1a with 2 proceeded smoothly in around 30%
conversion at room temperature even in 1 h, and the trans(syn)-
N,O-acetal adduct 3a was formed preferentially with high
selectivity (>9:1) during the initial stage of the reaction (Chart 1).
On the other hand,
cyclohexanecarboxaldehyde (1n) showed a different tendency;
in this case, the anti-aldol adduct was observed as the major
a
similar investigation using
During optimization of the reaction conditions, it was found that
the selectivity increased as the reaction time was prolonged for
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Chemistry - An Asian Journal
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product during the initial stage of the reaction, although the final
major product was trans-N,O-acetal adduct 3 (Chart 2). A
possible explanation was that the reaction of aromatic aldehyde
1a was obtained under kinetic control and that the reaction of
aliphatic aldehyde 1n was formed under thermodynamic control.
However, we thought that this was not likely based on a
consideration of similar types of aldol reactions. Another
possible explanation was that the rate of the isomerization in the
reaction of 1a was too fast to be observed on the time scale of
the NMR experiments shown in Chart 1.
reactions because of the easy retro-aldol processes,[9] but the
present case appears to be a rare example of a highly
stereoselective aldol-type reaction that proceeds under
thermodynamic control. A key factor might be that the cyclization
product cis-3 is not formed from anti-aldol product 4.[16]
Chart 3 Change of the trans-3a/anti-4a ratio at the initial stage of the addition
reaction of 1a with 2 in DCE at 25 C in the presence of Zn(HMDS)OTf (20
mol%) determined by MICCS-NMR analysis. In the MICCS system, the rate of
change in the trans/anti ratio was slower than that in a standard NMR
experiment because the low mixing efficiency of the components led to lower
levels of conversion (MICCS-NMR: 15 min, 2.4% yield / standard NMR: 20 min,
5% yield).
Chart 1 Change of the trans-3a/anti-4a ratio at the initial stage of the addition
reaction of 1a with 2 in DCM-d2 at 25 C in the presence of Zn(HMDS)OTf (10
mol%) measured with a standard NMR spectrometer.
OTf
HMDS Zn
Ph
N
H
Ph
Ph
N
N
O
N
R
trans-3
Ph
H
Zn(HMDS)OTf
TfO
Zn
N
OTf
N
Ph
N
Zn
N
Ph
R
N
Ph
Ph
N
Ph
2
A
Ph
O
O
R
cis-C
H
HMDS
1
TfO
Ph
N
R
OTf
Zn
N
N
Zn
N
Ph
Ph
N
O
Zn
O
Ph
Ph
N
Kinetic
control
OTf
Ph
anti-B
Thermodyn-
amic control
O
R
R
trans-C
Ph
N
R
Ph
N
N
N
Chart 2 Change of the trans-3n/anti-4n ratio at the initial stage of the addition
reaction of 1n with 2 in DCM-d2 at 25 C in the presence of Zn(HMDS)OTf (10
mol%) measured with a standard NMR spectrometer.
Ph
Ph
Zn
O
R
OH
OTf
syn-B
anti-4
Three key roles played by the zinc catalyst
Ph
Ph
N
Zn
Ph
N
R
Zn
O
N
N
Ph
N
N
Zn+
+
To elucidate the interesting phenomena of the isomerization,
we then conducted 1H microchanneled cell for synthesis
monitoring (MICCS) NMR analysis to observe the very early
stage of the reaction of 1a (Chart 3).[15] The reaction of 1a with 2
was monitored in the presence of Zn(HMDS)OTf with a MICCS
system. Interestingly, the results revealed that anti-aldol product
4a was obtained preferentially at the very early stage of the
reaction. This result strongly suggested that the kinetically
favored product in the reaction of 1a was also anti-4a, and the
trans-N,O-acetal adduct 3a corresponding to syn-aldol adduct
was a thermodynamically favored product. In the reaction of 1a,
isomerization of 4a to 3a would be very fast compared with the
reactions of aliphatic aldehydes, presumably because the
aromatic group affects the acidity of the hydroxyl groups of the
aldol adducts to enhance the retro-aldol process.[9g] From these
experiments, it was suggested that the addition reaction of 1
with 2 would proceed kinetically to afford the anti-aldol product
selectively (Figure S3), but that the product would isomerize
during the reaction to give the trans-N,O-acetal adduct with high
selectivity. High levels of stereoselectivity are usually obtained
under kinetic control in typical base-catalyzed direct-type aldol
Ph
R
Zn
TfO
O
–O
syn-B'
R
OTf
Ph
1
2
syn-B
Zn
TfO
Ph
N
Zn
N
N
N
Ph
Ph
Ph
R
OH
O
anti-4
trans-C
R
Scheme 2 Proposed catalytic cycle and key roles of the zinc catalyst
A proposed reaction mechanism is shown in Scheme 2. Schiff
base 2 is deprotonated to form zinc anion intermediate A, which
reacts with aldehyde 1 to afford anti-aldol intermediate anti-B
under kinetic control. Intermediate anti-B further gives anti-aldol
adduct anti-4 after protonation before cyclization to form
sterically unstable cis-C. However, the thermodynamic stability
of the anti-aldol adduct anti-4 is not sufficient under the reaction
conditions; therefore, a retro-aldol process from anti-4 through
deprotonation by the catalyst occurs to form intermediate A
again. This retro-aldol process was also confirmed by NMR
spectroscopic analysis (Scheme S2 and Figure S1).
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[8]
a) A. Dornow, K. Bruncken, Chem. Ber. 1950, 83, 189-193; b) S. Conti,
S. Cossu, G. Giacomelli, M. Falorni, Tetrahedron 1994, 50, 13493-
13500; c) S. Cossu, S. Conti, G. Giacomelli, M. Falorni, Synthesis 1994,
1429-1432; d) G. I. Georg, G. C. B. Harriman, M. Hepperle, J. S.
Clowers, D. G. Vander Velde, R. H. Himes, J. Org. Chem. 1996, 61,
2664-2676; e) D. Raatz, C. Innertsberger, O. Reiser, Synlett 1999,
1907-1910; f) J. L. G. Ruano, J. Aleman, Org. Lett. 2003, 5, 4513-4516;
g) D. Enders, C. Grondal, M. Vrettou, G. Raabe, Angew. Chem. Int. Ed.
2005, 44, 4079-4083; h) Y. Wang, Q.-F. He, H.-W. Wang, X. Zhou, Z.-Y.
Huang, Y. Qin, J. Org. Chem. 2006, 71, 1588-1591.
Intermediate
A
reacts with
1
in
a
stepwise aldol
addition/cyclization pathway through formation of syn-aldol
intermediate syn-B to afford N,O-acetal intermediate trans-C
under thermodynamic control.[17] The intermediate trans-C was
further protonated to afford N,O-acetal adduct trans-3 with
regeneration of Zn(HMDS)OTf. Enhanced Lewis acidity of the
Zn hybrid species might accelerate the addition step
efficiently.[18] In the catalytic cycle, it was revealed that
Zn(HMDS)OTf played three major roles (Scheme 2, bottom
scheme). The first is promoting the desired aldol reaction to
afford syn-aldol intermediate syn-B through C–C bond formation.
The second is promoting the intramolecular cyclization of syn-B
into trans-C. The third is promoting the retro-aldol process
through C–C bond-cleavage reaction of the anti-aldol adduct
anti-4.
[9]
For related direct-type aldol reactions of glycine Schiff base, see:
review a) C. Nájera, J. M. Sansano, Chem. Rev. 2007, 107, 4585-4671;
For other representative examples, see: b) M. J. O’Donnell, W. D.
Bennett, S. Wu, J. Am. Chem. Soc. 1989, 111, 2353–2355; c) M.
Horikawa, J. Busch-Petersen, E. J. Corey, Tetrahedron Lett. 1999, 40,
3843–3846; d) T. Ooi, M. Taniguchi, M. Kameda, K. Maruoka, Angew.
Chem. Int. Ed. 2002, 41, 4542–4544; e) N. Yoshikawa, M. Shibasaki,
Tetrahedron 2002, 58, 8289–8298; f) J. B. MacMillan, T. F. Molinski,
Org. Lett. 2002, 4, 1883–1886; g) T. Ooi, M. Kameda, M. Taniguchi, K.
Maruoka, J. Am. Chem. Soc. 2004, 126, 9685–9694; h) B. Seashore-
Ludlow, S. Torssell, P. Somfai Eur. J. Org. Chem. 2010, 3927-3933; i)
R. Rahmani, M. Matsumoto, Y. Yamashita, S. Kobayashi, Chem. Asian
J. 2012, 7, 1191-1194; j) S. Lou, A. Ramirez, D. A. Conlon, Adv. Synth.
Catal. 2015, 357, 28-34.
In summary, we have developed a newly designed zinc Lewis
acid/metal amide hybrid catalyst for aldol-type additions of 2-
picolylamine Schiff base to aldehydes. It was found that only the
hybrid catalyst Zn(HMDS)OTf showed high activity; neither
Lewis acid Zn(OTf)2 nor metal amide Zn(HMDS)2 had catalyst
activity. The desired reactions proceeded smoothly in the
presence of Zn(HMDS)OTf to afford the trans-N,O-acetal
adducts as syn-aldol adduct equivalents, in good to high yields
with high selectivities. The obtained N,O-acetal adduct was
converted into a precursor of a biologically active compound.
Whereas initial NMR experiments suggested an apparent
inconsistency in the results, final MICCS NMR analysis indicated
that the observed high stereoselectivities were generated under
thermodynamic control rather than under kinetic control. This is
a rare example of highly stereoselective aldol-type reaction
under thermodynamic control. Furthermore, in this study we
have revealed the strong potential of Lewis acid/metal amide
hybrid catalysts as highly efficient, simple one-molecule
acid/base catalysts. Further investigations including asymmetric
catalysis and the development of other hybrid catalysts are
ongoing.
[10] For related catalytic asymmetric [3+2] cycloadditions of Schiff base of
2-picolylamine, see: S. Padilla, R. Tejero, J. Adrio, J. C. Carretero Org.
Lett. 2010, 12, 5608-5611.
[11] a) Y. Cui, Y. Yamashita, S. Kobayashi, Chem. Commun. 2012, 48,
10319-10321; b) Y. Cui, W. Li, T. Sato, Y. Yamashita, S. Kobayashi,
Adv. Synth. Catal. 2013, 355, 1193-1205; c) Y. Saito, Y. Yamashita, S.
Kobayashi, Chem. Lett. 2015, 44, 976-977.
[12] KHMDS could also promote the reaction, but the selectivity was lower
than Zn(HMDS)OTf. See Table S1 in the Supporting Information (SI).
[13] The data have been deposited with the Cambridge Crystallographic
Data Centre as CCDC 1433949.
[14] See also ref. 9h for a related cyclic product.
[15] a) M. Nakakoshi, M. Ueda, S. Sakurai, K. Asakura, H. Utsumi, O.
Miyata, T. Naito, Y. Takahashi. Magn. Reson. Chem. 2007, 45, 989;
For an application of the MICCS system for analysis of the early stage
of
a reaction, see: b) J. Nakano, K. Masuda, Y. Yamashita, S.
Kobayashi, Angew. Chem. Int. Ed. 2012, 51, 9525-9529.
[16] In aldol-type reactions of glycine Schiff bases, both trans- and cis-cyclic
products could form (ref. 9h), which did not go back to the
corresponding aldol intermediates under typical catalytic reaction
conditions. See also ref. 9g.
Keywords: Lewis acid • metal amide • catalyst • aldol-type
addition • MICCS
[17] In this step, it is difficult to distinguish between a stepwise aldol
[1]
a) Lewis Acids in Organic Synthesis (Ed.: H. Yamamoto), Wiley-VCH
Verlag GmbH, Weinheim, 2000; b) Acid Catalysis in Modern Organic
Synthesis (Eds.: H. Yamamoto, K. Ishihara), Wiley-VCH Verlag GmbH
& Co. KGaA, Weinheim, 2008; c) S. Kobayashi, R. Matsubara, Chem.
Eur. J. 2009, 15, 10694; d) N. Kumagai, M. Shibasaki, Angew. Chem.
Int. Ed. 2011, 50, 4760-4772.
addition/cyclization pathway and
a
concerted 1,3-dipole [3+2]
cycloaddition pathway at the current stage; however, judging from the
exclusive formation of trans-N,O-acetal adduct and anti-aldol adduct
(without formation of any cis-N,O-acetal adduct and syn-aldol adduct), it
is reasonable to consider that the reaction would proceed through a
stepwise pathway.
[2]
[3]
Y. Yamashita, S. Kobayashi, Chem. Eur. J. 2013, 19, 9420-9427.
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Soc. 2010, 132, 3262-3263; b) Y. Yamashita, T. Imaizumi, S.
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[18] Lewis acidity of Zn(HMDS)OTf was evaluated by DFT calculations of
Zn(NH2)2, Zn(NH2)OTf and Zn(OTf)2. Lewis acidity of Zn(NH2)OTf was
stronger than Zn(NH2)2 but weaker than Zn(OTf)2. See Supporting
Information.
[4]
[5]
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For internal use, please do not delete. Submitted_Manuscript

Chemistry - An Asian Journal
10.1002/asia.201600682
COMMUNICATION
Layout 2:
COMMUNICATION
Yasuhiro Yamashita, Kodai Minami, Yuki
Saito, and Shū Kobayashi*
Page No. – Page No.
Development of a Simple Adjustable
Zinc Acid/Base Hybrid Catalyst for C–
C and C–O Bond-Formation and C–C
Bond-Cleavage Reactions
A newly designed zinc Lewis acid/base catalyzes aldol-type additions of 2-
picolylamine Schiff base to afford syn-aldol adduct equivalents, trans-N,O-acetal
adducts, as major products in high yields with high selectivities. The zinc catalyst
plays three important roles: promotion of the aldol process (C–C bond formation),
the cyclization process to the N,O-acetal product (C–O bond formation), and the
retro-aldol process from the anti-aldol adduct to the syn-aldol adducts (C–C bond
cleavage and C–C bond formation).
For internal use, please do not delete. Submitted_Manuscript