Indium- and zinc-catalyzed enantioselective amide propargylation of aldehydes with stannylated allenyl amides

Article abstract of DOI:10.1039/C9OB00040B

The catalytic enantioselective propargylation of aldehydes with newly prepared stannyl allenyl amides is described. The reaction has been accomplished by using catalytic amounts of indium chloride, zinc chloride, and a chiral BINOL derivative, affording amide-functionalized homopropargyl alcohols in excellent yields and enantioselectivities.

Full text of DOI:10.1039/C9OB00040B

View Article Online
View Journal
Organic &
Biomol ec ular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: T. Sengoku, I.
Ikeda, K. Ai, M. Takahashi and H. Yoda, Org. Biomol. Chem., 2019, DOI: 10.1039/C9OB00040B.
Volume 14 Number
1
7
January 2016 Pages 1–372
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Page 1 of 5
O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
View Article Online
DOI: 10.1039/C9OB00040B
Organic & Biomolecular Chemistry
COMMUNICATION
Indium− and zinc−catalyzed enantioselective amide
propargylation of aldehydes with stannylated allenyl amides
a
a
a
a
a
Tetsuya Sengoku, Ikuhei Ikeda, Keisuke Ai, Masaki Takahashi and Hidemi Yoda*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Catalytic enantioselective propargylation of aldehydes with newly pyrazole,2 isoxazole,3 triazole,4 pyrrole,5 and indolizine.6 The
prepared stannyl allenyl amide is described. The reaction has been great synthetic potential of alkynamide has attracted the
accomplished by using catalytic amounts of indium chloride, zinc attention of synthetic chemists, and therefore various
chloride, and
a chiral BINOL derivative, affording amide- derivatives have been stepwisely synthesized through
functionalized homopropargyl alcohols in excellent yields and amidation of alkynyl acids or aminocarbonylation of terminal
7
enantioselectivities.
alkene (Scheme 1a).
Meanwhile, direct installation of an alkynyl amide unit through
amido-functionalized propargylation of aldehydes or ketones
(we call them amide propargylation) is attractive in terms of
step economy because it is possible to prepare homopropargyl
alcohols 4 bearing a synthetically useful amide functionality in
(
a) Synthetic approaches to the compounds including -alkynyl amides (alkynamides)
CO2H
H
CONHR
RNH2
O
aldehyde
ketone
amidation

M
R'
NHR
alkynamide
1
RNH2, CO
CONHR
R'
(M = metal)
amino-
carbonylation
amide-
propargylation
M
8
R'
2
two steps starting from alkynamide 3 (Scheme 1b). However,
to our knowledge, no reports describing successful studies on
amide propargylation have appeared previously, probably due
to the lack of suitable synthetic methodologies that enable an
(
b) Enantioselective addition of stannylated allenyl (or propargyl) amides to aldehydes
(This work)
O
O
R'CHO
OH
CONHR
O
access to amide-functionalized propargylating agents such as 1
NHR
chiral catalyst
R'

9,10

and 2.
In the meantime, during our continuing efforts to
R'
3
or 2
base
Bu3SnCl
4
5
1
develop carbonyl-functionalized allylation, we have shown that
(M = SnBu3)
11
stannylated methacrylamides
A
and their analogous
1
2
(
c) Enantioselective addition of stannylated methacrylamides to aldehydes
boronates are available through stannylation or boration of
dianion intermediates generated by deprotonation of
methacrylamides (Scheme 1c). These reagents underwent
addition to aldehydes under the influence of chiral catalyst to
(Our previous work)
O
CONHR
OH
RHN
O
H+
R'CHO
O
X
In-pybox
R'
H
R'
H
give enantioenriched allyl adducts B, which were efficiently
converted into methylene lactones C in acidic media.11b–e
X = H
n-BuLi, t-BuOK
B
C
SnBu3 (A)
Bu3SnCl
Scheme 1. Syntheses and reactions of allyl/allenyl amides
Considering the superior acidity of the propargylic proton of 2-
butynamides 3 relative to that of the allylic proton in
methacrylamides, we assumed that comparable dianion
approach starting from 3 would lead to stannylated allenyl
amides 1 or propargyl amides 2. These reagents would react
with aldehydes to provide amide-functionalized homopropargyl
alcohols 4, which should be transformed into δ-lactones 5
through hydrogenation followed by cyclization (Scheme 1b). In
this communication, we report the preparation of a new series
of stannylated allenyl amides and successful application to the
enantioselective amide propargylation of aldehydes.
α-Alkynyl amide (alkynamide) is a useful unit for the synthesis
of heterocyclic systems. For instance, compounds bearing this
unit can be converted to biologically relevant lactams through
metal-catalyzed cyclization. Alkynamide also serves as an
electron-deficient alkyne in [3+2] cycloadditions with dipoles or
ylides to furnish a variety of heteroaromatic systems such as
1
a. Department of Applied Chemistry, Faculty of Engineering, Shizuoka University, 3-
5
-1 Johoku, Naka-ku, Hamamatsu 432-8561, Japan.
Electronic Supplementary Information (ESI) available: X-ray data for compound 7.
1
13
Experimental details, characterisation data, H and C NMR spectra and HPLC charts
of new compounds. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
Page 2 of 5
COMMUNICATION
Journal Name
base
InX , ZnX2 (20 mol %)
chiral ligand L (25 mol %)
O
3
CONHR
THF, -78 ºC, 30 min
View Article Online
CONHPh
CONHR
OH
DOI: 10.1039/C9OB00040B
NHR

SnBu3
Bu3Sn
PhCHO
1a
then Bu3SnCl, -78 ºC
MeCN (0.5 M), MS 3 Å
rt, time

Ph
3
1
2
4a
Table 1. Stannylation of 3 under various basic conditionsa
chiral ligand L
R'
6
3
R
L2 (R = R' = H, (S)-BINOL)
L3 (R = Ph, R' = H)
Entry
3 (R)
3a (Ph)
3a
Base (eq)
Time
1 [%]
2 [%]
O
O
N
OH L4 (R = H, R' = Ph)
[
h]
1
N
N
L5 (R = H, R' = t-Bu)
L6 (R = H, R' = p-tolyl)
OH
1
2
3
n-BuLi (2.3)
t-BuOK (2.8)
LDA (3.0)
LiCl (1.0)
LDA (3.0)
HMPA (4.5)
LDA (3.0)
LiHMDS (3.0)
NaHMDS
1a (22)
1a (28)
1a (7)
-
-
-
Ph
Ph
L7 (R = H, R' = 1-naphthyl)
L8 (R = H, R' = 2,4,6-i-Pr -phenyl)
3
L1: (S,S)-Ph-pybox
R' 6'
3'
R
1
1
Table 2. Screening of metal reagents and chiral ligands in the reaction of benzaldehyde
with 1aa
3a
Entry
InX
3
ZnX
2
L
Time
[h]
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
Yieldb
[%]
65
31
40
76
73
72
63
38
64
74
75
82
74
82
55
51
Erc
4
5
6
3a
3a
3a
1
2
2
1a (45)
1a (4)
1a
(trace)
1b (23)
1c (52)
1d (38)
-
-
-
1
2
3
4
5
6
7
8
9
In(OTf)
In(OTf)
In(OTf)
In(OTf)
In(OTf)
InCl
InCl
InCl
InCl
3
3
3
3
3
–
–
L1
L2
L1
L2
L2
L2
L2
L2
L3
L4
L5
L6
L7
L8
L8
L8
43:57
62:38
49:51
80:20
70:30
86:14
81:19
84:16
58:42
90:10
88:12
90:10
88:12
94:6
(3.0)
ZnCl
ZnCl
2
7
8
9
3b (p-Cl-C
3c (p-MeO-C
3d (p-Me-C
6
H
4
)
LDA (3.0)
LDA (3.0)
LDA (3.0)
1b
1
1
-
-
-
2
6
H
4
)
Zn(OTf)
ZnCl
Zn(OTf)
–
2
2
6
H
4
)
3
3
3
3
2
a
All reactions were carried out with 3 (1.0 equiv.), base, and Bu
in dry THF at -78 °C. The reaction mixture was warmed to 0 °C over 1 h.
3
SnCl (3.0 equiv.)
b
ZnCl
2
ZnCl2
ZnCl2
Inspired by the previous works relating ester-functionalized
propargylating agents,
10
11
InCl3
InCl3
1
3
we expected that reaction of
aldehydes with 1 would efficiently provide 4 in the presence of
Lewis acid. Therefore, our first objective was to develop a
scalable synthetic method for 1 (Table 1). In the initial attempt
to carry out the stannylation of 3a under the same reaction
conditions for the synthesis of A, the reaction proceeded
sluggishly with poor conversion after 2 h. The desired product
a could be readily isolated as air-insensitive solid through silica
gel column chromatography (22% yield, entry 1). Use of
LDA−LiCl that is the literature conditions employed for the
synthesis of ester analogs resulted in 28% yield of the product
1
1
1
1
1
2
3
4
5
6
InCl
InCl
InCl
InCl
–
3
3
3
3
ZnCl
ZnCl
ZnCl
–
2
2
2
88:12
52:48
ZnCl
2
aAll reactions were carried out with benzaldehyde (1.0 equiv.) and 1a (1.2 equiv.)
in dry MeCN in the presence of InX (20 mol %), ZnX (20 mol %), L (25 mol %), and
MS 3 Å at rt. Isolated yield of 4a. The er values were determined by HPLC analysis
1
3
2
b
c
using Daicel Chiralpak IC.
9
e
(
(
Table 1, entry 2). After further screening of bases and additives
Table 1, entries 3–6), it was revealed that deprotonation with
allylation with A,11 chiral pybox and BINOL ligands L1,2 were
expected to serve as a potential ligand for controlling facial
selectivity on the carbonyl plane. In fact, they had a positive
effect on the stereochemical outcome of the reaction between
benzaldehyde and 1a, albeit the observed enantioselectivities
were very low (Table 2, entries 1 and 2). The selectivity was
significantly enhanced to 80:20 by adding zinc chloride as a
cocatalyst for the reaction using BINOL ligand (Table 2, entry 4),
although the reaction in the presence of indium triflate, zinc
chloride, and pybox gave an almost racemic product (Table2,
entry 3). Further improvement was realized by varying indium
and zinc reagents (Table 2, entries 5–7) with the best result
3
1
equivalents of LDA was the key to obtaining the good yield of
a (45% yield) as shown in entry 4 of Table 1. Thus, we
1
4
established a new synthetic procedure that allows access to
sufficient quantities (hundreds of milligrams) of N-aryl-
substituted stannyl allenyl amides 1a–d.
1
5,16
With the stannylated allenyl amide 1 in hand, we attempted
amide propargylation by mixing benzaldehyde and 1a (molar
ratio 1:1.2) in acetonitrile. In the absence of any additives, the
aldehyde was gradually consumed with predominant formation
of the allenyl adduct 6a (22% yield). Similar results were
obtained by using scandium triflate or ytterbium triflate as an
additive, giving 6a in respective yields of 37 and 32% (Table S1,
entries 1 and 2). As a result of our screening of metal additives,
we fortunately found that a selectivity switch occurred on the
reaction performed with zinc or indium reagent, in which the
desired propargyl product 4a was obtained as a major
regioisomer (Table S1, entries 3–6). Among them, the case with
indium triflate gave the best result by enabling 4a to be formed
(72% yield, 86:14 er) being obtained using a pair of catalytic
indium chloride and zinc chloride (Table 2, entry 6). We also
performed the reaction only in the presence of indium chloride
and BINOL as a control experiment (Table 2, entry 8). In this
case, 1a was isolated in poor yield (38%), although the product
enantioselectivity was detected at the same level as that
1
8
observed in entry 6.
1
7
Subsequently, we optimized the substituents of the BINOL
ligand in order to further improve enantioselectivity. Screening
of the reactions with 6,6’-disubstituted BINOLs were made
because 6,6’-diphenyl BINOL L4 exhibited greater
in 61% yield (Table S1, entry 4).
We then examined enantioselective synthesis of 4a by adding a
chiral ligand to the reaction using indium triflate (Table 2). On
the basis of our successful results on the enantioselective
2
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 5
O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
Journal Name
COMMUNICATION
InCl3, ZnCl2 (20 mol %)
O
CONHR'
SnBu3
View Article Online
039/C9OB0003)40B
2.6 (c 1.00, CHCl
L8 (25 mol %)
OH
OH
CONHR'
CONHPh
1
) H2, Pd/C
O
DO
[
I

:
]D1 0- 3. 1
R
CHO
4a
94:6 er)

MeCN (0.5 M), MS 3 Å
rt, 18 h
R
2) p-TsOH•H O
(
2
Ph
(R)-5a (ref. 20):
[]D +34.4 (c 1.0, CHCl3)
1
4
5
a (79%, 95:5 er)
Cl
OH

CONHPh
OH

CONHPh
O
OH
OH
n-C9H19
N
H
4
4
b: 66% yield
b: 80:20 er
4c: 74% yield
4c: 83:17 er
4m: 80% yield
4ma
1) TBAF (86%)
4
o
ODPS
:
91:9 er
(
95:5 er)
2) recrystallyzation
7 (>99:1 er)
OH
CONHPh
OH
R
CONHPh
ORTEP diagram for X-ray structure of 7
R
R = Me (4d)
: 70% yield
87:13 er
R = OMe (4e) : 75% yield
90:10 er
: 72% yield
92:8 er
R = ODPS (4n) : 80% yield
R = Me (4g) : 78% yield R = OTBS (4j) : 91% yield
90:10 er : 97:3 er
R = OMe (4h) : 77% yield R = OTIPS (4k) : 91% yield
90:10 er : 96:4 er
: 77% yield R = ODPS (4l) : 89% yield
:
:
:
:
R = Cl (4f)
R = Cl (4i)
:
:
81:19 er
: 98:2 er
:
92:8 er
Scheme 3. Determination of the absolute configurations of 4a and 4o
R
O
4j,k were obtained in 97:3 and 96:4 ers, respectively. As for the
amide substituents on 1, both electron-donating and electron-
withdrawing groups were tolerated, and 4o–q were produced
R = Cl (4o)
: 87% yield
95:5 er
R = OMe (4p) : 89% yield
96:4 er
R = Me (4q) : 87% yield
97:3 er
OH
:
N
H
:
21,22
in high yields and excellent er values.
ODPS
:
Finally, we focused on the confirmation of the absolute
Scheme 2. Scope of amide propargylation: The er values were determined by HPLC
analysis using Daicel Chiralpak IC. The absolute configurations of 4d–n, p and q were configuration of the newly formed stereocenter (Scheme 3). In
tentatively assigned by analogy (see Scheme 3)
order to probe this issue, we examined the transformation of
2
3
4
a into known compound 5a. Alkyne moiety in 4a (94:6 er)
enantioselectivity than 3,3’-diphenyl derivative L3 (Table 2,
entries 9 and 10). Use of BINOL derivatives bearing phenyl, t-
butyl, p-tolyl or 1-naphthyl substituents at the 6 and 6’ positions
was successfully hydrogenated in the presence of Pd/C in
methanol to give the corresponding saturated amide, which
was in turn subjected to lactone cyclization under acidic
conditions to afford 5a in 64% two-step yield with no erosion of
stereointegrity (95:5 er). The spectral data for 5a were identical
to those in the literature except for the opposite sign of optical
rotation. Thus, the absolute configuration of the major
enantiomer of 4a was determined to be S. Furthermore, as part
of efforts to provide mechanistic insight for the unique ortho-
siloxy effect, we attempted to determine the stereochemistry
of 4o through the single-crystal X-ray diffraction analysis using
(
8
L4–L7) led to a modest increase in selectivity to give 4a in
8:12–90:10 ers (Table 2, entries 10–13). The selectivity
reached up to 94:6 er without compromising the yield by using
,4,6-triisopropylphenyl derivative L8 (Table 2, entry 14).
2
Notably, in control experiments in the absence of each metal
reagent, enantiomeric ratios of 4a were 88:12 (only with indium
chloride, table 2, entry 15) and 52:48 (only with zinc chloride,
table 2, entry 16), respectively. These results suggest that the
stereoselectivity should be mainly ascribed to the formation of
24
the anomalous dispersion method. The DPS group of 4o (95:5
1
9,20
indium-BINOL complex.
Then, we turned our efforts to
er) was removed by treatment with tetrabutylammonium
fluoride (TBAF). The product 7, whose enantiomeric purity was
maintained during the deprotection, was further purified by
recrystallization from ethyl acetate/hexane to afford X-ray
quality crystals (>99:1 er). The single-crystal X-ray diffraction
analysis showed that the molecules adopt the chiral
optimize the reaction solvent under the comparable conditions
in entry 14. However, reactions in all the tested solvents such as
dichloromethane, chloroform, and toluene resulted in poor
yields and low selectivities (28–41% yields, 60:40–78:22 ers).
Thus, we decided to employ the conditions in entry 14 for
further investigations.
1 1 1
orthorhombic space group P2 2 2 with the Flack parameter as
Next, we evaluated the substrate scope of the reaction (Scheme
low as 0.03(5), clearly demonstrating that the absolute
2
). Under the optimum reaction conditions, alkyl substrates
24,25
configuration of the newly formed stereocenter is S.
The
such as decanal and pivalaldehyde provided the corresponding
adducts 4b,c with moderate enantioselectivities (80:20 and
results suggests that the amide propargylation of aryl aldehydes
would proceed in the same manner to give the S adducts as a
8
3:17 ers, respectively). Benzaldehydes bearing electron-
26
major enantiomer.
donating or electron-withdrawing groups at the para- or ortho-
position gave comparable results to that with benzaldehyde
In conclusion, we have developed the catalytic enantioselective
propargylation of aldehydes with stannyl allenyl amides newly
prepared from propargyl amides. A variety of aldehydes were
efficiently coupled with the propargylating reagents under the
influence of InCl , ZnCl , and a chiral BINOL derivative to afford
3 2
the corresponding amide-functionalized homopropargyl
(
4d–i, 70–77% yields, 81:19–92:8 ers). We have to point out that
ortho-siloxy substituent, especially tert-butyldiphenylsilyloxy
DPSO) group at the ortho-position, exerted a beneficial effect
(
on the enantioselectivity (4l, 98:2 er). Analogously, the products
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
Page 4 of 5
COMMUNICATION
Journal Name
Y. Dong, S. Sun, F. Yang, Y. Zhu, W. Zhu, H. Qiao,VYie.wWArtuiclaenOdnliYne.
alcohols directly in excellent yields and enantioselectivities. This
report represents the first example of catalytic enantioselective
amide propargylation, which will provide new opportunities for
the future development of pharmaceutically attractive
molecules. Further investigations on mechanistic details of
catalytic asymmetric process and synthetic application of this
work are currently underway.
Wu, Org. Chem. Front., 2016, 3, 720–724; (f) J. Hwang, J.
DOI: 10.1039/C9OB00040B
Choi, K. Park, W. Kim, K. H. Song and S. Lee, Eur. J. Org.
Chem., 2015, 2235–2243; (g) H. Li, C. Pan, Y. Cheng and C.
Zhu, Tetrahedron Lett., 2013, 54, 6679–6681; (h) S. T. Gadge,
M. V. Khedkar, S. R. Lanke and B. M. Bhanage, Adv. Synth.
Catal., 2012, 354, 2049–2056; (i) Y. Lee, Y. Motoyama, K.
Tsuji, S.-H. Yoon, I. Mochida and H. Nagashima,
ChemCatChem, 2012, 4, 778–781; (j) P. A. Donets, K. Van
Hecke, L. Van Meervelt and E. V. Van der Eycken, Org. Lett.,
2
009, 11, 3618–3621; (k) T. Suda, K. Noguchi, M. Hirano and
Conflicts of interest
There are no conflicts to declare.
K. Tanaka, Chem. Eur. J., 2008, 14, 6593–6596; (l) S. Duan, K.
Cress, K. Waynant, E. Ramos-Miranda and J. W. Herndon,
Tetrahedron, 2007, 63, 2959–2965; (m) W. Xu, A. Kong and
X. Lu, J. Org. Chem., 2006, 71, 3854–3858; (n) J. M.
Concellón, H. Rodríguez-Solla and C. Concellón, Tetrahedron
Lett., 2004, 45, 2129–2131; (o) Y. Izawa, I. Shimizu and A.
Yamamoto, Bull. Chem. Soc. Jpn., 2004, 77, 2033–2045; (p) B.
Gabriele, G. Salerno, L. Veltri and M. Costa, J. Organomet.
Chem., 2001, 622, 84–88.
Acknowledgements
We thank Prof. Mitsuru Kondo (Shizuoka University) for
assistance with X-ray analysis. We also thank Mr. Takuto
Kajihara (Shizuoka University) for partial support of this
research. This work was supported financially in part by JSPS
Kakenhi Grant number 17K05858 from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
8
For synthetic utility of functionalized honopropargyl
alcohols, see: (a) X. Wang, M. Emoto, A. Sugimoto, Y.
Miyake, K. Itto, M. Amasaka, S. Xu, H. Hirata, H. Fujii and H.
Arimoto, Tetrahedron Lett., 2014, 55, 2146–2149; (b) P. A.
Allegretti and E. M. Ferreira, J. Am. Chem. Soc., 2013, 135,
1
7266–17269; (c) S. Chandrasekhar, S. V. Balaji and G.
Rajesh, Tetrahedron Lett., 2010, 51, 5164–5166; (d) L. S.
Hegedus, P. Ranslow, M. Achmatowicz, C. De Los Rios, C.
Hyland, E. M. Garcia-Frutos and S. Salman, Pure Appl. Chem.,
Notes and references
1
(a) Y. He, Z. Li, K. Robeyns, L. Van Meervelt and E. V. Van der
Eycken, Angew. Chem. Int. Ed., 2018, 57, 272–276; (b) T. L.
Vacala, P. R. Carlson, A. Arreola-Hester, C. G. Williams, E. W.
Makhoul and P. A. Vadola, J. Org. Chem., 2018, 83, 1493–
2
006, 78, 333–339; (e) T. M. Willson, P. Kocienski, K.
Jarowicki, K. Issac, A. Faller, S. F. Campbell and J. Bordner,
Tetrahedron, 1990, 46, 1757–1766; (f) A. G. M. Barrett, R. A.
E. Carr, S. V. Attwood, G. Richardson and N. D. A. Walshe, J.
Org. Chem., 1986, 51, 4840–4856.
Stannylated/silylated allenyl esters (or propargyl esters) have
been synthesized, see: (a) G. Chai, R. Zeng, C. Fu and S. Ma,
Eur. J. Org. Chem., 2013, 148–154; (b) P. Maity and S. D.
Lepore, J. Org. Chem., 2009, 74, 158–162; (c) C. Park and P.
H. Lee, Org. Lett., 2008, 10, 3359–3362; (d) M. A. Silvestri, D.
C. Bromfield and S. D. Lepore, J. Org. Chem., 2005, 70, 8239–
1
501; (c) D. A. Petrone, I. Franzoni, J. Ye, J. F. Rodríguez, A. I.
Poblador-Bahamonde and M. Lautens, J. Am. Chem. Soc.,
017, 139, 3546–3557; (d) T. Vacala, L. P. Bejcek, C. G.
Williams, A. C. Williamson and P. A. Vadola, J. Org. Chem.,
017, 82, 2558–2569; (e) L. Pawar and F. C. Pigge,
9
1
2
2
Tetrahedron Lett., 2013, 54, 6067–6070; (f) Y. Hayashi, F.
Inagaki and C. Mukai, Org. Lett., 2011, 13, 1778–1780; (g) W.
Hess and J. W. Burton, Adv. Synth. Catal. 2011, 353, 2966–
8
2
241; (e) S. D. Lepore, Y. He and P. Damisse, J. Org. Chem.,
004, 69, 9171–9175.
2
2
2
970; (h) A. Pinto, L. Neuville and J. Zhu, Tetrahedron Lett.,
009, 50, 3602–3605; (i) H. Imase and K. Tanaka, Chem. Lett.,
009, 38, 1152–1153; (j) S. Tang, P. Peng, S. F. Pi, Y. Liang, N.
0 For selected examples of enantioselective propargylation of
aldehydes with allenyl metal reagents, see: (a) T. Thaima, F.
Zamani, C. J. T. Hyland and S. G. Pyne, Synlett, 2017, 49,
X. Wang and J. H. Li, Org. Lett., 2008, 10, 1179–1182; (k) K.
M. Brummond, T. O. Painter, D. A. Probst and B. Mitasev,
Org. Lett., 2007, 9, 347–349; (l) W. S. Cheung, R. J. Patch and
M. R. Player, J. Org. Chem., 2005, 70, 3741–3744.
P. K. Mykhailiuk, Angew. Chem. Int. Ed., 2015, 54, 6558–
6
1
461–1480; (b) J. Chen, B. Captain and N. Takenaka, Org.
Lett., 2011, 13, 1654–1657; (c) S. Konishi, H. Hanawa and K.
Maruoka, Tetrahedron: Asymmetry, 2003, 14, 1603–1605;
2
3
(
d) S. E. Denmark and T. Wynn, J. Am. Chem. Soc., 2001, 123,
561.
6
199–6200; (e) C.-M. Yu, S.-K. Yoon, K. Baek and J.-Y. Lee,
(a) A. Baglieri, L. Meschisi, F. De Sarlo and F. Machetti, Eur. J.
Org. Chem., 2016, 4643–4655; (b) J. S. Oakdale, R. K. Sit and
V. V. Fokin, Chem. Eur. J., 2014, 20, 11101–11110; (c) L. Barr,
S. F. Lincoln and C. J. Easton, Chem. Eur. J., 2006, 12, 8571–
Angew. Chem. Int. Ed., 1998, 37, 2392–2395; (f) C.-M. Yu, S.-
K. Yoon, H.-S. Choi and K. Baek, Chem. Commun., 1997, 763–
7
64.
1
1 (a) T. Sengoku, K. Kokubo, M. Sakamoto, M. Takahashi and
H. Yoda, Org. Biomol. Chem., 2017, 15, 320–323; (b) M.
Takahashi, Y. Murata, F. Yagishita, M. Sakamoto, T. Sengoku
and H. Yoda, Chem. Eur. J., 2014, 20, 11091–11100; (c) Y.
Murata, M. Takahashi, F. Yagishita, M. Sakamoto, T. Sengoku
and H. Yoda, Org. Lett., 2013, 15, 6182–6185; (d) T. Suzuki, J.
Atsumi, T. Sengoku, M. Takahashi and H. Yoda, J.
8
580.
4
(a) L. Cao, R. Jiang, Y. Zhu, X. Wang, Y. Li and Y. Li, Eur. J. Org.
Chem., 2014, 2687–2693; (b) Q. Cai, J. Yan and K. Ding, Org.
Lett., 2012, 14, 3332–3335; (c) S. J. Coats, J. S. Link, D.
Gauthier and D. J. Hlasta, Org. Lett., 2005, 7, 1469–1472.
S. Kamijo, C. Kanazawa and Y. Yamamoto, J. Am. Chem. Soc.,
5
6
7
2
005, 127, 9260–9266.
Organomet. Chem., 2010, 695, 128–136; (e) T. Suzuki, T.
Sengoku, M. Takahashi and H. Yoda, Tetrahedron Lett., 2008,
S. Bonte, I. O. Ghinea, R. Dinica, I. Baussanne and M.
Demeunynck, Molecules, 2016, 21, 332.
4
9, 4701–4703.
(a) R. Zhang, Z.-Y. Gu, S.-Y. Wang and S.-J. Ji, Org. Lett., 2018,
1
2 (a) T. Sengoku, Y. Kamiya, A. Kawakami, M. Takahashi and H.
Yoda, Eur. J. Org. Chem., 2017, 6096–6098; (b) T. Sengoku, A.
Sugiyama, Y. Kamiya, R. Maegawa, M. Takahashi and H.
Yoda, Eur. J. Org. Chem., 2017, 1285–1288.
2
0, 5510–5514; (b) L. Veltri, S. V. Giofrè, P. Devo, R. Romeo,
A. P. Dobbs and B. Gabriele, J. Org. Chem., 2018, 83, 1680–
1
6
685; (c) B. Gao and H. Huang, Org. Lett., 2017, 19, 6260–
263; (d) B. Yu, P. Yang, X. Gao, Z. Z. Yang, Y. F. Zhao, H. Y.
Zhang and Z. M. Liu, New J. Chem., 2017, 41, 9250–9255; (e)
4
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
Journal Name
COMMUNICATION
1
3 (a) B. M. Trost, W. M. Seganish, C. K. Chung and D. Amans,
Chem. Eur. J., 2012, 18, 2948–2960; (b) S. G. Nelson, W. S.
Cheung, A. J. Kassick and M. A. Hilfiker, J. Am. Chem. Soc.,
1.077 and Flack absolute structure parameter = 0.03(5) for
View Article Online
3534 reflections and 220 parameters (CCDC deposition
DOI: 10.1039/C9OB00040B
number 1878739).
26 For a possible transition state, see Figure S2 in the
Supporting Information.
2
002, 124, 13654–13655; (c) H. Kagoshima, T. Uzawa and T.
Akiyama, Chem. Lett., 2002, 31, 298–299.
1
1
4 Regioisomer 2 was not observed throughout these
investigations.
5 The preparation of an ester analog of 1a resulted in failure
because stannylation of α-alkynyl ester gave complex
mixture under the comparable conditions.
6 Preparation of N-pentyl derivative of 3 met with failure
because purification of the reaction products was hampered
by their poor stability to silica gel. We also attempted to
synthesize γ-ethyl derivative of 1, however, stannylation of
N-phenyl-2-hexynamide under the optimized conditions
resulted in a complex mixture.
1
1
1
7 The reaction of acetophenone with 1a in the presence of
catalytic In(OTf) resulted in decomposition of the stannyl
3
reagent, indicating the high chemoselectivity of the reaction.
8 On the basis of the results in entries 2, 4, 6 and 8, transition
state of the reaction catalyzed with InCl
presumed to be similar, but not identical, to that with
2
In(OTf) and ZnCl . It seems that the main role of ZnCl in the
3 2
and ZnCl is
3
2
former reaction is not to affect the stereochemistry but
simply to increase the reaction rate.
1
9 (a) R. Takita, K. Yakura, T. Ohshima and M. Shibasaki, J. Am.
Chem. Soc., 2005, 127, 13760–13761; (b) Y.-C. Teo and T.-P.
Loh, Org. Lett., 2005, 7, 2539–2541; (c) Y.-C. Teo, J.-D. Goh
and T.-P. Loh, Org. Lett., 2005, 7, 2743–2745; (d) Y.-C. Teo,
K.-T. Tan and T.-P. Loh, Chem. Commun., 2005, 1318–1320.
0 Zinc chloride seems to promote dissociation of the allenyl
carbon-stannane bond based on the results of NMR
experiments (see Figure S1 in the Supporting Information).
1 The reaction of α-ketoester with 1a provided the
corresponding adduct 8 in good yield (75%), albeit with
2
2
7
5:25 er.
1a
O
InCl3, ZnCl2 (20 mol %)
HO CO Me
CONHPh
2
L8 (25 mol %)
CO2Me
8
MeCN (0.5 M), MS 3 Å
rt, 14 h
(
75%, 75:25 er)
2
2 We attempted to evaluate the effect of the amide N–H
group of 1 on the stereochemical outcome of the
propargylation. The reaction of benzaldehyde with 1e under
the optimum conditions resulted in a complex mixture.
Meanwhile, nonsubstituted allenyl stannane 1f gave the
corresponding product 4s in an almost racemic form. These
results indicate that the amide N–H group would play an
important role in good reaction efficiency as well as high
stereodifferentiation.
ArCHO
CON(Me)Ph
OH
CON(Me)Ph
InCl3, ZnCl2 (20 mol %)
L8 (25 mol %)

SnBu3
MeCN (0.5 M), MS 3 Å
rt, 18 h
4r
1e
ODPS (complex mixture)
ArCHO
InCl3, ZnCl2 (20 mol %)
L8 (25 mol %)
H
OH

SnBu3
MeCN (0.5 M), MS 3 Å
4s
1f
-20 °C, 3 h
ODPS (40%, 59:41 er)
2
2
2
3 D. Koszelewski, D. Paprocki, A. Brodzka and R. Ostaszewski,
Tetrahedron: Asymmetry, 2017, 28, 809–818.
4 H. D. Flack, Acta Crystallogr., Sect. A: Fundam. Crystallogr.,
1
983, 39, 876–881.
1 1 1
5 Crystal data for 6: orthorhombic, space group P2 2 2 , a =
5
.7177(5) Å, b = 7.7029(6) Å, c = 35.315(3) Å, V = 1555.4(2)
3
-3
-1
Å , Z = 4, ρ = 1.425 Mgm , μ(MoKα) = 0.265 mm , T = 173 K;
2
in the final least–squares refinement cycles on F , the model
converge at R1 = 0.0461 (I > 2σ(I)), wR2 = 0.1286, and GOF =
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins