Gold(I)-Catalyzed Cascade Cyclization of Anilines with Diynes: Controllable Formation of Eight-Membered Ring-Fused Indoles and Propellane-Type Indolines

Article abstract of DOI:10.1021/acs.joc.9b03256

Heterocycle-fused indoles or indolines are distributed widely in a variety of natural products, bioactive agents, and pharmaceuticals. Herein, we describe the development of gold-catalyzed cascade reactions of anilines with diynes to form eight-membered r

Full text of DOI:10.1021/acs.joc.9b03256

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Article
Gold(I)-Catalyzed Cascade Cyclization of Anilines with
Diynes: Controllable Formation of Eight-Membered
Ring-Fused Indoles and Propellane-Type Indolines
Ayuta Yamaguchi, Shinsuke Inuki, Yusuke Tokimizu, Shinya Oishi, and Hiroaki Ohno
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03256 • Publication Date (Web): 08 Jan 2020
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Gold(I)-Catalyzed Cascade Cyclization of Anilines
with Diynes: Controllable Formation of Eight-
Membered Ring-Fused Indoles and Propellane-Type
Indolines
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Ayuta Yamaguchi, Shinsuke Inuki*, Yusuke Tokimizu, Shinya Oishi, and Hiroaki Ohno*
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Abstract: Heterocycle-fused indoles or indolines are distributed widely in a variety of natural
products, bioactive agents and pharmaceuticals. Herein, we describe the development of gold-
catalyzed cascade reactions of anilines with diynes to form eight-membered ring-fused indoles and
propellane-type indolines, both of which proceed through an intramolecular 5-endo-dig
hydroamination followed by an 8-endo-dig cycloisomerization. Controllable formation of eight-
membered ring-fused indoles and propellane-type indolines was achieved through selection of the
ligands and/or solvents. Protic solvents such as alcohols or IPr ligands favored the formation of
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eight-membered ring-fused indoles, whereas the use of Buchwald’s type ligands and/or non-polar
solvents gave propellane-type indoline predominantly. This reaction provides rapid access to two
types of fused nitrogen heterocycles from simple aniline derivatives.
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INTRODUCTION
Heterocycle-fused indoles or indolines are core structures of various natural products, bioactive
agents and pharmaceuticals.1,2 Indoles fused with sp -rich medium-sized rings are important
3
3
scaffolds that escape ‘flatland’ compound libraries for drug discovery. Propellane-type indolines
bearing a clear three-dimensional structure are also attractive because appropriate functional
groups can be introduced to the indoline template in the desired direction. In view of these features,
considerable efforts have been made to explore efficient strategies for the synthesis of those
structures.4-6
Gold-catalyzed cascade reactions are powerful synthetic methods for the construction of medium-
5
sized ring-fused indoles. In 2006, Echavarren et al. developed a facile annulation of eight-
membered ring-fused indoles by cyclization with alkyne in the presence of Au(III) species
7
(Scheme 1A). Our group has reported a direct and concise synthetic method for the generation of
2,3-fused indoles, using a gold-catalyzed cascade cyclization of diynes through an intramolecular
cascade 5-endo-dig hydroamination followed by a 6- or 7-endo-dig cycloisomerization (Scheme
8
1
B). We also reported that gold-catalyzed cascade cyclization of 2-alkynyl-N-propargylanilines
provides propellane-type indolines via rearrangement of the propargyl group (Scheme 1C).9
Following these works, we have designed a direct synthetic method for the formation of eight-
membered ring-fused indoles, such as oxocine-fused indoles 2, through an intramolecular cascade
5-endo-dig hydroamination followed by an 8-endo-dig cycloisomerization (Scheme 1D). During
the course of this study, we found that a propellane-type indoline 3 was obtained as a side product.
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Echavarren and coworkers also observed related indoline formation in limited cases, depending
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on the substrate structure. However, controllable formation of these two heterocycles from easily
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available diyne substrates based on reaction conditions has not been reported. Herein, we report
ligand- and/or solvent-controlled divergent access to oxocine-fused indoles 2 and propellane-type
indolines 3 via gold-catalyzed cascade cyclization (Scheme 1D).
Scheme 1. Related researches and this work.
RESULTS AND DISCUSSION
We initiated our study by optimizing the reaction conditions of the cascade cyclization of the N-
methylaniline 1a bearing two alkyne moieties (Table 1). The reaction of 1a with 5 mol %
PPh
3
AuNTf
2
in i-PrOH at 80 °C yielded no observation of the desired oxocine-fused indole 2a
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(
entry 1). Changing the catalyst to IPrAuNTf
along with, unexpectedly, a propellane-type indoline 3a in 27% yield (entry 2). Use of
IPrAuSbF ·MeCN caused a decrease in the yield of 2a (42%, entry 3). The reaction in MeOH and
2
gave the oxocine-fused indole 2a in 65% yield
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EtOH improved the yield of 2a (74% and 82%, entries 4 and 5). Interestingly, when using 1,2-
dichloroethane or toluene instead of i-PrOH as a solvent, the selectivity was switched, resulting in
the favorable production of the propellane-type indoline 3a (entries 6 and 7). Further investigation
revealed that the reaction with Buchwald’s type ligands such as JohnPhos or BrettPhos instead of
IPr also gave indoline 3a as the major form (entries 8–10). Taken together, choices of the catalysts
and/or solvents were found to be crucial for controlling the formation of the two different products:
the use of IPr ligands and alcoholic solvents provided the oxocine-fused indole 2a predominantly,
whereas the use of Buchwald’s type ligands and/or non-polar solvents favored the formation of
propellane-type indoline 3a.
Table 1. Optimization of the reaction conditions.
b,c
Yield (%)
a
Entry
Catalyst
solvent
Temp (℃)
2
a
3a
0
1
2
3
4
5
6
7
8
PPh
3
AuNTf
2
i-PrOH
i-PrOH
i-PrOH
MeOH
EtOH
80
80
80
60
60
80
80
80
0
IPrAuNTf
2
65
42
27
IPrAuSbF
6
·MeCN
25
IPrAuNTf
IPrAuNTf
IPrAuNTf
IPrAuNTf
2
2
2
2
74
9
82 (85)
4
11 (7)
86
DCE
toluene
i-PrOH
10
66
JohnPhosAuNTf
2
8 (8)
88 (81)
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JohnPhosAuSbF
6
·MeCN
i-PrOH
i-PrOH
80
80
6
8
86
80
1
0
BrettPhosAuNTf
2
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a
b
1
The ligand structures are shown above. Determined by H NMR spectroscopy using 1,2,4,5-
tetrachloro-3-nitrobenzene as an internal standard. Yields in parentheses are the isolated yield on
a 1.0 mmol scale.
c
With the two optimized reaction conditions for the formation of 2a (Table 1, entry 5 as condition
A) and 3a (entry 8 as condition B) in hand, we proceeded to evaluate the substrate scope of the
reaction (Table 2). The use of anilines with halogen (F, Cl, Br) groups at the m-position to the
alkyne resulted in the formation of the desired products 2b (68%), 2c (64%) and 2d (62%) under
condition A, and 3b (67%), 3c (79%) and 3d (82%) under condition B (entries 1–6). Anilines 1e
and 1f bearing an electron-donating methyl or methoxy group also gave the desired fused-indoles
2
e/f and indolines 3e/f (entries 7-10). Unfortunately, an electron-withdrawing cyano group-
containing substrate 1g gave much lower yields of 2g (17% under condition A) and no propellane-
type indoline products using both conditions (entries 11 and 12). The indole immediate resulting
from the first cyclization was observed. Thus, the poor yields of 2g can be explained by the low
nucleophilicity of the indole intermediate, assuming that a cyano group does not inhibit these
reactions (vide infra, Table 3). The influence of the substituted position of the aniline substrates
on the reaction course was evaluated using Br substituted derivatives. In the case of the aniline 1h
bearing a Br group at the o-position to the alkyne (entries 13 and 14), the reaction under condition
A produced no oxocine-fused indole, whereas the reaction under condition B furnished propellane-
type indoline 3h in a moderate yield (44%). When using m- or p-brominated anilines 1i and 1j,
respectively, the cascade reaction worked well to provide the corresponding oxocine-fused indoles
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i (64%) and 2j (71%) under condition A, and propellane-type indolines 3i (79%) and 3j (80%)
under condition B (entries 15–18). These results clearly demonstrated that steric repulsion between
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the o-Br group and phenyl group interferes with the formation of the oxocine of 2h.
Table 2. Substrate scope (1).
Product
Isolated Yield)
Entry
Substrate
Condn.
(
Ph
O
R1
NH
Me
1
2
A
B
2b (68%)
2b (22%)
3b (3%)
1
b
1
(
R = F)
3b (67%)
3
4
A
B
2c (64%)
2c (13%)
3c (trace)
3c (79%)
1
c
1
(
R = Cl)
5
6
A
B
2d (62%)
2d (11%)
3d (6%)
1d
1
(R = Br)
3d (82%)
7
8
A
B
2e (77%)
2e (6%)
3e (3%)
1
e
1
(R = Me)
3e (77%)
9
A
B
2f (75%)
2f (16%)
3f (5%)
1
f
1
(
R = OMe)
1
0
3f (65%)
a
1
1
1
2
A
2g (17%)
2g (5%)
3g (0%)
3g (0%)
1
g
1
(
R = CN)
B
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A
B
2h (0%)
2h (0%)
3h (0%)
1
h
3h (44%)
b
1
1
5
6
A
B
2i (64%)
2i (6%)
3i (<19% )
1
i
3i (79%)
1
7
A
B
2j (71%)
2j (9%)
3j (trace)
3j (80%)
1j
18
a
The second portion of IPrAuNTf
2
(5 mol %) was added after the reaction mixture was stirred for
b
6.5 h. Containing small amounts of impurities.
Next, the substrate scope at the terminal phenyl ring was explored (Table 3). Electron-
withdrawing halogen (Br, Cl) and cyano substituents at the p-position on the phenyl rings were
tolerated by both conditions (2k: 73%, 2l: 56% and 2m: 73% under condition A, and 3k: 77%, 3l:
69% and 3m: 74% under condition B). The reactions of 1n or 1o bearing an electron-donating
groups (Me or MeO) at the p-position gave the corresponding fused indoles 2n and 2o in moderate
1
1
8
or low yields using condition A (53% and 22% , respectively, entries 7 and 9). In contrast, the
reaction of 1n and 1o under condition B gave the desired indolines 3n and 3o, respectively, in
good yields (76% and 67%, entries 8 and 10). The evaluation of the substitution position on the
phenyl ring was performed using Cl-substituted derivatives. The m-chloro derivative 1p underwent
the desired reaction to afford the corresponding 2p and 3p in good yields (entries 11 and 12). The
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o-Cl derivative 1q showed good reactivity to afford the fused indole 2q in 70% yield, whereas
condition B was less efficient, resulting in a lower yield of 2q (27%) and selectivity (2p:3p = ca.
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1:1; entry 14). The aniline 1r bearing a naphth-2-yl group instead of a phenyl group provided the
desired products 2r and 3r in 63% and 52% yields, respectively (entries 15 and 16). In contrast,
the aniline 1s bearing a methyl group at the alkyne terminus displayed low reactivity in the
formation of 2s and 3s (entries 17 and 18). In this case, using DCE as the solvent, afforded the
propellane-type indoline 3s in good yield (82%, entry 19).
Table 3. Substrate scope (2).
Substrate
Product
(Isolated Yield)
Entry
2
Condn.
(
R )
a
1
2
A
B
2k (73%)
2k (8%)
3k (<10% )
1
k
2
(R = Cl)
3k (77%)
a
3
4
A
B
2l (56%)
2l (4%)
3l (<15% )
1
l
2
(R = Br)
3l (69%)
a
5
6
A
B
2m (73%)
2m (6%)
3m (<11% )
1
m
2
(R = CN)
3m (74%)
b
7
8
A
2n (53%)
2n (10%)
3n (12%)
3n (76%)
1
n
2
(R = Me)
B
b
a
9
A
2o (22%)
3o (<14% )
1o
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(R = OMe)
1
0
B
2o (0%)
3o (67%)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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5
5
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1
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a
1
1
1
2
A
B
2p (71%)
2p (8%)
3p (<7% )
1p
3p (74%)
a
1
1
3
4
A
B
2q (70%)
2q (27%)
3q (<12% )
1q
3q (26%)
a
15
A
B
2r (63%)
2r (0%)
3r (<9% )
1r
1
6
3r (52%)
c
1
1
7
8
A
2s (16%)
2s (5%)
3s (8%)
3s (34%)
3s (82%)
1s
B
d
19
C
2s (trace)
a
b
Containing small amounts of impurities. The second portion of IPrAuNTf
after the reaction mixture was stirred for 1 h. The reaction was carried out in i-PrOH using
IPrAuNTf (5 mol %) and MS3Å at 80 °C. The reaction was carried out under entry 6 of Table
2
(5 mol %) was added
c
d
2
1
.
We next examined the reaction of substrates bearing a variety of functional groups on anilines
and linker moieties (Table 4). The use of unprotected aniline derivative 1t provided the desired
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products 2t and 3t in low yields under respective conditions (entries 1 and 2). Changing the methyl
group to a benzyl group did not affect the cascade reaction (entries 3 and 4). When using 1v bearing
a shorter carbon tether (n = 0), the seven-membered ring-fused indole 2v was obtained in 63%
yield (condition A) and 44% yield (condition B). However, no propellane-type indoline 3v was
observed under both conditions (entries 5 and 6), presumably because of the ring strain in 3v. The
use of 1w bearing a longer carbon tether (n = 2) did not afford the nine-membered ring-fused
indoles 2w; however, the propellane-type indoline 3w was produced under condition B but in low
yield (28%, entry 8). In sharp contrast, treatment of sulfonamide 1x under conditions A and B
produced only the ring-fused indole 2x (67% and 63%, respectively) without producing the
propellane-type indoline 3x (entries 9 and 10).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 4. Substrate scope (3).
Substrate
(R , n, Z)
Product
(Isolated Yield)
Entry
3
Condn.
1
2
A
B
2t (32%)
3t (7%)
1
t
(H, 1, O)
2t (0%)
3t (18%)
3
4
A
B
2u (56%)
2u (8%)
3u (trace)
3u (77%)
1u
(Bn, 1, O)
5
A
2v (63%)
3v (0%)
1v
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(Me, 0, O)
6
B
2v (44%)
3v (0%)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
8
A
B
2w (0%)
2w (0%)
3w (0%)
1w
(Me, 2, O)
3w (28%)
9
A
B
2x (63%)
2x (67%)
3x (0%)
3x (0%)
1
x
(Me, 1, NTs)
10
We conducted several experiments to gain insight into the mechanism of the cascade reaction
Scheme 2). Initially, the cascade reaction was performed at lower temperature (40 °C), which
(
resulted in the production of an allene 4a as a plausible intermediate, along with the fused indole
2
a and indoline 3a. Interestingly, allene 4a subjected to condition A (favoring the formation of the
9
oxocine-fused indoles 2) afforded 2a (4%) and 3a (91%). These results strongly indicated that the
allene 4a is the intermediate of the propellane-type indoline 3a and not the oxocine-fused indole
2
a.
Scheme 2. Gold-catalyzed cyclization of 1a.
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1
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1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Next, an optically active 1y with a methyl group at the propargylic position was prepared. We
first expected that the cascade reaction of 1y would give the corresponding optically active
oxocine-fused indole 2y as a single enantiomer, via 5-endo-dig hydroamination and 8-endo-dig
cycloisomerization followed by protodeauration of 1yC (Scheme 3). Quite surprisingly, the
reaction of (S)-1y under condition A provided the fused indole 2y (35% yield) and the indoline 3y
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(35% yield) with complete loss of optical activity [The reaction of (S)-1y under condition B gave
1
2
the oxocine-fused indole 2y (<31 %, 0 % ee) without providing propellane-type indoline 3y] .
Additionally, the reaction of 1y was conducted with the shorter reaction time or the lower reaction
temperature to give the corresponding allene intermediates 4y, whose optical activities were also
13
lost completely. These results suggested that the catalytic cycle involves the formation of an
achiral cationic intermediate such as 1yD, resulting from the ring-opening reaction of vinyl-gold
7
b
intermediate 1yC. Formation of racemic 2y and 3y is rationalized by gold-catalyzed cyclization
of the vinyl-gold derivative 1yD. However, racemization of the optically active allene 4y by the
action of the gold catalyst cannot be ruled out.14
Scheme 3. Gold-catalyzed cyclization of 1y.
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On the basis of these experiments, a proposed reaction mechanism is shown in Scheme 4. As
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
reported in our previous work, activation of the alkyne by cationic gold, as depicted in A,
promotes 5-endo-dig cyclization followed by protodeauration to give the indole 5. Subsequently,
the activation of the second alkyne leads to the 8-endo-dig hydroarylation of 5 to form a vinyl-
gold intermediate C. The eight-membered ring of intermediate C is easily opened to generate a
cationic intermediate D, which could return to C by nucleophilic attack of the hydroxy group to
the highly reactive conjugated diene. Intermediate C undergoes protodeauration to generate the
oxocine-fused indole 2. Alternatively, elimination of gold from intermediate D may occur to
1
5
9
provide allene 4, which is converted to the propellane-type indoline 3, as we reported previously.
The reverse reaction of allene 4 to vinyl-gold C should be much slower than formation of G
because the reaction of 4a produced only a small amount of 2a under condition A (4%, Scheme
2
). Noteworthy, Bi et al. have computationally demonstrated that direct formation of the cationic
intermediate G from E by reaction at the indole 2 position is favored over the ring expansion
pathway through the four-membered ring F.16
The significant effects of the reaction solvent and ligand can be partly rationalized as follows:
protic solvents such as alcohol promote protodeauration of vinyl-gold intermediate C, thus
contributing to the formation of oxocine-fused indoles (Table 1, entries 2–5). Electron-donating
ligands such as IPr ligands are also known to accelerate protodeauration,17 resulting in the
predominant formation of the fused indoles. However, further investigation is necessary to
elucidate the effects of the ligand.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4. Proposed reaction mechanism.
CONCLUSION
In conclusion, we have developed controllable formation of eight-membered ring-fused indoles
and propellane-type indolines via gold-catalyzed cascade cyclization. This reaction gives quick
access to various ring-fused indoles and indolines from simple aniline derivatives, depending on
the ligands or solvents employed. Examination with an aniline derivative bearing a chiral center
demonstrated that these types of cascade cyclization reactions proceed via the ring-opened
intermediate D. Further studies including an investigation of the exact reaction mechanism and
application to the synthesis of biologically-active compounds are now in progress.
EXPERIMENTAL SECTION
1
General Methods. H NMR spectra were recorded using a JEOL ECA-500 spectrometer at 500
MHz frequency. Chemical shifts are reported in δ (ppm) relative to Me
4
Si [in CDCl or DMSO]
3
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1
3
as internal standard. C NMR spectra were recorded using a JEOL ECA-500 and a JNM ECZ600R,
and referenced to the residual solvent signal. IR spectra were obtained on a JASCO FT/IR-4100
spectrometer. Exact mass (HRMS) spectra were recorded on a Shimadzu LC-ESI-IT-TOF-MS
equipment (ESI). Column chromatography was performed using a forced flow (flash
chromatography) of the indicated solvent system on Wakogel C-300E (Wako), Chromatorex NH-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0

DM1020 (Fuji Silysia) or Biotage Isolera flash purification system on Presep Silica Gel Type M


(Wako), Presep Silica Gel Type L (Wako) or Biotage ZIP ISOLUTE NH (Biotage). All the
heating experiments were performed in an oil bath. The Compounds S1b, S1c, S1g, S1i, S1j, S3a,
1
8
19
20
9
9
9
S3b, S3c are commercially available. The known Compounds S1h , S1j , S2a , S2d , S2e , S2f ,
9
21
22
23
24
25
1
S2k , S3d , S4 , S5f , S5g , S6 were synthesized according to the literatures. The H NMR
26
27
28
spectra of S2c , S2g and S5b were in good accordance with those reported in literature.
Structures of S1a, S1b, S1c, S1g, S1h, S1i, S1j, S2a-S2j, S3a-S3d, S4, S5a-S5e, S6, S7, S8 are
shown in Schemes S1-S5.
Preparation of the Cyclization Precursor.
4
-Fluoro-2-iodo-N-methylaniline (S2b). To a stirred solution of 4-fluoro-2-iodoaniline (S1b)
1.16 g, 4.90 mmol) in THF (16 mL) was added MeLi (1.16 M in Et O; 4.65 mL, 5.39 mmol) at ‒
8 ℃ under argon. After the mixture was stirred for 1 h at this temperature, MeI (0.366 mL, 5.89
mmol) was added to the mixture. The mixture was gradually warmed to room temperature and
stirred for 12 h at this temperature. The reaction was quenched with saturated aqueous NH Cl. The
resulting mixture was extracted with EtOAc twice. The combined organic layer was washed with
brine, dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (hexane/EtOAc = 40/1) to give S2b (630 mg, 51%) as a red oil; IR
(
2
7
4
2
4
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-
1
1
(
neat cm ): 3408 (NH); H NMR (500 MHz, CDCl
3
) δ: 2.83 (s, 3H), 3.95-4.04 (br m, 1H), 6.45
(
dd, J = 8.9, 4.9 Hz, 1H), 6.98 (ddd, J = 8.9, 8.9, 2.9 Hz, 1H), 7.40 (dd, J = 8.0, 2.9 Hz, 1H);
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
C{ H} NMR (125 MHz, CDCl ) δ: 31.5, 83.4 (d, JC-F = 8.4 Hz), 109.5 (d, JC-F = 7.2 Hz), 115.8
3
(
d, JC-F = 21.6 Hz), 125.3 (d, JC-F = 25.2 Hz), 145.1 (d, JC-F = 2.4 Hz), 154.5 (d, JC-F = 238.7 Hz);
+
HRMS (ESI-TOF) m/z: [M + H] calcd for C
7
7
H FIN 251.9680; found 251.9679.
4
-Chloro-2-iodo-N-methylaniline (S2c). According to the procedure described for the
preparation of S2b, 4-chloro-2-iodoaniline (S1c) (991 mg, 3.91 mmol) was converted into S2c
271 mg, 26%) by the reaction with MeLi (1.16 M in Et O; 4.05 mL, 4.69 mmol) and MeI (292
(
2
L, 4.69 mmol) in THF (6.5 mL) at ‒78 ℃ to room temperature for 5 h. Column chromatography:
1
silica gel (gradient 1% to 5% EtOAc in hexane); H NMR (500 MHz, CDCl
3
) δ: 2.87 (d, J = 5.2
Hz, 3H), 4.15-4.24 (br m, 1H), 6.45 (d, J = 8.6 Hz, 1H), 7.20 (dd, J = 8.6, 2.3 Hz, 1H), 7.62 (d, J
1
26
= 2.3 Hz, 1H). The H NMR spectra was in good agreement with that reported.
3-Iodo-4-(methylamino)benzonitrile (S2g). According to the procedure described for the
preparation of S2b, 4-amino-3-iodobenzonitrile (S1g) (452 mg, 1.85 mmol) was converted into
S2g (210 mg, 44%) by the reaction with MeLi (1.16 M in Et O; 1.91 mL, 2.22 mmol) and MeI
2
(150 L, 2.41 mmol) in THF (6.2 mL) at ‒78 ℃ to room temperature for 1 h. Column
1
chromatography: silica gel (hexane/EtOAc = 10/1); H NMR (400 MHz, CDCl
3
) δ: 2.94 (d, J =
5
.2 Hz, 3H), 4.76-4.85 (br m, 1H), 6.49 (d, J = 8.6 Hz, 1H), 7.48 (dd, J = 8.6, 1.7 Hz, 1H), 7.88
1
(
d, J = 1.7 Hz, 1H). The H NMR spectra was in good agreement with that reported.27
3-Bromo-2-iodo-N-methylaniline (S2h). According to the procedure described for the
preparation of S2b, 3-bromo-2-iodoaniline (S1h) (244 mg, 0.818 mmol) was converted into S2h
78.9 mg, 31%) by the reaction with MeLi (1.16 M in Et O; 0.847 mL, 0.982 mmol) and MeI (65.9
(
2
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8
9

L, 1.06 mmol) in THF (2.7 mL) at ‒78 ℃ to room temperature for 10 h. Column chromatography:
(
gradient 1% to 5% EtOAc in hexane) and amine silica gel (hexane only); colorless oil; IR (neat
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
1
cm ): 3401 (NH); H NMR (500 MHz, CDCl
3
) δ: 2.88 (d, J = 5.2 Hz, 3H), 4.47-4.58 (br m, 1H),
1
3
1
6.43 (d, J = 8.0 Hz, 1H), 7.00 (dd, J = 8.0, 1.1 Hz, 1H), 7.10 (dd, J = 8.0, 8.0 Hz, 1H); C{ H}
NMR (125 MHz, CDCl
3
) δ: 31.4, 92.0, 107.7, 120.8, 130.1, 130.5, 150.6; HRMS (ESI-TOF) m/z:
+
[M + H] calcd for C
7
H
8
BrIN 311.8879; found 311.8874.
5
-Bromo-2-iodo-N-methylaniline (S2i). According to the procedure described for the
preparation of S2b, 5-bromo-2-iodoaniline (S1i) (473 mg, 1.59 mmol) was converted into S2i (335
mg, 68%) by the reaction with MeLi (1.16 M in Et O; 1.64 mL, 1.91 mmol) and MeI (129 L,
.06 mmol) in THF (5.3 mL) at ‒78 ℃ to room temperature for 10 h. Column chromatography:
2
2
-1
1
(
gradient 1% to 5% EtOAc in hexane); yellow solid; mp 78-80 ℃; IR (neat cm ): 3401 (NH); H
NMR (500 MHz, CDCl ) δ: 2.87 (d, J = 5.2 Hz, 3H), 4.23-4.29 (br m, 1H), 6.57 (dd, J = 8.6, 2.3
3
13
1
Hz, 1H), 6.64 (d, J = 2.3 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H); C{ H} NMR (125 MHz, CDCl
3
) δ:
+
30.8, 82.7, 112.7, 121.1, 123.7, 139.6, 149.2; HRMS (ESI-TOF) m/z: [M + H] calcd for C
7
H
8
BrIN
311.8879; found 311.8880.
[3-(But-3-yn-1-yloxy)prop-1-yn-1-yl]benzene (S5a). To a suspension of NaH (532 mg, 13.3
mmol) in anhydrous THF (15 mL) at 0 ℃ was added dropwise 3-butyn-1-ol (S3a) (777 mg, 11.1
mmol). After the mixture was stirred for 30 min, a solution of (3-bromoprop-1-yn-1-yl)benzene
(S4) (2.38 g, 12.2 mmol) in THF (3.5 mL) was added to the reaction mixture at 0 ℃. The mixture
was stirred at room temperature for additional 7.5 h, and then diluted with water. The resulting
mixture was extracted with EtOAc twice. The combined organic layer was washed with brine,
dried over Na
2
SO , filtered, and concentrated in vacuo. The residue was purified by column
4
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
chromatography on silica gel (gradient 1% to 5% EtOAc in hexane) to give S5a (1.46 g, 73%) as
-1
1
a yellow oil; IR (neat cm ): 2235 (C≡C); H NMR (500 MHz, CDCl
3
) δ: 2.02 (t, J = 2.9 Hz, 1H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
2.54 (td, J = 6.9, 2.9 Hz, 2H), 3.73 (t, J = 6.9 Hz, 2H), 4.43 (s, 2H), 7.28-7.34 (m, 3H), 7.43-7.47
1
3
1
(
m, 2H); C{ H} NMR (125 MHz, CDCl
3
) δ: 19.7, 58.9, 67.9, 69.4, 81.0, 84.7, 86.4, 122.5, 128.3
+
(
2C), 128.5, 131.7 (2C); HRMS (ESI-TOF) m/z: [M + Na] calcd for C13
H12NaO 207.0780; found
207.0779.
[
3-(Prop-2-yn-1-yloxy)prop-1-yn-1-yl]benzene (S5b). According to the procedure described
for the preparation of S5a, pent-4-yn-1-ol (S3b) (0.135 mL, 2.29 mmol) was converted into S5b
155 mg, 40%) by the reaction with S4 (491 mg, 2.52 mmol) in THF (1.3 mL), NaH (82.3 mg,
(
3.43 mmol) in THF (2.5 mL) at room temperature for 5 h. Column chromatography: silica gel
1
(
gradient 1% to 3% EtOAc in hexane); H NMR (500 MHz, CDCl
3
) δ: 2.48 (t, J = 2.4 Hz, 1H),
1
4.33 (d, J = 2.4 Hz, 2H), 4.50 (s, 2H), 7.30-7.50 (m, 5H). The H NMR spectra was in good
agreement with that reported.28
[3-(Hex-5-yn-1-yloxy)prop-1-yn-1-yl]benzene (S5c). According to the procedure described for
the preparation of S5a, pent-4-yn-1-ol (S3c) (0.221 mL, 2.38 mmol) was converted into S5c (382
mg, 81%) by the reaction with S4 (464 mg, 2.38 mmol) in THF (1.0 mL), NaH (105 mg, 2.62
mmol) in THF (2.0 mL) at room temperature for 6.5 h. Column chromatography: silica gel
-1
1
(
gradient 1% to 5% EtOAc in hexane); yellow oil; IR (neat cm ): 2335 (C≡C); H NMR (500
MHz, CDCl ) δ: 1.85 (tt, J = 6.3, 6.3 Hz, 2H), 1.95 (t, J = 2.6 Hz, 1H), 2.33 (td, J = 6.3, 2.6 Hz,
H), 3.69 (t, J = 6.3 Hz, 2H), 4.37 (s, 2H), 7.28-7.33 (m, 3H), 7.42-7.47 (m, 2H); C{ H} NMR
3
1
3
1
2
(125 MHz, CDCl
3
) δ: 15.2, 28.5, 58.9, 68.4, 68.5, 83.8, 85.2, 86.1, 122.6, 128.2 (2C), 128.4, 131.7
+
(
2C); HRMS (ESI-TOF) m/z: [M + H] calcd for C14
H15O 199.1117; found 199.1118.
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N-(But-3-yn-1-yl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide
(S5d).
A
mixture of N-(but-3-yn-1-yl)-4-methylbenzenesulfonamide (S3d) (185 mg, 0.829 mmol) and
CO (229 mg, 1.66 mmol) in dry MeCN (6.0 mL) was added S4 (178 mg, 0.911 mmol) in dry
1
1
1
1
1
1
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1
1
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2
2
2
2
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7
8
9
0
K
2
3
MeCN (2.3 mL) at room temperature. The mixture was stirred under reflux for 2 h, and then diluted
with water. The resulting mixture was extracted with EtOAc twice. The combined organic layer
was washed with brine, dried over Na
2
SO , filtered, and concentrated in vacuo. The residue was
4
purified by column chromatography on silica gel (gradient 6% to 19% EtOAc in hexane) to give
-1
S5d (261 mg, 93%) as a white solid; mp 84-85 ℃; IR (neat cm ): 2253 (C≡C), 1160 (S=O), 1348
1
(
S=O); H NMR (500 MHz, CDCl
3
) δ: 2.03 (t, J = 2.6 Hz, 1H), 2.34 (s, 3H), 2.57 (td, J = 7.4, 2.6
Hz, 2H), 3.44 (t, J = 7.4 Hz, 2H), 4.42 (s, 2H), 7.09 (d, J = 8.6 Hz, 2H), 7.22-7.30 (m, 5H), 7.78
1
3
1
(
d, J = 8.6 Hz, 2H); C{ H} NMR (125 MHz, CDCl ) δ: 19.0, 21.4, 38.1, 45.5, 70.3, 80.8, 81.7,
3
85.6, 121.9, 127.6 (2C), 128.1 (2C), 128.5, 129.5 (2C), 131.4 (2C), 135.7, 143.6; HRMS (ESI-
+
TOF) m/z: [M + H] calcd for C20
H
19NO S 338.1209; found 338.1205.
2
(S)-[3-(But-3-yn-1-yloxy)but-1-yn-1-yl]benzene (S5e). To a suspension of NaH (651 mg, 16.3
mmol) in anhydrous THF (16 mL) at 0 ℃ was added dropwise a solution of (S)-4-phenylbut-3-
yn-2-ol (S6) (1.83 g, 12.5 mmol) in THF (4.9 mL). After the mixture was stirred for 30 min, 3-
bromopropan-1-ol (2.09 g, 15.0 mmol) was added to the reaction mixture at 0 ℃. The mixture was
stirred at room temperature for additional 7 h, and then diluted with water. The resulting mixture
was extracted with EtOAc twice. The combined organic layer was washed with brine, dried over
Na
2
SO , filtered, and concentrated in vacuo. The residue was purified by column chromatography
4
on silica gel (gradient 5% to 30% EtOAc in hexane) to give S7 (1.14 g, <45%), including
inseparable impurities, as a yellow oil. To a solution of S7 (1.14 g, ca. 7.80 mmol) including
impurities in CH
2
Cl (7.8 mL) were added TEMPO (122 mg, 0.78 mmol) and DAIB (2.77 g, 8.59
2
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5
6
mmol) at room temperature. After being stirred for 2 h, the mixture was washed with a saturated
aqueous solution of Na
were washed with aqueous NaHCO
vacuo to give crude S8 as a red oil. To a solution of crude S8 in MeOH (9.8 mL) were added
Bestmann Reagent (1.65 g, 8.59 mmol) and K CO (1.29 g, 9.37 mmol) at 0 ℃. The mixture was
warmed to room temperature and stirred for 2 h. The reaction was quenched with saturated aqueous
NH Cl. The resulting mixture was extracted with EtOAc twice. The combined organic layer was
washed with brine, dried over Na SO , filtered, and concentrated in vacuo. The residue was
2
S
2
O
3
and extracted with CH
2
Cl
2
twice. The combined organic extracts
0
1
2
3
4
5
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7
8
9
0
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2
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4
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7
8
9
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2
3
4
5
6
7
8
9
0
3
and brine, dried over Na
2
SO , filtered, and concentrated in
4
2
3
4
2
4
purified by column chromatography on silica gel (gradient 2% to 5% EtOAc in hexane) to give
S5e (352 mg, 23%, 2 steps) as a colorless oil; []25
-1
D
‒150.0 (c 1.24, CHCl
3
); IR (neat cm ): 2249
1
(
C≡C); H NMR (500 MHz, CDCl
3
) δ: 1.52 (d, J = 6.7 Hz, 3H), 2.00 (t, J = 2.7 Hz, 1H), 2.52 (ddd,
J = 7.0, 7.0, 2.7 Hz, 2H), 3.60 (dt, J = 12.6, 7.0 Hz, 1H), 3.90 (dt, J = 12.6, 7.0 Hz, 1H), 4.43 (q, J
1
3
1
=
6.7 Hz, 1H), 7.27-7.32 (m, 3H), 7.41-7.46 (m, 2H); C{ H} NMR (125 MHz, CDCl ) δ: 19.8,
3
22.0, 65.8, 66.6, 69.3, 81.1, 85.0, 88.7, 122.5, 128.2 (2C), 128.3, 131.6 (2C); HRMS (ESI-TOF)
+
m/z: [M + H] calcd for C14
H15O 199.1117; found 199.1123.
N-Methyl-2-{4-[(3-phenylprop-2-yn-1-yl)oxy]but-1-yn-1-yl}aniline (1a). A mixture of 2-
iodo-N-methylaniline (S2a) (1.43 g, 6.1 mmol), S5a (1.24 g, 6.7 mmol), PdCl (PPh (216 mg,
.3 mmol), CuI (58.0 mg, 0.3 mmol), and Et N (2.7 mL, 18 mmol) in DMF (20 mL) was stirred at
room temperature under Ar for 11 h. The mixture was diluted with saturated aqueous NH Cl. The
resulting mixture was extracted with EtOAc twice. The combined organic layer was washed with
brine, dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (hexane/acetone = 20/1) to give 1a (1.03 g, 58%) as a purple oil; IR
2
)
3 2
0
3
4
2
4
-1
1
(
neat cm ): 3297 (NH); H NMR (500 MHz, CDCl ) δ: 2.82 (t, J = 6.9 Hz, 2H), 2.87 (d, J = 5.2
3
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Hz, 3H), 3.82 (t, J = 6.9 Hz, 2H), 4.46 (s, 2H), 4.69-4.74 (br m, 1H), 6.55 (d, J = 8.0 Hz, 1H), 6.59
(dd, J = 8.0, 8.0 Hz, 1H), 7.18 (dd, J = 8.0, 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.28-7.34 (m,
1
1
1
1
1
1
1
1
1
1
2
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2
2
2
2
2
2
2
3
3
3
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3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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0
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3
1
3
8
H), 7.43-7.47 (m, 2H); C{ H} NMR (125 MHz, CDCl ) δ: 21.0, 30.2, 58.9, 68.3, 78.4, 84.9,
3
6.4, 92.2, 107.7, 108.7, 115.9, 122.5, 128.3 (2C), 128.5, 129.4, 131.7 (3C), 150.0; HRMS (ESI-
+
TOF) m/z: [M + H] calcd for C20
H20NO 290.1539; found 290.1540.
4
-Fluoro-N-methyl-2-{4-[(3-phenylprop-2-yn-1-yl)oxy]but-1-yn-1-yl}aniline
According to the procedure described for the preparation of 1a, 4-fluoro-2-iodo-N-methylaniline
S2b) (293 mg, 1.17 mmol) was converted into 1b (247 mg, 69%) by the reaction with S5a (236
mg, 1.28 mmol), PdCl (PPh (40.9 mg, 0.0583 mmol), CuI (11.1 mg, 0.0583 mmol) and Et
0.51 mL) in DMF (3.9 mL) at room temperature for 6 h. Column chromatography: silica gel
(1b).
(
2
3
)
2
3
N
(
(
-1
1
hexane/acetone = 20/1) : yellow oil; IR (neat cm ): 3422 (NH); H NMR (500 MHz, CDCl
.82 (t, J = 6.9 Hz, 2H), 2.85 (d, J = 5.2 Hz, 3H), 3.82 (t, J = 6.9 Hz, 2H), 4.46 (s, 2H), 4.52-4.59
(br m, 1H), 6.45 (dd, J = 8.9, 4.9 Hz, 1H), 6.91 (ddd, J = 8.9, 8.9, 2.9 Hz, 1H), 6.97 (dd, J = 8.9,
3
) δ:
2
13
1
2
.9 Hz, 1H), 7.28-7.35 (m, 3H), 7.43-7.47 (m, 2H); C{ H} NMR (125 MHz, CDCl
3
) δ: 20.9,
30.7, 59.0, 68.1, 77.5, 84.7, 86.5, 93.2, 108.2 (d, JC-F = 9.6 Hz), 109.3 (d, JC-F = 8.4 Hz), 116.1 (d,
JC-F = 22.8 Hz), 117.9 (d, JC-F = 22.8 Hz), 122.4, 128.3 (2C), 128.5, 131.7 (2C), 146.8, 154.2 (d,
+
J
C-F = 233.9 Hz); HRMS (ESI-TOF) m/z: [M + H] calcd for C20
H
19FNO 308.1445; found
308.1450.
4
-Chloro-N-methyl-2-{4-[(3-phenylprop-2-yn-1-yl)oxy]but-1-yn-1-yl}aniline
According to the procedure described for the preparation of 1a, 4-chloro-2-iodo-N-methylaniline
S2c) (259 mg, 0.966 mmol) was converted into 1c (218 mg, 41%) by the reaction with S5a (192
(1c).
(
mg, 1.06 mmol), PdCl
2
(PPh
3
)
2
(33.9 mg, 0.0483 mmol), CuI (9.20 mg, 0.0483 mmol) and Et N
3
(0.42 mL) in DMF (3.2 mL) at room temperature for 5 h. Column chromatography: silica gel
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-
1
1
(
hexane/acetone = 20/1): yellow oil; IR (neat cm ): 3410 (NH); H NMR (500 MHz, CDCl
.81 (t, J = 6.9 Hz, 2H), 2.84 (d, J = 5.2 Hz, 3H), 3.81 (t, J = 6.9 Hz, 2H), 4.46 (s, 2H), 4.69-4.74
br m, 1H), 6.45 (d, J = 8.6 Hz, 1H), 7.12 (dd, J = 8.6, 2.3 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1H), 7.28-
3
) δ:
2
0
1
2
3
4
5
6
7
8
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0
1
2
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5
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7
8
9
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8
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8
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2
3
4
5
6
7
8
9
0
(
1
3
1
7
.34 (m, 3H), 7.43-7.46 (m, 2H); C{ H} NMR (125 MHz, CDCl ) δ: 21.0, 30.3, 59.0, 68.1, 77.3,
3
84.7, 86.5, 93.4, 109.0, 109.7, 120.2, 122.4, 128.3 (2C), 128.5, 129.2, 131.0, 131.7 (2C), 148.6;
+
HRMS (ESI-TOF) m/z: [M + Na] calcd for C20
H18ClNNaO 346.0969; found 346.0966.
4
-Bromo-N-methyl-2-{4-[(3-phenylprop-2-yn-1-yl)oxy]but-1-yn-1-yl}aniline
(1d).
According to the procedure described for the preparation of 1a, 4-bromo-2-iodo-N-methylaniline
(S2d) (195 mg, 0.624 mmol) was converted into 1d (159 mg, 69%) by the reaction with S5a (127
mg, 0.687 mmol), PdCl
2
(PPh
3
)
2
(21.9 mg, 0.0312 mmol), CuI (5.94 mg, 0.0312 mmol) and Et N
3
(
(
0.27 mL) in DMF (2.1 mL) at room temperature for 7 h. Column chromatography: silica gel
-
1
1
hexane/acetone = 20/1): yellow oil; IR (neat cm ): 3414 (NH); H NMR (500 MHz, CDCl ) δ:
3
2.81 (t, J = 6.6 Hz, 2H), 2.84 (d, J = 5.2 Hz, 3H), 3.81 (t, J = 6.6 Hz, 2H), 4.46 (s, 2H), 4.70-4.76
(
br m, 1H), 6.41 (d, J = 8.6 Hz, 1H), 7.23-7.26 (m, 1H), 7.28-7.35 (m, 4H), 7.43-7.46 (m, 2H);
1
3
1
C{ H} NMR (125 MHz, CDCl ) δ: 21.0, 30.2, 59.0, 68.1, 77.2, 84.7, 86.5, 93.6, 106.9, 109.5
3
1
10.2, 122.4, 128.3 (2C), 128.5, 131.7 (2C), 132.1, 133.8, 149.0; HRMS (ESI-TOF) m/z: [M +
+
Na] calcd for C20
H
18BrNNaO 390.0464; found 390.0461.
N,4-Dimethyl-2-{4-[(3-phenylprop-2-yn-1-yl)oxy]but-1-yn-1-yl}aniline (1e). According to
the procedure described for the preparation of 1a, 2-iodo-N,4-dimethylaniline (S2e) (260 mg, 1.05
mmol) was converted into 1e (185 mg, 58%) by the reaction with S5a (213 mg, 1.16 mmol),
PdCl
2
(PPh
3
)
2
(37.0 mg, 0.0527 mmol), CuI (10.0 mg, 0.0527 mmol) and Et N (0.46 mL) in DMF
3
(3.5 mL) at room temperature for 9 h. Column chromatography: silica gel (hexane/acetone = 20/1):
-1
1
yellow oil; IR (neat cm ): 3407 (NH); H NMR (500 MHz, CDCl ) δ: 2.19 (s, 3H), 2.81 (t, J = 6.9
3
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Hz, 2H), 2.85 (d, J = 4.0 Hz, 3H), 3.82 (t, J = 6.9 Hz, 2H), 4.46 (s, 2H), 4.51-4.56 (br m, 1H), 6.48
(d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 7.08 (s, 1H), 7.28-7.35 (m, 3H), 7.44-7.47 (m, 2H);
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
C{ H} NMR (125 MHz, CDCl ) δ: 20.1, 21.0, 30.5, 59.0, 68.3, 78.5, 84.8, 86.4, 91.8, 107.6,
3
108.9, 122.5, 125.0, 128.2 (2C), 128.5, 130.0, 131.7 (2C), 132.1, 147.9; HRMS (ESI-TOF) m/z:
+
[M + H] calcd for C21
H22NO 304.1696; found 304.1694.
4-Methoxy-N-methyl-2-{4-[(3-phenylprop-2-yn-1-yl)oxy]but-1-yn-1-yl}aniline
(1f).
According to the procedure described for the preparation of 1a, 2-bromo-4-methoxy-N-
methylaniline (S2f) (365 mg, 1.69 mmol) was converted into 1f (92.1 mg, 17%) by the reaction
with S5a (335 mg, 1.86 mmol), PdCl
2
(PPh
3
)
2
(59.2 mg, 0.0843 mmol), CuI (16.1 mg, 0.0843
mmol) and Et N (0.74 mL) in DMF (5.6 mL) at 80 ℃ for 5 h. Column chromatography: silica gel
3
-1
(
hexane/acetone = 20/1 and gradient 2% to 15% EtOAc in hexane): blue oil; IR (neat cm ): 3407
1
(
NH); H NMR (500 MHz, CDCl ) δ: 2.82 (t, J = 6.6 Hz, 2H), 2.84 (s, 3H), 3.72 (s, 3H), 3.82 (t,
3
J = 6.6 Hz, 2H), 4.37-4.40 (br m, 1H), 4.46 (s, 2H), 6.51 (d, J = 8.6 Hz, 1H), 6.82 (dd, J = 8.6, 2.9
13
1
Hz, 1H), 6.86 (d, J = 2.9 Hz, 1H), 7.28-7.34 (m, 3H), 7.43-7.47 (m, 2H); C{ H}NMR (125 MHz,
CDCl
3
) δ: 21.0, 31.0, 55.9, 59.0, 68.2, 78.3, 84.8, 86.4, 92.3, 108.3, 110.1, 116.3, 116.8, 122.5,
+
1
28.3 (2C), 128.5, 131.8 (2C), 145.0, 150.6; HRMS (ESI-TOF) m/z: [M + H] calcd for C21
H
22NO
2
320.1645; found 320.1641.
4
-(Methylamino)-3-{4-[(3-phenylprop-2-yn-1-yl)oxy]but-1-yn-1-yl}benzonitrile
According to the procedure described for the preparation of 1a, 3-iodo-4-
methylamino)benzonitrile (S2g) (195 mg, 0.757 mmol) was converted into 1g (199 mg, 84%) by
the reaction with S5a (153 mg, 0.833 mmol), PdCl (PPh (26.6 mg, 0.0379 mmol), CuI (7.21
mg, 0.0379 mmol) and Et N (0.33 mL) in DMF (2.5 mL) at room temperature for 8 h. Column
chromatography: silica gel (hexane/acetone = 20/1 and gradient 1% to 25% EtOAc in hexane):
(1g).
(
2
)
3 2
3
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6
-
1
1
orange oil; IR (neat cm ): 3410 (NH), 2217 (C≡N); H NMR (500 MHz, CDCl
3
) δ: 2.81 (t, J =
6
.3 Hz, 2H), 2.90 (d, J = 5.2 Hz, 3H), 3.82 (t, J = 6.3 Hz, 2H), 4.46 (s, 2H), 5.34-5.39 (br m, 1H),
.50 (d, J = 8.6 Hz, 1H), 7.28-7.34 (m, 3H), 7.41 (dd, J = 8.6, 1.7 Hz, 1H), 7.42-7.45 (m, 2H), 7.47
0
1
2
3
4
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6
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
1
3
1
(
d, J = 1.7 Hz, 1H); C{ H} NMR (125 MHz, CDCl ) δ: 20.9, 29.8, 59.0, 67.9, 76.3, 84.6, 86.6,
3
94.4, 97.6, 108.2, 108.3, 120.0, 122.3, 128.3 (2C), 128.6, 131.7 (2C), 133.4, 135.2, 152.5; HRMS
+
(
ESI-TOF) m/z: [M + Na] calcd for C21
H
18
N NaO 337.1311; found 337.1304.
2
3
-Bromo-N-methyl-2-{4-[(3-phenylprop-2-yn-1-yl)oxy]but-1-yn-1-yl}aniline
According to the procedure described for the preparation of 1a, S2h (163 mg, 0.524 mmol) was
converted into 1h (37.3 mg, 19%) by the reaction with S5a (106 mg, 0.576 mmol), PdCl (PPh
18.4 mg, 0.0262 mmol), CuI (4.99 mg, 0.0262 mmol) and Et N (0.23 mL) in DMF (1.7 mL) at
room temperature for 11 h. Column chromatography: silica gel (hexane/acetone = 20/1): yellow
(1h).
2
)
3 2
(
3
-1
1
oil; IR (neat cm ): 3413 (NH); H NMR (500 MHz, CDCl
3
) δ: 2.84-2.90 (m, 5H), 3.85 (t, J = 6.6
Hz, 2H), 4.48 (s, 2H), 4.94-5.00 (br m, 1H), 6.46 (d, J = 8.3 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H),
13
1
7
.00 (dd, J = 8.3, 8.3 Hz, 1H), 7.28-7.35 (m, 3H), 7.42-7.47 (m, 2H); C{ H} NMR (125 MHz,
CDCl
3
) δ: 21.2, 30.3, 59.0, 68.1, 77.5, 84.7, 86.5, 97.0, 107.1, 109.5, 119.4, 122.4, 125.2, 128.3
+
(
2C), 128.5, 129.7, 131.7 (2C), 151.5; HRMS (ESI-TOF) m/z: [M + H] calcd for C20
H19BrNO
368.0645; found 368.0641.
5
-Bromo-N-methyl-2-{4-[(3-phenylprop-2-yn-1-yl)oxy]but-1-yn-1-yl}aniline (1i). According
to the procedure described for the preparation of 1a, 5-bromo-2-iodo-N-methylaniline (S2i) (256
mg, 0.819 mmol) was converted into 1i (216 mg, 71%) by the reaction with S5a (166 mg, 0.901
mmol), PdCl
2
(PPh
3
)
2
(28.8 mg, 0.0410 mmol), CuI (7.80 mg, 0.0410 mmol) and Et N (0.36 mL)
3
in DMF (2.7 mL) at room temperature for 10 h. Column chromatography: silica gel
-1
1
(
hexane/acetone = 20/1): yellow oil; IR (neat cm ): 3407 (NH); H NMR (500 MHz, CDCl ) δ:
3
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.80 (t, J = 6.6 Hz, 2H), 2.85 (d, J = 5.2 Hz, 3H), 3.81 (t, J = 6.6 Hz, 2H), 4.46 (s, 2H), 4.78-4.83
(br m, 1H), 6.66 (d, J = 1.7 Hz, 1H), 6.70 (dd, J = 8.0, 1.7 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 7.29-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
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4
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5
6
0
1
2
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5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
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3
4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
7
8
.34 (m, 3H), 7.42-7.46 (m, 2H); C{ H} NMR (125 MHz, CDCl ) δ: 21.0, 30.1, 59.0, 68.1, 77.6,
3
4.7, 86.5, 93.3, 106.6, 111.6, 118.7, 122.4, 123.6, 128.3 (2C), 128.6, 131.7 (2C), 132.6, 150.9;
+
HRMS (ESI-TOF) m/z: [M + H] calcd for C20
H19BrNO 368.0645; found 368.0643.
2-Bromo-N-methyl-6-{4-[(3-phenylprop-2-yn-1-yl)oxy]but-1-yn-1-yl}aniline
(1j).
According to the procedure described for the preparation of S2h, 2-bromo-6-iodoaniline (S1j) (543
mg, 1.82 mmol) was converted into S2j (170 mg, <30%) including impurities by the reaction with
MeLi (1.09 M in Et
2
O; 2.01 mL, 2.19 mmol) and MeI (147 L, 2.37 mmol) in THF (6.1 mL) at ‒
78 ℃ to room temperature for 2.5 h. Column chromatography: silica gel (gradient 1% to 5%
EtOAc in hexanes) and amine silica gel (hexane only); According to the procedure described for
the preparation of 1a, S2j (142 mg, ca. 0.425 mmol) including impurities was converted into 1j
(53.3 mg, ca. 32%) by the reaction with S5a (92.4 mg, 0.502 mmol), PdCl
.0228 mmol), CuI (4.34 mg, 0.0228 mmol) and Et N (0.20 mL) in DMF (1.5 mL) at room
temperature for 9 h. Column chromatography: silica gel (gradient 2% to 5% EtOAc in hexanes
2
(PPh
3
2
) (16.0 mg,
0
3
-1
1
and gradient 1% to 3% EtOAc in hexane): yellow oil; IR (neat cm ): 3418 (NH); H NMR (500
MHz, CDCl ) δ: 2.80 (t, J = 6.9 Hz, 2H), 3.16 (s, 3H), 3.81 (t, J = 6.9 Hz, 2H), 4.32-4.38 (br m,
H), 4.44 (s, 2H), 6.57 (dd, J = 8.0, 8.0 Hz, 1H), 7.25 (dd, J = 8.0, 1.1 Hz, 1H), 7.29-7.33 (m, 3H),
3
1
7
5
1
3
1
.37 (dd, J = 8.0, 1.1 Hz, 1H), 7.43-7.46 (m, 2H); C{ H} NMR (125 MHz, CDCl ) δ: 21.0, 34.6,
3
8.9, 68.0, 79.5, 84.8, 86.4, 91.8, 112.8, 113.3, 119.8, 122.5, 128.3 (2C), 128.5, 131.8 (2C), 132.8,
+
133.5, 148.8; HRMS (ESI-TOF) m/z: [M + H] calcd for C20
H19BrNO 368.0645; found 368.0638.
N-Methyl-2-(4-{[3-(trimethylsilyl)prop-2-yn-1-yl]oxy}but-1-yn-1-yl)aniline (S9). A mixture
of 2-iodo-N-methylaniline (S2a) (729 mg, 3.11 mmol), [3-(but-3-yn-1-yloxy)prop-1-yn-1-
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5
5
5
5
6
yl]trimethylsilane (S5f) (618 mg, 3.43 mmol), PdCl
.156 mmol), and Et N (1.36 mL, 9.34 mmol) in DMF (10.4 mL) was stirred at room temperature
under Ar for 13 h. The mixture was diluted with saturated aqueous NH Cl. The resulting mixture
was extracted with EtOAc twice. The combined organic layer was washed with brine, dried over
Na SO , filtered, and concentrated in vacuo. The residue was purified by column chromatography
on silica gel (gradient 2% to 5% EtOAc in hexane) to give S9 (294 mg, 33%) as an orange oil: IR
2
(PPh
3
)
2
(109 mg, 0.156 mmol), CuI (29.7 mg,
0
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
2
4
-1
1
(
neat cm ): 3410 (NH); H NMR (500 MHz, CDCl
3
) δ: 0.19 (s, 9H), 2.78 (t, J = 6.9 Hz, 2H), 2.90
(d, J = 5.2 Hz, 3H), 3.74 (t, J = 6.9 Hz, 2H), 4.23 (s, 2H), 4.67-6.73 (br m, 1H), 6.56 (d, J = 7.7
Hz, 1H), 6.60 (dd, J = 7.7, 7.7 Hz, 1H), 7.19 (dd, J = 7.7, 7.7 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H);
13
1
C{ H} NMR (125 MHz, CDCl
3
) δ: ‒0.27 (3C), 20.8, 30.2, 58.9, 68.2, 78.3, 91.5, 92.1, 101.1,
+
1
07.6, 108.6, 115.8, 129.3, 131.6, 149.9; HRMS (ESI-TOF) m/z: [M + Na] calcd for
17
C H24NNaOSi 308.1441; found 308.1434.
N-Methyl-2-[4-(prop-2-yn-1-yloxy)but-1-yn-1-yl]aniline (S10). To a stirred mixture of S9
1.07 g, 3.74 mmol) in MeOH (7.5 mL) was added K CO (517 mg, 1.07 mmol). After being
(
2
3
stirred at room temperature for 30 min, the mixture was filtered. The filtrate was evaporated to
dryness and the residue was purified by column chromatography on silica gel (gradient 2% to 5%
-1
EtOAc in hexane) to give S10 (645 mg, 81%) as an orange oil: IR (neat cm ): 3401 (NH), 2248
1
(
C≡C); H NMR (500 MHz, CDCl
3
) δ: 2.47 (t, J = 2.3 Hz, 1H), 2.78 (t, J = 6.9 Hz, 2H), 2.89 (d,
J = 5.2 Hz, 3H), 3.75 (t, J = 6.9 Hz, 2H), 4.23 (d, J = 2.3 Hz, 2H), 4.66-4.72 (br m, 1H), 6.56 (d,
J = 7.7 Hz, 1H), 6.60 (dd, J = 7.7, 7.7 Hz, 1H), 7.19 (dd, J = 7.7, 7.7 Hz, 1H), 7.24 (d, J = 7.7 Hz,
1
3
1
1H); C{ H} NMR (125 MHz, CDCl
3
) δ: 20.9, 30.3, 58.2, 68.3, 74.6, 78.3, 79.4, 92.1, 107.6,
+
108.7, 115.9, 129.4, 131.7, 150.0; HRMS (ESI-TOF) m/z: [M + H] calcd for C14
H16NO 214.1226;
found 214.1222.
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-(4-{[3-(4-Chlorophenyl)prop-2-yn-1-yl]oxy}but-1-yn-1-yl)-N-methylaniline
(1k).
According to the procedure described for the preparation of 1a, S10 (127 mg, 0.595 mmol) was
converted into 1k (138 mg, 71%) by the reaction with 1-chloro-4-iodobenzene (156 mg, 0.655
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mmol), PdCl
2
(PPh
3
)
2
(20.9 mg, 0.0298 mmol), CuI (5.67 mg, 0.0298 mmol) and Et N (0.26 mL)
3
in DMF (1.9 mL) at room temperature for 7 h. Column chromatography: silica gel (gradient 2%
-1
1
to 10% EtOAc in hexane and hexane/acetone = 20/1): yellow oil; IR (neat cm ): 3410 (NH); H
NMR (500 MHz, CDCl ) δ: 2.80 (t, J = 6.9 Hz, 2H), 2.85 (s, 3H), 3.79 (t, J = 6.9 Hz, 2H), 4.43 (s,
H), 4.67-4.74 (br m, 1H), 6.52-6.56 (m, 1H), 6.56-6.61 (m, 1H), 7.16-7.20 (m, 1H), 7.22-7.28 (m,
3
2
1
3
1
3H), 7.34-7.38 (m, 2H); C{ H} NMR (125 MHz, CDCl
3
) δ: 20.9, 30.2, 58.8, 68.4, 78.4, 85.2,
8
5.8, 92.1, 107.6, 108.7, 115.9, 120.9, 128.6 (2C), 129.4, 131.7, 132.9 (2C), 134.5, 150.0; HRMS
+
(
ESI-TOF) m/z: [M + Na] calcd for C20H18ClNNaO 346.0969; found 346.0966.
2-(4-{[3-(4-Bromophenyl)prop-2-yn-1-yl]oxy}but-1-yn-1-yl)-N-methylaniline
(1l).
According to the procedure described for the preparation of 1a, S10 (101 mg, 0.475 mmol) was
converted into 1l (110 mg, 63%) by the reaction with 1-bromo-4-iodobenzene (148 mg, 0.523
mmol), PdCl
2
(PPh
3
)
2
(16.7 mg, 0.0238 mmol), CuI (4.53 mg, 0.0238 mmol) and Et N (0.21 mL)
3
in DMF (1.6 mL) at room temperature for 3 h. Column chromatography: silica gel (hexane/acetone
-1
1
= 20/1): yellow oil; IR (neat cm ): 3405 (NH); H NMR (500 MHz, CDCl
H), 2.87 (d, J = 5.2 Hz, 3H), 3.80 (t, J = 6.9 Hz, 2H), 4.44 (s, 2H), 4.68-4.73 (br m, 1H), 6.55 (d,
J = 8.6 Hz, 1H), 6.60 (dd, J = 8.6, 8.6 Hz, 1H), 7.19 (dd, J = 8.6, 8.6 Hz, 1H), 7.24 (d, J = 8.6 Hz,
3
) δ: 2.81 (t, J = 6.9 Hz,
2
1
3
1
1
H), 7.30 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.3 Hz, 2H); C{ H} NMR (125 MHz, CDCl ) δ: 21.0,
3
30.3, 58.9, 68.4, 78.4, 85.3, 86.0, 92.1, 107.6, 108.7, 115.9, 121.4, 122.8, 129.4, 131.6 (2C), 131.7,
+
133.2 (2C), 150.0; HRMS (ESI-TOF) m/z: [M + Na] calcd for C20
H18BrNNaO 390.0464; found
3
90.0466.
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2
2
2
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3
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3
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6
4
-[3-({4-[2-(Methylamino)phenyl]but-3-yn-1-yl}oxy)prop-1-yn-1-yl]benzonitrile
(1m).
According to the procedure described for the preparation of 1a, S10 (103 mg, 0.482 mmol) was
converted into 1m (127 mg, 84%) by the reaction with 4-iodobenzonitrile (121 mg, 0.530 mmol),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
PdCl
2
(PPh
3
)
2
(16.9 mg, 0.0241 mmol), CuI (4.59 mg, 0.0241 mmol) and Et N (0.21 mL) in DMF
3
(1.6 mL) at room temperature for 9 h. Column chromatography: silica gel (gradient 6% to 25%
-1
1
EtOAc in hexane): orange oil; IR (neat cm ): 3416 (NH), 2227 (C≡N); H NMR (500 MHz,
CDCl ) δ: 2.82 (t, J = 6.9 Hz, 2H), 2.87 (d, J = 5.2 Hz, 3H), 3.81 (t, J = 6.9 Hz, 2H), 4.47 (s, 2H),
.66-4.71 (br m, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.60 (dd, J = 8.0, 8.0 Hz, 1H), 7.19 (dd, J = 8.0,
3
4
1
3
1
8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H); C{ H}
NMR (125 MHz, CDCl ) δ: 21.0, 30.3, 58.8, 68.6, 78.5, 84.8, 89.4, 92.0, 107.6, 108.9, 111.9,
16.0, 118.3, 127.4, 129.5, 131.8, 132.0 (2C), 132.2 (2C), 150.0; HRMS (ESI-TOF) m/z: [M +
3
1
+
Na] calcd for C21
H
18
2
N ONa 337.1311; found 337.1314.
N-Methyl-2-(4-{[3-(p-tolyl)prop-2-yn-1-yl]oxy}but-1-yn-1-yl)aniline (1n). According to the
procedure described for the preparation of 1a, S10 (106 mg, 0.497 mmol) was converted into 1n
(
120 mg, 80%) by the reaction with 1-iodo-4-methylbenzene (119 mg, 0.546 mmol), PdCl
2
(PPh
)
3 2
(
17.4 mg, 0.0248 mmol), CuI (4.73 mg, 0.0248 mmol) and Et N (0.22 mL) in DMF (1.7 mL) at
3
room temperature for 9 h. Column chromatography: silica gel (gradient 1% to 5% EtOAc in
-1
1
hexane): yellow oil; IR (neat cm ): 3412 (NH); H NMR (500 MHz, CDCl
3
) δ: 2.35 (s, 3H), 2.81
t, J = 6.9 Hz, 2H), 2.87 (s, 3H), 3.81 (t, J = 6.9 Hz, 2H), 4.45 (s, 2H), 4.70-4.74 (br m, 1H), 6.55
d, J = 8.0 Hz, 1H), 6.59 (dd, J = 8.0, 8.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 2H), 7.18 (dd, J = 8.0, 8.0
(
(
1
3
1
Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H); C{ H} NMR (125 MHz, CDCl
3
) δ:
21.0, 21.5, 30.3, 59.0, 68.3, 78.4, 84.0, 86.6, 92.2, 107.7, 108.7, 115.9, 119.4, 129.0 (2C), 129.4,
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31.6 (2C), 131.7, 138.6, 150.0; HRMS (ESI-TOF) m/z: [M + Na] calcd for C21
H
21NNaO
3
26.1515, found 326.1519.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
-(4-{[3-(4-Methoxyphenyl)prop-2-yn-1-yl]oxy}but-1-yn-1-yl)-N-methylaniline
(1o).
According to the procedure described for the preparation of 1a, S10 (125 mg, 0.587 mmol) was
converted into 1o (63.3 mg, 34%) by the reaction with 1-iodo-4-methoxybenzene (137 mg, 0.587
mmol), PdCl
2
(PPh
3
)
2
(20.6 mg, 0.0293 mmol), CuI (5.59 mg, 0.0293 mmol) and Et
3
N (0.26 mL)
in DMF (2.0 mL) at 60 ℃ for 3 h. Column chromatography: silica gel (gradient 4% to 20% EtOAc
-1
1
in hexane): orange oil; IR (neat cm ): 3411 (NH); H NMR (500 MHz, CDCl ) δ: 2.81 (t, J = 6.6
3
Hz, 2H), 2.87 (d, J = 4.0 Hz, 3H), 3.79-3.83 (m, 5H), 4.44 (s, 2H), 4.70-4.74 (br m, 1H), 6.55 (d,
J = 7.4 Hz, 1H), 6.59 (dd, J = 7.4, 7.4 Hz, 1H), 6.83 (d, J = 8.6 Hz, 2H), 7.18 (dd, J = 7.4, 7.4 Hz,
1
3
1
1
3
H), 7.24 (d, J = 7.4 Hz, 1H), 7.39 (d, J = 8.6 Hz, 2H); C{ H} NMR (125 MHz, CDCl ) δ: 21.0,
3
0.3, 55.3, 59.0, 68.2, 78.4, 83.4, 86.4, 92.2, 107.7, 108.7, 113.9 (2C), 114.5, 115.9, 129.4, 131.7,
+
133.2 (2C), 150.0, 160.0; HRMS (ESI-TOF) m/z: [M + Na] calcd for C21
H21NNaO
2
342.1465;
found 342.1474.
2
-(4-{[3-(3-Chlorophenyl)prop-2-yn-1-yl]oxy}but-1-yn-1-yl)-N-methylaniline
(1p).
According to the procedure described for the preparation of 1a, S10 (186 mg, 0.873 mmol) was
converted into 1p (219 mg, 78%) by the reaction with 1-chloro-3-iodobenzene (208 mg, 0.873
mmol), PdCl
2
(PPh
3
)
2
(30.6 mg, 0.0436 mmol), CuI (8.31 mg, 0.0436 mmol) and Et N (0.38 mL)
3
in DMF (2.9 mL) at room temperature for 4 h. Column chromatography: silica gel (gradient 4%
-1
1
to 15% EtOAc in hexane): yellow oil; IR (neat cm ): 3425 (NH); H NMR (500 MHz, CDCl
.80 (t, J = 6.9 Hz, 2H), 2.86 (d, J = 2.9 Hz, 3H), 3.79 (t, J = 6.9 Hz, 2H), 4.43 (s, 2H), 4.68-4.73
(br m, 1H), 6.54 (d, J = 8.0 Hz, 1H), 6.59 (dd, J = 8.0, 8.0 Hz, 1H), 7.16-7.20 (m, 1H), 7.20-7.23
3
) δ:
2
13
1
(
m, 1H), 7.23-7.26 (m, 1H), 7.27-7.33 (m, 2H), 7.43 (s, 1H); C{ H} NMR (125 MHz, CDCl ) δ:
3
29
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