Double Addition of Alkynyllithium Reagents to Amides/Lactams: A Direct and Flexible Synthesis of 3-Amino-1,4-diynes Bearing an Aza-Quaternary Carbon Center

Article abstract of DOI:10.1021/acs.joc.9b01416

An efficient and mild protocol for the direct and flexible synthesis of 3-amino-1,4-diynes bearing an aza-quaternary carbon from tertiary amides and lactams has been established. The one-pot method consists of in situ activation of amides with trifluoromethanesulfonic anhydride, followed by double addition of alkynyllithium reagents at a concentration of 0.5 mol·L^-1 in dichloromethane. This constitutes an extension of the method of direct reductive bisalkylation of amides that allows both employing alkynyllithium reagents as the first-addition nucleophiles and incorporating an alkynyl group as the first-introduced group.

Full text of DOI:10.1021/acs.joc.9b01416

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Article
Double Addition of Alkynyllithium Reagents to Amides/
Lactams: A Direct and Flexible Synthesis of 3-Amino-1,4-
diynes Bearing an Aza-Quaternary Carbon Center
Hang Chen, Ying-Hong Huang, Jian-Liang Ye, and Pei-Qiang Huang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01416 • Publication Date (Web): 17 Jun 2019
Downloaded from http://pubs.acs.org on June 18, 2019
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Double Addition of Alkynyllithium Reagents to Amides/ Lactams: A Direct and
Flexible Synthesis of 3-Amino-1,4-diynes Bearing an Aza-Quaternary Carbon
Center
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Hang Chen, Ying-Hong Huang, Jian-Liang Ye, and Pei-Qiang Huang*
aDepartment of Chemistry, Fujian Provincial Key Laboratory of Chemical Biology,
College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian
3
61005, P. R. China
Email: pqhuang@xmu.edu.cn.
ABSTRACT: An efficient and mild protocol for the direct and flexible synthesis of
3-amino-1,4-diynes bearing an aza-quaternary carbon from tertiary amides and lactams has been
established. The one-pot method consists of in situ activation of amides with
trifluoromethanesulfonic anhydride follows by double addition of alkynyllithium reagents at a
-1
concentrated of 0.5 molꞏL in dichloromethane. This constitutes an extension of the method of direct
reductive bisalkylation of amides that allows both employing alkynyllithium reagents as the
first-addition nucleophiles, and incorporating an alkynyl group as the first-introduced group.
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INTRODUCTION
1
2
Aza-quaternary carbon centres (α-tertiary amines) and propargylic amines are key
structural motifs found in many natural products and medicinal agents. Although a
number of methods have been developed for the preparation of propargylic amines,2
the entrance to those containing an aza-quaternary centre is limited.3-5 On the other
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hand, the rich chemistry of alkyne rends 3-substituted 1,4-diynes versatile building
blocks for the synthesis of 1,4-diene-containing natural products,7a heterocyclic
7
b
7c
7d
libraries, medicinal agents, and materials. In recent years, several approaches to
8
3
-amino-1,4-diynes (amino skipped diynes) have appeared. However, the synthesis
of 3-amino-1,4-diyne motif bearing an aza-quaternary carbon is rare, with only one
9
fully elaborated method (Scheme 1, a), and one isolated example described in a
8
e
report of Maruoka (Scheme 1, b). Thus, it is highly desirable to develop flexible
approaches to this class of building blocks from cheap and easily available feedstocks.
Amides are ubiquitous in nature and are products of numerous synthetic methods.
Thus, the transformation of amides is essential for many total syntheses of natural
products and medicinal agents. However, due to their high stability, only
multistep-methods are available. In recent years, the direct transformation of amides
has attracted considerable attention.10-13 In this context, we reported in 2010 a method
for the direct reductive di- and bis-alkylation of amides,11d which involves the in situ
activation of an amide with trifluoromethanesulfonic anhydride (Tf
2
O) followed by
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double addition of a Grignard reagent or by successive addition of a Grignard reagent
and a different organometallic reagent (RMgX or RLi)(Scheme 2, a,b). Featuring both
the cleavage of C=O double bonds and formation of two C-C bonds in one pot, and
the use of common organometallic reagents as nucleophiles, the method is quite
efficient and versatile that has found synthetic applications.13
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Scheme 1. Reported Methods for the Synthesis of 3-Amino-1,4-diynes Bearing
Aza-quaternary Carbons (a and b)
Scheme 2. Reported Methods: Direct Reductive Di- or Bis-Alkylation of Tertiary
Amides (a,b) and Reductive Mono-Alkylation of Secondary Amides (c-e)
involving the Use of Alkynide as A Nucleophile; Highlight of This Work (f)
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Huang (2013)11c
Huang (2010)11d
one-pot
H
1
) Tf O, DTBMP
R1
O
2
R2
R
CH CI , 78 °C;
2
2
R'
R'
N
R
N
(a)
1
2
) R MgX, 78 °C
then rt, 1 h;
N
R''
R''
Bn
H
2
2
C
A
3) R Li or R MgX
trace
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(
R MgX
H
MgBr)
one-pot
Et
1
) Tf O, DTBMP
2
O
(b)
N
N
R
o
2
) EtMgBr, 78 C; rt
R
H
3
) Ph
or
Li
R = Me, Allyl
70% and 72%
MgBr
Charette (2012)11e
O
Nc-Hex
Tf O, 2-F-Pyr.
2
(
c)
c-Hex
N
H
R
MgBr
R
CO Me 88%
CO Me
2
2
R = (CH ) OTBS
Huang (2012)11f
2 2
1) Tf O, 2-F-Pyr.
2
O
Cl
O
n-Bu
(d)
Ph
Li
N
H
Ph
Ph
Ph
2) HCl
75%
Huang (2015)11b
R
one-pot
Tf O, 2-F-Py, CH Cl
2
2
2
O
Et SiH
3
R2
R2
R1
(e)
R1
N
N
BF •Et O
H
H
3
2
1
Ph
nHex
Li
Li
2
(72-81%)
This work:
R4
R4
one-pot
Tf O, DTBMP
O
2
R2
R1
R2
N
(f)
R4
Li (c, 2)
N
R1
R3
R3
1
3
However, the method has two shortcomings. First, in performing the reductive
bisalkylation, only Grignard reagents can be used as the first-addition nucleophiles,
use of organolithium reagents led to complex products. Second, attempted double
addition with ethynyl Grignard reagent was unsuccessful.11c Although, RCCMgBr
1
1e
and by our group11c,f as effective
and PhCCLi have been used by Charette
nucleophiles for the addition to activated secondary amides (Scheme 2, b-e), however,
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only mono-addition leading to imines (or to ketones after hydrolysis) were possible.
The double addition of RCCMgBr and PhCCLi to either tertiary or secondary
amides are previously unknown.
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Herein we disclose that alkynyl lithium reagents could be used as the first-addition
nucleophiles for the reductive dialkynylation of tertiary amides which opens an
efficient access to 3-amino-1,4-diynes bearing aza-quaternary centre (Scheme 2, f).
Moreover, a concentration effect was observed, which not only resulted in a
significant improvement of yield for the reductive dialkynylation using alkynyllithium
reagents, but also allowed using phenylethynyl Grignard reagents as nucleophiles for
the same purpose.
RESULTS AND DISCUSSION
In view of developing a general method for the direct reductive dialkynylation of
amides and lactams, we selected N-benzyl--lactam (1a) as a model compound and
(
phenylethynyl)lithium as a nucleophile. At the outset of our investigation, we called
for the conditions that we established previously11d with minor modification. In the
event, in the presence of 2,6-di-tert-butyl-4-methylpyridine10f (DTBMP, 1.1 equiv),
lactam 1a was treated with trifluoromethanesulfonic anhydride (Tf O) at 78 C, and
2
the in situ generated activated species of lactam was captured by
o
(
phenylethynyl)lithium (3.0 equiv) at 78 C, and the mixture was stirred at rt for 1 h.
In this manner, the desired 3-amino-1,4-diyne (3a) was obtained in 65% yield (Table
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, entry 1). After many trials in order to optimize the conditions, we observed that
reaction concentration has a significant impact on yield of the reaction. By increasing
-1
-1
concentration from 0.1 molꞏL to 0.5 molꞏL , yield was increased from 65% to 95%
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(
Table 1, entry 2). Further increase of concentration to 0.75 molꞏL resulted in a drop
of yield (87%, entry 3). On the other hand, decreasing the equivalents of RLi to 2.5
resulted in a lower yield (91%, entry 4).
Table 1. Reaction Optimization-I: Concentration and Equivalents of Lithium
Alkynides
Yield
(%)a
Entry
n
c (mol/L)
1
3.0
3.0
3.0
2.5
0.1
0.5
65
2
95
3
0.75
0.5
87
4
91
a
Isolated yields.
Next, effect of base additive was examined. Noteworthy is that even in the absence of
base, the desired product was still obtained in 71% yield (Table 2, entry 1). Although
2
-Cl-pyridine or 2-F-pyridine (entries 2 and 3) has little effect on the yield,
introduction of DTBMP as a base additive substantially increased the yield to 95%
(entries 4 and 5). Moreover, use of 1.1 equiv of DTBMP is enough to ensure a
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high-yielding transformation. It is worth mentioning that during the chromatographic
separation of the product, the expensive base additive DTBMP could be readily and
concomitantly recovered and reused.
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Table 2. Reaction Optimization-II: Base Additive
Yield/
(%)a
Entry
Base
n
1
2
3
4
5
none
0
71
2-Cl-Pyr.
2-F-Pyr.
DTBMP b
DTBMP
1.1
1.1
1.1
2.0
71
77
95
95
a
Isolated yields. b DTBMP could be recovered
during chromatographic isolation of products.
With the optimized reaction conditions in hand, reaction scope was investigated and
the results are listed in Tables 3 and 4. As can be seen from Table 3, the one-pot
reductive dialkynylation reaction can be extended to N-benzyl--lactam (1b),
N-benzyl--lactam (1c), as well as N-allyl--lactam (1d) (Table 3, entries 2-4), and the
dialkynylation products 3b-3d were obtained in 90%, 83%, and 89% yield,
respectively. Besides lactams, benzamide (1e,1j) (Table 3, entry 5a,10), aromatic
amides bearing either an electron-donating group (Me, OMe, 1f, 1g) (Table 3, entries
6
and 7) or an electron-withdrawing group (F) at para-position of the phenyl ring (1h)
(Table 3, entry 8) turned out to be viable substrates, and the corresponding
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4
-amino-1,4-diynes 3e-3h were obtained in good to excellent yields. The reaction of
N,N-dibenzyl-o-methylbenzamide (1i) produced the corresponding product 3i in a
moderate yield of 76% reflecting the steric effect (Table 3, entry 9). Aliphatic amides
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k, 1l, and 1m reacted smoothly to yield the desired 3k, 3l, and 3m in 91%, 70% and
90% yield, respectively (Table 3, entries 11-13a). The observed moderate yield from
l as compare to that from the long-chain amide 1k may be attributed to the volatility
1
of 3l.
In view of synthesizing functionalized 3-amino-1,4-diynes, we proceeded to examine
the chemoselective reductive dialkynylation of functionalized amides.
Table 3. Scope of Amides
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1) Tf O, DTBMP, DCM
2
Ph
Ph
O
–78 °C, 30 min
R2
R1
R2
N
R3
2
) Ph
(3 equiv, c = 0.5 M)
78 °C to rt, 1 h
Li (2a)
N
R1
R3
3
1
–
1
1
1
1
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1
1
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Entry
Substrate
Product (Yield)a
Ph
n
n
O
N
N
Bn
Ph
Bn
3
3
3
a (n = 1, 95%)
b (n = 2, 90%)
c (n = 3, 83%)
1
2
3
1a (n = 1)
1b (n = 2)
1c (n = 3)
Ph
O
N
N
4
Ph
1
d
3d (89%)
Ph
Bn
Ph
O
Bn
N
N
X
Bn
X
Bn
3e (X = H, 84%)
81%)
1
e (X = H)
5
5
6
7
8
9
a
b
1.00 g, 3.32 mmol
1f (X = p-Me)
1g (X = p-MeO)
1h (X = p-F)
(
3f (X = p-Me, 82%)
3g (X = p-MeO, 81%)
3h (X = p-F, 81%)
3i (X = o-Me, 76%)
1i (X = o-Me)
Ph
Ph
O
Me
Me
1
0
N
N
Me
Me
1j
3j (95%)
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Product (Yield)a
Entry
Substrate
O
Ph
Bn
Ph
Bn
N
R
N
R
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Bn
Bn
11
12
1k (R = n-C11H23
1l (R = Me)
)
3k (R = n-C11H23, 91%)
3l (R = Me, 70%)
Ph
Ph
O
Me
Me
N
N
Me
Me
13a
13b
1m
3m (90%)
(85%)
1.00 g, 5.64 mmol
Ph
Ph
O
Bn
Bn
1
1
4
5
N
Ph
N
Ph
Bn
Bn
3n (73%)
1
n
o
Ph
Ph
O
Bn
N
Bn
N
Bn
Me
Bn
Me
1
3
o (82%)
Ph
Ph
Bn
O
Bn
N
N
Bn
Bn
1
6
Bn
N
Bn
Bn
N
n
n
O
O
Bn
O
Bn
(
n = 3)
(n = 3)
1
p
3p (65%)
Ph
Bn
O
N
N
N
Ph
O
Bn
Bn
Bn
1
7
Bn
Bn
N Bn
N Bn
N
Bn
Bn
O
Bn
O
1q
q (67%; 66%b)
3
BnO
BnO
Ph
N
O
N
1
8
PMB
1r
PMB
Ph
3r (91%)
a
b
Isolated yields.
Tf O (3.3 equiv), DTBMP (3.3 equiv), alkynyllithium (9.0 equiv).
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Significantly, ,-unsaturated amides 1n and 1o reacted chemoselectively at the
carbonyl group to give highly unsaturated products 3n and 3o in 73% and 82% yield,
respectively (Table 3, entries 14 and 15). It is worth noting that, subjecting of diamide
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
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9
0
1
2
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9
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8
9
0
1p and triamide 1q to the standard conditions employing 3.0 equiv of alkynide, 3p
and 3q, resulted from the reaction at only one carbonyl group, were obtained in 65%
and 67% yield, respectively (Table 3, entries 16 and 17). In the case of triamide 1q,
even with the use of triple amount of reagents (Tf O/DTBMP, 3.3 equiv; alkynide, 9.0
2
equiv), still the dialkynylation product 3q was obtained in 66% yield. Employing the
enantio-enriched lactam (S)-1r, derived from Huang’s building block,13b as a chiral
substrate, the enantiomeric piperidine (S)-3r was isolated in excellent yield (Table 3,
entry 18).
Next, we turned our attention to the scope of alkynyllithium reagents (Table 4). In
addition to aromatic alkynyl lithium 2a, aliphatic alkynyl lithium reagents such as 2b
and 2d also reacted in excellent yields (95% and 96%). A good yield (87%) of 3t was
obtained
Cyclopropylethynyl)lithium (2d) served as an excellent nucleophile whereas the
reaction of 3-Me-but-3-en-1-yn-1-yllithium (2e) afforded 3w in a moderate yield
71%). Significantly, the addition of phenylethynyl lithium bearing a CF substituent
from
the
reaction
of
lithium
trimethylsilylethynide
2d.
(
(
3
at the aromatic ring (2f) furnished the corresponding product 3x in high yield, and the
reaction of (p-fluorophenyl)ethynyl lithium (2g) proceeded smoothly to afford 3y in
1
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
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1% yield. It is worth mentioning that the synthesis of molecules incorporating a CF
3
or a F is a very important objective for the development of pharmaceuticals,
agrochemicals, and functional materials.14 However, attempted addition of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
p-nitrophenyl)ethynyl lithium 2h met with failure. Nevertheless, alkynyl lithium
reagents bearing sensitive groups such as benzyloxymethyl (2i),
(tert-butyldimethylsilyl)oxy)methyl] (2j), (N,N-diethylamino)methyl (2k), and even
Table 4. Scope of Lithium Alkynides
[
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0
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2
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8
9
0
a
b
c
d
Isolated yields. b Yield based the recovered starting material.
The solution of activated amide was added to alkynyl lithium solution.
Yield based the recovered starting material.
-1
-1
c (amide) = 0.09 molꞏL , c (alkynyl lithium) = 0.05 molꞏL .
chloromethyl (2l) are also effective nucleophiles to produce the corresponding
-amino-1,4-diynes 3ab – 3ae in 78%, 80%, 74%, and 81% yield, respectively.
Although attempted addition of lithium reagent 2m generated in situ from ethyl
3
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propiolate failed to the desired product 3u, the reaction of alkynide derived from
propiolaldehyde acetal (2n) proceeded smoothly to yield 3af in 75% yield. In view of
1
5
16
the widespread use of heterocycles in medicinal agents and functional materials,
0
1
2
3
4
5
6
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8
9
0
1
2
3
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8
9
0
1
2
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7
8
9
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1
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3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
incorporation of heterocycles on the nucleophilic partner was envisioned. Interestingly,
the reaction of (thiophen-2-ylethynyl)lithium (2o) produced 3ag in a good yield
(
78%), and alkynyl lithium (2p) bearing a pyridinyl group could also serve as a
nucleophile to produce the desired product 3ah at a moderate yield (47%, 71% brsm).
Finally, the reaction of the dilithium reagent 2q, generated in situ from deca-1,9-diyne,
afforded macrocyclic diyne 3ai in 38% yield. Considering the fact that the formation
of the second C-C bond involves the intramolecular addition of a sp-hybrid alkynide,
linked via a C -chain to the first-added alkynyl group, to the same electrophilic carbon
6
center, this annulation reaction is significant.
As a further demonstration of synthetic utility of the reaction, gram-scale synthesis
was examined. The gram-scale reactions of 1e with 2a (Table 3, entry 5b) and 1m
with 2a (Table 3, entry 13b) proceeded smoothly to give 3e and 3m in 81% and 85%
yield, respectively.
Noteworthy is that although we failed to undertake the diethynylation of amides with
ethynyl Grignard reagent (Scheme 2, a), under the current optimized reductive
dialkynylation conditions developed for alkynyllithium reagents, the reactions of
17
phenylethynyl Grignard reagents 2r and 2s proceeded smoothly to yield 3e albeit in
1
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moderate yields (68% and 72%) (Scheme 3, a). Encouraged by these results, the
reductive diethynylation of amide 1e with ethynyllithium was further attempted,
however, only some starting amide was recovered even with a large excess of
ethynyllithium (Scheme 3, b).
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
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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 3. Employment of Phenylethynyl Grignard Reagents (a) and
Ethynyllithium (b) for the Reductive Dialkynylation of Amides
In conclusion, we have developed a protocol for the one-pot transformation of C=O
double bond of common amides/lactams into two C-C bonds with alkynyllithium
reagents. Furthermore, in contrast with the failure with ethynyl Grignard reagent,
under the optimized conditions, we were able to perform the reductive
gem-alkynylation with phenylethynyl Grignard reagents 2r and 2s. This not only
paved a direct and versatile entry to 3-amino-1,4-diynes bearing an aza-quaternary
carbon, but also expanded the methodology of the direct reductive bisalkylation of
amides on two aspects: the successful use of a type of organolithium reagents
(
alkynyllithium reagents) as the first-addition nucleophiles, and thus allowed the
1
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5
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5
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introduction of unsaturated groups (alkynyl groups) as the first-incorporated
nucleophiles. Further efforts to extend this methodology are underway and the results
will be reported in due course.
0
1
2
3
4
5
6
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8
9
0
1
2
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8
9
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9
0
EXPERIMENTAL SECTION
1
13
General: H NMR and C NMR spectra were recorded on a spectrometer at 400, 500,
1
600 MHz and 100, 125, 150 MHz, respectively. Chemical shifts (δ) of H NMR and
13C NMR respectively referenced to an internal standard (Me
Si, 0 ppm for H NMR
1
4
13
and CDCl , 77.0 ppm for C NMR). Melting points were determined on a Yanaco
3
MP-500 micro melting point apparatus and were uncorrected. Optical rotations were
measured with an Anton Paar MCP 500 polarimeter. Infrared spectra were measured
with a Nicolet Avatar 330 FT-IR spectrometer using film KBr pellet techniques.
HRMS spectra were recorded using a Bruker microFlex MALDI TOF MS/MS
high-resolution mass spectrometer equipped with Fourier transform ion cyclotron
resonance-Mass Spectrometry (FTICR-MS). Silica gel (300-400 mesh) was used for
flash column chromatography (FC). Trifluoromethanesulfonic anhydride (Tf O) was
2
distilled over phosphorous pentoxide. Dry dichloromethane were distilled over
calcium hydride under argon. THF was distilled over sodium benzophenone ketyl
under argon. All reactions were carried out under an argon atmosphere. Alkynes
(
2a-2q), n-BuLi, iPrMgClꞏLiCl and other commercial reagents were used as received.
The freshly prepared alkynyllithium reagents 2a-2q and phenylethynyl Grignard
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reagents 2r, 2s were titrated before use with salicylaldehyde phenylhydrazone
according to the literature procedure.18
Synthesis of amides 1a-1r.
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
9a
19b
19c
19d
19c
19e
19f
19c
19g
The known amides 1a-1c , 1d , 1e-1g , 1h , 1i , 1j , 1k , 1l , 1m and
19i
1
n19h were synthesized from acyl chlorides and amines by known procedure , and
spectral data of the known amides match those reported.19
The new amides 1o, 1r, and known amide 1p, 1q were synthesized according to the
following specific procedure.
N,N-Dibenzylbut-2-ynamide (1o)
According to a literature procedure,19j to a cooled (0 °C) solution of 2-butynoic acid
(252 mg, 3 mmol, 1.0 equiv) in DCM (7.5 mL, 0.4 M) were added
dicyclohexylcarbodiimide (619 mg, 3 mmol, 1.0 equiv) and dibenzylamine (577 μL, 3
mmol, 1.0 equiv). The reaction was allowed to warm up to room temperature and
stirred for 12 hours at room temperature. The solution was filtered through a short pad
of silica gel, and washed with DCM. After being concentrated under reduced pressure,
the resulting oil was purified by flash chromatography on silica gel eluting with
EtOAc/hexane (1/5) to give amide 1o (719 mg, yield: 91%) as a light yellow oil. IR
(
film): 3030, 2921, 2853, 2246, 2213, 1700, 1628, 1495, 1450, 1423, 1363, 1238,
-1
1
1074, 976, 733, 699 cm ; H NMR (500 MHz, CDCl
3
): δ 7.39-7.34 (m, 2H),
7
.34-7.26 (m, 4H), 7.24 (d, J = 6.9 Hz, 2H), 7.19 (d, J = 6.9 Hz, 2H), 4.67 (s, 2H),
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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1
3
1
4
1
4
2
.49 (s, 2H), 2.00 (s, 3H) ppm; C{ H} NMR (125 MHz, CDCl
3
): δ 155.1, 136.3,
36.2, 128.8 (2C), 128.7 (2C), 128.4 (2C), 127.9, 127.7 (2C), 127.6, 89.8, 73.4, 51.3,
+
+
6.1, 4.1 ppm; HRMS (ESI) m/z calcd for [C18
64.1386.
H18NO] (M+H ): 264.1383; found:
0
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6
6
N ,N ,N ,N -Tetrabenzyladipamide (1p)
Oxalyl chloride (1.27 mL, 15.0 mmol, 3.0 equiv) and a catalytic amount of DMF
0.15 mL) were added to a stirred solution of adipic acid (731 mg, 5.0 mmol, 1.0
equiv) in CH Cl (20.0 mL, 0.25 M) at 0 °C. The mixture was stirred at room
(
2
2
temperature for 4 h, then the reaction mixture was concentrated under reduced
pressure to give a crude acyl chloride. The crude acyl chloride was dissolved in
anhydrous CH
flask containing dibenzylamine (2.88 mL, 15.0 mmol, 3.0 equiv), Et
mmol, 3.0 equiv), DMAP (122 mg, 1.0 mmol, 0.2 equiv) and CH Cl (10 mL) at 0 °C.
2
Cl
2
(10 mL), and the solution was added dropwise to a round-bottom
3
N (2.08 mL, 15.0
2
2
The reaction was slowly warmed to room temperature and stirred for 4 h. The reaction
mixture was washed with 1N HCl (2 × 15 mL), and the aqueous phases were
extracted with CH
2
Cl
2
(3 × 20 mL). The combined organic phases were dried over
anhydrous Na SO
2
4
, filtered, and concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel eluting with EtOAc/hexane (1/2)
to give amide 1p (1.64 g, yield: 65%) as a white solid. Mp: 121-123 ºC; IR (film):
3
029, 2922, 1645, 1605, 1495, 1452, 1422, 1362, 1301, 1215, 1141, 1080, 1029, 953,
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-
1 1
7
4
33, 699 cm ; H NMR (400 MHz, CDCl ): δ 7.38-7.24 (m, 12H), 7.20 (d, J = 6.8 Hz,
3
H), 7.12 (d, J = 7.3Hz, 4H), 4.59 (s, 4H), 4.42 (s, 4H), 2.52-2.32 (m, 4H), 1.78-1.72
m, 4H) ppm; 13C{ H} NMR (125 MHz, CDCl
1
): δ 173.3 (2C), 137.5 (2C), 136.6
(
(
3
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
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2
3
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9
0
2C), 128.96 (4C), 128.60 (4C), 128.3 (4C), 127.6 (2C), 127.4 (2C), 126.4 (4C), 49.9
(2C), 48.2 (2C), 33.0 (2C), 25.1 (2C) ppm; HRMS (ESI) m/z calcd for
+
+
[C
34
H
36
N
2
O
2
Na] (M+Na ): 527.2669; found: 527.2677.
1
1
3
3
5
5
N ,N ,N ,N ,N ,N -Hexabenzylbenzene-1,3,5-tricarboxamide (1q)
Oxalyl chloride (3.81 mL, 45.0 mmol, 4.5 equiv) and a catalytic amount of DMF
(
0.46 mL) were added to a stirred solution of 1,3,5-benzenetricarboxylic acid (2.1 g,
0 mmol, 1.0 equiv) in CH Cl (40 mL, 0.25 M) at 0 °C. The mixture was stirred at
1
2
2
room temperature for 4 h. The reaction mixture was concentrated under reduced
pressure to give a crude acyl chloride as a solid. The crude acyl chloride was added to
a round-bottom flask containing dibenzylamine (8.65 mL, 45.0 mmol, 4.5 equiv),
Et
CH
stirred for 4 h. The reaction mixture was diluted with CH
with 1N HCl (2 × 30 mL) and H O (3 × 80 mL). The organic phases were dried over
anhydrous Na SO , filtered and concentrated under reduced pressure. The residue was
3
N (6.24 mL, 45.0 mmol, 4.5 equiv), DMAP (367 mg, 3.0 mmol, 0.3 equiv) and
Cl (80 mL) at 0 °C. The reaction was slowly warmed to room temperature and
Cl (300 mL), and washed
2
2
2
2
2
2
4
purified by flash chromatography on silica gel eluting with EtOAc/hexane (1/2) to
give amide 1q (4.64 g, yield: 62%) as a white foam solid. Mp: 58-60 ºC; IR (film):
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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
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6
062, 3030, 2924, 1640, 1495, 1452, 1431, 1412, 1364, 1306, 1236, 1171, 1079, 1029,
-1 1
49, 900, 734, 699 cm ; H NMR (500 MHz, CDCl
3
): δ 7.63 (s, 3H), 7.34 (br s, 9H),
.25 (br s, 9H), 7.19 (d, J = 5.7 Hz, 6H), 7.00 (d, J = 5.5 Hz, 6H), 4.63 (s, 6H), 4.16 (s,
0
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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
13
1
H) ppm; C{ H} NMR (125 MHz, CDCl ): δ 170.3 (3C), 137.1 (3C), 136.4 (3C),
3
135.7 (3C), 128.95 (6C), 128.81 (6C), 128.4 (6C), 127.78 (3C), 127.74 (3C), 126.8
(
[
(
6C), 126.2 (3C), 51.4 (3C), 47.2 (3C) ppm; HRMS (ESI) m/z calcd for
+
+
C
51
H
45
N
3
O
3
Na] (M+ Na ): 770.3359; found: 770.3366.
S)-5-(Benzyloxy)-1-(4-methoxybenzyl)piperidin-2-one (1r)
To a solution of the known (3S)-benzyloxyglutarimide 520 (1.02 g, 3.0 mmol, 1.0
equiv) in THF (15 mL, 0.2 M) at –30 °C was added NaBH (227 mg, 18.0 mmol, 6.0
equiv) in one portion. The resulting suspension was stirred at –30 °C for 15 min
before quenching with a saturated aqueous solution of NaHCO (8 mL). After
4
3
completion of the addition, the mixture was stirred for 1 h and then filtered through
Celite. The filtrate was concentrated under reduced pressure. The residue was
extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over
anhydrous Na
2
SO
4
, filtered, and concentrated under reduced pressure. The residue
Cl (30 mL) under nitrogen. To the resulting solution
was dissolved in anhydrous CH
2
2
were added triethylsilane (4.79 mL, 30.0 mmol, 10.0 equiv) and boron trifluoride
etherate (1.14 mL, 9.0 mmol, 3.0 equiv) dropwise at –78 °C. After being stirred at
–78 °C for 6 h, the reaction mixture was allowed to warm to room temperature. and
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stirred overnight. The reaction was quenched with a saturated aqueous solution of
NaHCO
3
(10 mL) and extracted with CH
2
Cl
2
(3 × 10 mL). The combined organic
layers were dried over anhydrous Na
2
SO , filtered, and concentrated under reduced
4
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
pressure. The residue was purified by flash chromatography on silica gel eluting with
EtOAc/hexane (2/1) to give the corresponding lactam 1r (693 mg, yield: 71%) as a
2
5
light yellow oil. [α]D +20.6 (c 1.0, CHCl ); IR (film): 3030, 2931, 2836, 1640, 1585,
3
-1
1
1
512, 1494, 1455, 1417, 1359, 1303, 1246, 1176, 1089, 1030, 817, 738, 699 cm ; H
NMR (400 MHz, CDCl ): δ 7.35-7.22 (m, 5H), 7.18 (d, J = 8.6 Hz, 2H), 6.82 (d, J =
3
8.6 Hz, 2H), 4.56 (d, J = 14.7 Hz, 1H), 4.51-4.43 (m, 2H), 4.40 (d, J = 11.8 Hz, 1H),
3
2
.77 (s, 3H), 3.32-3.24 (m, 2H), 2.79-2.53 (m, 1H), 2.41 (dt, J = 17.6, 5.9 Hz, 1H),
.07-1.89 (m, 3H) ppm; 13C{ H} NMR (100 MHz, CDCl
1
): δ 169.3, 159.0, 138.0,
3
129.4 (2C), 129.0, 128.4 (2C), 127.7, 127.4 (2C), 114.0 (2C), 70.6, 70.3, 55.3, 50.5,
+
+
4
3
9.3, 28.3, 25.9 ppm; HRMS (ESI) m/z calcd for [C20
H
23NO Na] (M+ Na ):
3
48.1570; found: 348.1569.
General Procedure for the Synthesis of 3-Amino-1,4-diynes 3a-3ai.
To a cooled (‒78 ºC) solution of amide 1 (0.5 mmol, 1.0 equiv) and
2
,6-di-tert-butyl-4-methylpyridine (0.55 mmol, 1.1 equiv) in CH
was added dropwise trifluoromethanesulfonic anhydride (Tf O) (93 μL, 0.55 mmol,
.1 equiv) via a syringe at ‒78 °C under Ar atmosphere. After being stirred for 30 min,
a freshly prepared solution of alkynyllithium 2 (3.0 equiv) in THF (0.5 M) was added,
2
Cl (3.0 mL, 0.17 M)
2
2
1
2
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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
and the resulting mixture was warmed to room temperature and stirred for 1 h. The
reaction was quenched with a saturated aqueous solution of Na
extracted with CH Cl (3 × 5 mL). The combined organic phases were dried over
anhydrous Na SO , filtered, and concentrated under reduced pressure. The residue
2
CO
3
(4.0 mL), and
2
2
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
was purified by flash chromatography on silica gel to give the corresponding tertiary
amine 3.
Lithium alkynides 2 solution were prepared from alkynes and n-BuLi solution
according to the literature procedure. 21a
Lithium acetylide 4 was prepared from acetylene and n-BuLi according to the
literature procedure. 21b
Phenylethynylmagnesium bromide 2r was prepared from phenylacetylene and
EtMgBr according to the literature procedure.21c
Phenylethynyl Grignard reagent 2s was prepared from phenylacetylene and
iPrMgClꞏLiCl according to the literature procedure.17
-Benzyl-2,2-bis(phenylethynyl)pyrrolidine (3a)22
1
Following general procedure, the reductive dialkynylation of lactam 1a (88 mg, 0.5
mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane
=
1/20), tertiary amine 3a (195 mg, yield: 95%) as a light yellow solid. Mp: 90.3-92.5
ºC; IR (film): 3060, 3030, 2957, 2823, 2221, 1600, 1573, 1498, 1454, 1443, 1364,
-1
1
1
305, 1268, 1190, 1166, 1115, 1071, 1028, 977, 921, 755, 690 cm ; H NMR (400
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MHz, CDCl
3
): δ 7.57-7.46 (m, 4H), 7.43 (d, J = 7.4 Hz, 2H), 7.36-7.29 (m, 7H),
7.28-7.21 (m, 2H), 3.95 (s, 2H), 2.75 (t, J = 7.3 Hz, 2H), 2.51 (t, J = 7.7 Hz, 2H),
.00-1.89 (m, 2H) ppm; 13C{ H} NMR (100 MHz, CDCl
1
): δ 139.7, 132.0 (4C),
2
3
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
129.1 (2C), 128.3 (8C), 126.9 (2C), 123.0, 87.9 (2C), 83.8 (2C), 58.3, 55.5, 49.9, 41.5,
+
+
21.1 ppm; HRMS (ESI) m/z calcd for [C27H24N] (M+H ): 362.1903; found:
3
62.1903.
1-Benzyl-2,2-bis(phenylethynyl)piperidine (3b)22
Following general procedure, the reductive dialkynylation of lactam 1b (95 mg, 0.5
mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane
=
1/20), tertiary amine 3b (169 mg, yield: 90%) as a light yellow solid. Mp: 81.3-83.6
ºC; IR (film): 3060, 3029, 2936, 2856, 2805, 2222, 1598, 1489, 1443, 1363, 1345,
-1 1
1328, 1279, 1261, 1149, 1127, 1096, 1069, 1027, 980, 912, 755, 738, 690 cm ; H
NMR (400 MHz, CDCl ): δ 7.55-7.46 (m, 4H), 7.43 (d, J = 7.2 Hz, 2H), 7.37-7.27 (m,
H), 7.23 (t, J = 7.3 Hz, 1H), 3.97 (s, 2H), 2.53 (t, J = 5.4 Hz, 2H), 2.27 (t, J = 5.8 Hz,
3
8
13
1
2H), 1.78-1.69 (m, 2H), 1.55-1.49 (m, 2H) ppm; C{ H} NMR (100 MHz, CDCl
3
): δ
40.0, 131.9 (4C), 129.1 (2C), 128.3 (6C), 128.2 (2C), 126.8, 123.0 (2C), 88.4 (2C),
4.5 (2C), 58.3, 55.8, 47.3, 40.2, 25.5, 21.2 ppm; HRMS (ESI) m/z calcd for
1
8
+
+
[C
28
H
25NK] (M+K ): 414.1619; found: 414.1619.
1
-Benzyl-2,2-bis(phenylethynyl)azepane (3c)22
Following general procedure, the reductive dialkynylation of lactam 1c (102 mg, 0.5
mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane
2
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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
=
1/20), tertiary amine 3c (162 mg, yield: 83%) as a light yellow solid. Mp: 85.0-86.9
ºC; IR (film): 3060, 3030, 2928, 2850, 2221, 1598, 1573, 1490, 1452, 1442, 1365,
-1 1
1
350, 1292, 1266, 1145, 1129, 1070, 1040, 1028, 992, 948, 755, 734, 690 cm ; H
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
NMR (400 MHz, CDCl ): δ 7.53-7.44 (m, 6H), 7.34-7.23 (m, 9 H), 4.08 (s, 2H),
3
2.74-2.59 (m, 2H), 2.45-2.32 (m, 2H), 2.01-1.86 (m, 2H), 1.59-1.50 (m, 2H),
.48-1.37 (m, 2H) ppm; 13C{ H} NMR (150 MHz, CDCl
1
): δ 141.2, 132.0 (4C),
1
1
3
29.1 (2C), 128.3 (4C), 128.2 (2C), 128.1 (2C), 126.8, 123.2 (2C), 90.7 (2C), 82.1
(2C), 58.7, 58.2, 53.5, 47.0, 44.0, 30.5, 22.6 ppm; HRMS (ESI) m/z calcd for
+
+
[C29H28N] (M+H ): 390.2216; found: 390.2216.
1
-Allyl-2,2-bis(phenylethynyl)pyrrolidine (3d)
Following general procedure, the reductive dialkynylation of lactam 1d (63 mg, 0.5
mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane
=
1/20), tertiary amine 3d (139 mg, yield: 89%) as a light yellow oil. IR (film): 3079,
3
032, 2958, 2920, 2812, 2220, 1643, 1598, 1573, 1498, 1443, 1418, 1348, 1305, 1273,
-1 1
1253, 1192, 1167, 1115, 1070, 1028, 994, 917, 755, 690 cm ; H NMR (400 MHz,
CDCl ): δ 7.55-7.42 (m, 4H), 7.37-7.26 (m, 6H), 6.13-5.93 (m, 1H), 5.28 (d, J = 17.1
Hz, 1H), 5.13 (d, J = 10.1 Hz, 1H), 3.46 (d, J = 6.5 Hz, 2H), 2.85 (t, J = 7.2 Hz, 2H),
3
13
1
2.49 (t, J = 7.8 Hz, 2H), 2.07-1.86 (m, 2H) ppm; C{ H} NMR (125 MHz, CDCl
3
): δ
136.3 (2C), 131.9 (4C), 128.3 (2C), 128.2 (4C), 122.8, 117.1, 87.4 (2C), 83.9 (2C),
+
+
5
3
7.9, 54.3, 50.0, 41.5, 20.9 ppm; HRMS (ESI) m/z calcd for [C23H21NNa] (M+H ):
34.1566; found: 334.1574.
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N,N-Dibenzyl-1,3,5-triphenylpenta-1,4-diyn-3-amine (3e)
Following general procedure, the reductive dialkynylation of amide 1e (151 mg, 0.5
mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane
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
=
1/20), tertiary amine 3e (205 mg, yield: 84%) as a light yellow solid. Mp:
119.7-121.9 ºC; IR (film): 3061, 3028, 2921, 2849, 2222, 1664, 1598, 1490, 1449,
-1 1
1372, 1262, 1134, 1090, 1069, 1028, 982, 800, 755, 691 cm ; H NMR (400 MHz,
CDCl ): δ 8.09 (d, J = 7.8 Hz, 2H), 7.42-7.22 (m, 17H), 7.12 (t, J = 7.3 Hz, 4H), 7.06
3
13
1
(
t, J = 7.3 Hz, 2H), 3.95 (s, 4H) ppm; C{ H} NMR (100 MHz, CDCl
3
): δ 142.3,
1
40.4 (2C), 131.9 (4C), 128.8 (4C), 128.4 (2C), 128.3 (2C), 128.22, 128.2 (4C), 128.0
(
2C), 127.7 (4C), 126.3 (2C), 122.7 (2C), 88.1 (2C), 86.7 (2C), 62.9, 55.5 (2C) ppm;
+
+
HRMS (ESI) m/z calcd for [C37H30N] (M+H ): 488.2373; found: 488.2376.
N,N-Dibenzyl-1,5-diphenyl-3-(p-tolyl)penta-1,4-diyn-3-amine (3f)
Following general procedure, the reductive dialkynylation of amide 1f (158 mg, 0.5
mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane
=
1/20), tertiary amine 3f (206 mg, yield: 82%) as a light yellow solid. Mp:
125.8-127.9 ºC; IR (film): 3060, 3028, 2922, 2847, 2223, 1599, 1506, 1490, 1453,
-
1 1
1
7
2
443, 1263, 1068, 1028, 983, 951, 805, 756, 691 cm ; H NMR (500 MHz, CDCl ): δ
3
.96 (d, J = 7.9 Hz, 2H), 7.37-7.31 (m, 4H), 7.31-7.23 (m, 10H), 7.18 (d, J = 7.9 Hz,
H), 7.11 (t, J = 7.4 Hz, 4H), 7.05 (t, J = 7.4 Hz, 2H), 3.94 (s, 4H), 2.34 (s, 3H) ppm;
1
3
1
C{ H} NMR (125 MHz, CDCl
3
): δ 140.2 (2C), 139.4, 138.0, 131.9 (4C), 129.0 (2C),
1
28.9 (4C), 128.4 (2C), 128.2 (4C), 127.9 (2C), 127.7 (4C), 126.3 (2C), 122.9 (2C),
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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
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5
5
5
5
5
5
5
5
5
6
8
8.3 (2C), 86.5 (2C), 62.6, 55.5 (2C), 21.2 ppm; HRMS (ESI) m/z calcd for
+
+
[C H31NNa] (M+Na ): 524.2349; found: 524.2348.
38
N,N-Dibenzyl-3-(4-methoxyphenyl)-1,5-diphenylpenta-1,4-diyn-3-amine (3g)
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
Following general procedure, the reductive dialkynylation of amide 1g (166 mg, 0.5
mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane
=
1/20), tertiary amine 3g (210 mg, yield: 81%) as a light yellow oil. IR (film): 3061,
3
030, 2949, 2837, 2223, 1599, 1507, 1490, 1454, 1442, 1251, 1170, 1069, 1029, 833,
-1 1
805, 755, 691 cm ; H NMR (400 MHz, CDCl
3
): δ 7.98 (d, J = 8.8 Hz, 2H), 7.35 (d,
J = 7.7 Hz, 4H), 7.31-7.27 (m, 6H), 7.24 (d, J = 7.7 Hz, 4H), 7.14-7.10 (m, 4H),
13
1
7
.08-7.04 (m, 2H), 6.90 (d, J = 8.7 Hz, 2H), 3.94 (s, 4H), 3.81 (s, 3H) ppm; C{ H}
NMR (150 MHz, CDCl ): δ 159.4, 140.5 (2C), 134.4, 131.9 (4C), 129.2 (2C), 128.8
(4C), 128.3 (2C), 128.1 (4C), 127.7 (4C), 126.2 (2C), 122.8 (2C), 113.5 (2C), 88.2
3
(2C), 86.4 (2C), 62.3, 55.4 (2C), 55.3 ppm; HRMS (ESI) m/z calcd for
+
+
[C H31NNaO] (M+Na ): 540.2298; found: 540.2294.
38
N,N-Dibenzyl-3-(4-fluorophenyl)-1,5-diphenylpenta-1,4-diyn-3-amine (3h)
Following general procedure, the reductive dialkynylation of amide 1h (160 mg, 0.5
mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane
=
1/20), tertiary amine 3h (205 mg, yield: 81%) as a light yellow solid. Mp:
1
1
52.5-154.9 ºC; IR (film): 3062, 3029, 2923, 2844, 2222, 1602, 1507, 1504, 1491,
-1
1
454, 1443, 1264, 1225, 1156, 1064, 1028, 983, 951, 838, 817, 756, 691 cm ; H
NMR (500 MHz, CDCl
3
): δ 8.03 (dd, J = 8.5, 5.4 Hz, 2H), 7.39-7.33 (m, 4H),
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.32-7.26 (m, 6H), 7.23 (d, J = 7.4 Hz, 4H), 7.12 (t, J = 7.3 Hz, 4H), 7.07 (t, J = 7.1
Hz, 2H), 7.03 (t, J = 8.6 Hz, 2H), 3.95 (s, 4H) ppm; 13C{ H} NMR (125 MHz,
1
CDCl
29.87 (d, JFC = 8.2 Hz, 2C), 128.9 (4C), 128.6 (2C), 128.3 (4C), 127.9 (4C), 126.5
(2C), 122.6 (2C), 115.0 (d, JFC = 21.9 Hz, 2C), 87.9 (2C), 87.0 (2C), 62.4, 55.6 (2C)
3
): δ 162.6 (d, JFC = 247.4 Hz), 140.3 (2C), 138.07 (d, J FC= 2.8 Hz), 132.0 (4C),
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
+
+
ppm; HRMS (ESI) m/z calcd for [C37H28FNNa] (M+H ): 528.2098; found: 528.2098.
N,N-Dibenzyl-1,5-diphenyl-3-(o-tolyl)penta-1,4-diyn-3-amine (3i)
Following general procedure, the reductive dialkynylation of amide 1i (158 mg, 0.5
mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane
=
1/20), tertiary amine 3i (191 mg, yield: 76%) as a light yellow solid; Mp:
131.4-133.7 ºC; IR (film): 3061, 3028, 2961, 2920, 2849, 2220, 1659, 1598, 1490,
-1 1
1454, 1443, 1383, 1261, 1081, 1027, 801, 755, 690 cm ; H NMR (400 MHz, CDCl
3
):
δ 8.14 (d, J = 7.3 Hz, 1H), 7.48-7.42 (m, 4H), 7.34-7.30 (m, 6H), 7.23-7.15 (m, 2H),
13
1
7
.12-7.00 (m, 11H), 3.96 (s, 4H), 2.87 (s, 3H) pm; C{ H} NMR (150 MHz, CDCl
3
):
δ 140.0, 138.3, 137.8, 132.6, 131.9 (4C), 129.4 (4C), 129.1, 128.5 (2C), 128.4, 128.3
(4C), 127.7 (4C), 126.3 (2C), 125.4 (2C), 122.9 (2C), 87.7 (2C), 87.0 (2C), 63.8, 56.1
+
(
2C), 21.6 ppm; HRMS (ESI) m/z calcd for [C38
24.2346.
H
31NNa]+ (M+Na ): 524.2349; found:
5
N,N-Dimethyl-1,3,5-triphenylpenta-1,4-diyn-3-amine (3j)
Following general procedure, the reductive dialkynylation of amide 1j (75 mg, 0.5
mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane
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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
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
=
1/20), tertiary amine 3j (159 mg, yield: 95%) as a light yellow oil. IR (film): 3059,
2
9
7
950, 2860, 2822, 2779, 1597, 1489, 1470, 1443, 1267, 1216, 1173, 1060, 1007, 995,
-1
1
66, 755, 690 cm ; H NMR (400 MHz, CDCl ): δ 7.94 (d, J = 7.7 Hz, 2H),
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
.58-7.44 (m, 4H), 7.38 (t, J = 7.5 Hz, 2H), 7.35-7.18 (m, 7H), 2.42 (s, 6H) ppm;
1
3
1
C{ H} NMR (150 MHz, CDCl
3
): δ 141.3, 131.9 (4C), 128.5 (2C), 128.29 (4C),
1
28.27 (2C), 128.2, 127.7 (2C), 122.8 (2C), 86.8 (2C), 86.3 (2C), 63.0, 40.5 (2C) ppm;
+
+
HRMS (ESI) m/z calcd for [C25H22N] (M+H ): 336.1747; found: 336.1750.
N,N-Dibenzyl-1-phenyl-3-(phenylethynyl)tetradec-1-yn-3-amine (3k)
Following general procedure, the reductive dialkynylation of amide 1k (190 mg, 0.5
mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane
=
1/20), tertiary amine 3k (257 mg, yield: 91%) as a light yellow oil. IR (film): 3062,
3
029, 2925, 2853, 2220, 1560, 1490, 1454, 1443, 1371, 1312, 1263, 1069, 1028, 958,
-1 1
755, 691 cm ; H NMR (400 MHz, CDCl
3
): δ 7.45-7.33 (m, 8H), 7.32-7.25 (m, 6H),
7
1
.19 (t, J = 7.3 Hz, 4H), 7.12 (t, J = 7.3 Hz, 2H), 4.04 (s, 4H), 2.02-1.91 (m, 2H),
13
1
.84-1.69 (m, 2H), 1.31-1.19 (m, 16H), 0.88 (t, J = 6.7 Hz, 3H) ppm; C{ H} NMR
): δ 140.90 (2C), 131.88 (4C), 128.82 (4C), 128.20 (6C), 127.88
4C), 126.45 (2C), 123.04 (2C), 116.23, 89.13 (2C), 84.32 (2C), 60.26, 55.79 (2C),
(100 MHz, CDCl
3
(
4
1.78, 31.97, 30.20, 29.63, 29.50, 29.47, 29.39, 25.25, 22.73, 14.15 ppm; HRMS (ESI)
+
+
m/z calcd for [C37H30N] (M+H ): 488.2373; found: 488.2376.
N,N-Dibenzyl-3-methyl-1,5-diphenylpenta-1,4-diyn-3-amine (3l)
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Following general procedure, the reductive dialkynylation of amide 1l (120 mg, 0.5
mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane
=
1/20), tertiary amine 3l (149 mg, yield: 70%) as a light yellow solid. Mp: 94.1-96.5
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
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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
ºC; IR (film): 3061, 3028, 2922, 2842, 2221, 1598, 1490, 1453, 1443, 1370, 1279,
-1 1
1167, 1118, 1070, 1027, 755, 691 cm ; H NMR (500 MHz, CDCl
3
): δ 7.47-7.41 (m,
4
7
1
H), 7.38 (d, J = 7.5 Hz, 4H), 7.33-7.27 (m, 6H), 7.21 (t, J = 7.4 Hz, 4H), 7.13 (t, J =
.2 Hz, 2H), 4.04 (s, 4H), 1.76 (s, 3H) ppm; 13C{ H} NMR (125 MHz, CDCl
1
): δ
3
41.05 (2C), 131.92 (4C), 128.67 (4C), 128.31 (2C), 128.26 (4C), 127.99 (4C),
126.54 (2C), 122.89 (2C), 89.79 (2C), 83.35 (2C), 55.89 (2C), 55.67, 30.98 ppm;
+
+
HRMS (ESI) m/z calcd for [C32H27NNa] (M+Na ): 448.2030; found: 448.2036.
N,N-Dimethyl-3-phenethyl-1,5-diphenylpenta-1,4-diyn-3-amine (3m)
Following general procedure, the reductive dialkynylation of amide 1m (89 mg, 0.5
mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane
= 1/20), tertiary amine 3m (80 mg, yield: 90%) as a light yellow solid. IR (film): 3025,
2
6
955, 2860, 1598, 1489, 1469, 1453, 1443, 1306, 1217, 1157, 1091, 1070, 1040, 755,
-1
1
90 cm ; H NMR (500 MHz, CDCl ): δ 7.53-7.48 (m, 4H), 7.35-7.26 (m, 10H),
3
1
3
1
7.22-7.18 (m, 1H), 3.15-3.03 (m, 2H), 2.54 (s, 6H), 2.38-2.28 (m, 2H) ppm; C{ H}
NMR (100 MHz, CDCl ): δ 142.0, 132.0 (4C), 128.6 (4C), 128.5 (2C), 128.4 (4C),
26.1, 122.9 (2C), 87.3 (2C), 84.8 (2C), 59.2, 42.7, 40.5 (2C), 31.7 ppm; HRMS (ESI)
3
1
+
+
m/z calcd for [C27H26N] (M+H ): 364.2060; found: 364.2067.
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