Synthesis of Highly Substituted Quinolines via a Tandem Ynamide Benzannulation/Iodocyclization Strategy

Article abstract of DOI:10.1021/acs.joc.5b01648

A two-stage "tandem strategy" for the regiocontrolled synthesis of very highly substituted quinolines is described. Benzannulation based on the reaction of cyclobutenones or diazo ketones with N-propargyl-substituted ynamides proceeds via a cascade of several pericyclic reactions to generate multiply substituted aniline derivatives. In the second stage of the tandem strategy, triflate derivatives of the phenolic benzannulation products undergo Larock cyclization upon exposure to iodine to form products that are further elaborated by methods such as palladium-catalyzed coupling to generate quinolines that can be substituted at every position of the bicyclic system.

Full text of DOI:10.1021/acs.joc.5b01648

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Article
Synthesis of Highly Substituted Quinolines via a Tandem
Ynamide Benzannulation/ Iodocyclization Strategy
Thomas P. Willumstad, Paul D. Boudreau, and Rick L. Danheiser
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01648 • Publication Date (Web): 10 Aug 2015
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Synthesis of Highly Substituted Quinolines via a Tandem Ynamide
Benzannulation/ Iodocyclization Strategy
Thomas P. Willumstad, Paul D. Boudreau, and Rick L. Danheiser*
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Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
Eꢀmail: danheisr@mit.edu
ABSTRACT: A twoꢀstage “tandem strategy” for the regiocontrolled synthesis of very highly substituted
quinolines is described. Benzannulation based on the reaction of cyclobutenones or diazo ketones with Nꢀ
propargylꢀsubstituted ynamides proceeds via a cascade of several pericyclic reactions to generate multiply
substituted aniline derivatives. In the second stage of the tandem strategy, triflate derivatives of the
phenolic benzannulation products undergo Larock cyclization upon exposure to iodine to form products
that are further elaborated by methods such as palladiumꢀcatalyzed coupling to generate quinolines that
can be substituted at every position of the bicyclic system.
INTRODUCTION
1
The introduction of the WoodwardꢀHoffmann rules fifty years ago provided chemists for the first
time with a unified framework for understanding the disparate processes that have come to be known as
2
pericyclic reactions. This new theoretical model played a key role in enabling the extensive application
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of pericyclic reactions in the chemical synthesis of complex molecules. Cascades of pericyclic reactions
afford a particularly effective strategy for the rapid assembly of complex organic compounds, and the
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design and invention of new synthetic methods based on pericyclic cascade processes has been a
particular goal of research in our laboratory. Cascades involving cycloadditions, electrocyclic reactions,
and sigmatropic rearrangements based on vinylꢀ and dienylketenes have been one focus of our research in
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,5
this area, and herein we describe the application of a pericyclic cascade process in a strategy for the
regiocontrolled synthesis of very highly substituted quinolines.
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The quinoline ring system is found in the structure of numerous natural products, pharmaceutical
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agents, advanced materials, and commercially significant compounds. The importance of quinolines as
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synthetic targets has stimulated the development of numerous useful methods, most of which involve the
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cyclization or annulation of aniline derivatives with formation of the nitrogen heterocyclic ring. While
these methods are generally effective for the synthesis of quinolines bearing mulitple substituents on the
heterocyclic ring, the synthesis of quinolines that bear a high level of substitution on the benzenoid ring
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remains a formidable challenge.
RESULTS AND DISCUSSION
The challenges associated with the efficient preparation of highly substituted quinolines derive in
many cases from the difficulties associated with the regiocontrolled synthesis of the requisite
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polysubstituted aniline precursors. Convergent benzannulation strategies provide an exceptionally
attractive approach for the regiocontrolled construction of multiply substituted benzenoid aromatic
5,11,12
systems. Our laboratory has developed two complementary benzannulation strategies
based on the
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3
reaction of alkynes and vinylketenes, and recently we have extended this chemistry to include ynamides
as benzannulation partners in tandem benzannulation/cyclization strategies leading to several classes of
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polycyclic carbocyclic and heterocyclic compounds.
For the synthesis of highly substituted quinolines, we envisioned the twoꢀstage “tandem” strategy
outlined in Scheme 1 which would begin with benzannulation employing Nꢀpropargyl ynamides of
general type 3. In the second stage of the tandem strategy, exposure of the Nꢀpropargyl aniline
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benzannulation products (4) to a suitable electrophilic reagent (“X ”) such as molecular iodine would
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afford dihydroquinolines that would be easily oxidized to quinolines. As a bonus,
trifluoromethylsulfonylation of the phenolic hydroxyl group could provide a useful handle for the further
elaboration of the quinoline products at Cꢀ7 by employing wellꢀestablished transitionꢀmetal catalyzed
coupling reactions.
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Scheme 1. Tandem Benzannulation-Electrophilic Cyclization Strategy for the Synthesis of
Quinolines
Operationally the vinylketeneꢀbased benzannulation outlined in Scheme 1 involves a single
synthetic step, but mechanistically it proceeds via a “cascade” involving up to four discrete pericyclic
transformations. In the original version of the benzannulation, thermolysis or irradiation of a
cyclobutenone serves as the triggering step for the cascade, effecting reversible fourꢀelectron electrocyclic
ring opening to produce the transient vinylketene intermediate 6. This vinylketene is immediately
intercepted by the ynamide reaction partner in a regioselective [2 + 2] cycloaddition that affords a new
cyclobutenone, 7. Under the conditions of the reaction, this intermediate undergoes reversible fourꢀ
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electron electrocyclic ring opening to generate the dienylketene 8, which rapidly cyclizes via 6ꢀπ
electrocyclic ring closure to furnish the desired Nꢀpropargyl aniline benzannulation product 4 following
tautomerization. In an alternate “secondꢀgeneration” version of the strategy, photochemical Wolff
rearrangement of αꢀdiazo ketones of type 2 serves as the triggering step for the benzannulation,
generating vinylketene intermediates 6 which then participate in the same cascade of pericyclic reactions
involved in the cyclobutenone version.
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At the outset of our investigation we recognized that in order for the strategy outlined in Scheme 1
to be successful, it would be necessary that the vinylketene [2 + 2] cycloaddition proceed
chemoselectively at the more electronꢀrich ynamide triple bond in 3 in the presence of the propargylic
alkyne and any other unsaturated moieties in the reaction substrates. Efficient benzannulation would also
require that the Nꢀpropargyl ynamide be stable under the thermal and photochemical reaction conditions,
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and not be diverted by competing processes such as [3,3]ꢀsigmatropic rearrangement.
Finally, success
would also depend on the rate of 6ꢀπ electrocyclic ring closure of 8 being faster than alternative reactions
such as intramolecular [2 + 2] cycloaddition of the ketene with the pendant alkyne.
Synthesis of Benzannulation Reaction Partners. The synthesis of the benzannulation
partners employed in our investigation was conveniently accomplished using previously developed
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methods. Cyclobutenones are available in 1–2 steps via keteneꢀalkyne cycloadditions, and the α,βꢀ
unsaturated diazo ketones that serve as vinylketene precursors were prepared by employing the
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detrifluoroacetylative diazo transfer protocol previously developed in our laboratory. For the synthesis
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of ynamides, we employed the closely related copperꢀpromoted Nꢀalkynylation methods pioneered in
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our laboratory and the laboratory of Hsung. Both methods involve the reaction of amine derivatives
with alkynyl bromides, which are themselves readily obtained from terminal alkynes (or silyl alkynes) by
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reaction with NBS in the presence of catalytic silver nitrate. Table 1 summarizes the synthesis of Nꢀ
propargyl ynamides 14, 15, and 16 from propargyl carbamates 9ꢀ11. In the case of these Nꢀpropargyl
ynamides, we found that slightly better yields were obtained by employing the Hsung protocol.
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Table 1. Synthesis of Ynamides via Copper-Catalyzed Alkynylation of Carbamates
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propargyl carbamate
alkynyl bromide
b
entry
ynamide
yield (%)
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R
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Ph
CH3
H
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Hex
Hex
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H
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isopropenyl
CH3
(CH ) OTBS
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2 2
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Conditions: carbamate (1.0 equiv), alkynyl bromide (1.2 equiv), CuSO •5H O (0.2 equiv), 1,10ꢀ
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phenanthroline (0.4 equiv), K PO (2.0 equiv), toluene, 80ꢀ85 °C, 49ꢀ70 h. . Isolated yield of products
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purified by column chromatography. For the preparation of 9 see ref. 23. For the preparation of 10 see
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ref. 24. For the preparation of 11, see the Experimental Section.
Cyclobutenone-Based Quinoline Synthesis. The feasibility of employing Nꢀpropargyl
ynamides in the cyclobutenone version of the benzannulation was examined by using readily available 3ꢀ
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butylcyclobutenone (17) as the vinylketene precursor. As expected from our previous studies with Nꢀ
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allyl ynamides,
the optimal conditions for benzannulation with Nꢀpropargyl ynamide 14 was found to
involve a staged heating protocol as outlined in Scheme 2. This procedure minimizes [3,3]ꢀsigmatropic
rearrangement of the 1,5ꢀdiyne moiety which occurs at temperatures above ca. 125 °C. In our optimized
benzannulation protocol, initial thermolysis was performed at 80 °C until all of the ynamide was
consumed. This led to a mixture of the desired benzannulation product and intermediate 4ꢀ
vinylcyclobutenone (i.e., 7 in Scheme 1). Further heating at 110 °C then converted the remaining
vinylcyclobutenone to the desired phenol product. As predicted, ketene [2 + 2] cycloaddition occurred
chemoselectively at the electronꢀrich ynamide π bond, and no products resulting from competitive
reaction at the other triple bond were detected.
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Scheme 2. Feasibility of the Tandem Benzannulation/Iodocyclization Strategy
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The next stage of our proposed tandem strategy called for electrophilic cyclization of the Nꢀ
propargyl aniline benzannulation products to generate the nitrogen heterocyclic ring. After considering
several alternatives, we decided to focus our attention on the excellent iodocyclization protocol introduced
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by Larock.
Attractive features of this method include its mild reaction conditions and the fact that the
products incorporate a carbonꢀiodine bond at Cꢀ3, providing opportunities for further synthetic
elaboration of the quinolines by metalation and transitionꢀmetal catalyzed coupling reactions. The
corresponding bromocyclization processes were not examined since Larock has reported that such
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reactions proceed in significantly lower yield as compared to the analogous iodocyclizations.
In the event, attempted cyclization of phenolic benzannulation products such as 18 resulted in the
formation of significant amounts of diiodide byproducts produced by iodination of the desired 7ꢀ
hydroxyquinolines at the position ortho to the hydroxyl group. Fortunately, we found that this side
reaction could be suppressed by conversion of the phenol to its triflate derivative prior to iodocyclization.
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This was a particularly attractive solution since the Cꢀ7 triflate would provide an additional handle for the
synthetic elaboration of the quinoline products.
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Trifluoromethylsulfonylation of 18 proceeded smoothly under standard conditions as shown in
Scheme 2, and we found that cleavage of the Boc group could be achieved in the same flask simply by
adding excess CF CO H to the reaction mixture and stirring at 0 °C to rt for 1 h. Exposure of 19 to the
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action of iodine in acetonitrile in the presence of NaHCO then led directly to the desired quinoline 20 in
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excellent overall yield from benzannulation product 18. As suggested by Larock, excess I presumably
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effects dehydrogenation of the dihydroquinoline initially generated in the cyclization. It should be noted
that we found that the optimal conditions for conversion of 19 to quinoline 20 require the use of twice the
amount of iodine and NaHCO employed by Larock in his studies.
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Diazo Ketone-Based Quinoline Synthesis. The photoꢀWolff rearrangement of α,βꢀ
unsaturated αꢀdiazo ketones provides an alternative means of generating the key vinylketene
intermediates involved in the pericyclic cascade mechanism of our benzannulation strategy.
This
“second generation” version of the benzannulation provides expeditious access to certain highly
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substituted aromatic systems that are not readily available by using the cyclobutenoneꢀbased method.
As shown in Table 2, Nꢀpropargyl ynamides participate in this variant of the benzannulation furnishing
very highly substituted Nꢀpropargyl anilines such as 23ꢀ25 in good yield. In the optimal protocol,
irradiation of a solution of ynamide and excess diazo ketone is carried out in dichloromethane to produce
a mixture of the desired phenol and varying amounts of the intermediate vinylcyclobutenone (i.e.,
intermediate 7 in Scheme 1). Brief heating of the crude product at reflux in toluene then serves to
complete the transformation of any vinylcyclobutenone present to the desired phenol. Conversion of the
benzannulation products to quinolines 26ꢀ28 was then accomplished in two steps using the procedure
previously developed for Nꢀpropargyl aniline 18. As illustrated with these examples, the tandem
benzannulation/cyclization strategy has the capability to furnish densely substituted quinolines including
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compounds with alkenyl substituents and quinolines bearing substituents at every position of the bicyclic
system.
Table 2. Synthesis of Quinolines via Tandem Benzannulation/Iodocyclization Strategy
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Conditions: ynamide (1.0 equiv), diazo ketone (2.5 equiv), CH Cl , hν, rt, 30ꢀ33 h; then toluene, reflux,
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equiv), Tf O (1.1ꢀ1.3 equiv), CH Cl , 0 ºC to rt, 1ꢀ2 h; then add TFA (20 equiv), 0 ºC to rt, 40ꢀ90 min. (2)
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I (6 equiv), NaHCO (4 equiv), MeCN, rt, 40ꢀ60 min. Overall yield for two steps from benzannulation
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product. Overall yield for three steps from ynamide.
Synthesis of a Bis-Quinoline. Scheme 3 describes the application of the tandem
benzannulation/cyclization strategy to the synthesis of bisꢀquinoline 32. Bromination of 1,6ꢀheptadiyne
was accomplished in 93% yield by reaction with NBS in the presence of catalytic silver nitrate, and Nꢀ
alkynylation using the Hsung protocol furnished the bisꢀynamide 30 in 59ꢀ60% yield. Benzannulation,
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trifluoromethylsulfonylation, and double iodocyclization then provided the expected bisꢀquinoline in good
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overall yield.
Scheme 3. Synthesis of Bis-quinoline 32
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In summary, the examples presented in Table 2 and Schemes 2 and 3 establish that Nꢀpropargyl
ynamides participate in both versions of the benzannulation without complications due to the competing
pericyclic processes discussed earlier, and without interference due to the presence of other unsaturated
moieties in the substrates. These results suggest that benzannulations involving Nꢀpropargyl ynamides
should proceed smoothly with the wide range of other cyclobutenones and vinylketenes that have been
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demonstrated to function as vinylketene precursors in our benzannulation.
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Synthetic Elaboration of Quinoline Products. As noted above, the quinolines produced in
the tandem benzannulation/iodocyclization strategy all incorporate iodo and trifluoromethylsulfonyloxy
substituents at the Cꢀ7 and Cꢀ3 positions of the bicyclic system. It was evident that the synthetic utility of
this methodology would be significantly enhanced if siteꢀselective replacement of these substituents with
a wide range of carbon moieties could be achieved.
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Knochel has reported procedures for the generation of a variety of magnesiated heterocycles under
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mild conditions by iodineꢀmagnesium exchange and this chemistry appeared to be ideally suited for the
chemoselective elaboration of our quinoline products at the Cꢀ3 position. In fact, as illustrated in Scheme
4
, exposure of 3ꢀiodoquinoline 20 to iꢀPrMgBr under Knochel’s conditions generates a Grignard
derivative that can be allylated after transmetallation to copper to afford quinoline 33 in good yield.
Scheme 4. Allylation of Iodoquinoline 20 via Iodine-Magnesium Exchange
The fact that oxidative addition of palladium generally takes place more rapidly with aryl and
heteroaryl iodides as compared to triflates suggested to us that it might be possible to achieve sequential
2
8,29
siteꢀselective crossꢀcoupling reactions of our benzannulation/iodocyclization products.
The examples
shown in Scheme 5 confirmed the feasibility of this approach. Suzuki coupling proceeded selectively at
the carbonꢀiodine bond in 20 as expected, and reaction of the product with phenylacetylene under
standard Sonogashira alkynylation conditions furnished quinoline 34 in good overall yield. In a similar
fashion, siteꢀselective Sonogashira coupling of 27 took place smoothly to provide a quinoline triflate that
was then reacted with methyl vinyl ketone under standard Heck reaction conditions to afford the highly
functionalized quinoline 35.
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9
Scheme 5. Synthetic Elaboration of Quinolines via Palladium-Catalyzed Coupling
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of Quinolines Unsubstituted at C-3. We next turned our attention to the
preparation of quinolines lacking a substituent at Cꢀ3. Two alternative strategies were developed.
Deiodination of 26 could be effected by reduction with tributyltin hydride, but better results were obtained
30,31
as shown in Scheme 6 by using catalytic Pd(OAc) in the presence of Et N and HCO H.
It should be
2
3
2
noted that a more direct route to the same quinoline (36) is available by employing the Hg(II)ꢀcatalyzed
2
5b
cyclization protocol introduced by Larock as outlined in Scheme 7.
Scheme 6. Deiodination of Quinoline 26
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7
8
9
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
Scheme 7. Hg(II)-Catalyzed Cyclization
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
CONCLUSION
An efficient tandem benzannulation/iodocyclization strategy for the synthesis of highly substituted
quinolines has been developed. Two alternative vinylketeneꢀbased benzannulation reactions involving Nꢀ
propargyl ynamides provide regiocontrolled access to highly substituted Nꢀpropargyl aniline derivatives,
and iodocyclization according to the method of Larock proceeds in good yield to afford polysubstituted
quinoline products that can be further elaborated by siteꢀselective carbonꢀcarbon bond forming reactions
to generate a diverse array of quinolines that can be substituted at every position of the bicyclic system if
desired.
EXPERIMENTAL SECTION
General Procedures. All reactions were performed in flameꢀdried or ovenꢀdried glassware under
a positive pressure of argon. Reaction mixtures were stirred magnetically unless otherwise indicated. Airꢀ
and moistureꢀsensitive liquids and solutions were transferred by syringe or cannula and introduced into
reaction vessels through rubber septa. Reaction product solutions and chromatography fractions were
concentrated by rotary evaporation at ca. 20 mmHg and then at ca. 0.1 mmHg (vacuum pump) unless
otherwise indicated. Thin layer chromatography was performed on precoated glassꢀbacked silica gel 60 Fꢀ
2
54 0.25 mm plates. Column chromatography was performed on silica gel 60 (230ꢀ400 mesh) or on basic
alumina (80ꢀ325 mesh).
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4
Materials. Commercial grade reagents and solvents were used without further purification except
as indicated below. Dichloromethane, diethyl ether, and tetrahydrofuran were purified by pressure filtration
through activated alumina. Toluene was purified by pressure filtration through activated alumina and Cu(II)
oxide. Acetonitrile and triethylamine were distilled under argon from calcium hydride. Triflic anhydride
was distilled under argon from P O . Iodine was ground to a fine powder before use. DMF was stirred over
5
6
7
8
9
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
5
CaH for 24 h and then distilled under argon from MgSO at 20 mmHg. Formic acid was distilled under
2
4
argon at 40 mmHg. Phenylacetylene, allyl bromide, and isopropenylacetylene were filtered through a plug
of activated alumina prior to use. NꢀBromosuccinimide was recrystallized from boiling water.
Triphenylphosphine was recrystallized from boiling hexanes. 4ꢀDMAP was recrystallized from boiling
toluene. Copper (I) iodide was extracted with THF for 24 h in a Soxhlet extractor and then dried under
vacuum (0.1 mmHg). LiCl was dried under vacuum (0.1 mmHg) at 150 ºC for 24 h before use. Molecular
sieves (4 Å) were dried under vacuum (0.1 mmHg) at 300 °C for 16 h before use. iꢀPropylmagnesium
3
2
bromide was prepared from magnesium turnings and 2ꢀbromopropane.
propylmagnesium bromide were titrated using menthol in THF with 1,10ꢀphenanthroline as an indicator.
Deactivated alumina was prepared by first generating Brockman I grade by heating 150 g of alumina at 250
C under vacuum (0.050 mm Hg) for 12ꢀ18 h, and then cooling under argon. The alumina was then
nꢀButyllithium and iꢀ
3
3
°
transferred to a 500ꢀmL Erlenmeyer flask with a screw cap and the requisite amount of water was added to
obtain the desired grade (grade II: 3%; grade III: 6%; grade IV: 10%; grade V: 15% w/w water). The
alumina was then vigorously shaken for 10ꢀ15 min until a free flowing powder was obtained. The powder
was allowed to stand at rt for 24 h with occasional mixing prior to use.
Instrumentation. Melting points were determined with a FisherꢀJohns melting point apparatus and
1
are uncorrected.
H NMR chemical shifts are expressed in parts per million (δ) downfield from
13
tetramethylsilane (with the CHCl peak at 7.27 ppm used as a standard).
C NMR chemical shifts are
3
expressed in parts per million (δ) downfield from tetramethylsilane (with the central peak of CHCl at 77.23
3
ppm used as a standard).
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2
3
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5
6
7
8
9
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
N-(tert-Butoxycarbonyl)-N-(3-phenylprop-2-yn-1-yl)-oct-1-yn-1-ylamine (14). A 100ꢀ
2
3
mL recovery flask equipped with a rubber septum and argon inlet needle was charged with carbamate 9
3.29 g, 14 mmol, 1.0 equiv), K PO (6.05 g, 28 mmol, 2.0 equiv), CuSO •5H O (0.356 g, 1.4 mmol, 0.10
(
3
4
4
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
equiv), 1,10ꢀphenanthroline (0.514 g, 2.9 mmol, 0.20 equiv), and 10 mL of toluene. A solution of 1ꢀ
2
0a
bromooctyne 12 (3.0 g, 16 mmol, 1.1 equiv) in 5 mL of toluene was added via cannula over 2 min (3
mL of toluene rinse). The septum was replaced with a coldꢀfinger condenser fitted with an argon inlet
adapter and the heterogeneous reaction mixture was stirred at 85 °C for 25 h. The resulting mixture was
allowed to cool to rt and CuSO •5H O (0.356 g, 1.4 mmol, 0.10 equiv) and 1,10ꢀphenanthroline (0.514 g,
4
2
2
.8 mmol, 0.20 equiv) were added. The reaction mixture was stirred at 88 °C for 24 h, allowed to cool to
rt, and diluted with 10 mL of EtOAc. The resulting mixture was filtered through a ca. 4ꢀg plug of Celite
with the aid of five 15ꢀmL portions of EtOAc, and the filtrate was concentrated to yield 6.69 g of redꢀ
brown oil. Purification by column chromatography on 150 g of silica gel (elution with 1% EtOAcꢀ
hexanes) afforded 3.88 g (80%) of ynamide 14 as a yellow oil: IR (neat) 2931, 2858, 2264, 1721, 1290,
ꢀ1 1
1
6
161 cm ; H NMR (400 MHz, CDCl ) δ 7.43ꢀ7.45 (m, 2H), 7.28ꢀ7.31 (m, 3H), 4.41 (s, 2H), 2.33 (t, J =
3
.8 Hz, 2H), 1.49ꢀ1.55 (m, 2H), 1.52 (s, 9H), 1.36ꢀ1.47 (m, 2H), 1.25ꢀ1.28 (m, 4H), 0.87 (t, J = 6.8 Hz,
1
3
3H); C NMR (100 MHz, CDCl ) δ 154.0, 131.9, 128.5, 128.3, 122.8, 84.6, 83.6, 82.6, 73.7, 70.4, 40.0,
3
+
+
3
3
1.5, 29.1, 28.6, 28.2, 22.7, 18.7, 14.2; HRMSꢀESI (m/z) [M + Na] calculated for C H NNaO :
22 29 2
62.2091, found: 362.2098.
N-(tert-Butoxycarbonyl)-N-(but-2-yn-1-yl)-oct-1-yn-1-amine (15). A 25ꢀmL pear flask
24
equipped with a rubber septum and argon inlet needle was charged with carbamate 10 (0.177 g, 1.0
mmol, 1.0 equiv), K PO (0.444 g, 0.21 mmol, 2.0 equiv), CuSO •5H O (0.026 g, 0.11 mmol, 0.10
3
4
4
2
equiv), 1,10ꢀphenanthroline (0.036 g, 0.21 mmol, 0.20 equiv), and 0.5 mL of toluene. A solution of 1ꢀ
2
0a
bromooctyne 12 (0.217 g, 1.2 mmol, 1.1 equiv) in 0.5 mL of toluene was added via cannula over 1 min
(0.5 mL of toluene rinse). The septum was replaced with a coldꢀfinger condenser fitted with an argon
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inlet adapter and the heterogeneous mixture was stirred at 85ꢀ90 °C for 24 h. The resulting mixture was
allowed to cool to rt and CuSO •5H O (0.0.26 g, 0.11 mmol, 0.10 equiv) and 1,10ꢀphenanthroline (0.036
3
4
5
6
7
8
9
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
4
2
g, 0.21 mmol, 0.20 equiv) were added. The reaction mixture was stirred at 85ꢀ90 °C for 26 h, allowed to
cool to rt, and diluted with 3 mL of EtOAc. The mixture was filtered through a ca. 2ꢀg plug of Celite with
the aid of five 5ꢀmL portions of EtOAc, and the filtrate was concentrated to yield 0.376 g of redꢀbrown
oil. Purification by column chromatography on 19 g of silica gel (elution with 3% EtOAcꢀhexanes)
afforded 0.239 g (83%) of ynamide 15 as a pale yellow oil: IR (neat) 2932, 2859, 2265, 1721, 1292, 1163
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 ; H NMR (500 MHz, CDCl ) δ 4.05ꢀ4.19 (m, 2H), 2.31 (t, J = 7.0 Hz, 2H), 1.83 (t, J = 2.2 Hz, 3H)
3
1
3
1
.48ꢀ1.55 (m, 2H), 1.49 (s, 9H), 1.36ꢀ1.45 (m, 2H), 1.24ꢀ1.34 (m, 4H), 0.89 (t, J = 7.0 Hz, 3H); C NMR
(
125 MHz, CDCl ) δ 154.4, 82.8, 81.0, 74.2, 73.8, 70.5, 40.1, 31.9, 29.4, 28.9, 28.5, 23.1, 19.0, 14.6, 4.1;
3
+
+
2
HRMSꢀDARTꢀESI (m/z) [M + NH ] calculated for C H N O : 295.2380, found: 295.2389.
4
17 31
2
34,35
N-(tert-Butoxycarbonyl)-1-tosyleth-1-ylamine (38).
A 50ꢀmL pear flask equipped with
a rubber septum and argon inlet needle was charged with tertꢀbutyl carbamate (0.703 g, 6.0 mmol, 1.0
equiv), sodium pꢀtoluensulfinate dihydrate (1.29 g, 6.0 mmol, 1.0 equiv), acetaldehyde (0.37 mL, 6.6
mmol, 1.1 equiv), formic acid (1.6 mL, 42.4 mmol, 7.0 equiv), 0.7 mL methanol, and 6 mL H O. The
2
septum was replaced with a coldꢀfinger condenser fitted with an argon inlet and the heterogeneous
reaction mixture was stirred at 70 °C for 1h. The condenser was replaced with a cap and the reaction was
cooled at 4 °C for 5 h. The resulting crystals were collected by filtration, washed with 30 mL of cold
water, and then transferred to a 25ꢀmL recovery flask and dried overnight at 0.1 mmHg to provide 1.36 g
34
(
76%) of carbamate 38 as a white solid: mp 108ꢀ109 ºC (lit. 104ꢀ106 °C); IR (neat) 3441, 2981, 2933,
ꢀ1
1
1
728, 1494, 1322, 1168, 1146 cm ; H NMR (500 MHz, CDCl ) δ 7.79 (d, J = 8.0 Hz, 2H), 7.33 (d, J =
3
8.0 Hz, 2H), 5.10 (d, J = 11.0 Hz, 1H), 4.83ꢀ4.88 (d, minor rotamer), 4.91ꢀ4.99 (qd, J = 7.0, 11.0 Hz, 1H),
4
.75ꢀ4.84 (m, minor rotamer), 2.44 (s, minor rotamer), 2.41 (s, 3H), 2.61 (d, J = 7.0 Hz, 3H) 1.22 (s, 9H),
13
1
.13 (s, minor rotamer); C NMR (125 MHz, CDCl ) δ 153.6, 145.1, 133.7, 129.9, 129.6, 80.9, 66.9,
3
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2
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7
8
9
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
+
+
2
3
8.1, 21.8, 13.2; HRMSꢀDARTꢀESI (m/z) [M + NH ] calculated for C H N O S : 317.1530, found:
4
14 25
2
4
17.1522.
N-(tert-Butoxycarbonyl)-5-methylhex-5-en-3-yn-2-ylamine (11).
3
6
A 50ꢀmL, threeꢀ
necked, roundꢀbottomed flask equipped with an argon inlet adapter, two rubber septa, and a thermocouple
probe was charged with isopropenylacetylene (0.23 mL, 0.16 g, 2.4 mmol, 2.0 equiv) and 10 mL of THF.
The reaction mixture was cooled to ꢀ20 °C and nꢀBuLi solution (2.6 M in hexanes, 0.95 mL, 2.5mmol, 2.1
equiv) was added dropwise over 5 min. The bright yellow reaction mixture was stirred at ꢀ20 °C for 20
min and then cooled to ꢀ78 °C. A solution of carbamate 38 (0.361 g, 1.2 mmol, 1.0 equiv) in 2.5 mL of
THF was added via cannula over 7 min (0.5 mL THF rinse). The reaction mixture was stirred at ꢀ78 °C
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
for 1 h, and then 4 mL of satd aq NH Cl was added dropwise over 2 min. The resulting mixture was
4
allowed to warm to rt and then diluted with 7 mL of H O and extracted with four 12ꢀmL portions of
2
CH Cl . The combined organic phases were washed with 40 mL of brine, dried over MgSO , filtered, and
2
2
4
concentrated to afford 0.247 g of a pale yellow solid. Column chromatography on 13 g of silica gel
(elution with 2% EtOAcꢀhexanes) afforded 0.228 g (90%) of carbamate 11 as a white solid: mp 71ꢀ72 ºC;
ꢀ1 1
IR (neat) 3456, 2980, 2932, 1719, 1453, 1368, 1244, 1173 cm ; H NMR (500 MHz, CDCl ) δ 5.22ꢀ5.26
3
(
m, 1H), 5.17ꢀ5.21 (m, 1H), 4.72ꢀ4.85 (m, 1H), 4.54ꢀ4.64 (m, 1H), 1.84ꢀ1.88 (m, 3H), 1.46 (s, 9H), 1.40
1
3
(d, J = 7.0 Hz, 3H); C NMR (125 MHz, CDCl ) δ 154.8, 126.6, 122.1, 89.0, 83.6, 79.9, 39.1, 28.6, 23.7,
3
+
+
2
3.1; HRMSꢀDARTꢀESI (m/z) [M + H] calculated for C H NO : 210.1489, found: 210.1486.
12 20 2
N-(tert-Butoxycarbonyl)-N-(4-((tert-Butyldimethylsilyl)oxy)but-1-yn-1-yl)-5-
methylhex-5-en-3-yn-2-ylamine (16). A 25ꢀmL pear flask equipped with a rubber septum and argon
37
inlet needle was charged with bromo alkyne 13 (0.319 g, 1.2 mmol, 1.2 equiv), carbamate 11 (0.209 g,
1.0 mmol, 1.0 equiv), K PO (0.425 g, 2.0 mmol, 2.0 equiv), CuSO •5H O (0.025 g, 0.1 mmol, 0.10
3
4
4
2
equiv), 1,10ꢀphenanthroline (0.036 g, 0.2 mmol, 0.20 equiv), and 1.4 mL of toluene. The septum was
replaced with a coldꢀfinger condenser fitted with an argon inlet adapter and the heterogeneous reaction
mixture was stirred at 85 °C for 24 h. The resulting mixture was allowed to cool to rt and CuSO •5H O
4
2
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(0.025 g, 0.1 mmol, 0.10 equiv) and 1,10ꢀphenanthroline (0.036 g, 0.2 mmol, 0.20 equiv) were added.
3
4
5
6
7
8
9
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
The reaction mixture was stirred at 85 °C for 46 h, allowed to cool to rt, and diluted with 5 mL of EtOAc.
The mixture was filtered through a ca. 2ꢀg plug of Celite with the aid of five 5ꢀmL portions of EtOAc, and
the filtrate was concentrated to yield 0.568 g of brown oil. Purification by column chromatography on 60
g of silica gel (elution with 2% EtOAcꢀhexanes) afforded 0.234 g (60%) of ynamide 16 as a yellow oil: IR
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
(neat) 2955, 2931, 2857, 2262, 1720, 1305, 1166, 1106 cm ; H NMR (500 MHz, CDCl ) δ 5.26ꢀ5.29 (m,
3
1
H), 5.20ꢀ5.22 (m, 1H), 5.03 (m, 1H), 3.74 (t, J = 7.5 Hz, 2H), 2.55 (t, J = 7.5 Hz, 2H), 1.87 (s, 3H), 1.49
1
3
(
s, 9H), 1.46 (d, J = 7.0 Hz, 3H), 0.89 (s, 9H), 0.65 (s, 6H); C NMR (125 MHz, CDCl ) δ 153.7, 126.5,
3
1
22.2, 86.7, 85.1, 82.7, 72.0, 68.9, 62.6, 42.3, 28.2, 26.1, 23.6, 23.2, 20.4, 18.5, ꢀ5.1; HRMSꢀESI (m/z) [M
+
+
+
Na] calculated for C H NNaO Si : 414.2435, found: 414.2447.
22 37 3
5-Butyl-2-hexyl-3-(N-tert-butoxycarbonyl(3-phenylprop-2-yn-1-yl)amino)-phenol
18). A 25ꢀmL pearꢀshaped flask equipped with a rubber septum and argon inlet needle was charged with
(
1
7
ynamide 14 (0.309 g, 0.92 mmol, 1.0 equiv), cyclobutenone 17 (0.141 g, 1.1 mmol, 1.25 equiv), and 2.3
mL of toluene. The septum was replaced with a coldꢀfinger condenser fitted with argon inlet adapter and
the reaction mixture was heated at 80 °C for 1.5 h and then at reflux for 1 h. Concentration of the reaction
mixture afforded 0.570 g of amber oil. Column chromatography on 60 g of silica gel (gradient elution
with 5ꢀ10% EtOAcꢀhexanes) provided 0.378 g (89%) of carbamate 18 as an offꢀwhite solid: mp 90ꢀ91 °C;
ꢀ1
1
IR (neat) 3365 (broad), 2956, 2929, 2858, 1673, 1435, 1394, 1367, 1163 cm ; H NMR (400 MHz,
CDCl , 60:40 mixture of rotamers) for the major rotamer: δ 7.28ꢀ7.42 (m, 5H), 6.76 (s, 1H), 6.61 (s, 1H),
3
5
.71 (bs, 1H), 4.80 (d, J = 17.5 Hz, 1H), 4.27 (d, J = 17.5 Hz, 1H), 2.34ꢀ2.62 (m, 4H), 1.49ꢀ1.63 (m, 4H),
1
.39 (s, 9H), 1.20ꢀ1.48 (m, 8H), 0.80ꢀ0.94 (m, 6H); additional resonances appeared for the minor rotamer
at: δ 6.67 (s, 1H), 6.49 (s, 1H), 6.20 (bs, 1H), 4.62 (d, J = 17.5 Hz, 1H), 4.23 (d, J = 17.5 Hz, 1H), 1.61 (s,
1
3
9
1
H); C NMR (100 MHz, CDCl , mixture of two rotamers) for the major rotamer: δ 155.5, 155.2, 141.0,
3
40.6, 131.6, 128.3, 128.1, 124.7, 123.2, 120.5, 115.8, 85.2, 83.6, 80.6, 40.6, 35.2, 33.1, 31.9, 30.1, 29.2,
28.3, 26.1, 22.8, 22.2, 14.2, 14.0; additional resonances appeared for the minor rotamer at: δ 155.6, 155.3,
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1
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1
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2
2
2
2
2
2
2
2
2
2
3
3
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3
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3
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41.5, 140.8, 131.8, 128.4, 128.2, 125.3, 120.0, 115.1, 85.7, 84.1, 81.2, 41.8, 33.4, 32.0, 30.2, 29.6, 28.5,
2.6. Anal. Calcd for C H NO : C, 77.71; H, 8.91; N, 3.02. Found: C, 77.54; H, 8.93; N, 3.02.
2
3
0
41
3
5-Butyl-2-hexyl-3-(3-phenylprop-2-ynylamino)phenyl
19). A 25ꢀmL pear flask equipped with a rubber septum and argon inlet needle was charged with phenol
8 (0.487 g, 1.1 mmol, 1.0 equiv), 4ꢀDMAP (0.206 g, 1.7 mmol, 1.6 equiv), and 5 mL of CH Cl . The
trifluoromethanesulfonate
(
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
2
2
yellow solution was cooled to 0 °C and triflic anhydride (0.25 mL, 1.5 mmol, 1.4 equiv) was added
dropwise by syringe over ca. 3 min. The reaction mixture was allowed to warm to rt and stirred for 2 h.
The resulting yellow slurry of white solid was cooled to 0 °C and trifluoroacetic acid (1.2 mL, 16 mmol,
1
5 equiv) was added dropwise over 5 min. The resulting golden orange solution was allowed to warm to
rt, stirred for 1 h, and then diluted with 25 mL of dichloromethane and washed with 25 mL of satd aq
K CO solution. The aqueous layer was extracted with three 10ꢀmL portions of CH Cl , and the
2
3
2
2
combined organic layers were washed with 50 mL of brine, dried over MgSO , filtered, and concentrated
4
to afford 0.777 g of a dark red oil. Column chromatography on 19 g of silica gel (elution with 1%
EtOAcꢀhexanes) afforded 0.480 g (92%) of triflate 19 as a pale yellow oil: IR (neat) 3449 (broad), 2958,
ꢀ1 1
2
6
931, 2860, 1416, 1213, 1141 cm ; H NMR (400 MHz, CDCl ) δ 7.47ꢀ7.54 (m, 2H), 7.31ꢀ7.40 (m, 3H),
3
.72 (s, 1H), 6.66 (s, 1H), 4.22ꢀ4.30 (m, 2H), 4.19 (bs, 1H), 2.61ꢀ2.74 (m, 4H), 1.59ꢀ1.75 (m, 4H), 1.34ꢀ
1
3
1.55 (m, 8H), 0.93ꢀ1.06 (m, 6H); C NMR (100 MHz, CDCl ) δ 148.5, 146.4, 143.3, 131.9, 128.5, 128.4,
3
1
22.9, 118.8 (q, J = 318 Hz), 117.5, 111.2, 110.5, 85.9, 83.8, 35.8, 34.8, 33.5, 31.7, 29.6, 28.1, 24.8, 22.8,
+
+:
2
2.5, 14.1, 14.0; HRMSꢀESI (m/z) [M + H] calculated for C H F NO S 496.2128; found 496.2111.
26 33
3
3
5
-Butyl-8-hexyl-3-iodo-4-phenylquinolin-7-yl trifluoromethanesulfonate (20). A 25ꢀ
mL pearꢀshaped flask equipped with a rubber septum and argon inlet needle was charged with triflate 19
(0.480 g, 0.97 mmol, 1.0 equiv), NaHCO (0.326 g, 3.9 mmol, 4.0 equiv), iodine (1.48 g, 5.8 mmol, 6.0
3
equiv), and 10 mL of CH CN. The reaction mixture was stirred at rt for 40 min, diluted with 30 mL of
3
Et O, and then washed with 12 mL of satd aq Na S O solution. The aqueous layer was extracted with
2
2
2
3
three 10ꢀmL portions of Et O, and the combined organic layers were washed with 25 mL of brine, dried
2
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over MgSO , filtered, and concentrated to afford 0.634 g of a yellow oil. Column chromatography on 91
4
3
4
5
6
7
8
9
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
5
6
g of silica gel (elution with 1% EtOAcꢀ5% benzeneꢀ94% hexanes) yielded 0.522 g (87%) of quinoline 20
ꢀ1 1
as a yellow oil: IR (neat) 2929, 1421, 1214, 1141 cm ; H NMR (400 MHz, CDCl ) δ 9.32 (s, 1H), 7.45ꢀ
3
7
2
.60 (m, 3H), 7.15ꢀ7.30 (m, 3H), 3.24ꢀ3.40 (m, 2 H), 2.02ꢀ2.19 (m, 2H), 1.66ꢀ1.76 (m, 2H), 1.43ꢀ1.53 (m,
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
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8
9
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1
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8
9
0
H), 1.30ꢀ1.41 (m, 4H), 1.17ꢀ1.26 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H) 0.83ꢀ0.93 (m, 2H), 0.72 (t, J = 7.2 Hz,
1
3
3H); C NMR (125 MHz, CDCl ) δ 156.2, 151.8, 148.3, 147.0, 144.7, 141.2, 132.8, 128.9, 128.9, 128.7,
3
1
27.5, 122.6, 118.8 (d, J = 318 Hz), 102.0, 35.8, 34.3, 31.8, 30.4, 29.8, 26.2, 22.8, 22.6, 14.3, 13.9;
+
+:
HRMSꢀESI (m/z) [M + H] calculated for C H F INO S 620.0938; found 620.0917.
26 30
3
3
2
-Hexyl-3-(N-tert-butoxycarbonyl-(3-phenylprop-2-yn-1-yl)amino)-5,6,7,8-
tetrahydronaphthalen-1-ol (23). A 20ꢀcm quartz tube (7 mm I.D., 10 mm O.D.) equipped with a
1
8
rubber septum and argon inlet needle was charged with diazo ketone 21 (0.276 g, 1.8 mmol, 2.5 equiv),
ynamide 14 (0.250 g, 0.74 mmol, 1.0 equiv), and 2.9 mL of CH Cl . The yellow solution was degassed
2
2
for 10 min with a stream of argon. The quartz tube was placed ca. 20 cm from a 450ꢀW Hanovia lamp
(quartz immersion well, cooled by recirculating tap water) and irradiated under argon at 25 ºC for 33 h.
The reaction mixture was transferred to a 25ꢀmL pear flask with the aid of two 4ꢀmL portions of CH Cl
2
2
and concentrated to afford 0.507 g of an orange oil. This material was dissolved in 3.7 mL of toluene, the
flask was equipped with a stir bar and coldꢀfinger condenser, and the reaction mixture was heated at
reflux for 2.5 h. The resulting mixture was concentrated to afford 0.515 g of a dark orange oil. Column
chromatography on 52 g of silica gel (elution with 5% EtOAcꢀhexanes) provided 0.241 g of a yellowꢀ
orange foam. This material was dissolved in ca. 10 mL of hot hexanes and then cooled at ꢀ20 ºC for 12 h.
The resulting crystals were collected by filtration, washed with 20 mL of cold hexane, and then
transferred to a 25ꢀmL pear flask and dried overnight at 0.1 mmHg to provide 0.158 g (58%) of carbamate
2
3 as an offꢀwhite solid: mp 124ꢀ126 ºC; IR (neat) 3428 (broad), 2929, 2858, 1685, 1490, 1436, 1394,
ꢀ1
1
1
367, 1307, 1246, 1162 cm ; H NMR (500 MHz, CDCl 50:50 mixture of rotamers) for the major
3,
rotamer: δ 7.36ꢀ7.47 (m, 2H), 7.23ꢀ7.36 (m, 3H), 6.75 (s, 1H), 5.13 (s, 1H), 4.75 (d, J = 18 Hz, 1H), 4.32
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(
d, J = 18 Hz, 1H), 2.65ꢀ2.80 (m, 2H), 2.45ꢀ2.65 (m, 4H), 1.68ꢀ1.92 (m, 4H), 1.60 (s, 9H), 1.35ꢀ1.58 (m,
4
H), 1.22ꢀ1.35 (bs, 4H), 0.87 (m, 3H); additional resonances appeared for the minor rotamer at: δ 6.66 (s,
1
3
1H), 4.94 (s, 1H), 4.59 (d, J = 18 Hz, 1H), 4.26 (d, J = 18 Hz, 1H), 1.41 (s, 9 H); C NMR (125 MHz,
CDCl , mixture of two rotamers) for the major rotamer: δ 155.2, 152.5, 138.8, 136.3, 131.8, 128.4, 128.2,
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
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8
9
0
1
24.2, 123.3, 123.0, 121.2, 86.1, 83.9, 80.8, 41.9, 40.8, 32.0, 30.2, 29.5, 29.4, 28.6, 26.3, 23.2, 22.9, 22.8,
14.3; additional resonances appeared for the minor rotamer at: δ 154.8, 152.2, 138.2, 135.8, 131.7, 128.3,
1
23.7, 122.1, 121.0, 85.7, 83.4, 80.4, 31.9, 28.5, 23.1; Anal. Calcd for C H NO ; C, 78.05; H, 8.52; N,
30 39 3
3
.03. Found: C, 77.81; H, 8.71; N, 3.03.
-Hexyl-3-(3-phenylprop-2-ynylamino)-5,6,7,8-tetrahydronaphthalen-1-yl
2
trifluoromethanesulfonate (37). A 25ꢀmL pear equipped with a rubber septum and argon inlet
needle was charged with phenol 23 (0.140 g, 0.30 mmol, 1.0 equiv), 4ꢀDMAP (0.093 g, 0.76 mmol, 2.5
equiv), and 1.7 mL of CH Cl . The yellow solution was cooled to 0 °C and triflic anhydride (0.07 mL,
2
2
0
.39 mmol, 1.3 equiv) was added dropwise by syringe over ca. 2 min. The reaction mixture was allowed
to warm to rt and stirred for 1 h. The resulting yellow slurry of white solid was cooled to 0 °C and
trifluoroacetic acid (0.45 mL, 6.1 mmol, 20 equiv) was added dropwise over 6 min. The resulting golden
orange solution was allowed to warm to rt and stirred for 1 h. The reaction mixture was then diluted with
15 mL of CH Cl and washed with 15 mL of satd aq K CO solution. The aqueous layer was extracted
2
2
2
3
with two 10ꢀmL portions of dichloromethane, and the combined organic layers were washed with 30 mL
of brine, dried over MgSO , filtered, and concentrated to afford 0.236 g of an orange semiꢀsolid. Column
4
chromatography on 5 g of silica gel (elution with 3% EtOAcꢀhexanes) afforded 0.137 g (91%) of triflate
ꢀ1
1
3
7 as a yellow oil: IR (neat) 3442, 2932, 2860, 1402, 1243, 1212, 1140, 919 cm ; H NMR (500 MHz,
CDCl ) δ 7.39ꢀ7.44 (m, 2H), 7.29ꢀ7.34 (m, 3H), 6.55 (s, 1H), 4.18 (d, J = 6.0 Hz, 2H), 3.92 (t, J = 6.0 Hz,
3
1
H), 2.78 (m, 2H), 2.72 (m, 2H), 2.60 (m, 2H), 1.74ꢀ1.80 (m, 4H), 1.49ꢀ1.57 (m, 2H), 1.35ꢀ1.42 (m, 2H),
1
3
1
.28ꢀ1.35 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H); C NMR (125 MHz, CDCl ) δ 146.8, 143.9, 137.9, 131.9,
3
128.6, 128.5, 122.9, 120.3, 119.1, 118.9 (q, J = 318 Hz), 112.1, 86.2, 83.7, 35.1, 31.7, 29.9, 29.6, 28.4,
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+
+:
2
5.4, 24.0, 22.4, 22.8, 22.7, 14.3; HRMSꢀESI (m/z) [M + H] calculated for C H F NO S 494.1971;
2
6
31
3
3
3
4
5
6
7
8
9
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
found 494.1980.
5-Hexyl-2-iodo-1-phenyl-7,8,9,10-tetrahydrobenzo[f]quinolin-6-yl
trifluoromethanesulfonate (26). A 25ꢀmL pear flask equipped with a rubber septum and argon inlet
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
needle was charged with triflate 37 (0.065 g, 0.13 mmol, 1.0 equiv), NaHCO (0.044 g, 0.52 mmol, 4.0
3
equiv), iodine (0.199 g, 0.78 mmol, 6.0 equiv), and 1.3 mL of CH CN. The reaction mixture was stirred
3
at rt for 45 min, diluted with 15 mL of Et O, and then washed with 15 mL of satd aq Na S O solution.
2
2
2
3
The aqueous layer was extracted with three 10ꢀmL portions of Et O, and the combined organic layers
2
were washed with 15 mL of brine, dried over MgSO , filtered, and concentrated to afford 0.082 g of a
4
yellow oil. Column chromatography on 20 g of silica gel (elution with 1% EtOAcꢀ5% benzeneꢀ94%
hexanes) provided 0.075 g (92%) of quinoline 26 as a pale yellow oil: IR (neat) 2932, 2861 1404, 1218,
ꢀ1 1
1
137 cm ; H NMR (400 MHz, CDCl ) δ 9.26 (s, 1H), 7.43ꢀ7.54 (m, 3H), 7.14ꢀ7.22 (m, 2H), 3.31ꢀ3.40
3
(m, 2H), 2.92 (t, J = 6.4 Hz, 2H), 2.14 (t, J = 6.2 Hz, 2H), 1.61ꢀ1.78 (m, 4H), 1.40ꢀ1.53 (m, 4H), 1.28ꢀ
1
3
1.40 (m, 4H), 0.92 (t, J = 7.0 Hz, 3H); C NMR (125 MHz, CDCl ) δ 155.4, 151.2, 147.0, 146.4, 145.9,
3
1
35.2, 133.4, 131.3, 129.4, 128.6, 128.5, 118.8 (q, J = 318 Hz), 102.4, 31.9, 31.6, 30.6, 29.9, 26.7, 25.8,
+
2
3.0, 22.8, 21.4, 14.3 (one carbon overlapped in the region 144ꢀ152); HRMSꢀESI (m/z) [M + H]
+
:
calculated for C H O F INS 618.0781; found 618.0795.
2
6
28
3 3
3
-(N-tert-butoxycarbonyl(but-2-yn-1-yl)amino)-2-hexyl-5,6-dimethylphenol (24).
A
2
0ꢀcm quartz tube (7 mm I.D., 10 mm O.D.) equipped with a rubber septum and argon inlet needle was
1
8
charged with diazo ketone 22 (0.450 g, 3.6 mmol, 2.5 equiv), ynamide 15 (0.398 g, 1.4 mmol, 1.0
equiv), and 6 mL of CH Cl . The yellow solution was degassed for 10 min with a stream of argon. The
2
2
quartz tube was placed ca. 20 cm from a 450ꢀW Hanovia lamp (quartz immersion well, cooled by
recirculating tap water) and irradiated under argon at 25 ºC for 30 h. The reaction mixture was transferred
to a 25ꢀmL pear flask with the aid of two 4ꢀmL portions of CH Cl and concentrated to afford 0.81 g of an
2
2
orange oil. This material was dissolved in 7 mL of toluene, the flask was equipped with a stir bar and
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coldꢀfinger condenser, and the reaction mixture was heated at reflux for 2.5 h. The resulting mixture was
concentrated to afford 0.832 g of a dark orange oil. Column chromatography on 85 g of silica gel (elution
with 3% EtOAcꢀhexanes) provided 0.420 g of a yellow solid. This material was dissolved with 10 mL of
pentane and then cooled at ꢀ20 ºC for 12 h. The resulting crystals were collected by filtration, washed
with 10 mL of cold pentane, and then transferred to a 25ꢀmL pear flask and dried overnight at 0.1 mmHg
to provide 0.290 g (55%) of carbamate 24 as an offꢀwhite solid: mp 89ꢀ91 ºC; IR (neat) 3419 (broad),
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
2
928, 2859, 1681, 1574, 1395, 1367, 1321, 1251, 1166 cm ; H NMR (500 MHz, CDCl , 60:40 mixture
3
of rotamers) for the major rotamer: δ 6.62 (s, 1H), 4.81 (s, 1H), 4.39 (d, J = 17 Hz, 1H), 4.04 (d, J = 17
Hz, 1H), 2.40ꢀ2.57 (m, 2H), 2.24 (s, 3H), 2.14 (s, 3H), 1.78 (s, 3H), 1.54 (s, 9H), 1.32ꢀ1.65 (m, 4H), 1.24ꢀ
1
.32 (m, 4H), 0.89 (t, J = 7.0 Hz, 3H); additional resonances appeared for the minor rotamer at: δ 6.72 (s,
1H), 5.06 (s, 1 H), 4.29 (d, J = 17 Hz, 1H), 3.97 (d, J = 17 Hz, 1H), 2.21 (s, 3H), 2.08 (s, 3 H), 1.81 (s, 3
1
3
H), 1.35 (s, 9 H); C NMR (125 MHz, CDCl , mixture of two rotamers) for the major rotamer: δ 155.2,
3
1
52.3, 138.3, 135.0, 124.1, 122.1, 121.4, 80.2, 79.6, 75.1, 40.5, 32.0, 30.2, 29.3, 28.5, 26.4, 22.9, 20.2,
14.3, 12.0, 3.9; additional resonances appeared for the minor rotamer at: δ 154.8, 152.6, 138.4, 135.5,
ꢀ
ꢀ
1
24.6, 80.6, 79.1, 75.6, 41.3, 31.9, 3.7 HRMSꢀDARTꢀESI (m/z) [M ꢀ H] calculated for C H NO ,
23 34 3
3
72.2544; found: 372.2548. Anal. Calcd for C H NO : C, 73.96; H, 9.44; N, 3.75. Found: C, 74.18; H,
23 35 3
9.50; N, 3.70.
3
-(But-2-yn-1-ylamino)-2-hexyl-5,6-dimethylphenyl trifluoromethanesulfonate (39).
A 25ꢀmL pear flask equipped with a rubber septum and argon inlet needle was charged with phenol 24
0.153 g, 0.41 mmol, 1.0 equiv), 4ꢀDMAP (0.125 g, 1.0 mmol, 2.5 equiv), and 2.4 mL of CH Cl . The
(
2
2
yellow solution was cooled to 0 °C and triflic anhydride (0.09 mL, 0.53 mmol, 1.3 equiv) was added
dropwise by syringe over ca. 3 min. The reaction mixture was allowed to warm to rt and stirred for 1 h.
The resulting yellow slurry of white solid was cooled to 0 °C and trifluoroacetic acid (0.61 mL, 8.2 mmol,
2
0 equiv) was added dropwise over 5 min. The resulting golden orange solution was allowed to warm to
rt and stirred for 40 min. The reaction mixture was then diluted with 10 mL of dichloromethane and
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washed with two 10ꢀmL portions of satd aq K CO solution. The aqueous layer was extracted with two
2
3
3
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5
6
7
8
9
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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
3
3
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4
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4
5
5
5
5
5
5
5
5
5
5
6
1
0ꢀmL portions of CH Cl , and the combined organic layers were washed with 30 mL of brine, dried over
2 2
MgSO , filtered, and concentrated to afford 0.303 g of a golden semiꢀsolid. Column chromatography on
4
5
g of silica gel (elution with 3% EtOAcꢀhexanes) afforded 0.149 g (90%) of triflate 39 as a yellow oil:
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ꢀ1 1
IR (neat) 3444, 2928, 2860, 1402, 1246, 1218, 1140, 909 cm ; H NMR (500 MHz, CDCl ) δ 6.57 (s,
3
1H), 3.90ꢀ3.94 (m, 2H), 3.83 (bs, 1H), 2.58ꢀ2.63 (m, 2H), 2.29 (s, 3H), 2.20 (s, 3H), 1.84 (t, J = 2.0 Hz,
13
3
H), 1.49ꢀ1.57 (m, 2H), 1.36ꢀ1.44 (m, 2H), 1.31ꢀ1.38 (m, 4H), 0.92 (t, J = 7.0 Hz, 3H); C NMR (125
MHz, CDCl ) δ 146.9, 144.1, 137.2, 118.9 (q, J = 318 Hz), 118.8, 118.5, 113.0, 79.5, 76.0, 34.5, 31.7,
3
+
+:
2
4
9.6, 28.2, 25.4, 22.8, 20.7, 14.2, 13.3, 3.6; HRMSꢀESI (m/z) [M + H] calculated for C H F NO S
19 27 3 3
06.1658; found: 406.1658.
8-Hexyl-3-iodo-4,5,6-trimethylquinolin-7-yl trifluoromethanesulfonate (27).
mL pearꢀshaped flask equipped with a rubber septum and argon inlet needle was charged with triflate 39
0.100 g, 0.25 mmol, 1.0 equiv), NaHCO (0.084 g, 0.99 mmol, 4.0 equiv), iodine (0.376 g, 1.5 mmol, 6.0
A 25ꢀ
(
3
equiv), and 2.5 mL of CH CN. The reaction mixture was stirred at rt for 30 min, diluted with 30 mL of
3
Et O, and then washed with two 15ꢀmL portions of satd aq Na S O solution. The aqueous layer was
2
2
2
3
extracted with two 15ꢀmL portions of Et O, and the combined organic layers were washed with 40 mL of
2
brine, dried over MgSO , filtered, and concentrated to afford 0.167 g of a yellow oil. Column
4
chromatography on 42 g of silica gel (elution with 10% benzeneꢀhexanes) furnished 0.103 g (79%) of
ꢀ1
quinoline 27 as a offꢀwhite waxy solid: mp 36ꢀ38 ºC; IR (neat) 2958, 2929, 2858 1406, 1217, 1138 cm ;
1
H NMR (500 MHz, CDCl ) δ 9.07 (s, 1H), 3.27ꢀ3.32 (m, 2H), 2.88 (s, 3H), 2.63 (s, 3H), 2.47 (s, 3H),
3
13
1
.59ꢀ1.68 (m, 2H), 1.38ꢀ1.46 (m, 2H), 1.27ꢀ1.36 (m, 4H), 0.89 (t, J = 7.0 Hz, 3H); C NMR (125 MHz,
CDCl ) δ 155.7, 147.0, 146.1, 145.8, 133.3, 132.9, 131.2, 130.3, 118.9 (q, J = 318 Hz), 102.6, 31.9, 31.5,
3
3
0.5, 29.8, 26.6, 22.8, 21.8, 15.3, 14.3; Anal. Calcd for C H F INO S: C, 43.11; H, 4.38; N, 2.65.
19 23 3 3
Found: C, 43.32; H, 4.33; N, 2.68.
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6
2
-(2-Hydroxyethyl)-5,6-dimethyl-3-((5-methylhex-5-en-3-yn-2-yl)amino)phenyl
trifluoromethanesulfonate (40). A 20ꢀcm quartz tube (7 mm I.D., 10 mm O.D.) equipped with a
1
8
rubber septum and argon inlet needle was charged with diazo ketone 22 (0.177 g, 1.43 mmol, 2.5 equiv),
ynamide 16 (0.224 g, 0.572 mmol, 1.0 equiv), and 2.4 mL of CH Cl . The yellow solution was degassed
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
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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
for 10 min with a stream of argon. The quartz tube was placed ca. 20 cm from a 450ꢀW Hanovia lamp
(quartz immersion well, cooled by recirculating tap water) and irradiated under argon at 25 ºC for 38 h.
The reaction mixture was transferred to a 25ꢀmL pear flask with the aid of two 4ꢀmL portions of CH Cl
2
2
and concentrated to afford 0.392 g of an orange oil. This material was dissolved in 3.0 mL of toluene, the
flask was equipped with a stir bar and coldꢀfinger condenser, and the reaction mixture was heated at
reflux for 2 h. The resulting mixture was concentrated to afford 0.362 g of an orange oil. Filtration
through a 4ꢀg plug of silica gel (elution with 80 mL of 2% EtOAcꢀhexanes) afforded 0.220 g of crude
phenol 25 as a yellow oil. This material was transferred to a 25ꢀmL pear flask equipped with a rubber
septum and argon inlet needle. 4ꢀDMAP (0.165 g, 1.35 mmol, 3.0 equiv) and 4.5 mL of CH Cl were
2
2
added and the yellow solution was cooled to 0 °C while triflic anhydride (0.09 mL, 0.15 g, 0.54 mmol, 1.2
equiv) was added dropwise by syringe over ca. 5 min. The reaction mixture was allowed to warm to rt
and stirred for 1.5 h. The resulting red slurry of white solid was cooled to 0 °C and trifluoroacetic acid
(1.04 mL, 1.54 g, 13.5 mmol, 30 equiv) was added dropwise over 15 min. The resulting brown solution
was allowed to warm to rt and stirred for 2 h. The reaction mixture was then diluted with 30 mL of
dichloromethane and washed with three 20ꢀmL portions of satd aq K CO solution. The combined
2
3
aqueous layers were extracted with two 10ꢀmL portions of CH Cl , and the combined organic layers were
2
2
washed with 50 mL of brine, dried over MgSO , filtered, and concentrated to afford 0.363 g of an orangeꢀ
4
brown oil. Column chromatography on 40 g of silica gel (elution with CH Cl ) afforded 0.125 g (54%) of
2
2
ꢀ
1 1
triflate 40 as a yellow oil: IR (neat) 3583, 3332, 2977, 2928, 2885, 1403, 1246, 1214, 1139, 913 cm ; H
NMR (500 MHz, CDCl ) δ 6.75 (s, 1H), 5.22ꢀ5.24 (m, 1H), 5.18ꢀ5.20 (m, 1H), 4.82 (bs, 1H), 4.24 (q, J =
3
6.5 Hz, 1H), 3.86ꢀ3.95 (m, 2H), 2.88ꢀ2.97 (m, 2H), 2.29 (s, 3H), 2.18 (s, 3H), 1.93 (bs, 1H), 1.83ꢀ1.87 (m,
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3
3
1
H), 1.56 (d, J = 6.5 Hz, 3H); C NMR (125 MHz, CDCl ) δ 147.1, 145.2, 138.1, 126.7, 122.6, 122.0,
3
3
4
5
6
7
8
9
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
18.8 (q, J = 318 Hz), 116.8, 115.0, 89.9, 83.8, 63.3, 41.9, 28.7, 23.7, 22.6, 20.9, 13.4; HRMSꢀESI (m/z)
+
+:
[M + H] calculated for C H F NO S 406.1294; found, 406.1294.
18
23
3
4
8
-(2-Hydroxyethyl)-3-iodo-2,5,6-trimethyl-4-(prop-1-en-2-yl)quinolin-7-yl
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
trifluoromethanesulfonate (28). A 25ꢀmL pearꢀshaped flask equipped with a rubber septum and
argon inlet needle was charged with triflate 40 (0.107 g, 0.26 mmol, 1.0 equiv), NaHCO (0.089 g, 1.1
3
mmol, 4.0 equiv), iodine (0.402 g, 1.6 mmol, 6.0 equiv), and 2.6 mL of CH CN. The reaction mixture
3
was stirred at rt for 1 h, diluted with 25 mL of Et O, and then washed with three 10ꢀmL portions of satd
2
aq Na S O solution. The combined aqueous layers were extracted with two 10ꢀmL portions of Et O, and
2
2
3
2
the combined organic layers were washed with 50 mL of brine, dried over MgSO , filtered, and
4
concentrated to afford 0.140 g of a yellow oil. Column chromatography on 21 g of silica gel (elution with
2
% Et OꢀCH Cl ) furnished 0.110 g (79%) of quinoline 28 as a yellow oil: IR (neat) 3357, 2957, 2920,
2 2 2
ꢀ1 1
2
870 1406, 1214, 1140 cm ; HꢀNMR (500 MHz, CDCl ) δ 5.50ꢀ5.53 (m, 1H), 4.98ꢀ5.01 (m, 1H), 4.90
3
(bs, 1H), 3.96ꢀ4.04 (m, 2H), 3.54ꢀ3.59 (m, 2H), 3.00 (s, 3H), 2.68 (s, 3H), 2.46 (s, 3H), 2.22ꢀ2.24 (m,
1
3
3
H); CꢀNMR (125 MHz, CDCl ) δ 159.8, 155.2, 149.2, 146.7, 146.1, 134.2, 130.2, 129.9, 125.9, 120.0,
3
+
1
18.8 (q, J = 318 Hz), 103.3, 63.4, 32.0, 30.1, 24.7, 20.3, 15.8; HRMSꢀESI (m/z) [M + H] calculated for
+
:
C H F INO S 530.0104; found, 530.0078.
18
20
3
4
1
,7-Dibromohepta-1,6-diyne (29). A 100ꢀmL, twoꢀnecked, roundꢀbottomed flask equipped
with an argon inlet adapter and glass stopper was charged with 1,6ꢀheptadiyne (0.62 mL, 5.4 mmol, 1.0
equiv), NBS (2.13 g, 11.9 mmol, 2.2 equiv), AgNO (0.100 g, 0.54 mmol, 0.1 equiv), and 18 mL of
3
acetone. The resulting mixture was stirred in the dark at rt for 1 h and then diluted with 25 mL of pentane
and 37 mL of water. The organic layer was washed with three 10ꢀmL portions of satd aq Na S O
3
2
2
solution and 25 mL of brine, dried over MgSO , filtered, and concentrated to yield 1.30 g of a pale yellow
4
oil. Filtration through a 6 g plug of silica gel (elution with pentane) afforded 1.25 g (93%) of alkynyl
bromide 29 as a pale yellow oil: IR (thin film) 2956, 2938, 2908, 2218, 1452, 1430, 1345, 1327, 1309,
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2
2
2
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4
4
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5
5
5
5
5
5
5
5
5
6
ꢀ
1
1
13
1
291 cm ; H NMR (500 MHz, CDCl ) δ 2.34 (t. J = 7.0 Hz, 4H), 1.73 (quint, J = 7.0 Hz, 2H); C NMR
3
+
+
(
125 MHz, CDCl ) δ 79.3, 38.9, 27.2,19.0; HRMSꢀESI (m/z) [M + H] calculated for C H Br ,
3
7
7
2
250.8892; found, 250.8901.
Di-N-(tert-butoxycarbonyl)-hepta-1,6-diyne-1,7-diylbis(3-phenylprop-2-ynylamine)
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
(
30). A 25ꢀmL pear flask equipped with a rubber septum and argon inlet needle was charged with
Error! Bookmark not defined.
carbamate 9
(0.238 g, 1.0 mmol, 2.5 equiv), K PO (0.350 g, 1.6 mmol, 4.0 equiv),
3 4
CuSO •5H O (0.041 g, 0.16 mmol, 0.40 equiv), 1,10ꢀphenanthroline (0.059 g, 0.33 mmol, 0.80 equiv),
4
2
1
,7ꢀdibromoheptaꢀ1,6ꢀdiyne 29 (0.103 g, 0.41 mmol, 1 equiv), and 1.6 mL of toluene. The septum was
replaced with a coldꢀfinger condenser fitted with an argon inlet adapter and the reaction mixture was
stirred at 80ꢀ85 °C for 52 h and then allowed to cool to rt. The resulting mixture was diluted with 5 mL of
EtOAc and filtered through a ca. 2ꢀg plug of Celite with the aid of five 5ꢀmL portions of EtOAc.
Concentration of the filtrate yielded 0.317 g of a brown oil. Purification by column chromatography on
6
4 g of Brockman II alumina (elution with benzene) afforded 1.73 g of a yellow oil which was further
purified by column chromatography on 18 g of silica gel (elution with 5% EtOAcꢀhexanes) to afford
.137 g (60%) of ynamide 30 as a yellow oil: IR (neat) 2979, 2933, 2265, 1720, 1490. 1389, 1291, 1160
0
ꢀ1 1
cm ; H NMR (500 MHz, CDCl ) δ 7.43ꢀ7.46 (m, 4H), 7.28ꢀ7.31 (m, 6H), 4.40 (s, 4H), 2.49 (t, J = 7.0
3
1
3
Hz, 4H), 1.77 (quint, J = 7.0 Hz, 2H), 1.51 (s, 18H); C NMR (125 MHz, CDCl ) δ 154.0, 132.0, 128.5,
3
+
1
28.4, 122.8, 84.7, 83.5, 82.7, 74.3, 69.5, 40.0, 28.6, 28.2, 17.8; HRMSꢀESI (m/z) [M + Na] calculated
+
for C H N NaO 573.2724; found, 573.2737.
35 38
2
4
2
,2’-(1,3-Propanedyil)bis-5,5’-butyl-3,3’-(3-phenylprop-2-ynylamino)phenyl
trifluoromethanesulfonate (31). A 25ꢀmL pearꢀshaped flask equipped with a rubber septum and
17
argon inlet needle was charged with ynamide 30 (0.140 g, 0.25 mmol, 1.0 equiv), cyclobutenone 17
(
0.073 g, 0.58 mmol, 2.3 equiv), and 1.2 mL of toluene. The septum was replaced with a coldꢀfinger
condenser fitted with argon inlet adapter and the reaction mixture was heated at 80 °C for 2.5 h and then
at reflux for 2.5 h. Concentration of the reaction mixture provided 0.243 g of crude phenol 41 as an
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orange solid. 4ꢀDMAP (0.155 g, 1.3 mmol, 5 equiv) and 1.7 mL dichloromethane were added and the
resulting orange solution was cooled at 0 °C while triflic anhydride (0.10 mL, 0.58 mmol, 2.3 equiv) was
added dropwise by syringe over ca. 5 min. The reaction mixture was allowed to warm to rt and stirred for
3
4
5
6
7
8
9
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
h. The resulting red slurry of white solid was cooled to 0 °C and trifluoroacetic acid (0.75 mL, 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
mmol, 40 equiv) was added dropwise over 10 min. The resulting redꢀbrown solution was allowed to
warm to rt and stirred for 1 h. The reaction mixture was then diluted with 20 mL of CH Cl and washed
2
2
with three 15ꢀmL of satd aq K CO solution, 20 mL of brine, dried over MgSO , filtered, and
2
3
4
concentrated to afford 0.386 g of a redꢀbrown solid. Column chromatography on 39 g of silica gel
(
gradient elution 30ꢀ50% CH Cl ꢀhexanes) furnished 0.136 g (62%) of triflate 31 as a white solid: mp 98ꢀ
2 2
ꢀ1
1
1
01 °C; IR (neat) 3446 (broad), 2959, 2933, 2862, 1406, 1222, 1141 cm ; H NMR (500 MHz, CDCl ) δ
3
7.36ꢀ7.40 (m, 4H), 7.25ꢀ7.32 (m, 6H), 6.65 (s, 2H), 6.49 (s, 2H), 4.21ꢀ4.27 (m, 2H), 4.15ꢀ4.20 (m, 4H),
.62ꢀ2.76 (m, 4H), 2.57 (t, J = 7.5 Hz, 4H), 1.77ꢀ1.86 (m, 4H), 1.59 (quint, J = 7.5 Hz, 4H), 1.35 (app
2
13
hex, J = 7.5 Hz, 4H), 0.90 (t, J = 7.5 Hz, 6H); C NMR (125 MHz, CDCl ) δ 148.3, 146.5, 143.8, 131.9,
3
128.4, 128.4, 123.0, 118.7 (q, J = 318 Hz), 116.5, 111.4, 110.4, 85.9, 83.6, 35.9, 34.6, 33.5, 26.4, 24.9,
2
3
2.5, 14.1; Anal. Calcd for C H F N O S : C, 59.85; H, 5.14; N, 3.25. Found: C, 60.08; H, 5.29; N,
43 44 6 2 6 2
.29.
8,8'-(1,3-Propanediyl)bis-5,5’-butyl-3,3’-iodo-4,4’-phenylquinolin-7,7’-yl
trifluoromethanesulfonate (32). A 25ꢀmL pearꢀshaped flask equipped with a rubber septum and
argon inlet needle was charged with triflate 31 (0.102 g, 0.12 mmol, 1.0 equiv), NaHCO (0.079 g, 0.95
3
mmol, 8.0 equiv), iodine (0.360 g, 1.4 mmol, 12.0 equiv), and 2.4 mL of CH CN. The reaction mixture
3
was stirred at rt for 1 h, diluted with 30 mL of Et O, and then washed with two 15ꢀmL portions of satd aq
2
Na S O solution. The aqueous layer was extracted with two 15ꢀmL portions of Et O, and the combined
2
2
3
2
organic layers were washed with 60 mL of brine, dried over MgSO , filtered, and concentrated to afford
4
0
.137 g of a yellow oil. Column chromatography on 14 g of silica gel (elution with 2% EtOAcꢀhexanes)
yielded 0.106 g (81%) of quinoline 32 as an offꢀwhite solid: mp 190ꢀ192 °C; IR (neat) 2959, 2931, 2873,
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2
2
2
2
2
2
2
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3
3
3
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3
3
3
3
3
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4
4
5
5
5
5
5
5
5
5
5
5
6
ꢀ
1 1
1
420, 1217, 1141 cm ; H NMR (500 MHz, CDCl ) δ 9.27 (s, 2H), 7.49ꢀ7.54 (m, 6H), 7.20ꢀ7.24 (m, 6H),
3
3
.45ꢀ3.54 (m, 4 H), 2.20 (quint, J = 7.5 Hz, 2H), 2.04ꢀ2.14 (m, 4 H), 1.22 (app quint, J = 7.5 Hz, 4H),
1
3
0.89 (app hex, J = 7.5 Hz, 4H), 0.72 (t, J = 7.5 Hz, 6H); C NMR (125 MHz, CDCl ) δ 156.1, 151.7,
3
1
48.3, 147.1, 144.7, 141.4, 132.0, 128.9, 128.8, 128.7, 127.5, 122.6, 118.8 (d, J = 318 Hz), 102.0, 35.9,
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
2
3
4
5
6
7
8
9
0
3
4.3, 30.5, 26.0, 22.6, 13.9; Anal. Calcd for C H F I N O S : C, 46.50; H, 3.45; N, 2.52. Found: C,
4
3
38 6 2
2
6 2
46.48; H, 3.46; N, 2.42.
5
-Butyl-8-hexyl-3-(2-propenyl)-4-phenylquinolin-7-yl trifluoromethanesulfonate (33).
A 10ꢀmL twoꢀnecked pear flask equipped with a rubber septum, argon inlet adapter, and thermocouple
probe was charged with quinoline 20 (0.102 g, 0.16 mmol, 1.0 equiv) and 0.5 mL of THF. The reaction
mixture was cooled at ꢀ30 °C while iꢀPrMgBr solution (0.47 M in THF, 0.37 mL, 0.17 mmol, 1.1 equiv)
was added dropwise over 5 min and the resulting goldꢀcolored solution was stirred for 1 h at ꢀ30 °C.
CuCN (2 mg, 0.016 mmol, 0.10 equiv) and then allyl bromide (0.018 mL, 0.025 g, 0.21 mmol, 1.2 equiv)
were added, and the resulting yellow solution was stirred at ꢀ30 °C for 1 h and then allowed to warm to 0
°C and treated with 1 mL of brine. The resulting mixture was diluted with 4 mL of brine and the aqueous
layer was separated and extracted with two 5ꢀmL portions of EtOAc. The combined organic phases were
dried over MgSO , filtered, and concentrated to afford 0.086 g of an orange oil. Purification by column
4
chromatography on 22 g of silica gel (elution with 1% EtOAcꢀhexanes) afforded 0.069 g of an orange oil
which was further purified by column chromatography on 22 g of silica gel (elution with 10% benzeneꢀ
hexanes) to afford 0.061 g (69%) of quinoline 33 as a yellow oil: IR (neat) 2958, 2931, 2859, 1582, 1421,
ꢀ
1 1
1
215, 1142, 830 cm ; H NMR (500 MHz, CDCl ) δ 8.88 (s, 1H), 7.43ꢀ7.49 (m, 3H), 7.23ꢀ7.27 (m, 2H),
3
7
.18 (s, 1H), 5.78ꢀ5.87 (m, 1H), 5.03 (dq, J = 1.5, 10.0 Hz, 1H), 4.87 (dq, J = 1.5, 17.0 Hz, 1H), 3.31ꢀ3.36
(m, 2H), 3.21 (dt, J = 1.5, 6.0 Hz, 2H), 2.09ꢀ2.15 (m, 2H), 1.71ꢀ1.79 (m, 2H), 1.47ꢀ1.54 (m, 2H), 1.30ꢀ
1
3
1
.41 (m, 4H), 1.18ꢀ1.27 (m, 2H), 0.85ꢀ0.95 (m, 5H), 0.72 (t, J = 7.3 Hz, 3H); C NMR (125 MHz,
CDCl ) δ 151.7, 147.7, 146.6, 146.4, 141.3, 139.7, 136.6, 132.3, 131.8, 129.1, 128.4, 128.2, 125.7, 122.0,
3
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The Journal of Organic Chemistry
1
2
1
16.8 (2C, q, J = 318 Hz), 35.5, 35.3, 34.3, 31.9, 30.4, 29.9, 26.2, 22.9, 22.6, 14.3, 13.9; HRMSꢀESI (m/z)
3
4
5
6
7
8
9
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
+
+:
[
M + H] calculated for C H F NO S 534.2284; found 534.2269.
29 35 3 3
5-Butyl-8-hexyl-3-(3-methoxyphenyl)-4-phenylquinolin-7-yl
trifluoromethanesulfonate (42). A 10ꢀcm threaded Pyrex tube (12 mm I.D., 18 mm O.D.) equipped
with a rubber septum and argon inlet needle was charged with 3ꢀmethoxyphenyl boronic acid (0.065 g,
0.43 mmol, 1.2 equiv), PdCl (dppf)•CH Cl (0.059 g, 0.07 mmol, 0.2 equiv), quinoline 20 (0.223 g, 0.36
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
2
2
mmol, 1.0 equiv), 2.8 mL of THF, and 0.7 mL of Cs CO solution (1.0 M in water, 0.23 g Cs CO , 0.7
2
3
2
3
mmol, 2.0 equiv). The resulting mixture was degassed for 10 min with a stream of argon, the septum was
replaced with a threaded Teflon cap, and the reaction mixture was heated at 45ꢀ50 °C for 20.5 h. The
reaction mixture was then diluted with 30 mL of EtOAc, washed with two 15ꢀmL portions of brine, dried
over MgSO , filtered, and concentrated to afford 0.282 g of a brown oil. Column chromatography on 30
4
3
8
g of silica gel (elution with 1% EtOAcꢀhexanes) yielded 0.169 g (78%) of quinoline 42 as a white solid:
ꢀ
1 1
mp 69ꢀ71 °C; IR (neat) 2957, 2930, 2860, 1581, 1419, 1218, 1142 cm ; H NMR (500 MHz, CDCl ) δ
3
8.95 (s, 1H), 7.23ꢀ7.32 (m, 4H), 7.15ꢀ7.10 (m, 3H), 6.74 (dd, J = 2.5, 8.3 Hz, 1H), 6.65 (dt, J = 1, 8.3 Hz,
1
H), 6.49ꢀ6.51 (m, 1H), 3.62 (s, 3H), 3.34ꢀ3.39 (m, 2H), 2.13ꢀ2.18 (m, 2H), 1.73ꢀ1.82 (m, 2H), 1.52 (app
quint, J = 7.5 Hz, 2H), 1.31ꢀ1.42 (m, 4H), 1.14ꢀ1.22 (m, 2H), 0.91 (t, J = 7.0 Hz, 3H) 0.83 (app hex, J =
1
3
7.5 Hz, 2H), 0.67 (t, J = 7.5 Hz, 3H); C NMR (125 MHz, CDCl ) δ 159.0, 150.9, 148.3, 147.0, 145.7,
3
1
1
41.9, 139.5, 139.3, 135.2, 132.3, 130.2, 129.0, 127.9, 127.9, 125.4, 122.8, 122.4, 118.8 (d, J = 318 Hz),
+
15.6, 113.2, 55.3 35.7, 34.3, 31.9, 30.4, 29.9, 26.2, 22.9, 22.6, 14.3, 13.9; HRMSꢀESI (m/z) [M + H]
+
:
calculated for C H F NO S 600.2390; found 600.2369.
3
3
37
3
4
5
-Butyl-8-hexyl-3-(3-methoxyphenyl)-4-phenyl-7-(phenylethynyl)quinoline (34).
A
25ꢀmL pear flask equipped with a rubber septum and argon inlet needle was charged with quinoline 42
(
0.131 g, 0.22 mmol, 1.0 equiv), LiCl (0.03 g, 0.66 mmol, 3.0 equiv), (Ph P) PdCl (0.015 g, 0.02 mmol,
3 2 2
0
.1 equiv), CuI (0.004 g, 0.02 mmol, 0.1 equiv), 1.4 mL of DMF, and 2.2 mL of Et N. The reaction
3
mixture was stirred for 5 min, phenylacetylene (0.04 mL, 0.04 g, 0.36 mmol, 1.6 equiv) was added, and
29
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