Synthesis of Highly Substituted Pyridines via [4 + 2] Cycloadditions of Vinylallenes and Sulfonyl Cyanides

Article abstract of DOI:10.1021/acs.joc.9b02628

A convergent strategy for the synthesis of multisubstituted pyridines is described. Vinylallenes combine with commercially available arylsulfonyl cyanides in Diels-Alder cycloadditions to generate isopyridine cycloadducts that are converted to pyridines upon further heating or addition of a base. The 2-sulfonylpyridine products undergo nucleophilic aromatic substitution reactions with oxygen and carbon nucleophiles to provide access to a variety of highly substituted pyridines.

Full text of DOI:10.1021/acs.joc.9b02628

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Article
Synthesis of Highly Substituted Pyridines via [4 + 2]
Cycloadditions of Vinylallenes and Sulfonyl Cyanides
Samuel Garrett Bartko, Philip J. Hamzik, Leandro Espindola, Christian Gomez, and Rick L. Danheiser
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02628 • Publication Date (Web): 04 Dec 2019
Downloaded from pubs.acs.org on December 7, 2019
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Synthesis of Highly Substituted Pyridines via [4 + 2] Cycloadditions of
Vinylallenes and Sulfonyl Cyanides
Samuel G. Bartko, Phillip J. Hamzik, Leandro Espindola, Christian Gomez, and Rick L. Danheiser*
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Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
E-mail: danheisr@mit.edu
ABSTRACT: A convergent strategy for the synthesis of multisubstituted pyridines is described.
Vinylallenes combine with commercially available arylsulfonyl cyanides in Diels-Alder cycloadditions to
generate isopyridine cycloadducts that are converted to pyridines upon further heating or addition of base.
The 2-sulfonylpyridine products undergo nucleophilic aromatic substitution reactions with oxygen and
carbon nucleophiles to provide access to a variety of highly substituted pyridines.
INTRODUCTION
The design and invention of new strategies for the synthesis of highly substituted pyridines
continues to command significant attention due to the incorporation of this heterocycle in the structures of
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a number of natural products, functional materials, and pharmaceutical compounds. In this area an
important challenge is the development of efficient methods with the ability to deliver unsymmetrical,
multisubstituted pyridines from readily available precursors.2 Transition-metal-catalyzed [2 + 2 + 2]
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cycloadditions involving nitriles and imine derivatives and convergent annulation strategies have been
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the focus of significant attention and provide some satisfactory solutions to this problem. A particularly
powerful approach to the synthesis of highly substituted pyridines employs hetero Diels-Alder reactions
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involving azadienes and azadienophiles. These [4 + 2] cycloadditions frequently proceed with excellent
regiochemistry and take place under metal-free conditions simply upon heating.
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One limitation of the aza Diels-Alder strategy is that it initially generates di- and
tetrahydropyridines, therefore requiring one or more additional steps to furnish the aromatic pyridine
oxidation state. Aromatization in some cases can be achieved by dehydrogenation, but this process often
requires harsh reaction conditions. An alternative approach employs suitably functionalized azadienes
designed to furnish the desired pyridine via cycloreversion or fragmentation following the cycloaddition
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reaction. Although a number of ingenious methods have been reported, the development of Diels-Alder
strategies that provide pyridines directly from readily available precursors without the need for post-
cycloaddition aromatization steps continues to be an active area of investigation.
Research in our laboratory has focused on the application of various classes of azadienophiles to
the synthesis of highly substituted pyridines.7 We have regarded Diels-Alder reactions of cyano
compounds to be particularly attractive since the resulting cycloadducts require the introduction of only
one additional degree of unsaturation to achieve the pyridine oxidation state. As outlined in Scheme 1,
this transformation can be accomplished via elimination (pathway a, LG = leaving group), cycloreversion
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pathway b), and by double-bond isomerization (pathways c and d). Our studies have focused on the
latter two pathways, particularly reactions of vinylallenes (pathway d) in which the isoaromatic
cycloadducts are expected to undergo isomerization to pyridines spontaneously or under very mild
conditions.
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Scheme 1. Strategies for the Synthesis of Pyridines via Cyano Diels-Alder Reactions
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Recent reports from our laboratory and that of Palenzuela have demonstrated the ability of
vinylallenes to serve as 4- cycloaddition partners in Diels-Alder strategies for the synthesis of pyridines.
In 2010, we described a formal [2 + 2 + 2] cycloaddition strategy for the synthesis of polycyclic pyridines
involving a two-stage pericyclic cascade mechanism (Scheme 2A).10 The cascade begins with an
intramolecular propargylic ene reaction that produces a vinylallene that is locked in an s-cis conformation.
This vinylallene is an unusually reactive Diels-Alder reaction partner11,12 and engages in [4 + 2]
cycloadditions with normally unreactive azadienophiles including unactivated cyano groups (Scheme 2A)
and heterosubstituted imine derivatives such as dimethylhydrazones and oximino ethers (Scheme 2B).13
The products generated in these cycloadditions isomerize to pyridines upon further heating or, in some
cases, upon addition of base. Initial attempts to extend these fully intramolecular processes to the more
challenging synthesis of pyridines via “bimolecular” [2 + 2 + 2] strategies were not successful.
Unactivated nitriles did not prove reactive enough to efficiently trap vinylallenes in intermolecular
cycloadditions, but we did discover that ethyl N-(tosyl)iminoacetate and commercially available tosyl
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cyanide do react and form intermediates that undergo elimination and isomerization to furnish pyridines
Scheme 2C).14 The products obtained from reactions of TsCN proved particularly useful since they react
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with carbon and heteroatom nucleophiles via addition/elimination pathways to provide products with a
variety of new substituents at C2 (vide infra).
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Scheme 2. Strategies for the Synthesis of Pyridines via [4 + 2] Cycloadditions of Vinylallenes
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One limitation associated with these previous methods is the constraint that the vinylallene be
generated via an intramolecular propargylic ene reaction, thus leading to tricyclic products in the case of
unimolecular reactions (Schemes 2A and 2B), and bicyclic systems in the case of the bimolecular variant
(Scheme 2C). The effectiveness of the hetero Diels-Alder reactions of tosyl cyanide with vinylallenes
generated by propargylic ene reactions led us to wonder whether this cycloaddition might proceed
efficiently with a wider range of vinylallenes prepared and isolated via alternative routes. Many
functionalized and multisubstituted vinylallenes are readily available by well-established methods,15
suggesting that vinylallene-tosyl cyanide cycloadditions, when applied in conjunction with
sulfonylpyridine substitution chemistry, might provide expeditious routes to a variety of highly
substituted pyridines (Scheme 2D).
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RESULTS AND DISCUSSION
Preparation of Vinylallenes via Organocopper Chemistry. The initial goal in our
investigation was to explore the effect of vinylallene substituents on the efficiency and regiochemistry of
cycloadditions with tosyl cyanide. The requisite vinylallenes for this study were prepared by S 2-type
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substitution reactions of propargylic alcohol derivatives with organocopper compounds, one of the most
general and reliable methods for the synthesis of substituted allenes.15,16 In this fashion a series of
vinylallenes was obtained in good yield in 2-3 steps via readily available propargylic ethers, benzoates,
and sulfonates.17 Scheme 3 describes a representative synthesis using this approach. In this case reaction
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of the methyl organocopper reagent with the mesylate derivative of 2 proceeded regioselectively to
furnish the desired vinylallene 3 in good yield, although reaction of the corresponding benzoate under the
same conditions afforded a mixture of allene 3 (35%) and the direct substitution product 4 (25%).
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Scheme 3. Synthesis of Vinylallene 3 via an Organocopper Substitution Reaction
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Optimization of Conditions for the Vinylallene-Tosyl Cyanide Cycloaddition. The
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application of tosyl cyanide as an azadienophile was pioneered by van Leusen in the 1970s and the
utility of this commercially available reagent in hetero Diels-Alder reactions has since been demonstrated
in a number of laboratories.14,20 Unfortunately, the reactions of tosyl cyanide with acyclic dienes were
found by van Leusen to be complicated by the generation of significant amounts of lactam byproducts.
These side products result from hydrolysis of the intermediate dihydropyridines,19b a process that is
autocatalytic in water, which is generated by disproportionation of the sulfinic acid formed in the
hydrolysis.21
Vinylallene 5 was chosen as the substrate for the optimization of conditions for the proposed
Diels-Alder/isomerization strategy (Table 1). Reaction of 5 with 1.1 equiv of tosyl cyanide in carefully
dried toluene at either room temperature or at reflux resulted in the formation of a complex mixture of
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products in which the major component was the lactam 8. Reaction in the presence of various bases to
scavenge any sulfinic acid that formed failed to effectively suppress hydrolysis and less hindered bases
were observed to react with tosyl cyanide. For example, both DBU and potassium t-butoxide were
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observed to react with tosyl cyanide even at room temperature, and an attempt to use (i-Pr) EtN as base
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(entry 5) led to a complex mixture due to reaction of the base with the dienophile.
We next turned our attention to performing the reaction in the presence of 4 Å molecular sieves as
a water scavenger. Heating the vinylallene at 50 °C overnight in the presence of sieves led to the
formation of cycloadduct 6 accompanied by only trace amounts of the lactam byproduct. We next found
that isomerization of the isopyridine cycloadduct to pyridine 7 could be conveniently achieved in the
same flask by cooling the reaction mixture to room temperature and adding either DBU or potassium t-
butoxide. By using freshly purified vinylallene, the desired pyridine could be isolated in 68% yield after
chromatographic purification. The regiochemical assignment for 7 was confirmed by differential nOe
experiments.
Table 1. Optimization of Conditions for the Cycloaddition of Vinylallene 5
entry
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reflux, 1 h
% 6
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dYield estimated by H NMR analysis; product was obtained in ca. 80% purity. eYield using freshly
purified vinylallene.
Scope of the Cycloaddition. With optimized conditions for the cycloaddition and in situ
isomerization in hand, we next turned our attention to investigating the scope of this strategy for the
synthesis of highly substituted pyridines. Table 2 summarizes our results for reactions using vinylallenes
generated by organocopper substitution reactions.
Table 2. Cycloadditions of Vinylallenes and Tosyl Cyanide
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Reaction of vinylallene with 1.1 equiv of TsCN in the presence of 4 Å MS (1:1 by weight) in toluene at
the indicated bath temperature. For entries 1-4 and 6, the reaction mixture was cooled to rt and treated
with 1.1 equiv of DBU at rt for 1-15 h. b Isolated yield of products purified by column chromatography.
cIn this case the vinylallene was slowly added (5 h) to the solution of TsCN and sieves.
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While the optimal conditions for cycloaddition of tetrasubstituted vinylallenes 3 and 5 were found
to involve heating overnight at 50-60 °C, the less substituted allene 9 required heating at 80 °C for 8 h to
achieve complete reaction (entry 3). The success of this cycloaddition is noteworthy as Palenzuela
reported that vinylallene 9 fails to undergo Diels-Alder reaction with N-benzylimines in the presence of
Lewis acids.22 Application of the cycloaddition/isomerization strategy to vinylallenes lacking substituents
at the allene terminus provides access to pyridines bearing methyl substituents (entries 4 and 5), and in the
case of the phenyl-substituted substrate 11, base treatment was not necessary as the initial cycloadduct
isomerized to pyridine 16 under the conditions of the cycloaddition.
Only a single regioisomeric pyridine was detected in the cycloadditions described in entries 1 to 5.
These results are consistent with previous observations on the regiochemical course of vinylallene Diels-
Alder reactions11,12 in which the favored transition state involves bond formation between the sp carbon of
the vinylallene and the more electron deficient atom of the dienophile  bond.23 Scheme 4 depicts this
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normal” regiochemical mode of cycloaddition with TsCN, which is favored electronically and also
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avoids a destabilizing steric interaction between R and the arylsulfonyl group that develops in the
transition state leading to the alternate regioisomer 22. Note also that the favored transition state involves
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approach of the dienophile from the face of the vinylallene opposite to the larger group (R ) on the
terminus of the allene,24 thus avoiding an unfavorable non-bonding interaction between R and the
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arylsulfonyl group.
Scheme 4. Alternatives for the Regiochemical Course of the Cycloaddition
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In contrast to the reactions in entries 1-5, reaction of vinylallene 12 lacking a substituent at the
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vinyl terminus (R ) gave a 66:34 mixture of the expected product 17 and the regioisomeric pyridine 18
(entry 6). We believe that the normal mode of addition is less favorable in this case due to the absence of
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an electron-donating alkyl group (R ), and the unfavorable steric interaction that develops between the
two ethyl groups in the transition state leading to 20. Consistent with this is the observation that related
substrates with bulky groups at the terminal position of the allene (e.g., cyclohexyl in place of ethyl at the
terminal position of 21) react very sluggishly and afford complex mixtures of products that include the
desired pyridines in only 5-10% yield. Note, however, that this limitation can be overcome by using more
reactive vinylallenes bearing electron-donating methoxy substituents (vide infra).
Synthesis and Cycloadditions of Vinylallenyl Ethers. We next turned our attention to
cycloadditions involving vinylallenes substituted with an electron-donating alkoxy group at the internal
vinylallene carbon. It was our expectation that vinylallenes of this type would be particularly reactive as
diene partners and that their cycloadditions would proceed with high regioselectivity. Allenyl ethers are
valuable synthetic building blocks and are easily prepared by base-promoted isomerization of propargylic
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2
3
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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
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5
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5
5
5
5
5
5
5
6
ethers.25 Scheme 5 outlines the preparation of allenyl ether 25. Addition of propynyllithium (generated
2
6
by Suffert’s procedure ) to cyclohexenecarbaldehyde furnished the propargylic ether 24 after trapping in
situ with methyl iodide. Isomerization to the alkoxyallene 25 then proceeded smoothly using the protocol
described by Frontier.27 All attempts to isolate and purify this allenyl ether were complicated by
decomposition that occurred upon concentration, and we consequently found it best to employ the ether
solution of 25 obtained from the aqueous workup directly and immediately in the cycloaddition. In this
fashion, the desired pyridine 26 was obtained in 51% overall yield from the propargylic ether by reaction
with tosyl cyanide and then DBU under the indicated conditions.
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 5. Synthesis and Cycloaddition of Vinylallenyl Ether 25
The facility of the Diels-Alder reaction of this methoxy-substituted vinylallene is noteworthy as
the cycloaddition in this case took place rapidly at room temperature. We next examined the reaction of
vinylallenyl ether 29 bearing a more sterically demanding cyclohexyl substituent (Scheme 6) and were
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pleased to find that this substrate underwent cycloaddition/isomerization with equal facility to afford the
-methoxy-substituted pyridine 30 in good overall yield.
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
Scheme 6. Synthesis and Cycloaddition of Vinylallenyl Ether 29
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
Synthesis and Cycloadditions of Vinylallenes Prepared by Sigmatropic Rearrangements.
2
8
Sigmatropic rearrangement involving propargylic alcohol derivatives provides another attractive route to
substituted allenes, and we next investigated the application of this chemistry in the synthesis of pyridines
substituted at the C4 position with functionalized side chains. As outlined in Scheme 7, the Johnson
orthoester and Eschenmoser rearrangements29 of enynyl alcohol 31 furnished convenient access to
vinylallenes 32 and 33, respectively, and reaction of each with tosyl cyanide produced the expected
isopyridines which isomerized to the desired pyridines upon exposure to DBU. The reaction of 32 with
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2
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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
tosyl cyanide was very slow at 60 °C and was best carried out at 90 °C. Similarly, the Diels-Alder
reaction of the vinylallenyl amide 33 required 24 h when effected at 50 °C and gave the desired pyridine
in only 31% yield after treatment with DBU. Attempts to carry out both sigmatropic rearrangement and
Diels-Alder reaction as a “one-flask” operation were not successful due to the interference of side
reactions involving reaction of tosyl cyanide at elevated temperature with the alcohols liberated in the
rearrangement step.
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 7. Synthesis and Cycloaddition of Vinylallenes 32 and 33
Synthesis of 7-Azaindoles. Azaindoles comprise a class of pharmacologically important
heterocyclic compounds that have been the subject of considerable recent interest from synthetic and
medicinal chemists.30 Schemes 8 and 9 outline the application of 2- and 3-(allenyl)pyrrole cycloadditions
for the synthesis of 7-azaindoles. Although Diels-Alder reactions of 2- and 3-vinylpyrroles are well
3
1
32
known, to our knowledge no cycloadditions involving allenypyrroles have been reported previously.
3
3
Addition of the known protected 3-formylpyrrole 36 to lithium phenylacetylide afforded the propargylic
methyl ether 37 in excellent yield after in situ trapping with methyl iodide. In this case isomerization to
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the allenyl ether was best achieved at -78 °C with catalytic potassium t-butoxide since metalation of the
pyrrole ring was observed in reactions with t-butyllithium using our prior protocol. Slow addition of tosyl
cyanide or benzenesulfonyl cyanide to the solution of allenyl ether and sieves at -78 °C and warming to
room temperature then provided the desired 7-azaindole.
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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4
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5
5
5
6
0
1
2
3
4
5
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7
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9
0
1
2
3
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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 8. Synthesis and Cycloaddition of Allenylpyrrole 38
As shown in Scheme 9, Diels-Alder reaction of tosyl cyanide with allenylpyrrole 43, which was
prepared via Eschenmoser rearrangement was also successful, and in this case isomerization of the initial
cycloadduct to the aromatic azaindole did not require the addition of base.
Scheme 9. Synthesis and Cycloaddition of Allenylpyrrole 43
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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
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
Ipso Substitution Reactions. The 2-sulfonyl groups attached at C2 of the new pyridine ring are
useful handles for further synthetic elaboration. Nucleophilic substitution reactions of both 2- and 4-
halopyridines as well as analogous sulfonyl pyridine derivatives are well documented.,34 Barlin and
3
5
Furukawa carried out key early work in this area, and these reactions have since been utilized for the
synthesis of a wide range of pyridines.36
Table 3 describes the scope of the nucleophilic aromatic substitution reactions of several of our
pyridine cycloadducts. Monocyclic pyridine 16 reacts with various alkyl and aryl Grignard reagents to
produce the corresponding substituted pyridines in generally good yield. In these cases, an excess of the
Grignard reagent is required for full conversion; with fewer equivalents a significant amount of unreacted
starting material is recovered. Cyanide is also a competent nucleophile for this reaction, although
elevated temperature is necessary for efficient reaction. Potassium ethoxide (generated in situ from KOt-
Bu and EtOH) reacts with 16 in THF at room temperature to afford ethoxypyridine 49 in excellent yield.
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Unfortunately, to date we have not developed conditions for the efficient substitution reactions of these
sulfonylpyridines with nitrogen nucleophiles.
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
Bicyclic sulfonylpyridine cycloadducts are also suitable substrates for ipso-substitution reactions.
For example, pyridine 7 reacts with an excess of CH MgBr to give the expected product 50, and pyridine
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
2
6 incorporating a methoxy substituent also undergoes the substitution reaction in good yield. Finally, 2-
pyridone 52 was obtained by reaction of pyridine 13 with potassium hydroxide generated according to the
procedure developed by Gassman and co-workers.37
Table 3. Ipso-Substitution Reactions of 2-Sulfonylpyridines
R
CH3
G
SO p-tol
2
conditions
Et
SO p-tol
2
N
conditions
N
7 G = CH , R = Et
3
16
13 G = CH , R = (CH ) Ph
Ph
3
2 3
26 G = OMe, R = Et
yield (%)a
yield (%)a
entry
conditions
product
entry
conditions
product
CH3
Et
CH3
45
CH MgBr (3.0 equiv)
7
Et
1
3
90
N
Ph
THF, reflux, 15 h
6
7
CH3MgBr (6 equiv)
THF, 70 °C, 1.5 h
H C
CH3
50
53
54
3
N
CH3
7
Et
Et
Pr
CH MgBr (12 equiv)
3
PrMgBr (3.0 equiv)
THF, reflux, 13 h
2
3
77-82
N
Ph
THF, rt, 24 h
46
Et
MeO
H3C
CH3
51
CH3
26
7
8
5
Ph
47
8
9
CH MgCl (12 equiv)
N
3
PhMgCl (6 equiv)
THF, reflux, 16 h
87
THF, rt, 16 h
N
Ph
(
CH ) Ph
2 3
13
CH3
O
7
KOt-Bu (6 equiv)
NaCN (5 equiv)
Et
Et
CN
4
5
86
91
NH
H O (2.0 equiv)
2
1
8-crown-6 (5 equiv)
52
N
THF, reflux, 16 h
DMF, reflux, 48 h
48
Ph
CH3
KOt-Bu (2.4 equiv)
EtOH (2.4 equiv)
THF, rt, 40 min
OEt
N
49
Ph
a
Isolated yield of products purified by column chromatography.
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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
CONCLUSION
We have developed a convergent method for the synthesis of highly substituted pyridines based on
the Diels-Alder reaction of vinylallenes with arylsulfonyl cyanides. An initial Diels-Alder addition leads
to isopyridine cycloadducts, which isomerize to the aromatic pyridines upon further heating or after
exposure to base. In the case of most alkyl- and aryl-substituted vinylallenes, optimal conditions for the
cycloaddition involve heating at 50-60 °C. For those cases in which reaction was found to be sluggish at
that temperature, heating at 80-95 °C brings about Diels-Alder reaction at a reasonable rate. In contrast,
cycloadditions of vinylallenes bearing electron-donating methoxy substituents undergo reaction at or
below room temperature.
0
1
2
3
4
5
6
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8
9
0
1
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3
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2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
The resulting 2-sulfonylpyridines undergo nucleophilic aromatic substitution reactions with
various nucleophiles. Further studies are underway in our laboratory aimed at the application of this
chemistry in the total synthesis of pyridine containing natural products.
EXPERIMENTAL SECTION
General Procedures. All reactions were performed in flame-dried or oven-dried glassware under a
positive pressure of argon. Reaction mixtures were stirred magnetically unless otherwise indicated. Air-
and moisture-sensitive 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 glass-backed silica gel 60 F-
2
54 0.25 mm plates. Column chromatography was performed on silica gel 60 (230-400 mesh) or on basic
alumina (80-325 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)
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
oxide. Triethylamine was distilled under argon from calcium hydride. DMF was stirred over CaH for 24 h
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
and then distilled under argon from MgSO at 20 mmHg. Phenylpropanal was distilled under reduced
4
pressure (98 °C at 12 mmHg), cyclohexenecarbaldehyde distilled under reduced pressure (86 °C at 60
mmHg), and acetaldehyde was distilled at atmospheric pressure. MsCl was distilled under reduced pressure
from P O (60 °C at 20 mmHg). Phenylacetylene and methyl iodide were filtered through a plug of activated
2
5
alumina prior to use. 4-DMAP 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). LiBr was dried under
vacuum (0.02 mmHg) at 200 ºC (bath temperature) for 18 h before use. Molecular sieves (4 Å) were dried
under vacuum (0.1 mmHg) at 300 °C for 16 h before use. n-Butyllithium was titrated using menthol in THF
with 1,10-phenanthroline as an indicator. CH C(OMe) NMe was distilled from CaH at atmospheric
3
2
2
2
pressure.
Instrumentation. Melting points were determined with a Fisher-Johns melting point apparatus and
1
are uncorrected. Infrared spectra were obtained using a Perkin Elmer 2000 FT-IR spectrophotometer. H
NMR and 13C NMR spectra were measured with Inova 500, Inova 300, Bruker 600, and Bruker 400
1
spectrometers. H Chemical shifts are expressed in parts per million () downfield from tetramethylsilane
(with the CHCl resonance at 7.27 ppm, the C H resonance at 7.15 ppm, or the CD Cl resonance at 5.33
3
6
6
2
2
ppm used as a standard). 13C NMR chemical shifts are expressed in parts per million () downfield from
tetramethylsilane (with the central peak of CHCl at 77.23 ppm used as a standard). High resolution mass
3
spectra (HRMS) were measured on a Bruker Daltronics APEXII 3 tesla Fourier transform mass spectrometer
or an Ion Sense AccuTOF 4G LC-Plus Q-TOF DART mass spectrometer.
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2
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
-(Cyclohex-1-en-1-yl)-5-phenylpent-1-yn-3-ol (2). A 100-mL, two-necked, round-bottomed
flask equipped with two rubber septa and an argon inlet needle was charged with cyclohexenylacetylene
0.584 g, 5.50 mmol, 1.2 equiv) and 40 mL of THF. The solution was cooled to -40 °C, and 1.81 mL of
(
n-butyllithium solution (2.33 M in hexane, 4.58 mmol, 1.0 equiv) was added dropwise via syringe over 5
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
min. The resulting solution was stirred at -40 °C for 30 min. A solution of 3-phenylpropionaldehyde
(
0.615 g, 4.58 mmol, 1.0 equiv) in 3 mL of THF was then added via cannula over 5 min, the cooling bath
was replaced with an ice bath, and the solution was stirred at 0 °C for 30 min. The reaction mixture was
treated with 13 mL of satd aq NH Cl solution and 10 mL of water, and the aqueous phase was separated
4
and extracted with three 30-mL portions of EtOAc. The combined organic extracts were washed with 70
mL of satd aq NaCl solution, dried over MgSO , filtered, and concentrated to furnish 1.31 g of a yellow
4
oil. Column chromatography on 30 g of silica gel (elution with 0-5% EtOAc-hexanes) afforded 1.073 g
(
97%) of 2 as a pale green oil: IR (NaCl) 3348, 2859, 2937, 2217, 1493, 1449, 1436, 1336, 1206, 1049,
-1 1
1
008, 919, 842, 800, 749 cm ; H NMR (500 MHz, CDCl ) δ 7.18-7.33 (m, 5 H), 6.11-6.16 (m, 1 H),
3
4.47-4.53 (t, J = 6.5 Hz, 1 H), 2.78-2.86 (t, J = 7.5 Hz, 2 H), 1.98-2.17 (m, 6 H), 1.84-1.94 (br s, 1 H),
13
1
1
8
.56-1.69 (m, 4 H); C{ H} NMR (125 MHz, CDCl ) δ 141.6, 135.6, 128.7, 128.6, 126.1, 120.3, 87.34,
3
+
7.29, 62.4, 39.7, 31.7, 29.4, 25.8, 22.5, 21.6; HRMS (DART-FTICR) m/z: [M + NH ] calcd for
4
C H NO 258.1852; found 258.1857.
1
7
24
5
-(Cyclohex-1-en-1-yl)hexa-3,4-dien-1-yl)benzene (3). A 25-mL, pear-shaped flask equipped
with a rubber septum and an argon inlet needle was charged with propargylic alcohol 2 and 0.5 mL of
THF. The solution was cooled at -10 °C and 0.13 mL of methylmagnesium bromide solution (2.8 M in
ether, 0.35 mmol, 1.0 equiv) was added dropwise via syringe over 4 min. The resulting solution was
stirred for 30 min at -10 °C and then cooled at -78 °C. Methanesulfonyl chloride (27 µL, 0.039 g, 0.35
mmol, 1.0 equiv) was added dropwise via microliter syringe over 1 min. The reaction mixture was stirred
for 30 min at -78 °C and then allowed to warm to rt and stirred for 1 h.
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4
A 25-mL, two-necked, pear-shaped flask equipped with two rubber septa and an argon inlet needle
was charged with LiBr (0.068 g, 0.790 mmol, 2.3 equiv), CuBr ( 0.119 g, 0.790 mmol, 2.3 equiv), and 3
mL of THF. The solution was cooled at 0 °C while 0.32 mL of methylmagnesium bromide solution (2.8
M in ether, 0.79 mmol, 2.3 equiv) was added dropwise via syringe over 2 min. The resulting mixture was
stirred at 0 °C for 30 min and then cooled to -78 °C.
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
The solution of mesylate prepared previously was added to the cuprate reaction mixture dropwise
via cannula over 5 min (0.25 mL THF wash) and the reaction mixture was then allowed to warm to rt and
stirred for 1 h. The reaction mixture was treated with 2 mL of satd aq NH Cl solution and 3 mL of water.
4
The resulting mixture was filtered through Celite under reduced pressure with the aid of hexanes, and the
aqueous phase of the filtrate was extracted with three 30-mL portions of hexanes. The combined organic
extracts were washed with 30 mL of satd aq NaCl solution, dried over MgSO , filtered, and concentrated
4
to furnish 0.096 g of a yellow oil. Column chromatography on 7 g of silica gel (elution with pentane)
afforded 0.058 g (70%) of 3 as a colorless oil: IR (NaCl) 2940, 2902, 2856, 2834, 2361, 1943, 1490,
-1 1
1452, 1364, 1335, 1272, 1237, 1135, 1077, 1029, 915, 841, and 756 cm ; H NMR (300 MHz, CDCl ) δ
3
7
2
.16-7.35 (m, 5 H), 5.65-5.71 (m, 1 H), 5.26-5.36 (m, 1 H), 2.76 (t, J = 7.5 Hz, 2 H), 2.32-2.42 (m, 2 H),
1
3
1
.12-2.22 (m, 2 H), 1.85-2.12 (m, 2 H), 1.81 (d, J = 2.4 Hz, 3 H), 1.55-1.70 (m, 4 H); C{ H} NMR (100
MHz, CDCl ) δ 204.4, 142.1, 134.0, 128.8, 128.4, 126.0, 122.4, 103.2, 91.6, 35.7, 31.3, 27.2, 26.2, 23.2,
3
+
2
2.6, 16.7; HRMS (DART-FTICR) m/z [M + H] calcd for C H 239.1794; found 239.1795.
1
8
23
3
-Ethyl-4-methyl-2-tosyl-5,6,7,8 tetrahydroquinoline (7). A 10-cm, threaded Pyrex tube (25
mm O.D.; 17 mm I.D.) equipped with a rubber septum fitted with an argon inlet needle was charged with
2
2
4
1
Å molecular sieves (0.150 g), tosyl cyanide (0.201 g, 1.11 mmol, 1.1 equiv), vinylallene 5 (0.150 g,
.01 mmol, 1.0 equiv), and 10 mL of toluene. The tube was sealed with a threaded Teflon cap and the
reaction mixture was heated at 50 °C for 12 h and then allowed to cool to rt. DBU (0.17 mL, 0.17 g, 1.1
mmol, 1.1 equiv) was added dropwise via syringe over 0.5 min, and the reaction mixture was stirred at rt
for 1 h. The resulting yellow suspension was washed with 20 mL of water and the aqueous phase was
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8
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
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5
5
6
extracted with three 20-mL portions of EtOAc. The combined organic layers were washed with 10 mL of
water, washed with 10 mL saturated NaCl solution, dried over MgSO , filtered, and concentrated to afford
4
0
.309 g of a yellow solid. Column chromatography on 30 g of silica gel (elution with 0-30% EtOAc-
hexanes) afforded 0.226 g (68%) of 7 as a white solid: mp 149–152 °C; IR (NaCl) 2985, 2936, 2870,
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
1
597, 1543, 1453, 1428, 1315, 1288, 1137, 1090, 1066, 810, 737, 678, 664 cm ; H NMR (500 MHz,
CDCl ) δ 7.82 (d, J = 8.0 Hz, 2 H), 7.24 (d, J = 8.0 Hz, 2 H), 3.17 (q, J = 7.5 Hz, 2 H), 2.63 (t, J = 6.5 Hz,
3
2 H), 2.59 (t, J = 6.0 Hz, 2 H), 2.37 (s, 3 H), 2.17 (s, 3 H), 1.67–1.76 (m, 4 H), 1.21 (t, J = 7.5 Hz, 3 H);
13
1
C{ H} NMR (125 MHz, CDCl ) δ 153.8 (2C), 147.3, 143.5, 137.9, 134.8, 134.1, 129.2, 128.9, 32.7,
3
+
2
6.9, 22.7, 22.3, 21.4, 20.9, 14.4, 14.1; HRMS (DART-FTICR) m/z [M + H] calcd for C H NO S
1
9
24
2
3
30.1522; found 330.1502. Confirmation of cycloaddition regiochemistry is based on differential nOe
experiments (500 MHz, CDCl ): 1.6% from 3.17 ppm to 7.82 ppm, 6.8% from 3.17 ppm to 2.17 ppm,
3
5
.7% from 3.17 ppm to 1.21 ppm.
1-(Cyclohex-1-en-1-yl)propa-1,2-dien-1-yl)benzene (10). A 25-mL, two-necked, round-
(
bottomed flask equipped with a rubber septum and an argon inlet adapter was charged with CuBr (0.039
38
g, 0.26 mmol, 0.2 equiv), propargyl ether S1 (0.200 g, 1.33 mmol, 1.0 equiv), and 8 mL of Et O. The
2
resulting solution was cooled at -30 °C, and 1.15 mL of phenylmagnesium bromide solution (3.0 M in
Et O, 3.32 mmol, 2.5 equiv) was added dropwise via syringe. The resulting solution was allowed to
2
warm to rt and stirred for 15 h. The reaction mixture was treated with 3 mL of satd aq NH Cl solution
4
and the resulting mixture was diluted with 3 mL of water. The resulting mixture was washed with three
2
0-mL portions of Et O, and the combined organic layers were washed with 15 mL of water and 15 mL of
2
satd aq NaCl solution, dried over MgSO , filtered, and concentrated to furnish 0.3 g of a pale-yellow oil.
4
Column chromatography on 20 g of silica gel (elution with hexanes) furnished 0.189 g (72%) of 10 as a
-1 1
pale-yellow oil: IR (thin film) 3031, 2928, 1929, 1598, 1490, 1446, 849, 762, and 699 cm ; H NMR
(
400 MHz, CDCl )  7.26-7.28 (m, 4 H), 7.21 (m, 1 H), 5.54 (m, 1 H), 5.02 (s, 2 H), 2.17 (m, 2 H), 2.06
3
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13
1
(
m, 2 H), 1.68 (m, 2 H), 1.58 (m, 2 H); C{ H} NMR (100 MHz, CDCl )  209.2, 136.8, 132.6, 129.2,
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
+
1
29.0, 127.4, 127.1, 127.0, 111.2, 27.7, 26.1, 23.2, 22.5; HRMS (DART-FTICR) m/z [M + H] calcd for
C H 197.1325; found 197.1337.
1
5
17
(
E)-(3-Ethylpenta-1,3,4-trien-1-yl)benzene (11). A 50-mL two-necked round-bottomed flask
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
9
equipped with two rubber septa and an argon inlet needle was charged with S2 (0.400 g, 2.32 mmol, 1.0
equiv), 20 mL of THF, and CuBr (0.066 g, 0.464 mmol, 0.2 equiv). The mixture was cooled at 0 °C and
ethylmagnesium bromide (3.0 M in Et O, 1.54 mL, 4.64 mmol, 2.0 equiv) was added dropwise via
2
syringe over 1 min. The resulting green solution was warmed to rt and stirred for 45 min and then 5 mL
of satd aq NH Cl solution was added followed by 5 mL of water. The aqueous phase was separated and
4
extracted with three 20-mL portions of Et O, and the combined organic layers were washed with 50 mL
2
of satd aq NaCl solution, dried over MgSO , filtered, and concentrated to give 0.399 g of a yellow solid.
4
Column chromatography on 50 g of silica gel (elution with hexanes) afforded 0.317 g (80%) of 11 as a
colorless solid: mp 38-41 °C; IR (film) 3031, 2965, 2933, 2913, 2872, 1928, 1448, 963, 861, and 690 cm-
1; 1
H NMR (500 MHz, CDCl )  7.47 (d, J = 7.5 Hz, 2 H), 7.37 (t, J = 7.5 Hz, 2 H), 7.27 (t, J = 7.5 Hz, 1
3
H), 6.79 (d, J = 16.5 Hz, 1 H), 6.55 (d, J = 16.5 Hz, 1 H), 5.06-5.07 (m, 2 H), 2.31-2.37 (m, 2 H), 1.22 (t,
1
3
1
J = 7.5 Hz, 3 H); C{ H} NMR (125 MHz, CDCl )  212.0, 137.8, 128.8, 127.3, 127.1, 127.0, 126.3,
3
+
1
1
06.6, 77.0, 21.3, 12.3; HRMS (DART-FTICR) m/z [M + H] calcd for C H 171.1168; found
1
3
15
71.1171.
6-Methylhept-6-en-4-yn-3-yl benzoate (S4). A 50-mL, two-necked round-bottomed flask
equipped with a stir bar, rubber septum, and an argon inlet adapter was charged with propargylic alcohol
40
S3 (0.314 g, 2.53 mmol, 1.0 equiv), 25 mL of CH Cl , and DMAP (0.031 g, 0.253 mmol, 0.1 equiv).
2
2
Triethylamine (0.49 mL, 0.36 g, 3.5 mmol, 1.4 equiv) and benzoyl chloride (0.41 mL, 0.50 g, 3.5 mmol,
.4 mmol) were added via syringe in that order and the resulting solution was stirred at rt for 5 h. The
1
reaction mixture was extracted with two 20-mL portions of 1 N aq HCl, 20 mL of satd aq NaHCO3
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8
9
1
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1
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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
5
5
5
5
6
solution, and 20 mL of satd aq NaCl solution, dried over MgSO , filtered, and concentrated to give ca. 1 g
4
of a colorless oil. Column chromatography on 25 g silica gel (elution with 0-50% CH Cl -hexanes)
2
2
afforded 0.570 g (99%) of S4 as a colorless oil: IR (NaCl) 3064, 2974, 2939, 2880, 2227, 1725, 1602,
-1 1
1452, 1375, 1267, 1177, 1106, 1069, 1026, 928, 901, and 710 cm ; H NMR (500 MHz, CDCl ) δ 8.08-
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
8
5
.12 (m, 2 H), 7.56-7.59 (m, 1 H), 7.44-7.48 (m, 2 H), 5.72 (t, J = 6.5 Hz, 1 H), 5.33-5.35 (m, 1 H), 5.25-
1
3
1
.27 (m, 1 H), 1.96 (app quint, J = 8.0 Hz, 2 H), 1.89-1.90 (m, 3 H), 1.11 (t, J = 7.5 Hz, 3 H); C{ H}
NMR (125 MHz, CDCl ) δ 165.7, 133.3, 130.3, 130.0, 128.5, 126.3, 122.9, 86.8, 85.6, 66.2, 28.5, 23.5,
3
+
9
.7; HRMS (DART) m/z [M + NH ] calcd for C H NO 246.1489; found 246.1488.
4
15 20
2
3
-Ethyl-2-methylhepta-1,3,4-triene (12). A 50-mL round-bottomed flask equipped with a rubber
septum and argon inlet needle was charged with LiBr (0.684 g, 7.88 mmol, 6.0 equiv) and then flame-
dried under vacuum (100 mTorr) for 5 min. The flask was cooled to rt under argon and 10 mL of THF
was added followed by CuBr (1.13 g, 7.88 mmol, 6.0 equiv). The solution was cooled at -60 °C as
EtMgBr (3.0 M in Et O, 2.62 mL, 7.88 mmol, 6.0 equiv) was added dropwise via syringe over 2 min and
2
the resulting brown solution was stirred at -60 °C for 10 minutes. A solution of propargylic benzoate S4
(0.300 g, 1.31 mmol, 1.0 equiv) in 2 mL of THF was added dropwise via cannula over 1 min (2 mL THF
rinse). The resulting mixture was allowed to warm to rt and stirred for 1 h. Satd aq NH Cl solution (10
4
mL) was added followed by 10 mL of pentane. The resulting mixture was filtered through a pad of Celite
with the aid of ca. 50 mL of pentane. The aqueous phase was separated and extracted with three 10-mL
portions of pentane and the combined organic layers were washed with 20 mL of satd NaCl solution,
dried over MgSO , filtered, and concentrated (0 °C, 40 Torr) to give ca. 0.2 g of a colorless oil. Column
4
chromatography on 25 g of silica gel (elution with pentane) afforded 0.135 g (76%) of 12 as a colorless
-1
1
oil: IR (NaCl) 3094, 2965, 2933, 2873, 2361, 2342, 1943, 1619, 1457, 1375, 1290, and 878 cm ; H
NMR (500 MHz, CDCl ) δ 5.45-5.48 (m, 1 H), 4.94-4.95 (m, 1 H), 4.87-4.88 (m, 1 H), 2.18-2.24 (m, 2
3
1
3
1
H), 2.05-2.11 (m, 2 H), 1.86 (s, 3 H), 1.07 (t, J = 7.5 Hz, 3 H), 1.04 (t, J = 7.0 Hz, 3 H); C{ H} NMR
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2
(
125 MHz, CDCl ) δ 204.5, 141.1, 110.1, 109.6, 96.0, 22.5, 22.3, 22.2, 13.6, 12.7; HRMS (DART-
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
+
FTICR) m/z [M + H] calcd for C H 137.1325; found 137.1332.
1
0
17
4
-Methyl-3-(3-phenylpropyl)-2-tosyl-5,6,7,8-tetrahydroquinoline (13). A 10-mL, pear-shaped
flask equipped with a rubber septum and an argon inlet needle was charged with 4 Å molecular sieves
0.045 g), tosyl cyanide (0.033 g, 0.19 mmol, 1.1 equiv), vinylallene 3 (0.040 g, 0.17 mmol, 1.0 equiv),
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
(
and 1.7 mL of toluene. The rubber septum was replaced with a reflux condenser fitted with a rubber
septum and argon inlet needle, and the reaction mixture was heated at 90 °C for 3 h. The resulting
mixture was allowed to cool to rt, 28 µL of DBU (0.028 g, 0.19 mmol, 1.1 equiv) was added dropwise via
syringe over 1 min, and the reaction mixture was stirred for 1 h at rt. The resulting yellow suspension
was washed with 5 mL of water and the aqueous phase was extracted with three 10-mL portions of
EtOAc. The combined organic extracts were washed with 20 mL of satd aq NaCl solution, dried over
MgSO , filtered, and concentrated to afford 0.085 g of a yellow oil. Preparative thin layer
4
chromatography (elution with 10% EtOAc-hexanes) afforded 0.048 g (68%) of 13 as a pale gum: IR
-1 1
(NaCl) 3026, 2934, 1598, 1430, 1298, 1140, 1087, 912, 813, 733, 665 cm ; H NMR (400 MHz, CDCl )
3
δ 7.83 (d, J = 8.4 Hz, 2 H), 7.15-7.35 (m, 7 H), 3.05-3.13 (m, 2 H), 2.69-2.82 (m, 4 H), 2.59 (m, 2 H),
1
3
1
2
.42 (s, 3 H), 2.06 (s, 3 H), 1.68-1.9 (m, 6 H); C{ H} NMR (100 MHz, CDCl ) 154.2, 153.5, 147.6,
3
143.9, 142.1, 137.8, 135.2, 132.8, 129.3, 129.1, 128.7, 128.5, 126.0, 36.4, 33.0, 31.9, 27.8, 27.2, 22.8,
+
2
2.4, 21.8, 14.4; HRMS (DART) m/z [M + H] calcd. for C H NO S; 420.1992, found 420.1971.
2
6
30
2
3
-Ethyl-2-tosyl-5,6,7,8-tetrahydroquinoline (14). A 10-cm, threaded Pyrex tube (25 mm O.D.;
1
7 mm I.D.) equipped with a rubber septum fitted with an argon inlet needle was charged with 4 Å
2
2
molecular sieves (0.100 g), tosyl cyanide (0.137 g, 0.754 mmol, 1.1 equiv), vinylallene 9 (0.092 g, 0.685
mmol, 1.0 equiv), and 7 mL of toluene. The tube was sealed with a threaded Teflon cap and the reaction
mixture was heated at 80 °C for 8 h and then allowed to cool to rt. DBU (0.11 mL, 0.114 g, 0.754 mmol,
1.1 equiv) was added dropwise via syringe over 0.5 min, and the reaction mixture was stirred at rt for 1 h.
The resulting yellow suspension was washed with 20 mL of water and the aqueous phase was extracted
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2
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
with three 20-mL portions of EtOAc. The combined organic layers were washed with two 10-mL
portions of water then 20 mL saturated NaCl solution, dried over MgSO , filtered, and concentrated to
4
afford 0.189 g of an orange oil. Column chromatography on 25 g of silica gel (elution with 0-30%
EtOAc-hexanes) afforded 0.085 g (39%) of 14 as a colorless oil: IR (NaCl) 3029, 2936, 2876, 1597, 1440,
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
1
300, 1145, 1090, 925, 814, 711, 674, and 587 cm ; H NMR (500 MHz, CDCl ) δ 7.85 (d, J = 8.5 Hz, 2
3
H), 7.28 (s, 1 H), 7.27 (d, J = 8.5 Hz, 2 H), 3.05 (q, J = 7.5 Hz, 2 H), 2.71-2.76 (m, 4 H), 2.39 (s, 3 H),
1
3
1
1.70-1.81 (m, 4 H), 1.23 (t, J = 7.5 Hz, 3 H); C{ H} NMR (125 MHz, CDCl ) δ 155.1, 152.9, 144.0,
3
1
40.2, 137.6, 136.6, 136.3, 129.4, 129.0, 32.0, 28.7, 24.4, 22.9, 22.4, 21.8, 15.7; HRMS (DART-FTICR)
+
m/z [M + H] calcd for C H NO S 316.1366; found 316.1345.
1
8
22
2
3
-Methyl-4-phenyl-2-tosyl-5,6,7,8 tetrahydroquinoline (15). A 10-cm, threaded Pyrex tube (25
mm O.D.; 17 mm I.D.) equipped with a rubber septum fitted with an argon inlet needle was charged with
Å molecular sieves (0.170 g), tosyl cyanide (0.120 g, 0.66 mmol, 1.1 equiv), and 3 mL of toluene. The
4
resulting suspension was heated at 95 °C, and a solution of vinylallene 10 (0.119 g, 0.60 mmol, 1.0 equiv)
in 3 mL of toluene was added dropwise via syringe pump over 5 h. The reaction mixture was stirred for
an additional 3 h at 95 °C, and was then allowed to cool to rt and 0.1 mL of DBU (0.100 g, 0.66 mmol,
1
.1 equiv) was added dropwise via syringe and the resulting suspension was stirred at rt for 1 h. The
resulting yellow suspension was washed with 20 mL of water and the aqueous phase was extracted with
three 20-mL portions of EtOAc. The combined organic layers were washed with 20 mL of water and 20
mL satd NaCl solution, dried over MgSO , filtered, and concentrated to afford 0.220 g of a pale-yellow
4
oil. Column chromatography on 40 g of silica gel (elution with 0-15% EtOAc-hexanes) afforded 0.093 g
-1 1
(
42%) of 15 as a colorless oil: IR (thin film) 2946, 2862, 1291, 1142, and 568 cm ; H NMR (400 MHz,
CDCl ) δ 7.92 (d, J = 8.2 Hz, 2 H), 7.47 (m, 2 H), 7.40 (m, 1 H) 7.34 (d, J = 8.5 Hz, 2 H), 7.03 (d, J = 8.2
3
Hz, 2 H) 2.82 (t, J = 6.4 Hz, 2 H), 2.46 (s, 3 H), 2.32 (s, 3 H) 2.30 (t, J = 6.3 Hz, 2 H) 1.77 (m, 2 H), 1.65
1
3
1
(m, 2 H); C{ H} NMR (100 MHz, CDCl ) δ 154.8, 154.0, 153.1, 144.1, 137.6, 137.2, 134.6, 129.4,
3
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2
1
29.3, 129.2, 128.2, 128.1, 128.0, 53.6, 32.8, 28.3, 22.7, 21.9, 15.7; HRMS (DART-FTICR) m/z [M + H]+
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
calcd for C H NO S 378.1528; found 378.1528.
2
3
24
2
4
-Ethyl-3-methyl-6-phenyl-2-tosylpyridine (16). A 16-cm, threaded Pyrex tube (38 mm O.D.,
17 mm I.D., 100 mL capacity) equipped with a rubber septum fitted with an argon inlet needle was
charged with 4 Å molecular sieves (0.780 g), tosyl cyanide (0.889 g, 4.93 mmol, 1.1 equiv), vinylallene
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 (0.763 g, 4.480 mmol, 1.0 equiv), and 45 mL of toluene. The tube was sealed with a threaded Teflon
cap, and the reaction mixture was heated at 50 °C for 24 h and then allowed to cool to rt. Concentration
gave 2.60 g of a yellow solid. Column chromatography on 140 g of silica gel (elution with CH Cl )
2
2
afforded 1.136 g (72%) of 16 as a white solid: mp 180-183 °C; IR (film) 3059, 2980, 2927, 2890, 1590,
-1 1
1
433, 1286, 1152, 1085, 775, and 668 cm ; H NMR (500 MHz, CDCl ) δ 7.95 (d, J = 8.5 Hz, 2 H), 7.65
3
(s, 1 H), 7.59-7.61 (m, 2 H), 7.41 (d, J = 8.0 Hz, 2 H), 7.30-7.34 (m, 3 H), 2.79 (s, 3 H), 2.78 (q, J = 7.5
1
3
1
Hz, 2 H), 2.51 (s, 3 H), 1.30 (t, J = 7.5 Hz, 3 H); C{ H} NMR (125 MHz, CDCl ) δ 157.2, 155.9, 152.6,
3
1
44.3, 137.3, 136.2, 129.8, 129.4, 129.2, 128.9, 128.7, 126.4, 121.7, 26.4, 21.8, 13.7, 13.2; HRMS
+
(DART-FTICR) m/z [M + H] calcd for C H NO S 352.1366; found 352.1354.
2
1
22
2
3
-Ethyl-4-methyl-2-propyl-6-tosylpyridine
(17)
and
4-Ethyl-5-methyl-3-propyl-2-
tosylpyridine (18). A 10-cm, threaded Pyrex tube (25 mm O.D.; 17 mm I.D.) equipped with a rubber
septum fitted with an argon inlet needle was charged with 4 Å molecular sieves (0.140 g), tosyl cyanide
(0.198 g, 1.09 mmol, 1.1 equiv), vinylallene 12 (0.135 g, 1.0 mmol, 1.0 equiv), and 10 mL of toluene.
The tube was sealed with a threaded Teflon cap and the reaction mixture was heated at 80 °C for 8 h and
then allowed to cool to rt. DBU (0.16 mL, 1.09 mmol, 1.1 equiv) was added dropwise via syringe over
0
.5 min, and the reaction mixture was stirred at rt for 15 h. The resulting yellow suspension was washed
with 20 mL of satd aq NH Cl and the aqueous phase was extracted with three 10-mL portions of EtOAc.
4
The combined organic layers were washed with 10 mL of satd NaCl solution, dried over MgSO , filtered,
4
and concentrated to afford ca. 0.4 g of a yellow oil. Column chromatography on 25 g of silica gel (elution
with 50-100% CH Cl -hexanes, then 0-5% EtOAc-CH Cl ) and combining fraction 0.102 g of impure 17
2
2
2
2
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and 0.078 g of impure 18, each as a yellow oil. The impure 17 was further purified via column
chromatography on 15 g of silica gel (elution with 0-30% Et O-pentane) to give 0.078 g (25%) of 17 as a
2
-1 1
colorless oil: IR (neat) 2969, 2872, 1597, 1577, 1455, 1314, 1148, 1086, 909, 729, and 672 cm ; H NMR
(500 MHz, CDCl ) δ 7.95 (d, J = 8.0 Hz, 2 H), 7.76 (s, 1 H), 7.30 (d, J = 8.0 Hz, 2 H), 2.75 (t, J = 7.5 Hz,
3
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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4
5
6
7
8
9
0
1
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0
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9
0
2
0
H), 2.66 (q, J = 7.5 Hz, 2 H), 2.40 (s, 3H), 2.38 (s, 3 H), 1.65-1.72 (m, 2 H), 1.10 (t, J = 7.5 Hz, 3 H),
1
3
1
.88 (t, J = 7.5 Hz, 3 H); C{ H} NMR (125 MHz, CDCl ) δ 161.2, 155.1, 147.1, 144.3, 140.0, 136.8,
3
+
129.6, 129.1, 122.3, 36.5, 22.0, 21.8, 21.8, 19.6, 14.1, 13.4; HRMS (DART-FTICR) m/z [M + H] calcd
for C H NO S 318.1522; found 318.1506.
1
8
24
2
The impure 18 was further purified via column chromatography on 15 g of silica gel (elution with
-30% Et O-pentane) to give 0.042 g (13%) of 18 as a colorless oil: IR (neat) 2967, 2872, 1596, 1456,
0
1
8
3
2
-1 1
299, 1287, 1140, 1070, 908, 728, and 685 cm ; H NMR (500 MHz, CDCl ) δ 8.10 (s, 1 H), 7.87 (d, J =
3
.0 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 3.07-3.10 (m, 2 H), 2.71 (q, J = 7.5 Hz, 2 H), 2.44 (s, 3 H), 2.30 (s,
1
3
1
H), 1.61-1.68 (m, 2 H), 1.14 (t, J = 7.5 Hz, 3 H), 1.10 (t, J = 7.5 Hz, 3 H); C{ H} NMR (125 MHz,
CDCl ) δ 155.4, 153.2, 147.4, 146.5, 144.1, 137.4, 135.6, 129.5, 129.1, 29.7, 25.2, 22.0, 21.8, 16.8, 14.9,
3
+
1
3.5; HRMS (DART-FTICR) m/z [M + H] calcd for C H NO S 318.1522; found 318.1512.
1
8
24
2
Confirmation of cycloaddition regiochemistry is based on differential nOe experiments (500 MHz,
CDCl ): 1.3% from 3.07-3.10 ppm to 7.87 ppm, 3.5% from 3.07-3.10 ppm to 2.71 ppm, 3.1% from 3.07-
3
3
.10 ppm to 1.61-1.68 ppm, 4.6% from 3.07-3.10 to 1.14 and 1.10.
-(1-Methoxybut-2-yn-1-yl)cyclohex-1-ene (24). A 100-mL, three-necked, round-bottomed
1
flask equipped with two rubber septa and a 20-mL graduated addition funnel fitted with a rubber septum
and an argon inlet needle was charged with vinyl bromide 23 (1.38 g, 11.40 mmol, 1.5 equiv) and 7.6 mL
of THF. The solution was cooled with a dry ice/acetone bath, and 6.93 mL of n-BuLi (2.41 M in hexanes,
6
.93 mL, 16.72 mmol, 2.2 equiv) was added dropwise via the addition funnel over 30 min (2-mL THF
rinse). The pale yellow solution was stirred at -78 °C for 2 h, and then a solution of cyclohexene
carboxaldehyde (0.837 g, 7.60 mmol, 1.0 equiv) in 2 mL of THF was added dropwise via cannula over 10
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2
min (1.8-mL THF rinse). The resulting solution was stirred for 45 min at -78 °C and then a solution of
methyl iodide (7.55 g, 53.2 mmol, 7.0 equiv) in 5 mL of THF was added via cannula over 3 min (2-mL
THF rinse). The resulting pale-yellow solution was allowed to warm to rt and stirred for 18 h. Saturated
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6
aq NH Cl solution (2 mL) and 6 mL of water were then added, and the aqueous phase was separated and
4
0
1
2
3
4
5
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7
8
9
0
1
2
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8
9
0
extracted with three 30-mL portions of ether. The combined organic layers were washed with 50 mL of
saturated aq NaCl solution, dried over MgSO , filtered, and concentrated to afford 1.406 g of a yellow oil.
4
Column chromatography on 45 g of silica gel (elution with 3% ether/hexanes) afforded 1.14 g (92%) of
-1
1
2
4 as a yellow oil: IR (NaCl) 2910, 2234, 1715, 1438, 1083 cm ; H NMR (300 MHz, CDCl )  5.86 (m,
3
1
H), 4.28 (m, 1 H), 3.29 (s, 3 H), 1.92-2.24 (m, 4 H), 1.88 (d, J=2.1 Hz, 3 H) 1.54-1.73 (m, 4 H);
1
3
1
C{ H} NMR (125 MHz, CDCl )  135.5, 126.3, 82.8, 76.6, 75.9, 55.4, 25.1, 24.1, 22.6, 22.4, 3.7;
3
+
HRMS (ESI) m/z [M + H] calcd for C H O 165.1274; found 165.1298.
1
1
17
3
-Ethyl-4-methoxy-2-tosyl-5,6,7,8-tetrahydroquinoline (26). A 25-mL, round-bottomed flask
equipped with a rubber septum and argon inlet needle was charged with 0.31 mL of t-BuLi (1.53 M in
pentane, 0.47 mmol, 1.1 equiv) followed by 0.07 mL of TMEDA (0.054 g, 0.47 mmol, 1.1 equiv). The
resulting yellow mixture was cooled at -78 °C while a pre-cooled solution of propargyl ether 24 (0.070 g,
0.43 mmol, 1.0 equiv) in 5 mL of ether was added dropwise over 5 minutes via cannula (1 mL ether
rinse). The resulting pale red reaction mixture was stirred for 15 min at -78 °C. MeOH (0.06 mL, 0.047
g, 1.48 mmol 3.5 equiv) was then added dropwise via syringe over 30 sec. After 5 min, the resulting
yellow solution was allowed to warm to rt and stirred for 35 min. Saturated aq NH Cl solution (1 mL),
4
and then 2.5 mL of saturated aq CuSO were added and the resulting mixture was stirred for 2 min. The
4
aqueous layer was separated, and the organic layer was washed with 10 mL of saturated aq NaCl solution,
dried over MgSO and then filtered into a 50-mL round bottomed flask containing a stir bar and 0.12 g of
4,
powdered 4Å MS. The flask was equipped with a rubber septum and flushed with argon for 30 sec. A
solution of TsCN (0.078 g, 0.43 mmol, 1.0 equiv) in 4 mL of THF was added (1 mL THF rinse) and the
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