Coupling Radical Homoallylic Expansions with C-C Fragmentations for the Synthesis of Heteroaromatics: Quinolines from Reactions of o-Alkenylarylisonitriles with Aryl, Alkyl, and Perfluoroalkyl Radicals

Article abstract of DOI:10.1021/acs.joc.7b00262

Selective addition of radicals to isonitriles can be harnessed for initiating reaction cascades designed to overcome the stereoelectronic restrictions on homoallylic ring expansion in alkyne reactions and to develop a new general route for the preparation of N-heteroaromatics. This method utilizes alkenes as synthetic equivalents of alkynes by coupling homoallylic ring expansion to yield the formal "6-endo" products with aromatization via stereoelectronically assisted C-C bond scission. Computational analysis of the homoallyic expansion potential energy surface reveals that the indirect 5-exo/3-exo/retro-3-exo path is faster than the direct 6-endo-trig closure, revealing the general exo-preference for the cyclization processes.

Full text of DOI:10.1021/acs.joc.7b00262

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Article
Coupling radical homoallylic expansions with C-C fragmentations
for the synthesis of heteroaromatics: Quinolines from reactions of
o-alkenylarylisonitriles with aryl, alkyl and perfluoroalkyl radicals
Christopher J. Evoniuk, Gabriel dos Passos Gomes, Michelle Ly, Frankie D. White, and Igor V. Alabugin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00262 • Publication Date (Web): 30 Mar 2017
Downloaded from http://pubs.acs.org on March 31, 2017
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Coupling radical homoallylic expansions with C-C fragmentations
for the synthesis of heteroaromatics: Quinolines from reactions of o-
alkenylarylisonitriles with aryl, alkyl and perfluoroalkyl radicals
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Christopher J. Evoniuk§, Gabriel dos Passos Gomes§, Michelle Ly, Frankie D. White and Igor V. Alaꢀ
bugin*
AUTHOR ADDRESS Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306-
4390. E-mail: alabugin@chem.fsu.edu
ABSTRACT: Selective addition of radicals to isonitriles can be harnessed for initiating reaction cascades designed to overcome the steꢀ
reoelectronic restrictions on homoallylic ring expansion in alkyne reactions and to develop a new general route for the preparation of Nꢀ
heteroaromatics. This method utilizes alkenes as synthetic equivalents of alkynes by coupling homoallylic ring expansion to yield the forꢀ
mal “6ꢀendo” products with aromatization via stereoelectronically assisted CꢀC bond scission. Computational analysis of the homoallyic
expansion potential energy surface reveals that the indirect 5ꢀexo/3ꢀexo/retroꢀ3ꢀexo path is faster than the direct 6ꢀendoꢀtrig closure, reꢀ
vealing
the
general
exoꢀpreference
for
the
cyclization
processes.
Introduction
Alkynes are attractive starting materials for the preparation of carbonꢀrich conjugated molecules.1 In particular, the 6ꢀendoꢀdig cyꢀ
clizations of alkynes open atomꢀeconomical access to functionalized polycyclic aromatic hydrocarbons (PAHs). However, the radiꢀ
cal version of this alkyne cyclization is plagued by selectivity problems. Instead of the desired 6ꢀendoꢀdig product, the reaction
often favors a fiveꢀmembered ring formation via the stereoelectronically preferred 5ꢀexoꢀdig path.2 We have recently established a
combination of 5ꢀexoꢀtrig cyclization of enynes with homoallylic ring expansion (HRE) and CꢀC fragmentation as an indirect but
efficient way to sixꢀmembered aromatic compounds that are inaccessible from the 6ꢀendoꢀdig cyclization of related bisꢀalkynes
(Scheme 1).3
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Scheme 1. Application of alkenes as alkyne equivalents in radical cascades terminated by fragmentation
1
This process, where alkenes are used as synthetic analogues of alkynes, takes advantage of the greater stereoelectronic flexibility of
alkyl radicals derived from alkenes in order to bypass the inefficient HRE of vinyl radicals derived from alkynes. In the alkyne
route, the HRE process stalls because the vinyl radical in the exoꢀdig product is constrained to orthogonality relative to the target
π−system (Scheme 2, left).4 In contrast, the HRE in the 5ꢀexoꢀtrig radical products that form from the alkene precursors can underꢀ
go conversion into the endoꢀproducts (Scheme 2, right).5 The CꢀC fragmentation adjusts the oxidation state of the sixꢀmembered
product of enyne cyclizations, rendering it fully aromatic.
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Scheme 2. Left: Stereoelectronic restriction on the 5-exo-dig ꢀ 6-endo-dig homoallylic ring expansion (HRE) Right: “Recy-
cling” 5-exo-trig products into 6-endo-trig products via homoallylic ring expansion. Z = CH2Ph, CH2OR.
Two conditions are important for the success of this transformation where alkenes serve as synthetic equivalents of alkynes in order
to bypass the unreliable endoꢀdig cyclization. First, the 5ꢀexoꢀtrig product should be capable of fast 3ꢀexoꢀtrig cyclization into a
relatively strained intermediate. Second, the CꢀZ bond should be sufficiently strong to be compatible with the radical conditions,
but the final CꢀZ bond scission should be faster than intramolecular quenching of the nonꢀaromatic sixꢀmembered intermediate in
order to complete the crossover to the formal 6ꢀendoꢀdig product.
The solution to the 2nd problem was identified based on our earlier work on the design of radical leaving groups.4a Although the
choice of the relatively strong CꢀC bond as the “weak link” may seem surprising, it prevents the premature fragmentation and deꢀ
creases the probability of undesired sideꢀreactions. Only when the evolution of the radical cascade places the radical center at the γꢀ
atom relative to a lone pair or a Ph group, the CꢀC fragmentation becomes sufficiently fast due to the activation of threeꢀelectron
a
ThroughꢀBond (TB) orbital interactions via the breaking bond (Scheme 3).4 These interactions facilitate the CꢀC bond scission that
furnishes the final cascade product.
Scheme 3. Activation of the stabilizing through-bond interactions in the C-C bond fragmentation of the properly substituted
6-endo products of enyne cyclizations
On the other hand, the 5ꢀexoꢀtrig/HRE sequence is not general because it is sensitive to the nature of reactants and can be interruptꢀ
ed at different stages. In particular, the HRE step is stopped and the 5ꢀexoꢀtrig products can be obtained in high yield when the exoꢀ
cyclic radical is stabilized by a conjugating substituent (Scheme 4).
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Scheme 4. Homoallylic ring expansion can be stopped by stabilization of the 5-exo-product.
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We were interested in expanding this approach to the preparation of Nꢀheterocyclic aromatic systems.6 In recent years, much work
has been devoted to developing methods for the construction of Nꢀheterocyles7 including examples of cascades of oꢀ
alkynylarylisonitriles.8 These transformations included a variety of mechanistic approaches such as nucleophile promoted, 8aꢀd phoꢀ
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e
tochemical 8 and cycloaromatization9 routes.
In particular, we envisioned the use of isonitriles in an analogous reaction of vinyl radicals. Reactions of isonitriles with radicals are
wellꢀknown to be selective and provide a vinyl (iminoyl) radical intermediate that seems to be wellꢀsuited for the cyclizaꢀ
tion/fragmentation cascade (Scheme 5).10 However, the subsequent selectivity in the reaction of such radicals in oꢀ
alkynylarylisonitrile systems (e.g., the ratio of 5ꢀexo vs. 6ꢀendo products) using HSnBu3/AIBN was found to be highly sensitive to
the alkyne substitution.8f,g
These observations motivated us to design an alternative isonitrile substrate that can use “alkenes as alkyne” equivalents as a potenꢀ
tialapproach to control the 5ꢀexo and 6ꢀendo competition.
Scheme 5. Top: Representation of the impact of cyclization partners on 5-exo/6-endo selectivity in alkynylisonitrile products
Bottom: Condensed mechanism for radical addition/cyclization cascade using alkenes as equivalents to alkynes
However, the earlier work by Fukuyama suggests that the initial 5ꢀexoꢀproducts do not undergo the ring expansion even for alkyl
substituted alkenes (where, otherwise, the 5ꢀexo products were not deactivated by resonance stabilization).11a Furthermore, the seꢀ
lectivity for the alkyl substituted substrates of this type agrees with the formation of the 5ꢀexo products reported later by Studer in
radical trifluoromethylations terminated by deprotonation/electron transfer.12a The goal of this paper was to understand whether this
reluctance towards HRE is general in these systems and, if not, develop a robust system for efficient cascade reactions (Scheme 6).
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Scheme 6. Literature precedents in radical cyclizations Top: o-alkynyl arylisonitriles. Bottom: o-alkenyl arylisonitriles
1
This work combines experiments and computations for understanding mechanistic details of the Nꢀheterocycle synthesis based on
radical 5ꢀexo/expansion/fragmentation cascade of oꢀalkenyl arylisonitriles. This methodology overcomes issues of low 6ꢀendoꢀdig
selectivity normally associated with radical cyclizations.
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Results and Discussion
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Synthesis of cyclization precursors: We have developed convenient routes to the diverse array of cyclization substrates from a
wide selection of inexpensive and readily available oꢀsubstituted aldehydes/halides (depicted in Scheme 7). The reliable Wittig,13
Heck14 and Suzuki15 reactions can be used to install the alkene functionality in good yields. For the Suzuki/Heck pathways the corꢀ
responding Eꢀisomer isonitriles were prepared in two steps – Pdꢀcatalyzed coupling of alkenes with 2ꢀhaloformamides, followed by
formamide → isonitrile conversion. The Wittig reactions of 2ꢀnitrobenzaldehydes afford the desired isonitriles in moderate to good
yields via a sequence of: nitro group reduction, amine formylation and subsequent dehydration. Wittig route provided a mixture of
cis/trans isomers in moderate to good yields.
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Scheme 7. Synthesis of o-alkenyl isocyanide substrates via routes that utilize Wittig (A), Heck (B) and Suzuki (C) coupling
reactions to install the alkenyl group onto the o-amino-substituted aromatic core.
The parent isonitrile 1a was used as a test substrate for investigating the scope of radical sources that can induce the cyclizaꢀ
tion/expansion/ fragmentation cascades.
Our initial studies turned to Snꢀcentered radicals that can be conveniently generated via the radical chain process from a suitable tin
hydride precursor and allows the installation of valuable Snꢀfunctionality in the final product.16 However, earlier literature preceꢀ
dents were discouraging.11 In particular, a thorough study of Fukuyama has shown that the 5ꢀexo indole products are formed in the
reactions of HSnBu3/AIBN with oꢀalkenylarylisonitriles, even when Z=CH2OR (Scheme 6). Indeed, we have reproduced this literaꢀ
ture report and observed only the 5ꢀexoꢀproduct formation from the CH2ORꢀsubstituted substrate 1a’ in the HSnBu3/AIBNꢀ
mediated reaction. This result drastically contrasts our observation of efficient ringꢀexpansion/fragmentation cascade in the analoꢀ
gous allꢀcarbon systems.4
We suspected that the variation in selectivity may stem from the difference in the position of Bu3Snꢀgroup relative to the radical
center in the two types of vinyl radicals.17 The Bu3Sn addition to enynes forms a βꢀSnꢀsubstituted radical where bulky ꢀSnBu3 moiꢀ
ety is placed away from the point of the new bond formation in the subsequent 3ꢀexoꢀstep. (Scheme 8, below). This radical readily
undergoes the HRE process because the 3ꢀexoꢀcyclization TS is not sterically hindered. In contrast, isonitriles act as a “1,1ꢀ
synthon” in radical additions, to form an αꢀSnꢀsubstituted iminoyl radical. Consequently, the initial product of the 5ꢀexo cyclization
of isonitrile has the bulky SnBu3ꢀgroup directly at the radical carbon involved in the initiation of subsequent HRE. The increased
steric hindrance should slow the 3ꢀexoꢀstep of sequence, explaining why the HRE cascade stops and only the indole products are
observed (Scheme 8, below).
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Scheme 8. Top: All carbon system allows for HRE process with using AIBN/HSnBu3. Bottom: α-SnBu3 prevents HRE in
isonitrile system.
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,
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Many radical species are known to add to isonitriles.10 11 12 However, much of this work relies on an Hꢀabstraction step (often with
peroxides) to generate the desired radical source (Scheme 9, left).18 In the literature cases, this step would often be compatible with
the subsequent transformations. Unfortunately, the “benzallylic” CꢀH bonds in our alkenes are sufficiently weak (BDE: ~ 84
kcal/mol)19 to undergo competing Hꢀabstraction even when such activated CꢀH bond substrates as aldehydes, formamides, and
ethers were used.20 Consequently, our exploratory attempts to initiate the cyclization/fragmentation cascades via CꢀH abstraction
from the above substrates resulted in complex mixtures.
Scheme 9. Examples of radical additions to isonitriles: (left) unsuccessful approaches based on C-H abstraction by perox-
ides, (right) successful oxidative and reductive methods.
On the other hand, iodoperfluorocarbons can be successfully used as radical precursors under initiation conditions reported by Stuꢀ
der and coworkers (Scheme 9).12a,21 For example, the reaction of 1b with perfluorohexyl iodide, yielded solely F1 as the product. In
a similar manner, reaction of isonitrile 1f with the Togni II reagent initiated the desired cascade with fragmentation/aromatization
cascade to yield F2 (Scheme 10).
Scheme 10. Perfluoro radicals successfully induce addition/cyclization/fragmentation cascade of o-alkenylarylisonitriles
In search of other general protocols that did not rely on Hꢀabstraction to generate radicals (Scheme 9),12, 22 we turned to organoꢀ
boron reagents that increasingly gain popularity as radical precursors.23, 24 We were also interested in testing whether the oxidative
activation of boronic acids by a mild oxidant can offer advantages for the manipulation of the oxidation state of reacting species
(i.e. radicals vs. cations). Furthermore, the synthetic utility of this methodology is enhanced by the wide variety of commercially
available boronic acids.
,
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To our delight, in the presence of Mn(acac)3 and phenyl boronic acid, substrate 1a underwent the selective 6ꢀendo cyclizaꢀ
tion/fragmentation cascade.25,26 Table 1 outlines the screening process that leads to the optimized conditions (entry 3) which yielded
exclusively the quinoline 2a in 86% yield. Slight excess (1.5 equiv.) of boronic acid was needed, presumably to compensate for the
side reactions such as radical dimerization.27 Elevated temperatures are required for full conversion (entries 3, 6, 7). Mn(acac)3 outꢀ
performed other oxidants during the screening process and was chosen for further studies. The optimized conditions were used to
study the substituent scope and limitation for the new transformation.
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Table 1. Optimization of reaction conditions.
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Entry
Oxidant
Equiv Solvent Temp Yield
b
◦C
%
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2
3
5
6
7
Mn(acac) 3
Mn(acac) 3
Mn(acac) 3
Mn(acac) 3
Mn(acac) 3
Mn(acac) 3
Mn(OAc) 3
ꢁ2H2O
1
2
3
3
3
3
3
C7H8
C7H8
C7H8
C7H8
C7H8
C7H8
90
17
64
86
90
90
reflux 82
rt
0
50
59
8
C7H8
90
67
9
Mn(OAc)2
Cu(OAc)2
AgNO3/
3
C7H8
C7H8
DCM/
H2O
90
90
0
0
10
3
0.2/3
11
90
0
Na2S2O8
12
13
14
Mn(acac) 3
Mn(acac) 3
Mn(acac)3
3
3
3
MeCN
C6H6
DMF
reflux 79
reflux 84
90
trace
Reaction conditions: isocyanide (0.1 mmol), boronic acid (1.5 equiv), specified amount of oxidant in 3 mL of solvent. Reactions
were stirred for 4 hours, with exception of r.t. reaction that was allowed to react for 24 hours. aNMR yield based on 1a.
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Table 2. Scope of Mn(III)-mediated transformations
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[a] Yield of isolated product from starting materials. [b] 3 equivalents of boronic acid were used. [c] ORTEP drawing of 2s; thermal
ellipsoids are set at a 50% probability level.
The scope of the reaction, in terms of both boronic acids and isonitriles, is quite broad, opening access to a variety of quinolines in
good yields. Both donor and acceptor functional groups were tolerated (Table 2). The products were characterized via a combinaꢀ
tion of spectroscopic techniques and, in the case of product 2s, via Xꢀray analysis. Successful formation of compound 2g suggests
that alkyl boronic acids are compatible with the reaction as well. The only exception was the alkenyl boronic acid that did not give
product 2r under the above conditions and yielded instead to a complex mixture of products unstable on SiO2.
More than twoꢀfold excess of the oxidant, required for achieving full conversion, hints at a further single electron transfer (SET)
oxidation of intermediate radicals.19a, This possibility was suggested for the Mn(III)/RB(OH)2ꢀmediated cyclization of isocyanoꢀ
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biphenyls, where a SET oxidation by the second equivalent of Mn(III) was postulated to generate a cationic intermediate that aroꢀ
matizes into phenanthridines via loss of a proton.29,30
Considering that the CH2Phꢀsubstituted substrate yielded excellent results, we proceeded to investigate the effect on the yield of
substituents at the terminus of the alkene and the selectivity of the cyclization/expansion/fragmentation cascade (Table 1). The
yields of desired quinoline products follow the trend of radical stability (benzyl>αꢀalkoxy>alkyl) for (Z: ꢀCH2Ph = 86%, ꢀCH2OMe
= 69%, ꢀC(CH3)3 = 19%). The dramatically lower quinoline yield for the fragmentation producing the tꢀBu radical can also be atꢀ
tributed to the steric hindrance of the bulky tertꢀbutyl group.
The effect of radicalꢀstabilizing groups on regioselectivity was observed in the case of a phenyl substituted alkene 1c, where excluꢀ
sive 5ꢀexo product formation was observed.11,12, In this case, the radical formed upon initial 5ꢀexo cyclization is stabilized by πꢀ
31
conjugation from the phenyl ring, which deactivates this species towards the HRE process.32
An intriguing result was observed for propyl substituted substrate, 1d. The alkyl group should not interfere with the HRE of the 5ꢀ
exo radical but is unable to provide stabilization in the fragmentation step. The overall massꢀbalance of this reaction is low. The 5ꢀ
exo product 2w was formed from 1d in 28%, but the yield of the desired quinoline 2a was even lower (8%, Table 3).
Table 3. Screening of alkene substituents
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Reaction conditions: isocyanide (0.1mmol), boronic acid (1.5 equiv), Mn(acac)3 (3 equiv), and toluene (3 mL) were heated at 90◦C
for 4 hours. Complete conversion was observed in all cases. aIsolated yield. bNMR yield based on starting material. cYield of isolatꢀ
ed major product with mixture of products.
In parallel, we prepared two structurally constrained bicyclic substrates 1j and 1i (Table 3). Contrary to the formerly discussed reꢀ
sults, the indene 1j yielded only the 6ꢀendo product, 2t, without the CꢀC scission (proposed mechanism shown in Scheme 12). In
the case of 1i, a major (2u, 57%) and minor product (2u’, 9%) were observed as an inseparable mixture (proposed mechanism
shown in Scheme 14).
We have also considered the cationic mechanism for our system. However, additional experimental studies (as well as computaꢀ
tions provided below) did not support the cationic pathway (Scheme 11). In particular, when we introduced nucleophilic species
into the reaction (equations 1, 2, and 3), we only observed the usual quinoline product, with only slightly reduced yields. It is
known that the CH3CN/H2O mixture can trap benzylic carbocations to form, upon hydrolytic workup, the respective Nꢀ
benzylacetamides.33 When toluene was replaced with a 4:1 mixture of CH3CN/H2O as the solvent (equation 4 below), only the
quinoline product was observed in 84% after the hydrolytic workup. The same reaction in dry CH3CN provided a similar yield
(79%) of the same quinoline product.
Additionally, we conducted the reaction in the presence of 2,2,6,6ꢀtetramethylpiperidine 1ꢀoxyl (TEMPO).34 Under these condiꢀ
tions, the observe the formation of TEMPOꢀPh as expected from successful trapping of the Ph radical.35 Furthermore, the unreacted
starting material was isolated in 91% (equation 5).
Scheme 11. Control experiments for evaluating the relative importance of cationic and radical reaction pathways
The available experimental results suggest the following mechanism (Scheme 12). The reaction begins with the formation of a carꢀ
bonꢀcentered radical in the reaction of Mn(III) and boronic acid.36 The chemoselective addition of this radical to the arylisonitrile
moiety generates the iminoyl radical A1 capable of the reactions outlined in Scheme 12. The “6ꢀendo” product A2 formation was
observed exclusively when an appropriate fragmenting group (i.e.,CH2Ph, ꢀCH2OMe) was installed. Potentially, the endoꢀproduct
can be either produced directly or form via HRE of the 5ꢀexoꢀtrig radical A3.
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Scheme 12. Proposed radical pathway for 6-endo product formation.
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The stereoelectronic factors in the CꢀC bond scission were probed via the reaction of the bicyclic substrates 1j and 1i. Both subꢀ
strates yield solely the 6ꢀendo products as outlined in Scheme 13Scheme 14. However, the sequence of reaction steps for 1j culmiꢀ
nated in a CꢀH scission instead of the usual CꢀC fragmentation. We attribute the lack of CꢀC fragmentation to structural constraint
that imposes the nearly perpendicular arrangement for the CꢀC bond and the radical orbital in B2. The same structural constraint
aligns the benzylic CꢀH bond with the radical, facilitating the CꢀH bond scission at the expense of the CꢀC fragmentation.
Scheme 13. Radical pathway for C-H bond cleavage in a stereoelectronically restricted cycle.
On the other hand, the saturated cycle in the tetrahydropyrane containing substrate 1i allows more flexibility in aligning the scissile
CꢀC bond with the radical. Furthermore, the strategically positioned oxygen atom in this molecule can assist in the CꢀC fragmentaꢀ
tion step by stabilizing the resulting radical. However, the ideal orbital alignment for this assistance is hampered by the cyclic conꢀ
straints. Whereas compound 1i produced exclusively the 6ꢀendoꢀproducts, the fragmentation step was not selective. The major
product, 2u resulted from a CꢀH cleavage whereas the minor product, 2u’ was formed via the CꢀC bond scission. The latter path
was continued by radical attack at the aromatic ring and subsequent rearomatization (a plausible mechanism is summarized in
Scheme 14).
Scheme 14. Proposed mechanism for tethered substrate product formation
Calculations were carried with the Gaussian 09 software package,37 using the M06ꢀ2X DFT functional38 with the 6ꢀ311++G(d,p)
basis set for all atoms. The implicit PCM39 solvation model was used to simulate the effects of toluene throughout the reaction
pathways. We also performed Natural Bond Orbital40 (NBO) analysis on key intermediates and transition states.
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Cationic vs. Radical: As the first step, we compared the energetics of radical and cationic pathways. In agreement with the experꢀ
imental results discussed above, the cationic 6ꢀendo cyclization/fragmentation sequence was found to be unlikely. Most notably, the
barrier for 6ꢀendo cyclization in the cationic pathway (Scheme 15, solid line) is 24 kcal/mol, much higher than the ~11 kcal/mol
barrier for the radical process (Scheme 15, dashed line). Although both cationic and radical 6ꢀendo cyclizations were found to be
exergonic, the driving force for the cationic ring closure was significantly lower than for the radical cyclization (ꢀ3.4 vs ꢀ28.9
kcal/mol, respectively). The largest difference was observed for thermodynamics of the fragmentation steps: fragmentation for the
cationic pathway is an uphill battle (+ 3.5 kcal/mol relative to the penultimate intermediate) whereas the radical fragmentation is 11
kcal/mol exergonic. These results provide additional strong support to a radical mechanism for the observed cascade transforꢀ
mation.
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Scheme 15. Gibbs Free Energy diagram for the cationic pathway shows that this an unlikely mechanism. Data for the re-
spective radical mechanism are shown in blue and with a dashed line.
These results, along with an agreement with the experimental observations, additional strong support to a radical mechanism for the
observed cascade transformation. In the following section, we provide a general outline of the observed cascade.
The importance of HRE path –direct vs. indirect pathways to the 6-endo-product: The ring expansion cascade is relatively
complex and involves a sequence of two fragmentations and two fragmentations. We plan to analyse the full details of substituent
and structural effects on the interplay of the individual steps in a separate paper. At the present stage, we will limit discussion to
relative energies of the direct and indirect routes to the final products. The most important message is that, even though the tricyclic
product of the 3ꢀexoꢀtrig cyclization A4b/A4c are slightly higher in energy than the 5ꢀexoꢀproduct A3b/A3c (due to strain accumuꢀ
lation) and although the retroꢀ3ꢀexoꢀtrig barrier for the conversion of A4b/A4c to the final 6ꢀendo product A2c was relatively high
(~14 kcal/mol relatively to A4b/A4c), the overall potential energy surface (PES) for the 5ꢀexoꢀ6ꢀendo HRE is much lower than
the PES for the direct 6ꢀendoꢀtrig closure (Scheme 16).
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Scheme 16. Gibbs Free Energy diagram for full radical cascade initiated by the addition of Me and Ph radicals, including
HRE, direct 6-endo path (shown in red) and fragmentation. See SI for the other full cascade PESs.
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Analysis of these calculated potential energy surfaces reiterates the importance of stereoelectronic concepts in the design of cyclizaꢀ
tion processes. Even though the direct 6ꢀendo cyclization is not as disfavored as its 4ꢀendo and 5ꢀendo cousins, the combination of
three exoꢀcyclizations (i.e., the 5ꢀexo/homoallylic expansion) is still energetically preferred over the “direct” endo path to the sixꢀ
membered product (Scheme 17). Avoiding the direct path in favor of a combination of indirect multiꢀstep route is reminiscent of the
commonly encountered situation in catalysis when an unfavorable singleꢀstep transformation is accomplished in a more favorable
way via a combination of elementary steps enabled by substrate/catalyst interactions.41 This is a manifestation of the general exoꢀ
trig preference for cyclizations.42
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Stereoelectronic attenuation of radical clocks: Interestingly, the two 3ꢀmembered TS’s in the cascade correspond to two alternaꢀ
tive “radicalꢀclock” ring openings of bicyclic radical A4c. A noteworthy feature in the competition between these reactions is that
the barrier for the more exergonic of the two analogous processes is higher. This difference reflects stereoelectronic factors inꢀ
volved in the CꢀC bond scission. Bicyclic restraints make orbital alignment different and hamper the CꢀC bond scission as illustratꢀ
ed by the TS geometries in Scheme 17. The more favourable TS has a much better overlap of the breaking CꢀC bond with the radiꢀ
cal center at N.
Scheme 17. Stereoelectronic attenuation of radical clocks by alignment (or lack of thereof) with the endocyclic π-system
Fragmentation step: The final step of the cascade consists in a fragmentation that results in an aromatic product and a H2CꢀX radiꢀ
cal. Different X groups can stabilize this radical fragment by hyperconjugation (alkyl groups), 2c,3e “halfꢀbonds” (lone pair donor,
such as MeO or NMe2), or conjugation (phenyl group). Scheme 18A depicts the barriers and reaction energies for departure of variꢀ
ous radicals. Since this reaction produces two products, it is expected for it to be an entropically driven process and therefore it
benefits from higher temperatures. The greater the stabilization of the radical formed, the more exergonic is this step. As one
would expect, the activation energy for such CꢀC scission also decreases as the fragmentations become more exergonic.
Scheme 18. Scope of radical leaving groups and relation between kinetics and thermodynamics of the C-C scission. Energies
in kcal/mol.
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The unique feature of these processes is that each substituent stabilizes TS more than the fully developed radical in product, as
a
shown in Scheme 18B. The quantum mechanical rationale for this remarkable behaviour is given in our earlier work.4 In short,
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through-bond interactions between the lone pair of X and the radical center are strengthened in the TS, producing large kinetic efꢀ
fects when compared to X=H, i.e., in absence of any stabilizing group.
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On the other hand, bicyclic constraints make the barrier for CꢀCH2(OR) bond scission much higher (~4 kcal/mol penalty in comparꢀ
ison to the CꢀCH2OR in the acyclic case). Furthermore, because the former scission does not result in the formation of two separate
molecules, the free energy of fragmentation is significantly less favorable and the overall process is endergonic (Scheme 19). Recyꢀ
clization at the adjacent benzene ring has a calculated barrier of ~12 kcal/mol and, even though this attack should break aromaticity,
the reaction is expected to be fairly exergonic (ꢂG = ꢀ10 kcal/mol). The alternative pathway for this intermediate would consist on
αꢀH abstraction by the radical source, coupled with aromatization of the pyridine core. This process is estimated to be extremely
exergonic under our reaction conditions (ꢂG = ꢀ73 kcal/mol). The results presented in Scheme 19 are in agreement with our experꢀ
imental results.
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Scheme 19. Effect of bicyclic constraints in the fragmentation step and possible capture of the fragmented radical (Energies
in kcal/mol at 363K).
Conclusions
This work presents a comprehensive study of radical cascades that transform oꢀalkenylarylisonitriles into substituted quinolines.
Although cascades initiated by Bu3Snꢀaddition to oꢀalkenylarylisonitriles stall at the 5ꢀexoꢀtrig state, the analogous reactions of
aryl, alkyl and perfluoroalkyl radicals to isonitriles lead to full homoallylic expansion cascade terminated by CꢀC scission and aroꢀ
matization. The relative efficiency of the final CꢀC bond scission can be controlled stereoelectronically by introducing additional
structural constraints. Use of an appropriate alkene partner allows for an efficient cyclization/fragmentation sequence that renders
alkenes as synthetic equivalents to alkynes and provides a new approach to the de novo assembly of the substituted quinoline core.
Experimental Section
General Information: Unless otherwise described, all reactions were performed with standard Schlenk techniques or with a balꢀ
1
loon to provide inert atmosphere. All H NMR spectra were run in CDCl3 on either 400 MHz or 600 MHz spectrometer. All 13C
NMR were run in CDCl3 on either 100 MHz or 150 MHz spectrometer. Proton chemical shifts are given relative to the residual
proton signal of CDCl3 (7.26 ppm). Carbon chemical shifts were internally referenced to CDCl3 (77.23 ppm) signal. Data are reꢀ
ported as follows: chemical shift in ppm (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, spt = septet, m = multiꢀ
plet), coupling constant (Hz), and integration. Infrared spectra (IR) were obtained on a Perkin Elmer Lambda 950 or Perkin Elmer
Spectrum 100; absorptions are reported in reciprocal centimeters. An AccuTOF mass spectrometer analyser was used to aquire high
resolution mass spectra (HRMS). Unless otherwise specified acetonitrile, toluene and THF were obtained from a SPSꢀ4 solvent
purification system. Hexanes for column chromatography and preparatory thin layer chromatography were distilled prior to use.
Dichloromethane and diꢀisopropylamine was distilled prior to use. All other solvents and chemicals were purchased from commerꢀ
cial suppliers and used as received without further purification.
Experimental Details:
General procedure for Wittig reaction: To a solution of the desired Wittig salt (1.2 equiv) in anhydrous THF at ꢀ78 °C was added
slowly nꢀBuLi (2.5 M in hexanes, 1.2 equiv). After 45 min, a solution of desired 2ꢀnitrobenzaldehyde (1 equiv) in THF was added
dropwise. The resulting solution was stirred for 1 h at ꢀ78 °C and then at room temperature for 12 h and quenched with saturated
NH4Cl solution. The aqueous phase was extracted with Et2O (3 × 30 mL), and the combined organic layers were washed with brine,
dried over anhydrous Na2SO4, and evaporated under reduced pressure. The crude was purified by column chromatography(hexane)
on silica gel affording the desired oꢀalkenylnitroarene.
1ꢀnitroꢀ2ꢀ(3ꢀphenylpropꢀ1ꢀenyl)benzene (S1a) was prepared following the general Wittig procedure as dark yellow oil (E:Z = 1:3,
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75%). H NMR (400 MHz, CDCl3) δ 8.12 – 8.05 (m, 3H), 7.96 – 7.90 (m, 1H), 7.65 – 7.58 (m, 4H), 7.58 – 7.55 (m, 1H), 7.50 –
7.19 (m, 27H), 6.98 (t, J = 10.4 Hz, 1H), 6.92 (d, J = 11.4 Hz, 3H), 6.39 (dt, J = 15.5, 7.0 Hz, 1H), 6.08 (dt, J = 11.4, 7.7 Hz, 3H),
3.64 (dd, J = 7.0, 1.0 Hz, 2H), 3.50 (dd, J = 7.7, 0.8 Hz, 6H). HRMS (ESI) m/z: [M]+: Calcd for C15H13NNaO2 262.0844, Found:
262.0845. Spectral data match those previously reported.26
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4ꢀfluoroꢀ1ꢀnitroꢀ2ꢀ(3ꢀphenylpropꢀ1ꢀenꢀ1ꢀyl)benzene (S1b) was prepared following the general Wittig procedure as a light brown oil
(E:Z = 1:3, 83%). Rf = 0.44 (hexanes/EtOAc 10:1). 1H NMR (400 MHz, CDCl3) δ 8.14 (dd, J = 8.7, 5.1 Hz, 1H), 8.00 (dd, J = 9.1,
5.2 Hz, 1H), 6.37 (d, J = 15.5 Hz, 1H), 6.09 (dt, J = 11.4, 7.7 Hz, 1H), 3.62 (d, J = 6.7 Hz, 1H), 3.48 (d, J = 7.6 Hz, 2H). 13C NMR
(101 MHz, CDCl3) δ 165.7, 163.2, 139.5, 136.2, 136.0, 135.9, 132.9, 128.8, 128.8, 128.8, 128.3, 127.8, 127.7, 126.7, 126.5, 126.2,
126.0, 118.7, 118.5, 115.3, 115.1, 39.6, 34.5. HRMS (ESI) m/z: [M+Na]+: Calcd for C15H12FNNaO2 280.0742, Found: 280.0744.
Spectral data match those previously reported.26
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1ꢀnitroꢀ2ꢀstyrylbenzene (S1c) was prepared following the general Wittig procedure to give 81% of the title compound (E:Z = 0.7:1)
as a light brown oil. Rf = 0.44 (hexanes/EtOAc 10:1). 1H NMR (400 MHz, CDCl3) δ 8.14 – 8.06 (m, 1H), 7.97 (dd, J = 8.1, 0.9 Hz,
1H), 7.78 (d, J = 7.5 Hz, 1H), 7.64 – 7.52 (m, 3H), 7.45 – 7.24 (m, 11H), 7.21 – 7.15 (m, 3H), 7.13 – 7.04 (m, 3H), 6.91 (d, J = 12.1
Hz, 1H), 6.78 (d, J = 12.1 Hz, 1H).13C NMR (101 MHz, CDCl3) δ 136.6, 136.0, 134.0, 134.0, 133.8, 133.8, 133.2, 133.2, 132.4,
132.0, 129.3, 129.0, 128.8, 128.7, 128.6, 128.4, 128.3, 128.2, 128.1, 127.7, 127.2, 126.6, 126.0, 124.9, 124.8, 123.7. HRMS (ESI)
m/z: [M]+: Calcd for C14H11NO2 225.0790, Found: 225.0801. Spectral data match those previously reported.26
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1ꢀnitroꢀ2ꢀ(pentꢀ1ꢀenꢀ1ꢀyl)benzene (S1d) was prepared following the general Wittig procedure to give 73% of the title compound
(E:Z = 1:2) as a light brown oil. Rf = 0.73 (hexanes/EtOAc 10:1). 1H NMR (400 MHz, CDCl3) δ 7.93 (dd, J = 8.2, 1.0 Hz, 1H), 7.86
– 7.76 (m, 1H), 7.60 – 7.43 (m, 2H), 7.41 – 7.24 (m, 3H), 6.80 (d, J = 15.7 Hz, 1H), 6.66 (d, J = 11.6 Hz, 1H), 6.20 (dt, J = 15.6,
6.9 Hz, 1H), 5.78 (dt, J = 11.6, 7.5 Hz, 1H), 2.20 (qd, J = 7.3, 1.5 Hz, 1H), 2.03 (qd, J = 7.5, 1.7 Hz, 2H), 1.57 – 1.43 (m, 1H), 1.42
– 1.31 (m, 2H), 0.93 (t, J = 7.4 Hz, 2H), 0.83 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 136.6, 134.5, 133.3, 132.8, 132.8,
132.6, 131.9, 128.3, 127.6, 127.3, 125.1, 125.0, 124.3, 124.3, 35.2, 30.4, 22.7, 22.2, 13.6, 13.6. HRMS (ESI) m/z: [M]+: Calcd for
C11H13NO2 191.0946, Found: 191.0942. Spectral data match those previously reported.26
General procedure for reduction of nitro group: To a solution of oꢀalkenylnitroarene (1 equiv.) in absolute ethanol was added
glacial acetic acid and iron powder (6 equiv.). The mixture was heated to reflux. After 6 h, the crude mixture was cooled and filꢀ
tered through a pad of Celite. The filtrate was concentrated in vacuo. Purification by flash chromatography on silica gel (Hexꢀ
anes:EtOAc) afforded desired oꢀalkenylaniline compounds.
2ꢀ(3ꢀphenylpropꢀ1ꢀenꢀ1ꢀyl)aniline (S2a) was prepared following general procedure for reduction of nitro group (S1a) yielding 1.1
g of a dark brown oil (E:Z = 1:3 , 85%). 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.04 (m, 31H), 6.81 – 6.69 (m, 7H), 6.67 (dd, J = 8.0,
1.0 Hz, 1H), 6.49 (d, J = 15.5 Hz, 1H), 6.44 (d, J = 11.1 Hz, 3H), 6.24 (dt, J = 15.5, 6.9 Hz, 1H), 5.99 (dt, J = 11.1, 7.5 Hz, 3H),
3.69 (s, 6H), 3.58 (d, J = 7.0 Hz, 3H), 3.52 (d, J = 7.5 Hz, 6H). 13C NMR (CDCl3, 100 MHz) 144.8, 143.4, 136.2,133.4, 130.2,
129.8, 128.9, 128.8, 128.6, 126.9, 126.5, 123.0, 121.0, 120.5, 56.6, 35.5, 31.5, 21.6. HRMS (ESI) m/z: [M]+: Calcd for C15H15N
209.1250, Found: 209.1260 Spectral data match those previously reported.26
4ꢀfluoroꢀ2ꢀ(3ꢀphenylpropꢀ1ꢀenꢀ1ꢀyl)aniline (S2b) was prepared following general procedure for reduction of nitro group (S1b) to
1
give 78% of the title compound (E:Z = 1:3) as a brown oil. Rf = 0.44 (hexanes/EtOAc 10:1). H NMR (400 MHz, CDCl3) δ 6.99
(dt, J = 9.5, 3.2 Hz, 1H), 6.67 (ddd, J = 8.4, 4.8, 1.4 Hz, 1H), 6.64 – 6.58 (m, 1H), 6.45 (d, J = 15.2 Hz, 1H), 6.40 (d, J = 11.4 Hz,
1H), 6.32 – 6.20 (m, 1H), 6.09 – 5.96 (m, 1H), 3.52 (d, J = 7.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 157.1, 154.8, 140.4, 133.8,
132.4, 128.8, 128.7, 128.7, 128.7, 1n28.5, 128.5, 126.4, 126.3, 126.1, 125.3, 124.0, 123.9, 116.2, 116.1, 115.9, 114.9, 114.7, 39.7,
34.8. HRMS (ESI) m/z: [M]+: Calcd for C15H15FN 228.1188, Found: 228.1199. Spectral data match those previously reported.26
2ꢀstyrylaniline (S2c) was prepared following general procedure for reduction of nitro group (S1c) to give 86% of the title comꢀ
1
pound (E:Z = 0.7:1) as a dark oil. Rf = 0.44 (hexanes/EtOAc 10:1). H NMR (400 MHz, CDCl3) δ 7.68 (dd, J = 8.1, 0.9 Hz, 1H),
7.64 – 7.58 (m, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.45 (dd, J = 7.7, 1.6 Hz, 2H), 7.41 – 7.25 (m, 6H), 7.18 (d, J = 16.1 Hz, 1H), 7.01 (t,
J = 7.5 Hz, 1H), 6.92 – 6.85 (m, 1H), 6.85 – 6.78 (m, 3H), 6.68 (d, J = 12.1 Hz, 1H), 3.84 (s, 4H). 13C NMR (101 MHz, CDCl3) δ
144.0, 143.7, 137.5, 136.6, 131.5, 130.0, 129.5, 128.7, 128.7, 128.7, 128.6, 128.6, 128.4, 128.2, 127.5, 127.4, 127.1, 126.4, 126.4,
124.2, 123.6, 123.0, 119.0, 118.3, 116.2, 115.4. HRMS (ESI) m/z: [M]+: Calcd for C14H14N 196.1126, Found: 196.1141. Spectral
data match those previously reported.26
2ꢀ(pentꢀ1ꢀenꢀ1ꢀyl)aniline (S2d) was prepared following general procedure for reduction of nitro group (S1d) to give 88% of the title
compound (E:Z = 1:2) as a light brown oil. Rf = 0.44 (hexanes/EtOAc 10:1). 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.28 (m, 1H),
7.21 – 7.04 (m, 1H), 6.90 – 6.65 (m, 1H), 6.54 – 6.42 (m, 1H), 6.35 (d, J = 11.3 Hz, 1H), 6.14 (dtd, J = 9.1, 6.9, 2.2 Hz, 1H), 5.85
(dtd, J = 9.5, 7.4, 2.1 Hz, 1H), 3.71 (s, 1H), 2.38 – 2.05 (m, 1H), 1.66 – 1.40 (m, 1H), 1.21 – 0.85 (m, 2H). 13C NMR (101 MHz,
CDCl3) δ 144.0, 143.4, 134.8, 133.1, 129.8, 128.0, 127.9, 127.4, 125.5, 125.0, 124.5, 123.4, 119.0, 118.0, 116.0, 115.6, 115.1, 35.6,
30.7, 23.0, 22.7, 13.9, 13.8. HRMS (ESI) m/z: [M]+: Calcd for C11H16N 162.1282, Found: 162.1295. Spectral data match those preꢀ
viously reported.26
General procedure for formamide preparation: A solution of oꢀalkenylaniline (1 equiv) and ethyl formate (8 equiv) in anhyꢀ
drous THF was added dropwise to a suspension of NaH (60% in mineral oil, 2.2 equiv) in anhydrous THF at 0 °C. Upon complete
addition the mixture was stirred at room temperature for 24 h, then the reaction was quenched with cold water. The solvents were
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removed under reduced pressure, and the residue was dissolved in ethyl acetate/water (5/1). The aqueous phase was extracted with
ethyl acetate (3 x 20 mL), the combined organic extracts were dried over anhydrous Na2SO4 and evaporated. The residue was
washed thoroughly with hexane (3 x 30 mL) and dried in vacuo to yield the desired formylamine, which was used in the following
step without further purification.
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General procedure for Suzuki reactions: To a solution of boronic acid (1.5 equiv), Pd(PPh3)4 (10 mol%) and K2CO3 (4 equiv) in
toluene, absolute ethanol, and water (5:2:1) was added Nꢀ(2ꢀhalophenyl)formamide (1 equiv). The mixture was then purged with N2
and refluxed for 24 h. The reaction was then cooled to room temperature and 20 mL of H2O were added and the resulting phases
were separated. The resulting aqueous phase was extracted with 3 x 10 mL ethyl acetate. The resulting organic phases were then
washed with water (1 x 20 mL) followed by a saturated solution of brine (1 x 20 mL). The resulting organic phase was then dried
using Na2SO4 and filtered. The solvent was removed under reduced pressure and the crude product was purified using flash chroꢀ
matography on silica gel (nꢀhexane/EtOAc 5:1 as eluent) to give the desired products which were used in the next step without
further purification.
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General procedure for dehydration of formamide to isonitrile: To a solution of Nꢀformyl amide (0.1 mmol, 1 equiv) in anhyꢀ
drous CH2Cl2 was added at 0 °C diisopropylamine (2.5 equiv), then dropwise over a period of 5 min POCl3 (1.5 equiv) was added.
The mixture was stirred at 0 °C for 2 h, then a saturated solution of Na2CO3 (2 mL) was added slowly. The mixture was transferred
into a separatory funnel, diluted with CH2Cl2 (20 mL), the organic phase was washed with a saturated solution of Na2CO3 (10 mL)
and brine (10 mL), then dried over anhydrous Na2SO4 and evaporated. The crude product was purified by flash chromatography
(Hexanes:EtOAc, 10:1) to give the desired oꢀalkenylarylisonitrile.
Procedure for preparation of ethylꢀ3ꢀ(2ꢀisocyanophenyl)acrylate (1e): To a one neck round bottom flask was added a magnetic stir
bar, 2ꢀiodoaniline (9.636 g, 44 mmol), ethyl acrylate (17.6 g, 176 mmol), Pd(OAc)2 (1 g, 4.45 mmol), P(oꢀtolyl)3 (2.7 g, 8.9 mmol),
triethylamine (15 mL), and CH3CN. The mixture was then purged with N2 and refluxed for 24 h. The mixture was then cooled to
room temperature and 20 mL of H2O were added and the resulting phases were separated. The resulting aqueous phase was extractꢀ
ed with 3 x 10 mL ethyl acetate. The resulting organic phases were then washed with water (1 x 20 mL) followed by a saturated
solution of brine (1 x 20 mL). The resulting organic phase was then dried using Na2SO4 and filtered. The solvent was removed unꢀ
der reduced pressure and the crude product was purified using flash chromatography on silica gel (nꢀhexane/EtOAc, 10:1 as eluent)
to give the desired aniline (87%) as a dark yellow oil. Formylation was followed by subsequent dehydration of the aniline according
to the general method for dehydration of formamide described above to yield 1f (200 mg, 63%) as a light brown oil. 1H NMR (400
MHz, CDCl3) δ 7.94 (d, J = 16.1 Hz, 1H), 7.77 – 7.56 (m, 1H), 7.50 – 7.31 (m, 1H), 6.51 (d, J = 16.0 Hz, 1H), 4.27 (q, J = 7.1 Hz,
1H), 1.41 – 1.25 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 168.9, 166.1, 137.7, 130.9, 130.8, 129.7, 127.8, 127.0, 122.6, 77.5, 77.2,
76.9, 61.0, 14.4. HRMS (ESI) m/z: [M]+: Calcd for C12H11NO2 201.0790, Found: 201.0796. Spectral data match those previously
reported.26
Procedure for preparation of 3ꢀ(2ꢀaminophenyl)propꢀ2ꢀenꢀ1ꢀol: To a flame dried round bottom flask was added ethyl 3ꢀ(2ꢀ
aminophenyl)acrylate (3.06 g, 16 mmol), magnetic stirꢀbar and dry THF (20 mL). The resulting mixture was placed into an ice bath
under an inert atmosphere of N2. To the resulting solution was added drop wise diꢀisobutyl aluminium hydride (37 mL, 1M in
THF). The resulting mixture was stirred for 8 h under N2 and was monitored by TLC. Upon completion of the reaction, MeOH and
H2O were added (10 mL each) and to the mixture was stirred for another 2 h. The resulting mixture was then filtered and the resultꢀ
ing phases were separated. The aqueous phase was extracted with 3 x 10 mL of ethyl acetate. The resulting organic phases were
then washed with water (1 x 20 mL) followed by a saturated solution of brine (1 x 20 mL). The resulting organic phase was then
dried using Na2SO4 and filtered. The solvent was removed under reduced pressure and the crude product was purified using flash
chromatography on silica gel (nꢀhexane/EtOAc 6:1 as eluent) to give the desired alcohol (87%) as a yellow oil. 1H NMR (400
MHz, CDCl3) δ 7.24 (dd, J = 7.7, 1.1 Hz, 1H), 7.08 (td, J = 7.9, 1.4 Hz, 1H), 6.84 – 6.72 (m, 1H), 6.70 – 6.57 (m, 2H), 6.17 (dt, J =
15.7, 5.3 Hz, 1H), 4.23 (d, J = 5.4 Hz, 2H), 3.87 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 143.6, 130.2, 128.5, 127.2, 125.9, 123.2,
119.1, 116.4, 77.5, 77.2, 76.9, 63.2. HRMS (ESI): Calcd for [2M + Na]+: Calcd for C18H22N2O2Na 321.1413, Found: 321.1399.
Spectral data match those previously reported.26
Procedure for preparation of 2ꢀ(3ꢀmethoxypropꢀ1ꢀenꢀ1ꢀyl)aniline (S2a’): 3ꢀ(2ꢀaminophenyl)propꢀ2ꢀenꢀ1ꢀol (0.110g, 0.737 mmol)
was treated with NaH (0.02 g, 0.8 mmol) in dry THF (10 mL). This solution was allowed to stir in an ice bath for 30 min. Then,
MeI (0.115 g, 0.81 mmol) was added to the solution. The reaction was stirred for 1 h and was monitored by TLC. Upon completion,
5 mL of water was added. The aqueous phase was separated and washed with ethyl acetate (1 x 20 mL). The organic phases were
collected and washed with water (1 x 20 mL) followed by saturated solution of brine (1 x 20 mL). The organic phases were separatꢀ
ed and dried using Na2SO4 and filtered. The solvent was removed under reduced pressure and the crude product was purified using
flash chromatography on silica gel (nꢀhexane/EtOAc, 10:1 as eluent) to give the desired 2ꢀ(3ꢀmethoxypropꢀ1ꢀenꢀ1ꢀyl)aniline (60%)
as a crème colored oil. 1H NMR (400 MHz, CDCl3) δ 7.27 (dd, J = 7.7, 1.4 Hz, 1H), 7.14 – 7.03 (m, 1H), 6.76 (ddd, J = 7.6, 1.1,
0.6 Hz, 1H), 6.72 – 6.54 (m, 1H), 6.17 (dt, J = 15.8, 6.0 Hz, 1H), 4.10 (dd, J = 6.0, 1.5 Hz, 1H), 3.75 (s, 1H), 3.41 (s, 1H). 13C NMR
(101 MHz, CDCl3) δ 143.9, 128.7, 128.1, 127.5, 127.5, 123.0, 118.9, 116.1, 77.5, 77.2, 76.9, 73.3, 58.0. HRMS (ESI) m/z: [M]+:
Calcd for C10H13NO 163.0997, found 163.1003. Spectral data match those previously reported.26
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Procedure for preparation of 1ꢀisocyanoꢀ2ꢀ(3ꢀmethoxypropꢀ1ꢀenꢀ1ꢀyl)benzene (1a’): Corresponding aniline was transformed into
the desired isonitrile via formamidation and dehydration following the general procedures above to give 73% (67 mg) of 1a’ as a
light brown oil. Rf = 0.44 (hexanes/EtOAc 10:1). 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H),
7.45 – 7.33 (m, 2H), 6.94 (d, J = 15.9 Hz, 1H), 6.40 (dt, J = 15.9, 5.8 Hz, 1H), 4.25 – 4.03 (m, 2H), 3.42 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 168.4, 133.3, 130.9, 129.5, 128.3, 127.3, 126.2, 77.5, 76.9, 72.9, 58.4, 29.8. HRMS (ESI) m/z: [M]+:Calcd for
C11H11NO 173.0841, found 173.0850. Spectral data match those previously reported.26
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1ꢀIsocyanoꢀ2ꢀ(3ꢀphenylpropꢀ1ꢀenꢀ1ꢀyl)benzene was prepared following the general procedure for formamidation and dehydration
to provide (1a): 240 mg, 75% (E:Z = 1:3); 1H NMR (400 MHz, Chloroformꢀd) δ 7.50 – 7.23 (m, 12H), 6.87 (dd, J = 15.7, 1.8 Hz,
0.3H), 6.76 (d, J = 11.5 Hz, 1H), 6.53 (dt, J = 15.8, 7.1 Hz, 0.3H), 6.17 (dt, J = 11.5, 7.6 Hz, 1H), 3.68 (d, J = 7.1 Hz, 0.6H), 3.64
(d, J = 7.6 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 166.6, 139.8, 139.3, 134.1, 134.0, 133.9, 129.7, 129.3, 129.0, 128.7, 128.6,
128.5, 128.3, 128.1, 127.9, 127.7, 127.1, 127.0, 126.5, 126.3, 126.3, 126.3, 126.2, 125.8, 125.1, 125.0, 39.6, 34.7. Spectral data
match those previously reported.26
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2ꢀ(3,3ꢀdimethylbutꢀ1ꢀenꢀ1ꢀyl)ꢀ1ꢀisocyanoꢀ4ꢀmethylbenzene was prepared following the general procedure for formamidation, Suꢀ
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zuki coupling and dehydration to yield (1a’’): 205 mg, 72%; H NMR (400 MHz, Chloroformꢀd) δ 7.38 – 7.32 (m, 1H), 7.20 (s,
1H), 7.06 – 6.91 (m, 1H), 6.60 (d, J = 16.2 Hz, 1H), 6.36 (d, J = 16.1 Hz, 1H), 2.36 (s, 3H), 1.17 (s, 9H). 13C NMR (101 MHz,
CDCl3) δ 165.9, 146.1, 139.5, 134.3, 133.8, 128.2, 126.9, 126.2, 119.3, 34.0, 29.5, 21.5. HRMS (ESI) m/z: [M]+: Calcd for
C14H17NNa 222.1257, found 222.1253.43
3ꢀ(2ꢀisocyanophenyl)ꢀ1Hꢀindene was prepared following the general procedure for formamidation, Suzuki coupling and dehydraꢀ
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tion to yield (1j): 103 mg, 50%; H NMR (600 MHz, Chloroformꢀd) δ 7.59 – 7.56 (m, 1H), 7.54 (ddd, J = 8.0, 6.7, 1.4 Hz, 2H),
7.49 (tt, J = 7.6, 1.2 Hz, 1H), 7.40 (td, J = 7.7, 1.5 Hz, 1H), 7.34 – 7.27 (m, 3H), 6.79 (s, 1H), 3.63 (s, 2H). 13C NMR (151 MHz,
CDCl3) δ 155.6, 143.7, 140.1, 134.8, 133.4, 130.1, 129.4, 128.5, 128.0, 126.3, 125.3, 124.3, 120.3, 38.9. Spectral data match those
previously reported.26
4ꢀ(2ꢀisocyanophenyl)ꢀ3,6ꢀdihydroꢀ2Hꢀpyran was prepared following the general procedure for formamidation, Suzuki coupling and
dehydration to yield (1i): 125 mg, 65%; 1H NMR (400 MHz, Chloroformꢀd) δ 7.22 (d, J = 7.9 Hz, 1H), 7.04 (m, 2H), 5.87 (s, 1H),
4.28 (q, J = 2.8 Hz, 2H), 3.89 (t, J = 5.4 Hz, 2H), 2.52 – 2.39 (m, 2H), 2.32 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 165.9, 139.7,
139.0, 132.4, 129.4, 128.5, 127.4, 127.3, 65.3, 64.2, 28.4, 21.2. HRMS (ESI) m/z: [M]+: Calcd for C13H13NNaO 222.0897, found
222.0895.
1ꢀIsocyanoꢀ2ꢀstyrylbenzene was prepared following the general procedure for formamidation and dehydration to provide (1c): 98
mg, 76% (E:Z = 0.7:1); 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.46 – 7.13 (m, 15H), 6.83
(d, J = 12.2 Hz, 1H), 6.68 (d, J = 12.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 167.2, 166.7, 136.4, 136.1, 134.5, 133.7, 133.6,
132.6, 130.0, 129.4, 128.8, 128.8, 128.8, 128.6, 128.3, 128.3, 128.3, 128.0, 128.0, 127.7, 127.2, 127.0, 126.9, 125.4, 124.5, 122.0,
49.0, 49.0, 21.6, 21.5. HRMS (ESI) m/z: [M]+: Calcd for C15H11N 205.0891, Found: 205.0844. Spectral data match those previously
reported.26
1ꢀIsocyanoꢀ2ꢀ(pentꢀ1ꢀenꢀ1ꢀyl)benzene was prepared following the general procedure for formamidation and dehydration to provide
(1d): 130 mg, 81% (E:Z = 1:2); 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.0 Hz, 1H), 7.33 (dd, J = 6.8, 2.5 Hz, 1H), 7.31 – 7.26
(m, 1H), 7.26 – 7.14 (m, 1H), 6.67 (d, J = 15.8 Hz, 1H), 6.50 (dd, J = 11.6, 1.5 Hz, 1H), 6.34 (dt, J = 15.7, 7.0 Hz, 1H), 5.88 (dt, J
= 11.6, 7.4 Hz, 1H), 2.21 (dqd, J = 22.2, 7.3, 1.5 Hz, 1H), 1.57 – 1.39 (m, 1H), 0.92 (dt, J = 24.1, 7.4 Hz, 1H). 13C NMR (101 MHz,
CDCl3) δ 166.5, 166.3, 136.4, 135.7, 134.5, 134.2, 129.8, 129.2, 128.8, 127.4, 127.3, 126.9, 126.7, 125.6, 124.0, 123.8, 35.3, 30.7,
22.7, 22.3, 13.7, 13.7. HRMS (ESI) m/z: [M]+: Calcd for C12H13N 171.1048, Found: 171.1061. Spectral data match those previously
reported.26
1ꢀIsocyanoꢀ4ꢀmethylꢀ2ꢀ(3ꢀphenylpropꢀ1ꢀenꢀ1ꢀyl)benzene was prepared following the general procedure for formamidation, Suzuki
coupling and dehydration to yield (1f): 120 mg, 59%; 1H NMR (600 MHz, CDCl3) δ 7.35 – 7.29 (m, 1H), 7.26 – 7.18 (m, 1H), 7.00
(dd, J = 8.1, 1.0 Hz, 1H), 6.76 (d, J = 15.7 Hz, 1H), 6.44 (dt, J = 15.7, 7.1 Hz, 1H), 3.60 (d, J = 7.1 Hz, 1H), 2.32 (s, 1H). 13C NMR
(151 MHz, CDCl3) δ 139.6, 139.5, 133.6, 133.6, 128.7, 128.7, 128.7, 128.6, 126.9, 126.5, 126.3, 125.2, 39.7, 21.7. HRMS (ESI)
m/z: [M]+: Calcd for C17H15N 233.1204, Found: 233.1216. Spectral data match those previously reported.26
4ꢀFluoroꢀ1ꢀisocyanoꢀ2ꢀ(3ꢀphenylpropꢀ1ꢀenꢀ1ꢀyl)benzene was prepared following the general procedure for formamidation and deꢀ
hydration to provide (1b): 313 mg, 56%, (E:Z = 1:3); 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.4 Hz, 1H), 7.49 – 7.23 (m, 12H),
6.93 – 6.82 (m, 1H), 6.76 (d, J = 11.5 Hz, 1H), 6.55 (t, J = 11.4 Hz, 1H), 6.17 (dt, J = 11.5, 7.6 Hz, 1H), 3.68 (d, J = 7.1 Hz, 1H),
3.64 (d, J = 7.6 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 166.6, 139.8, 139.3, 134.1, 134.0, 129.7, 129.3, 129.0, 128.7, 128.6, 128.5,
128.3, 128.1, 127.9, 127.7, 127.1, 127.0, 126.5, 126.3, 126.2, 125.8, 125.1, 125.0, 77.5, 77.2, 76.9, 34.7. HRMS (ESI) m/z: [M]+:
Calcd for C15H12FN 237.0952, Found: 237.0960. Spectral data match those previously reported.26
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Ethyl (E)ꢀ5ꢀchloroꢀ2ꢀisocyanoꢀ3ꢀ(3ꢀphenylpropꢀ1ꢀenꢀ1ꢀyl)benzoate was prepared following the general procedure for
formamidation, Suzuki coupling and dehydration to yield (1g): 87 mg, 77%; 1H NMR (600 MHz, Chloroformꢀd) δ 7.83 (d, J = 2.4
Hz, 1H), 7.50 (dd, J = 2.4, 0.6 Hz, 1H), 7.37 (d, J = 1.0 Hz, 1H), 7.32 (t, J = 7.7 Hz, 2H), 7.25 (d, J = 7.9 Hz, 1H), 6.56 (d, J = 15.8
Hz, 1H), 6.27 (dt, J = 15.8, 7.0 Hz, 1H), 4.46 (q, J = 7.2 Hz, 3H), 3.71 (d, J = 7.0 Hz, 1H), 1.45 (t, J = 7.2 Hz, 4H). 13C NMR (151
MHz, CDCl3) δ 173.7, 163.4, 140.7, 136.7, 135.1, 133.9, 133.3, 129.5, 129.3, 128.9, 128.7, 127.9, 126.5, 124.4, 62.5, 35.9, 14.2.
HRMS (ESI) m/z: [M]+: Calcd for C19H16ClNNaO2 348.0767, found 348.0761.
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1ꢀIsocyanoꢀ2ꢀ(3ꢀphenylpropꢀ1ꢀenꢀ1ꢀyl)naphthalene was prepared following the general procedure for formamidation, Suzuki couꢀ
pling and dehydration to yield (1h): 110 mg, 79%; 1H NMR (600 MHz, Chloroformꢀd) δ 8.17 (dd, J = 8.5, 1.0 Hz, 1H), 7.88 – 7.80
(m, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.69 – 7.60 (m, 2H), 7.54 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.38 (dd, J = 8.0, 7.2 Hz, 2H), 7.34 –
7.27 (m, 3H), 7.08 (d, J = 15.7 Hz, 1H), 6.63 (dt, J = 15.7, 7.1 Hz, 1H), 3.71 (dd, J = 7.1, 1.5 Hz, 2H). 13C NMR (151 MHz, CDCl3)
δ 170.3, 139.3, 134.8, 132.4, 131.7, 129.2, 128.8, 128.7, 128.7, 128.3, 128.2, 128.1, 127.0, 126.5, 125.7, 123.3, 122.3, 39.8. HRMS
(ESI) m/z: [M]+: Calcd for C20H16N 270.1282, found 270.1297.
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General Procedure for the Mn(III) Mediated Radical Cyclization with boronic acids and o-alkenylisonitriles: To an ovenꢀ
dried 10 mL single neck round bottom flask, isonitrile (0.2 mmol), boronic acid (0.3 mmol), Mn(acac)3 (0.6 mmol) and dry toluene
(4.0 mL) were added sequentially under an atmosphere of nitrogen. The mixture was stirred at 90 °C and monitored by TLC for 4 h
or until completion under an atmosphere of nitrogen. The reaction mixture was then allowed to cool to room temperature and diꢀ
rectly purified by column chromatography on silica gel to afford the desired products.
2ꢀPhenylquinoline (2a):
35 mg, 86%; 1H NMR (600 MHz, CDCl3) δ 8.25 – 8.15 (m, 4H), 7.88 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.74 (t, J = 7.6
Hz, 1H), 7.59 – 7.51 (m, 3H), 7.48 (t, J = 7.3 Hz, 1H). 13C NMR (151 MHz, CDCl3) δ 157.5, 148.4, 139.8, 136.9, 129.9, 129.8,
129.5, 129.0, 127.7, 127.6, 127.3, 126.4, 119.2. Spectral data match those previously reported.26
6ꢀPhenylꢀ7Hꢀindeno[2,1ꢀc]quinoline (2t):
42 mg, 72%; 1H NMR (600 MHz, CDCl3) δ 8.76 (d, J = 8.3 Hz, 1H), 8.49 (d, J = 7.8 Hz, 1H), 8.32 (d, J = 8.3 Hz, 1H), 7.94 (d, J =
7.3 Hz, 1H), 7.78 (t, J = 7.5 Hz, 1H), 7.69 (dd, J = 10.9, 7.6 Hz, 1H), 7.52 (ddd, J = 17.6, 14.4, 7.5 Hz, 3H), 4.18 (s, 1H). 13C NMR
(151 MHz, CDCl3) δ 156.5, 148.5, 145.7, 145.2, 141.0, 140.6, 134.5, 130.9, 129.0, 128.9, 128.9, 128.8, 128.4, 127.5, 126.8, 125.3,
124.5, 124.1, 123.6, 37.9. HRMS (ESI) m/z: [M]+: Calcd for C22H16N 294.1282, Found: 294.1298. Spectral data match those previꢀ
ously reported.26
9ꢀmethylꢀ5ꢀphenylꢀ1,4ꢀdihydroꢀ2Hꢀpyrano[3,4ꢀc]quinoline (2u):
31 mg, 57%; 1H NMR (400 MHz, Chloroformꢀd) δ 8.05 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 1.0 Hz, 1H), 7.61 – 7.40 (m, 6H), 4.75 (s,
2H), 4.15 (t, J = 5.8 Hz, 2H), 3.31 – 3.17 (m, 2H), 2.58 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 156.6, 136.7, 131.4, 129.9, 129.0,
128.7, 128.6, 128.6, 128.5, 128.5, 126.4, 126.3, 121.4, 67.2, 64.7, 25.1, 22.1. HRMS (ESI) m/z: [M]+: Calcd for C19H17NNaO
298.1210, found 298.1212
8ꢀmethylꢀ2ꢀphenylꢀ4,5ꢀdihydroꢀ7Hꢀoxepino[5,4,3ꢀde]quinoline (2u’): 2 mg, 9%; 1H NMR (600 MHz, Chloroformꢀd) δ 7.62 – 7.58
(m, 1H), 7.58 – 7.40 (m, 3H), 5.28 (s, 1H), 3.95 (t, J = 5.4 Hz, 1H), 2.94 – 2.82 (m, 1H), 2.57 (s, 1H). HRMS (ESI): Calcd for
C19H18NO 276.1388, found 276.1392. We were unable to obtain 13CNMR do to the inseparable mixture with 2u and low quantity.
3ꢀBenzylideneꢀ2ꢀPhenylindoline (2v):
38 mg, 68%; 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.36 (d, J = 7.4 Hz, 3H), 7.28 (d, J = 8.1 Hz, 1H), 7.18 (dd, J = 6.2, 2.5
Hz, 2H), 7.08 (t, J = 6.3 Hz, 6H), 6.96 (t, J = 7.5 Hz, 1H), 6.62 (t, J = 7.6 Hz, 1H), 5.32 (s, 1H). 13C NMR (101 MHz, CDCl3) δ
145.6, 135.9, 133.4, 129.4, 129.2, 128.5, 128.3, 128.0, 127.8, 125.7, 122.0, 122.0, 121.1, 119.4, 114.9, 110.4, 50.0. HRMS (EI):
Calcd for C22H16N 294.1282, Found: 294.1298. Spectral data match those previously reported.26
3ꢀButylꢀ2ꢀPhenylꢀ1Hꢀindole (2w):
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14 mg, 28%; H NMR (600 MHz, CDCl3) δ 8.01 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.56 (dd, J = 8.1, 1.0 Hz, 2H), 7.47 (t, J = 7.7
Hz, 3H), 7.39 – 7.36 (m, 2H), 7.22 – 7.18 (m, 1H), 7.16 – 7.12 (m, 1H), 2.94 – 2.83 (m, 2H), 1.72 (dt, J = 15.4, 7.7 Hz, 2H), 1.48 –
1.38 (m, 3H), 0.93 (t, J = 7.4 Hz, 4H). 13C NMR (151 MHz, CDCl3) δ 138.9, 136.1, 134.2, 130.5, 129.5, 129.5, 129.0, 128.1, 127.6,
122.3, 119.6, 119.5, 114.3, 110.9, 33.4, 29.9, 24.5, 23.1. HRMS (ESI) m/z: [M]+: Calcd for C18H18N 248.1439, Found: 248.1452.
Spectral data match those previously reported.26
2ꢀ(4ꢀMethylphenyl)quinoline (2b):
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36 mg, 82%; 1H NMR (400 MHz, CDCl3): δ 2.36 (s, 3H), 7.25, (d, J = 8.3 Hz, 2H), 7.35ꢀ7.45, (m, 1H), 7.60ꢀ7.75, (m, 3H), 8.00ꢀ
8.05 (m, 3H), 8.15 (d, J = 4.4 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 21.1, 118.5, 125.8, 126.8, 127.2, 127.3, 128.0, 129.3, 129.4,
136.4, 136.6, 139.1, 148.0, 156.9. Spectral data match those previously reported.26
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2ꢀ(4ꢀFluorophenyl)quinoline (2c):
33 mg, 76%; 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.7 Hz, 1H), 8.20 – 8.14 (m, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.74 (ddd, J =
8.4, 6.9, 1.5 Hz, 1H), 7.54 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.22 (dd, J = 9.7, 7.8 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ = 163.8,
156.2, 148.2, 136.8, 135.8, 129.7, 129.4, 129.3, 127.4, 127.1, 126.3, 118.6, 115.7. Spectral data match those previously reported.26
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2ꢀ(Quinolinꢀ2ꢀyl)benzonitrile (2d):
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32 mg, 71%; H NMR (400 MHz, CDCl3) δ 8.33 – 8.24 (m, 2H), 8.21 – 8.12 (m, 1H), 7.91 – 7.84 (m, 1H), 7.82 – 7.73 (m, 3H),
7.70 – 7.66 (m, 1H), 7.59 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H). 13C NMR (CDCl3, 101 MHz) δ: 112.7, 118.5, 118.8, 127.1, 127.5, 128.0,
132.5, 137.2, 143.6, 148.2, 154.8. Spectral data match those previously reported.26
2ꢀ(3,5ꢀDimethoxyphenyl)quinoline (2e):
43 mg, 82%; 1H NMR (600 MHz, CDCl3) δ 8.22 (d, J = 8.6 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.87 – 7.81 (m, 2H), 7.76 – 7.71 (m,
1H), 7.54 (dd, J = 11.0, 3.9 Hz, 1H), 7.33 (d, J = 2.2 Hz, 2H), 6.59 (t, J = 2.2 Hz, 1H), 3.91 (s, 6H). 13C NMR (151 MHz, CDCl3) δ
161.3, 157.2, 148.3, 142.0, 136.9, 129.9, 129.8, 127.6, 127.5, 126.5, 119.3, 105.8, 101.8, 55.7. HRMS (ESI) calculated for
C17H15NO2Na [M + Na]+ m/z 288.0093, found 288.0103. Spectral data match those previously reported.26
2ꢀ(2ꢀThienyl)quinoline (2f):
1
29 mg, 68%; H NMR (400 MHz, CDCl3): δ 7.11ꢀ7.18 (m, 1H), 7.42ꢀ7.47 (m, 2H), 7.61ꢀ7.74 (m, 4H), 8.05 (d, J = 8.1 Hz, 1H),
8.07 (d, J = 7.5 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 117.1, 125.7, 125.9, 127.0, 127.4, 128.0, 128.5, 129.0, 129.7, 136.5,
145.2, 147.9, 152.2. Spectral data match those previously reported.26
2ꢀIsobutylquinoline (2g):
25 mg, 69%; 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.06 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.74 (dd, J = 8.2, 0.8 Hz, 1H),
7.44ꢀ7.40 (m, 1H), 7.67ꢀ7.63 (m, 1H), 7.20 (d, J = 8.4 Hz, 1H), 2.81 (d, J = 7.4 Hz, 2H), 2.20 (q, J = 6.8 Hz, 1H), 0.95 (s, 6H). 13
C
NMR (CDCl3, 101 MHz) δ: 162.2, 148.0, 135.9, 129.2, 128.9, 127.5, 126.7, 125.6, 122.0, 48.3, 29.4, 22.6. Spectral data match
those previously reported.26
2ꢀ(Naphthalenꢀ1ꢀyl)quinoline (2h):
1
34 mg, 68%; H NMR (CDCl3, 400 MHz) δ: 7.47 (t, J = 7.6 Hz, 1H), 7.52 (t, J = 6.9 Hz, 1H), 7.60 (t, J = 7.6 Hz, 2H), 7.72 (t, J
=6.8 Hz, 2H), 7.78 (t, J = 7.1 Hz, 1H), 7.91ꢀ7.96 (m, 3H), 8.14 (d, J = 8.4 Hz, 1H) , 8.23 (d, J = 8.3 Hz, 1H), 8.30 (d, J = 8.4 Hz,
1H); 13C NMR (CDCl3, 101 MHz) δ: 123.2, 125.3, 125.9, 126.5, 127.0, 127.5, 127.7, 128.4, 129.1, 129.7, 131.3. Spectral data
match those previously reported.26
2ꢀ(2ꢀBromophenyl)quinoline (2i):
1
44 mg, 78%; H NMR (400 MHz, CDCl3) δ 8.21 (dd, J = 16.3, 8.4 Hz, 2H), 7.88 (d, J = 8.1 Hz, 1H), 7.76 (ddd, J = 8.5, 6.9, 1.4
Hz, 1H), 7.71 (dd, J = 8.3, 1.8 Hz, 2H), 7.64 (dd, J = 7.6, 1.7 Hz, 1H), 7.62 – 7.56 (m, 1H), 7.46 (td, J = 7.4, 1.0 Hz, 1H), 7.31 (td,
J = 7.7, 1.7 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 158.9, 148.1, 141.8, 135.8, 133.4, 131.7, 130.1, 129.9, 129.8, 127.9, 127.7,
127.3, 127.2, 127.0, 122.9, 122.0, 120.0. Spectral data match those previously reported.26
2ꢀ(Pyridinꢀ4ꢀyl)quinoline (2j):
25 mg, 62%; 1H NMR (CDCl3, 400 MHz) δ: 8.80 (d, J = 5.7 Hz, 2H), 8.31 (d, J = 8.6 Hz, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.09 (d, J =
6.0 Hz, 2H), 7.93 (d, J = 8.6 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.76ꢀ7.80 (m, 1H), 7.61 (t, J = 7.5 Hz,1H). 13C NMR (CDCl3, 101
MHz) δ: 118.2, 121.4, 127.0, 127.4, 127.6, 129.8, 129.9, 137.0, 146.3, 148.1, 150.3, 154.1. Spectral data match those previously
reported.26
4ꢀ(6ꢀmethylquinolinꢀ2ꢀyl)benzaldehyde (2k):
36 mg, 77%; 1H NMR (600 MHz, Chloroformꢀd) δ 10.10 (s, 1H), 8.32 (d, J = 8.1 Hz, 2H), 8.17 (d, J = 8.5 Hz, 1H), 8.08 (d, J = 8.5
Hz, 1H), 8.04 – 7.98 (m, 2H), 7.87 (d, J = 8.5 Hz, 1H), 7.69 – 7.48 (m, 2H), 2.56 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 192.2,
154.9, 147.1, 145.4, 137.2, 136.6, 136.6, 132.5, 130.3, 129.7, 128.1, 127.7, 126.5, 119.1, 21.8. HRMS (ESI) m/z: [M]+: Calcd for
C17H14NO 248.1077, found 248.1081.
6ꢀFluoroꢀ2ꢀphenylquinoline (2l):
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38 mg, 86%; 1H NMR (600 MHz, CDCl3) δ 8.21 – 8.11 (m, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.50 (dddd, J = 21.6, 19.9, 9.1, 5.1 Hz,
1H). 13C NMR (151 MHz, CDCl3) δ 161.3, 156.9, 145.5, 139.5, 136.3, 132.4, 132.3, 129.6, 129.1, 127.9, 127.6, 120.1, 119.9, 110.7,
110.6. Spectral data match those previously reported.26
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6ꢀFluoroꢀ2ꢀ(4ꢀfluorophenyl)quinoline (2m):
36 mg, 76%; 1H NMR (600 MHz, CDCl3) δ 8.15 (ddd, J = 9.5, 7.6, 5.4 Hz, 3H), 7.85 (d, J = 8.6 Hz, 1H), 7.53 – 7.48 (m, 1H), 7.44
(dd, J = 8.7, 2.8 Hz, 1H), 7.25 – 7.18 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 164.8, 163.2, 161.4, 159.7, 155.8, 145.5, 136.4,
136.4, 135.7, 132.3, 132.2, 129.5, 129.4, 127.8, 127.7, 120.2, 120.1, 119.5, 116.1, 115.9, 110.7, 110.6. Spectral data match those
previously reported.26
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6ꢀFluoroꢀ2ꢀ(pꢀtolyl)quinoline (2n):
39 mg, 82%; 1H NMR (600 MHz, CDCl3) δ 8.15 (dt, J = 4.9, 2.8 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.49
(td, J = 8.8, 2.8 Hz, 1H), 7.43 (dd, J = 8.8, 2.8 Hz, 1H), 7.34 (dd, J = 7.9, 0.5 Hz, 1H), 2.44 (s, 1H). 13C NMR (151 MHz, CDCl3) δ
145.5, 139.7, 136.7, 136.2, 132.3, 132.2, 129.8, 129.8, 127.8, 127.5, 120.0, 119.8, 119.7, 110.7, 110.5, 21.5. Spectral data match
those previously reported.26
6ꢀMethylꢀ2ꢀphenylquinoline (2o):
37 mg, 85%; 1H NMR (600 MHz, CDCl3) δ 8.14 (dd, J = 7.9, 4.1 Hz, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.59
(s, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.46 (d, J = 7.0 Hz, 1H), 7.42 (d, J = 3.7 Hz, 1H), 2.55 (s, 1H). 13C NMR
(151 MHz, CDCl3) δ 136.3, 132.1, 129.6, 129.3, 129.2, 129.0, 128.0, 128.0, 127.6, 127.4, 126.5, 125.7, 119.2, 21.8. Spectral data
match those previously reported.26
6ꢀMethylꢀ2ꢀ(pꢀtolyl)quinoline (2p):
1
39 mg, 83%; H NMR (600 MHz, CDCl3) δ 8.11 (d, J = 8.6 Hz, 1H), 8.05 (d, J = 8.0 Hz, 3H), 7.82 (d, J = 8.6 Hz, 1H), 7.57 (s,
1H), 7.55 (dd, J = 8.6, 1.7 Hz, 1H), 7.32 (d, J = 8.2 Hz, 2H), 2.54 (s, 3H), 2.43 (s, 4H). 13C NMR (151 MHz, CDCl3) δ 156.7, 147.0,
139.3, 137.1, 136.1, 136.1, 132.0, 129.7, 129.5, 127.5, 127.3, 126.5, 119.0, 21.8, 21.7. Spectral data match those previously reportꢀ
ed.26
Ethyl 6ꢀchloroꢀ2ꢀ(4ꢀmethoxyphenyl)quinolineꢀ8ꢀcarboxylate (2q):
46 mg, 67%; 1H NMR (600 MHz, Chloroformꢀd) δ 8.20 (d, J = 8.5 Hz, 1H), 8.11 (s, 1H), 7.95 (m, 1H), 7.88 (d, J = 2.4 Hz, 1H),
7.03 (d, J = 8.4 Hz, 1H), 4.57 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 1.51 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 167.1,
161.6, 157.3, 143.8, 136.2, 131.3, 130.8, 129.4, 129.2, 129.2, 127.9, 119.5, 114.4, 62.0, 55.6, 14.6. IR cmꢀ1: 3070, 2927, 1721,
1612, 1440, 1322, 1290, 1101, 769, 795. HRMS (ESI) m/z: [M]+: Cald for C19H17ClNO3 342.0897, found 342.0890; mp: 179ꢀ184◦C
2ꢀ(2ꢀbromophenyl)benzo[h]quinoline (2s):
53 mg, 80%; 1H NMR (600 MHz, Chloroformꢀd) δ 9.41 (d, J = 7.3 Hz, 1H), 8.23 (d, J = 8.2 Hz, 4H), 7.98 – 7.91 (m, 4H), 7.89 (d,
J = 8.2 Hz, 2H), 7.85 (d, J = 8.8 Hz, 4H), 7.81 (ddd, J = 7.6, 1.8, 0.8 Hz, 4H), 7.79 – 7.67 (m, 18H), 7.50 (tt, J = 7.5, 1.1 Hz, 4H),
7.33 (dddd, J = 8.1, 7.3, 1.7, 0.9 Hz, 4H). 13C NMR (151 MHz, CDCl3) δ 157.0, 146.3, 141.9, 135.6, 133.9, 133.7, 132.4, 131.8,
129.9, 128.4, 128.1, 127.9, 127.8, 127.2, 125.3, 125.2, 125.0, 123.2, 122.2. HRMS (ESI) m/z: [M]+ Calcd for C19H13BrN 334.0231,
found 334.0227.
6ꢀfluoroꢀ2ꢀ(perfluorohexyl)quinoline (F1):
34 mg, 37%; 1H NMR (400 MHz, Chloroformꢀd) δ 8.31 (d, J = 8.7 Hz, 1H), 8.27 (dd, J = 9.3, 5.3 Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H),
7.61 (td, J = 8.7, 2.8 Hz, 1H), 7.53 (dd, J = 8.5, 2.9 Hz, 1H). 13C NMR (151 MHz, Chloroformꢀd) δ 162.5, 160.8, 144.5, 137.0 (d, J
= 6.4 Hz), 133.0 (d, J = 9.6 Hz), 128.8 (d, J = 18.5 Hz), 121.3 (d, J = 25.9 Hz), 119.0, 110.6 (d, J = 21.9 Hz). 19F NMR (376 MHz,
Chloroformꢀd) δ ꢀ80.8 (t, J = 10.1 Hz, 3F), ꢀ108.6 – ꢀ110.1 (m, 1F), ꢀ113.4 (t, J = 13.8 Hz, 2F), ꢀ121.4 (dt, J = 33.3, 14.4 Hz, 3F), ꢀ
122.3 – ꢀ123.3 (m, 3F), ꢀ126.1 (t, J = 16.0 Hz, 2F). HRMS (ESI) m/z: [M]+: Calcd for C15H5F14N 465.0196, found 465.0196.
6ꢀmethylꢀ2ꢀ(trifluoromethyl)quinoline (F2):
23 mg, 54%; 1H NMR (400 MHz, Chloroformꢀd) δ 8.25 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 9.3 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.68
– 7.62 (m, 2H). HRMS (ESI) m/z: [M]+: Calcd for C11H9F3 212.0689, found: 212.0687. Spectral data matched literature.44
ASSOCIATED CONTENT
Supporting Information
This material is available free of charge on the ACS Publications website at http://pubs.acs.org. Compound characterization data (PDF),
crystallographic data of 2s (CIF), geometries and energies of all computed structures.
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AUTHOR INFORMATION
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Corresponding Author
*alabugin@chem.fsu.edu
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§C.J.E and G.d.P.G. contributed equally to this work. All authors have given approval to the final version of the manuscript.
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ACKNOWLEDGMENT
This study was supported by the National Science Foundation (Grant CHEꢀ1465142). We are also grateful to NSF XSEDE (TGꢀ
CHE160006) and RCC FSU for computational resources. G.d.P.G. is grateful to IBM for the 2016 IBM Ph.D Scholarship.
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5ꢀexoꢀcyclizations of oꢀalkenylarylisocyanides: (a) Zhang, B.; Studer, A. Org. Lett. 2014, 16, 1216. (b) Mitamura, T.; Iwata, K.; Ogawa, A. J.
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