Regioselectivity in the nucleophile trapping of arynes: The electronic and steric effects of nucleophiles and substituents

Article abstract of DOI:10.1021/ol403237z

The regioselectivity in nucleophile trapping is investigated with arynes generated directly from bis-1,3-diynes. The regioselectivity is profoundly influenced by not only the nature of nucleophiles but also the substituents on the arynes, which is the con

Full text of DOI:10.1021/ol403237z

Letter
pubs.acs.org/OrgLett
Regioselectivity in the Nucleophile Trapping of Arynes: The
Electronic and Steric Effects of Nucleophiles and Substituents
Rajdip Karmakar, Sang Young Yun, Kung-Pern Wang, and Daesung Lee*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, United States
S
* Supporting Information
ABSTRACT: The regioselectivity in nucleophile trapping is
investigated with arynes generated directly from bis-1,3-diynes.
The regioselectivity is profoundly influenced by not only the
nature of nucleophiles but also the substituents on the arynes,
which is the consequence of both the unfavorable steric
interaction between the incoming nucleophile and the nearby
substituent and the inherent electronic bias induced by
different substituents on the arynes.
Scheme 1. Reactions of an Aryne with and without Catalyst
variety of new addition reactions of arynes have been
1
Areported in the literature recently. Although they show
high reactivity toward nucleophiles due to their low-lying
LUMO,2 arynes have only been engaged in a relatively small
number of useful reactions under traditional settings. This is
mainly because of the limited availability of suitably function-
alized precursors and a lack of efficiency in consumption of the
resultant aryne intermediates. The development of protocols
relying on the fluoride-induced 1,2-elimination of 1-trimethyl-
silyl-2-aryl triflate has significantly relieved these limitations.3
Alternatively, cycloaddition-based formation of arynes has
emerged in the investigations by Ueda,4 and Johnson,5 which
was further extended by Hoye as the hexadehydro Diels−Alder
reaction.6
Recently, we also took advantage of the hexadehydro Diels−
Alder reaction of bis-1,3-diynes to generate arynes7 and used
them for an intramolecular ene reaction7b,8 to generate various
benzo-fused carbo- and heterocyclic products (Scheme 1). We
also achieved alkane C−H functionalization by using these
aryne species in the presence of silver salts (AgOTf or AgSbF6)
as catalysts.7a Employing stoichiometric amounts of silver-
bound nucleophiles, such as AgBF4, AgCF3, and AgSCF3, we
were able to promote the addition of nontraditional
nucleophiles such as fluoride, the trifluoromethyl anion, and
trifluoromethylthiolate with these arynes.7c,9 In addition to the
intramolecular ene and C−H insertion reactions, excellent
regioselectivity in fluorination was observed regardless of the
substituent on the aryne intermediates; yet, trifluoromethyla-
tion and trifluoromethylthiolation showed strong substituent
dependency.
only by the steric and electronic factors on the arynes but also
by the nature of the involved nucleophiles.
First, we examined a representative substrate 1 that contains
a triethylsilyl group as the regiochemistry-controlling element
(Table 1). Carboxylic acids such as acetic acid and propiolic
acid afforded o-2a and o-2b as single isomers devoid of m-2a
and m-2b in 86 and 65% yield (entries 1 and 2). For the
addition of alcohols, sterically undemanding methanol
(MeOH) afforded o-2c in 84% yield (entries 3), while
isopropanol provided a mixture of o-2d and m-2d in 59%
yield with a 3.9:1 ratio (entry 4). The reduced selectivity with
isopropanol may be the consequence of an increased steric
interaction between the silyl group and the isopropyl group.11
To elucidate the factors dictating the observed regioselectiv-
ity, we further examined three classes of arynes (1, 3, and 4)
containing different substituents using oxygen- and nitrogen-
based nucleophiles.6a,10 Herein we report general regioselectiv-
ity trends of nucleophile additions that can be controlled not
Received: August 1, 2013
Published: December 6, 2013
© 2013 American Chemical Society
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dx.doi.org/10.1021/ol403237z | Org. Lett. 2014, 16, 6−9

Organic Letters
Letter
which is the same product of the diethylamine adduct (entry 7).
The formation of m-2g from triethylamine and an aryne
intermediate should involve the formation of a putative
zwitterionic intermediate as shown followed by its dispropor-
tionation to the product and a molecule of ethylene. Because of
the multistep nature of the process, the yield of this reaction is
slightly lower (80 vs 90%) than that from the simple addition of
diethylamine. In addition, the regioselectivity of the addition of
amines to the silyl group containing aryne favorably generating
m-2g and m-2h is in contrast with that of silylbenzynes
reported by Akai and co-workers.12
Table 1. Regioselectivity in Addition of Oxygen- and
Nitrogen-Based Nucleophiles to Arynes Containing a Silyl
Substituent
Considering the strong directing effect of the triethylsilyl
substituent demonstrated by bis-1,3-diyne 1 in Table 1, we
examined the regioselectivity of the reactions with bis-1,3-diyne
3 and 4, where the silyl group of 1 is replaced with a butyl
group, and the position of the NTs group is also reversed in 4
(Table 2). For the reactions of 3, with oxygen- and nitrogen-
based nucleophiles, mixtures of products o-5a−d and m-5a−d
were obtained with good to marginal selectivities in the range
10:1−1.4:1 (entries 1−4). The selectivity trend in these
reactions is the consequence of the similar electronic and
steric environment of both the carbon centers undergoing
nucleophilic addition, where on one side there is a butyl group
and on the other side there is a CH2NTs moiety. The reversal
of selectivity with triethylamine is noteworthy (entry 4).
In contrast, single isomers were obtained from all the
reactions of an ynamide-containing bis-1,3-diyne 4 with every
nucleophile examined (entries 5−9). The addition of
trifluoroethanol and silver triflate (AgOTf) followed by
subsequent protonation afforded the expected o-6a and o-6b
in 91 and 82% yield, respectively (entries 5 and 6). However,
the addition of silver trifluoroacetate (AgOCOCF3) to the same
aryne intermediate provided only water adduct o-6c (entry 7).
Careful examination of the crude reaction mixture indicated
that the trifluoroacetate adduct was indeed formed quantita-
tively, but it readily hydrolyzed during purification on silica gel.
Because under the current reaction format the direct addition
of water could not be achieved efficiently, the trifluoroacetate
formation followed by its spontaneous deacylation constitutes
an alternative approach for an effective water addition to arynes.
The uniform regioselectivity of the nucleophile addition with
arynes derived from bis-1,3-diyne 4 containing an ynamide
tether is the consequence of a strong electronic effect of the
NTs moiety, directing the addition of nucleophiles exclusively
at the meta-position (or the ortho-position of the butyl).13
While examining unsymmetrical bis-1,3-diyne 7a, containing
two different substituents on the terminal position of bis-1,3-
diyne, we noticed intriguing regioselectivity in the initial
hexadehydro Diels−Alder reaction (Scheme 2). Because there
is no sizable electronic bias in these bis-1,3-diynes, we expected
that aryne intermediates 8 and 8′ should be formed in roughly
equal amounts, wherein only 8 would afford the intramolecular
nucleophile trapped product 9 with a maximum 50% yield. To
our surprise, however, 9 was produced in 87% yield, which
clearly implies that the cycloaddition step to form aryne
intermediate 8 should be much more favorable than that of 8′.
In conclusion, we investigated the regioselectivity of
nucleophile trapping of the arynes formed from bis-1,3-diynes
that contain different electronic and steric biasing elements.
The reactions of these arynes with a series of oxygen- and
nitrogen-based nucleophiles reveal that the selectivity is
profoundly influenced not only by the nature of nucleophiles
but also by the substituents on the arynes. This is the
a
Isolated yield after SiO2 chromatography (same yield with silver
b
catalyst). The low yield is caused by the formation of hydrogen
adduct (ref 11). No addition product with t-BuOH.
c
While the reaction with primary amines provided mixtures of
o-2e/m-2e (88%, 1:2.8, entry 5) and o-2f/m-2f (70%, 1:1.8,
entry 6), those with secondary and tertiary amines afforded
single isomers m-2g and m-2h in 90, 71, and 80% yield,
respectively (entries 7−9). It is worthwhile to note that the
addition of triethylamine afforded product m-2g (entry 9),
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Letter
Table 2. Regioselectivity in Addition of Oxygen- and
Nitrogen-Based Nucleophiles to Arynes Containing Butyl
Substituent
Scheme 2. Formation of Aryne Intermediates and Their
Intramolecular Trapping of Nucleophiles
(entries 5 and 6 in Table 1) or an exclusive pathway for 2° and
3° amines (entries 7−9 in Table 1). For the NTs-substituted
arynes, regardless of nucleophile, the addition is exclusively
controlled by its electronic effect (entries 5−9 in Table 2). The
regioselectivity of the nucleophile addition can be explained by
the structural distortion of the aryne core caused by the
respective substituents, as demonstrated by the DFT
calculations of Houk and co-workers for simpler systems.14
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: dsunglee@uic.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from UIC (LAS AFS) and the National
Science Foundation (CHE 0955972) is greatly acknowledged.
We are grateful to Mr. Furong Sun of the University of Illinois
at Urbana−Champaign for high resolution mass spectrometry
data.
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