Dichlorination of (hexadehydro-diels-alder generated) benzynes and a protocol for interrogating the kinetic order of bimolecular aryne trapping reactions

Article abstract of DOI:10.1021/ol403258c

The efficient dichlorination of benzynes prepared by the hexadehydro-Diels-Alder (HDDA) reaction is reported. Cycloisomerization of a triyne substrate in the presence of dilithium tetrachlorocuprate is shown to provide dichlorinated products A by capture

Full text of DOI:10.1021/ol403258c

Letter
pubs.acs.org/OrgLett
Dichlorination of (Hexadehydro-Diels−Alder Generated) Benzynes
and a Protocol for Interrogating the Kinetic Order of Bimolecular
Aryne Trapping Reactions
Dawen Niu, Tao Wang, Brian P. Woods, and Thomas R. Hoye*
Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States
S
* Supporting Information
ABSTRACT: The efficient dichlorination of benzynes prepared by the
hexadehydro-Diels−Alder (HDDA) reaction is reported. Cycloisome-
rization of a triyne substrate in the presence of dilithium
tetrachlorocuprate is shown to provide dichlorinated products A by
capture of the benzyne intermediate. A general strategy for discerning
the kinetic order of an external aryne trapping agent is presented. It
merely requires measurement of the competition between bimolecular
vs unimolecular trapping events (here, dichlorination vs intramolecular
Diels−Alder (IMDA) reaction to give A vs B, respectively) as a
function of the concentration of the trapping agent.
rynes represent a very old and well-studied class of
reactive intermediates in organic chemistry. Since the
capable of activating the relatively inert Csp2−Cl bonds.7
Classically, aryl chlorides are made from the Sandmeyer
reaction or electrophilic aromatic halogenation. One of the
benzyne trapping reactions we have reported5a is that with an
HBr source to produce the monobromoarenes 3a and 3b
(Scheme 1). Since then, we have observed that treatment with
various ammonium chlorides gives a similar outcome, namely
the formation of monochlorides 4a and 4b.
1,2-Dichlorobenzene derivatives, the principal subject of the
investigations reported here, are seen in target compounds of
interest, as represented by the structures 5a−d (Figure 1). The
preparation of ortho-dichlorinated arenes is more challenging
than that of monochloroarenes. There are only a few reports of
direct 1,2-dihalogenation of arynes. These are limited to (i)
A
report over a century ago of what is now recognized as the first
example of a transformation consistent with a benzyne species,1
many methods for aryne generation have been developed.2
Most commonly used is the strategy introduced by Kobayashi
in 1983, in which ortho-TMSPhOTf (or a substituted variant) is
treated with a fluoride ion to generate the aryne under mildly
basic conditions.3 This method, because of its operational ease
and broad functional group compatibility, spurred renewed
interest in aryne trapping chemistry.4 Recently, we reported the
generality of a transformation we call the hexadehydro-Diels−
Alder (HDDA) reaction. This thermal cycloisomerization of a
triyne precursor (e.g., 1) constitutes a reagent- and byproduct-
free method for making benzyne intermediates of considerable
structural complexity (e.g., 2). This convenient conversion of a
triyne substrate to aryne intermediate has enabled us and others
to explore aspects of intrinsic aryne reactivity,5,6 including the
discovery of entirely new modes of trapping reactions.5b,6a
However, despite the numerous (and multifaceted) aryne
trapping reactions that have been developed to date, rarely has
it been possible to probe kinetic aspects of these powerful
transformations. This is not a trivial problem because the
benzyne forming reaction rather than its subsequent trapping is
nearly always the rate-limiting event. Certainly there is no
report of a general strategy for studying the kinetics of aryne
trapping [e.g., for deducing the kinetic order of the trapping
reactant(s)].
a
Scheme 1
a
Monohalo arene formation [3 or 4; 70−80% yield (3a:3b = 13:1;
4a:4b = 6:1)] through net hydrogen halide addition to the benzyne 2
formed via the HDDA reaction of the triyne 1.
Aryl chlorides are commonly encountered in, for example,
agrochemicals, pharmaceuticals, natural products, and photonic
materials. Aryl chlorides have also grown in importance as
synthetic intermediates in light of improved methodologies
Received: November 11, 2013
Published: December 13, 2013
© 2013 American Chemical Society
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Figure 1. Examples of 1,2-dichlorinated target compounds (5a,
Agrylin, platelet reducing agent for treatment of thrombocytosis; 5b,
indacrinone, diuretic developed for treatment of gout and hyper-
tension; 5c, kutznerides, antimicrobial cyclic peptides; and 5d, for
organoelectronic applications).
diiodination8,9 (with I2) or dibromination8a (with Br2), in
which the reactions tend to proceed less effectively for arynes
more elaborate than those of benzyne itself (from anthranilic
acid or ortho-TMSPhOTf)8c and (ii) vicinal, mixed fluoroha-
logenation via silver(I)-promoted, net addition of FCl, FBr, or
FI to HDDA-generated benzynes.6b We are not aware of any
examples of aryne dichlorination. A strategy to make 1,2-
dichlorinated arenes from triynes via the intermediate benzynes
is reported here. It is additionally important that, in the course
of these studies, a simple but general protocol that can be used
to gain insight to various kinetic aspects of aryne trapping
events has also been developed.
Figure 2. (a) Identification of Li2CuCl4 as an effective reagent for
dichlorination of the benzyne derived from tetrayne 6. (b) H NMR
We initially explored the possibility of trapping the HDDA-
generated benzyne 2 with either I2 or Br2. We were not
surprised that this experiment did not produce observable
amounts of the desired dihalobenzenes (i.e., 3/4 where X = Y =
I or Br). In general, one practical feature of HDDA chemistry is
that the alkynes in the triyne reactant need to be compatible
with the agents intended to trap the intermediate benzynes
under the conditions required to generate the benzyne. For
example, addition of Cl2 (and Br2) to alkynes is relatively fast
and is not expected to be compatible with most HDDA
substrates. However, various metal halides are known to act as
milder dihalogen surrogates for some dihalogen addition
reactions.10 We have learned that dilithium tetrachlorocuprate
(Li2CuCl4) functions as an effective dichlorinating agent of
HDDA-generated benzynes and report those observations here.
We used the symmetrical tetrayne 6 for our initial
explorations; it is both quite easy to prepare and has relatively
high reactivity as an HDDA substrate. When a solution of 6 in
CH3CN was heated in the presence of FeCl3, no desired
dichlorination product 7 was formed, as judged by GC or TLC
analysis (entry 1, Figure 2a). The first indication of a successful
outcome was seen with the use of CuCl2 in acetonitrile.
Addition of 6 and warming the resulting solution to 68 °C led
to the formation of 7 in 67% yield following purification. Use of
Li2CuCl4, formed in situ by mixing CuCl2 with solid LiCl, in
acetonitrile gave the desired dichlorination product in a similar
yield. The efficiency of the reaction was increased when the
solvent was changed to THF; 7 was isolated in 85% yield.
Under these conditions, no noticeable amount of dihydroge-
nation (by THF)5b or HCl addition products derived from
competitive trapping of the intermediate benzyne was observed.
Notably, dioxane was an ineffective solvent for this trans-
formation, presumably due to the low solubility of Li2CuCl4, a
feature that stands in contrast to its high solubility in THF.
We next probed some of the scope of this Li2CuCl4-mediated
dichlorination reaction. Products 8a−h (Figure 3a) encompass
1
spectrum of the crude product mixture following simple extractive
workup of the entry 4 experiment.
dichlorinated isoindoline, isoindolone, isobenzofuran, indane,
and fluorenone skeletons. These results show that a variety of
functional groups are tolerated in the triyne precursors and/or
the benzenoid products. They include toluenesulfonamide,
ketone, ester, amide, carbonate, alkyl or aryl chloride, silyl ether,
silyl alkyne, alkene, and an (electron rich) aromatic ring.
However, we have observed that triyne substrates containing a
free alcohol or terminal alkyne are not compatible with the
reaction conditions.
Notably, each of the benzyne precursors to 8i and 8j bears an
intramolecular trap. In the absence of an external trapping
agent, an efficient aromatic Diels−Alder5a or aromatic ene5c
reaction within the intermediate benzyne occurs to give 9i or
9j, respectively (Figure 3b). However, in the presence of
Li2CuCl4 these intramolecular trapping modes were largely if
not completely superseded by chlorination to instead produce
8i or 8j.
In the course of sorting out some of the details of these
competition reactions, we noticed that, for the case of products
8k vs 9k, the extent of formation of the latter could not be
entirely suppressed (Figure 4). Moreover, the amount of 9k
formed was dependent on the concentration of the Li2CuCl4
used in any given experiment. This led us to consider in further
detail the factors that are relevant to this pair of competing
events. The Diels−Alder adduct 9k results from unimolecular
cycloaddition within the benzyne 11.11 On the other hand,
reaction between 11 and the chlorination agent is intermo-
lecular and the rate of that trapping event should be, therefore,
dependent on the concentration of Li2CuCl4. The ratio of rate
equations for the formation of 8k and 9k can be expressed as
shown in eq 1 which, rewritten, is eq 2. When Li2CuCl4 is
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Figure 4. (a) Competition experiment involving the intramolecular
Diels−Alder (IMDA) reaction of benzyne 11 vs the bimolecular
trapping by Li2CuCl4 to give 9k vs 8k. (b) Product ratios at varying
concentrations of Li2CuCl4 (20 equiv in each case) and the log−log
plot from which the kinetic order was obtained.
Figure 3. (a) Products (8a−h) of dichlorination (10 equiv of
Li2CuCl4, [substrate]0 = 0.03 M in THF) of various HDDA-derived
arynes. The green dashed line indicates the C−C bonds formed in the
HDDA reaction. (b) Competitive dichlorination (to 8i or 8j) vs
intramolecular benzyne trapping by aromatic ene (to 9i)5c or Diels−
Alder (to 9j)5a reaction, respectively.
species is involved up through the rate-limiting step in the
product-forming phase of the reaction.
In conclusion, we have developed a new and efficient
benzyne dichlorination reaction using the mild oxidizing agent,
dilithium tetrachlorocuprate. We have shown that various types
of 1,2-dichlorinated products can be accessed. The conditions
are compatible with a considerable variety of functional groups
in the benzyne precursor and resultant benzenoid product. In
the course of the studies, we have also developed a strategy for
probing some important kinetic aspects of benzyne trapping
reactions. In particular, we made use of the competitive
intramolecular Diels−Alder (IMDA) reaction of benzyne 11 as
an internal clock reaction and observed the change in ratio of
the dichlorination to IMDA products as a function of the
concentration of the dichlorinating agent. Thereby, we have
shown that the dichlorination of benzyne 11 has a first order
dependence on the concentration of Li2CuCl4. This protocol is
noteworthy because kinetic studies of the reactions of arynes
are challenging, given that the formation, not the trapping, of
these highly reactive intermediates is virtually always the rate
limiting event. This protocol, determining the change in
product ratios arising from a bimolecular vs an intramolecular
trapping reaction as a function of concentration of the trapping
agent, represents an approach we believe applicable for
studying the molecularity of many other classes of intermo-
lecular aryne trapping reactions. Such studies are in progress.
present in excess, eq 2 can be approximated by eq 3, which can
also be expressed as eq 4.
The product ratio of 8k to 9k was measured at a series of
different concentrations of Li2CuCl4, and the results are given
in Figure 4b. The slope of the plot of ln[8k]/[9k] vs
ln[Li2CuCl4] shows that formation of 8k has a first-order
dependence on [Li2CuCl4], indicating that only one copper
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Letter
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, and copies of
1H and 13C NMR spectra for all isolated compounds.This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hoye@umn.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This investigation was supported by a grant awarded by the
U.S. Department of Health and Human Services (National
Institute of General Medical Sciences, GM-65597).
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