Three-component coupling of arynes and organic bromides

Article abstract of DOI:10.1002/anie.201104858

Magic trio: Arynes are easily coupled with neutral nucleophiles and organic bromides to afford functionalized bromoarenes depending upon the nucleophile (Nu). The three-component coupling proceeds through the formation of bromine ate complexes, and can be applied to the synthesis of multisubstituted isoquinolines and benzo[b]oxepines having pharmacological activity. Copyright

Full text of DOI:10.1002/anie.201104858

Communications
DOI: 10.1002/anie.201104858
Multicomponent Reactions
Three-Component Coupling of Arynes and Organic Bromides**
Hiroto Yoshida,* Yuji Asatsu, Yasuhiro Mimura, Yu Ito, Joji Ohshita, and Ken Takaki
Arynes have been versatile tools in synthetic organic chemis-
try for the facile construction of benzoannulated structures
and multisubstituted arenes.[1] Despite the labile and transient
propargylic ether moiety remained intact (4h–4j), and more-
over, the functionalized iodoarene 4k could be synthesized by
use of phenylethynyl iodide.[10] Next, we examined the three-
component coupling with substituted arynes. The respective
products from dimethylbenzynes (4l and 4m) and cyclo-
ꢀ
character arising from the highly strained C C bonds, the use
of a suitable combination of nucleophiles and electrophiles
allows arynes to serve as connectors between these two
components, thus leading to various three-component cou-
pling reactions of high synthetic significance; in the reaction
zwitterions (1,n-dipoles) generated from the arynes and
nucleophiles act as key intermediates.[2,3] In view of the fact
that almost all three-component coupling reactions reported
so far employ classic electrophiles (e.g., carbonyl compounds,
sulfonylimines, and CO2) as the third component,[4] there
should be a number of unexploited three-component coupling
reactions with potential synthetic utility that would be made
feasible by employing a new type of third component. We
report herein that 1,3- or 1,4-dipoles generated in situ from
arynes can be captured by alkynyl (or polyfluoroaryl)
bromides, which serve as a source of bromine cations and
alkynyl (or polyfluoroaryl) anions,[5] thus leading to the direct
construction of functionalized bromoarenes having diverse
structures.
We first conducted the reaction of benzyne (from 1a and
KF/[18]crown-6),[6]
1,1,3,3-tetramethylbutyl
isocyanide
(tOctNC; 2a), and phenylethynyl bromide (3a) in DME at
ꢁ
ꢁ
08C, and observed that two C C bonds and a C Br bond
formed all in one pot to give the three-component coupling
product 4a in 88% yield (Scheme 1).[7] As described in
Scheme 2, the reaction would be triggered by formation of the
zwitterion (1,3-dipole) 5 from benzyne and 2a.[8] Subsequent
nucleophilic attack of the aryl anionic moiety on the bromo
moiety of 3a produces the phenylacetylide 7 and an aryl–Br
bond in 8 through the bromine ate complex 6,[9] with
ꢁ
subsequent C C bond formation between 7 and the nitrilium
cation 8 to furnish 4a. Products derived from various alkynyl
bromides bearing a substituted aryl (4b–4d), thienyl (4e), or
enynyl (4 f) moieties were obtained. The doubly coupled
product 4g was produced from 1,4-bis(bromoethynyl)ben-
zene in 66% yield (Scheme 1). The reaction was also
applicable to aliphatic alkynyl bromides whose acetal or
[*] Prof. H. Yoshida, Y. Asatsu, Y. Mimura, Y. Ito, Prof. J. Ohshita,
Prof. K. Takaki
Department of Applied Chemistry, Graduate School of Engineering
Hiroshima University
Higashi-Hiroshima 739-8527 (Japan)
E-mail: yhiroto@hiroshima-u.ac.jp
Scheme 1. Three-component coupling of arynes, an isocyanide, and
alkynyl halides. Reaction conditions: aryne precursor (0.30 mmol,
2 equiv), isocyanide (0.23 mmol, 1.5 equiv), alkynyl halide (0.15 mmol,
1 equiv), KF (0.60 mmol, 4 equiv), [18]crown-6 (0.60 mmol, 4 equiv),
DME (2 mL). Yields are of isolated products. [a] 1a (4 equiv), 2a
(3 equiv), alkynyl bromide (1 equiv), KF (8 equiv), [18]crown-6
(8 equiv). [b] 1a (1 equiv), 2a (1 equiv), alkynyl iodide (1 equiv), KF
(4 equiv), [18]crown-6 (2 equiv). DME=1,2-dimethoxyethane, Tf=tri-
fluoromethanesulfonyl, TMS=trimethylsilyl.
[**] This work was financially supported by Grants-in-Aid for Challenging
Exploratory Research (23655043) from the MEXT (Japan). We thank
the Central Glass Co. Ltd. for a generous gift of trifluoromethane-
sulfonic anhydride.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201104858.
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Angew. Chem. Int. Ed. 2011, 50, 9676 –9679

Scheme 4. Synthesis of isoquinolines from 10a. DMF=N,N’-dimethyl-
formamide.
Scheme 2. Proposed mechanism for the reaction of isocyanides.
1008C, the isoquinoline 12a was produced in 72% yield.[16]
The annulation could be applied to electron-rich and elec-
tron-deficient diarylacetylenes to furnish the variously sub-
stituted triarylisoquinolines 12b–12d, albeit in moderate
yield.
In view of the fact that organic halides are an excellent
third component for capturing 1,3-dipoles, we further inves-
tigated the reaction of 1,n-dipoles derived from arynes and
other nucleophiles, and found that cyclic ethers performed
well in the three-component coupling.[17] The three-compo-
nent coupling was found to selectively proceed when benzyne
was treated with 3a in THF at 08C, thus providing a 78%
yield of 1-bromo-2-(6-phenylhex-5-ynyloxy)benzene (13a)
(Scheme 5).
A variety of alkynyl bromides were efficiently coupled
with benzyne and THF to give the products (13b–13 f), and
furthermore an electrophilic cyano group in (4-cyanopheny-
l)ethynyl bromide (13g) was tolerable throughout the reac-
tion despite the intermediacy of aryl and alkynyl anionic
species (Scheme 6), thus showing the high functional group
compatibility of the reaction. In addition, 9a and 1-bromo-
2,3,5,6-tetrafluorobenzene (9c) gave the corresponding prod-
ucts (13h and 13i) in 82 and 78% yield, respectively, whereas
the reaction of 1-bromo-2,4,6-trifluorobenzene (9d!13j) or
9b (no reaction) resulted in lower yields. Similar to the case of
alkane-condensed arynes (4n and 4o) were afforded in high
yields, and the reaction of 3-methoxybenzyne took place with
perfect regioselectivity, thus leading to the sole formation of
4p in 69% yield.[11]
Besides alkynyl halides, bromopentafluorobenzene (9a)
and 1-bromo-2,6-difluorobenzene (9b) proved to serve as a
source of bromine cations and aryl anions to give the products
10a and 10b, respectively, when reacted with benzyne and
tOctNC (Scheme 3). The present reaction exhibits broad
substrate scope for isocyanides, and thus the products arising
from isocyanides having 1-adamantyl (10c), tBu (10d), Cy
(10e), or 2,6-di(isopropyl)phenyl (10 f) substituents readily
underwent the three-component coupling.[12]
The resulting ortho-iminobromoarene 10a could be
directly converted into multisubstituted isoquinolines, which
constitute an important class of biologically active com-
pounds such as berberine,[13] palmatine,[14] and papaverine[15]
(Scheme 4). By treating 10a with diphenylacetylene (11a) in
the presence of [Pd(tBu3P)2] and sodium carbonate in DMFat
ꢁ
4g, dual installation of the 1,4-dipole into both of the C Br
bonds of 1,4-dibromotetrafluorobenzene readily occurred to
provide a 90% yield of 13k.[18]
Finally, we found that oxetane could be transformed into
the three-component coupling product 14a in the reaction
with benzyne and 3a (Scheme 7). Other alkynyl bromides
(14b–14d) also smoothly reacted with benzyne and oxetane,
and the reaction of 3,3-dimethyloxetane furnished a 50%
yield of 14e. In marked contrast, the use of a three- or six-
membered cyclic ether (cyclohexene oxide or tetrahydro-
pyran) in the reaction with benzyne and 3a did not afford the
three-component coupling product at all.[19]
Synthetic utility of the three-component coupling was
demonstrated by the total synthesis of a benzo[b]oxepine-
based nonsteroidal estrogen, which is a new candidate or lead
compound for treatment and prevention of an estrogen-
deficient syndrome such as osteoporosis, Alzheimer’s, and
cardiovascular diseases (Scheme 8).[20] Thus, oxetane was
regioselectively coupled with 4-chloro-5-methoxybenzyne
(from 15) and (4-benzyloxyphenyl)ethynyl bromide (16) to
produce 17,[21] which was then transformed into a vicinal
Scheme 3. Three-component coupling of benzyne, isocyanides, and
polyfluoroaryl bromides. Reaction conditions: aryne precursor
(0.27 mmol, 1.8 equiv), isocyanide (0.23 mmol, 1.5 equiv), aryl bro-
mide (0.15 mmol, 1 equiv), KF (0.54 mmol, 3.6 equiv), [18]crown-6
(0.54 mmol, 3.6 equiv), DME (2 mL). Yields are of isolated products.
Angew. Chem. Int. Ed. 2011, 50, 9676 –9679
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Communications
Scheme 7. Three-component coupling of benzyne, oxetanes, and
alkynyl bromides. Reaction conditions: aryne precursor (0.40 mmol,
2 equiv), oxetane (0.20 mmol, 1 equiv), alkynyl halide (0.40 mmol,
2 equiv), KF (0.80 mmol, 4 equiv), [18]crown-6 (0.80 mmol, 4 equiv),
DME (2 mL). Yields are of isolated products.
Scheme 5. Three-component coupling of benzyne, THF, and alkynyl (or
polyfluoroaryl) bromides. Reaction conditions: (for alkynyl bromide)
aryne precursor (0.40 mmol, 2 equiv), alkynyl bromide (0.20 mmol,
1 equiv), KF (0.80 mmol, 4 equiv), [18]crown-6 (0.80 mmol, 4 equiv),
THF (2 mL); (for aryl bromide) aryne precursor (0.30 mmol, 1.5 equiv),
aryl bromide (0.20 mmol, 1 equiv), KF (0.60 mmol, 3 equiv), [18]crown-
6 (0.60 mmol, 3 equiv), THF (2 mL). Yields are of isolated products.
[a] 1a (3 equiv), aryl bromide (1 equiv), KF (6 equiv), [18]crown-6
(6 equiv). THF=tetrahydrofuran.
Scheme 8. Synthesis of benzo[b]oxepine: a) 15 (2 equiv), oxetane
(1 equiv), 16 (2 equiv), KF (4 equiv), [18]crown-6 (4 equiv), DME,
ꢁ
ꢁ158C, 27 h. b) 17 (1 equiv), (pin)B B(pin) (1.1 equiv), [Pt(PPh3)4]
(8 mol%), DMF, 808C, 22 h. c) 18 (1 equiv), Cs2CO3 (1.2 equiv), [Pd-
(tBu3P)2] (5 mol%), H2O (33 equiv), DME, 808C, 24 h. d) Cs2CO3
(1.2 equiv), H2O (33 equiv), DME, 808C, 24 h. e) 19 (1 equiv), H2
(4 atm), 10% Pd/C (30 mol%), MeOH, RT, 48 h. f) 20 (1 equiv), Na
(14 equiv), tBuOH (5 equiv), THF, 708C, 65 h.
In conclusion, we have disclosed a novel three-component
coupling reaction of arynes, isocyanides (or cyclic ethers), and
organic halides, where in situ-generated 1,3- or 1,4-dipoles are
effectively captured by halogen cations and alkynyl (or
polyfluoroaryl) anions. Moreover, the resulting functional-
ized bromoarenes have been demonstrated to be versatile
intermediates in synthesizing multisubstituted isoquinolines
and benzo[b]oxepine of pharmacological activity. Further
studies on aryne-based multicomponent coupling reactions of
this type as well as on application of the present methodology
to the total synthesis of biologically active compounds are in
progress.
Scheme 6. Proposed mechanism for the reaction of THF.
diborylalkene 18 through the platinum-catalyzed diborylation
using bis(pinacolato)diboron ((pin)B–B(pin)).[22] An intra-
molecular Suzuki–Miyaura coupling at the aryl–Br bond of 18
accompanied by base-induced proto-deborylation afforded
the benzo[b]oxepine 19, whose alkenyl moiety was hydro-
genated along with removal of the benzyl moiety to give 20.
Finally, the target benzoxepine 21 could be obtained by the
dechlorination using Na/tBuOH (24% overall yield based on
oxetane).[23]
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[5] Such behavior of alkynyl halides was reported in a reaction with
ketone enolates. See: A. Trofimov, N. Chernyak, V. Gevorgyan,
J. Am. Chem. Soc. 2008, 130, 13538.
[6] a) Y. Himeshima, T. Sonoda, H. Kobayashi, Chem. Lett. 1983,
1211; b) D. PeÇa, A. Cobas, D. Pꢀrez, E. Guitiꢁn, Synthesis 2002,
1454.
Experimental Section
General procedure for the three-component coupling of arynes,
isocyanides, and alkynyl halides: A Schlenk tube equipped with a
magnetic stirring bar was charged with KF (0.60 mmol) and
[18]crown-6 (0.60 mmol). The tube was evacuated at room temper-
ature for 1 h with stirring before addition of DME (1 mL) and an
alkynyl bromide (0.15 mmol) under an argon atmosphere. Then an
isocyanide (0.23 mmol), an aryne precursor (0.30 mmol), and DME
(1 mL) were added at 08C, and the resulting mixture was stirred at
08C. The mixture was diluted with ethyl acetate and filtered through a
Celite plug. The organic solution was washed three times with brine
and dried over MgSO4. Evaporation of the solvent followed by
recycling preparative HPLC gave the product.
[7] The reaction of benzyne, 2a and 3a in THF also gave 4a in 74%
yield.
[8] For a review on nucleophilic coupling with arynes, see: S. V.
Kessar in Comprehensive Organic Synthesis Vol. 4 (Eds.: B. M.
Trost, I. Flemming), Pergamon, Oxford, 1991, p. 483.
[9] Although there is no hard evidence for the formation of the ate
complex as an intermediate, the mechanism should be plausible,
because this step is similar to metal–halogen exchange, which
proceeds through formation of an ate complex. See: a) H. J.
Reich, D. P. Green, N. H. Phillips, J. Am. Chem. Soc. 1989, 111,
3444; b) H. J. Reich, D. P. Green, N. H. Phillips, J. Am. Chem.
Soc. 1991, 113, 1414.
Received: July 12, 2011
Published online: September 2, 2011
Keywords: arenes · arynes · multicomponent reactions ·
[10] The reaction of benzyne, 2a, and phenylethynyl chloride did not
afford the three-component coupling product at all.
.
natural products · synthetic methods
[11] Such a regioselectivity is generally observed in the nucleophilic
coupling reactions with 3-methoxybenzyne; see Ref. [2].
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isocyanide), and 9a became sluggish, giving a 36% yield of the
three-component coupling product.
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