The aromatic ene reaction

Article abstract of DOI:10.1038/nchem.1797

The ene reaction is a pericyclic process in which an alkene with an allylic hydrogen atom (the ene donor) reacts with a second unsaturated species (the enophile) to form a new product with a transposed π-bond. The aromatic ene reaction, in which the alkene component is embedded in an aromatic ring, has only been reported in a few (four) instances and has proceeded in low yield (≤6%). Here, we show efficient aromatic ene reactions in which a thermally generated aryne intermediate engages a pendant m-alkylarene substituent to produce a dearomatized isotoluene, itself another versatile but rare reactive intermediate. Our experiments were guided by computational studies that revealed structural features conducive to the aromatic ene process. We proceeded to identify a cascade comprising three reactions: (1) hexadehydro-Diels-Alder (for aryne generation), (2) intramolecular aromatic ene and (3) bimolecular Alder ene. The power of this cascade is evident from the structural complexity of the final products, the considerable scope, and the overall efficiency of these multistage, reagent- and by-product-free, single-pot transformations.

Full text of DOI:10.1038/nchem.1797

ARTICLES
PUBLISHED ONLINE: 17 NOVEMBER 2013 | DOI: 10.1038/NCHEM.1797
The aromatic ene reaction
Dawen Niu and Thomas R. Hoye
*
The ene reaction is a pericyclic process in which an alkene with an allylic hydrogen atom (the ene donor) reacts with a
second unsaturated species (the enophile) to form a new product with a transposed p-bond. The aromatic ene reaction, in
which the alkene component is embedded in an aromatic ring, has only been reported in a few (four) instances and has
proceeded in low yield (≤6%). Here, we show efficient aromatic ene reactions in which a thermally generated aryne
intermediate engages a pendant m-alkylarene substituent to produce a dearomatized isotoluene, itself another versatile
but rare reactive intermediate. Our experiments were guided by computational studies that revealed structural features
conducive to the aromatic ene process. We proceeded to identify a cascade comprising three reactions: (1) hexadehydro-
Diels–Alder (for aryne generation), (2) intramolecular aromatic ene and (3) bimolecular Alder ene. The power of this
cascade is evident from the structural complexity of the final products, the considerable scope, and the overall efficiency
of these multistage, reagent- and by-product-free, single-pot transformations.
ne reactions1, which involve the attack of an alkene (the ene
donor) by an unsaturated enophile (A¼B or A;B), are well
known in organic chemistry2. In the process, an allylic hydro-
a
The minimal strucutural elements for an aromatic ene reaction:
E
gen atom is transferred to the enophile and the alkene p-bond is
transposed (that is, C1¼C2–C3–H þ A¼B to H–B–A–C1–C2¼C3).
Aromatic ene reactions—those in which an arene bearing a benzylic
C–H bond serves as the ene donor (see 1 to 2, Fig. 1a)—are extre-
mely rare. The only (four) reported examples involve o-benzyne
(3) itself as the enophile. Each proceeds in low yield (≤6%) and is
presumed to follow the pathway shown in Fig. 1b (that is, 1 to 5
via 4)3,4. The competing formation of bimolecular [4þ2] Diels–
Alder reaction products between o-benzyne (3, now acting as a die-
nophile) and toluene (the diene) perhaps has contributed to the fact
that this fundamentally intriguing but rare type of ene reaction has
remained unexplored and unexploited.
A
Aromatic ene
A
Rearomatized
product(s)
H
B
B
reaction
H
H
Enophile
1
2
A substituted isotoluene
b
The only reported aromatic ene reaction(s):
CO2–
Heat
PhMe
+
N2
H
Arynes are known to function as enophiles5. The earliest examples
were sporadic and isolated in their nature, but recent studies have
established synthetically useful ene reaction protocols involving
arynes as the enophile (Fig. 2a,b). Lautens and colleagues have
reported the wide scope of intramolecular ene reactions of (classically
generated) benzyne derivatives like 7 (from 6) in which pendent
alkenes cyclize efficiently to provide annelated products like 8
(refs 6, 7). We recently described the intramolecular ene reaction of
aryne 10 to give 11 (ref. 8). Cheng and co-workers have demonstrated
the generality of a bimolecular propargylic ene reaction between an
aryne (for example, 3, generated from 12 by the method of
Kobayashi9) and an alkyne (see 13) to give an allene (see 14)10. Lee
and colleagues have recently reported the considerable scope of
reactions like 10 to 11 as well as an intramolecular propargylic ene
reaction (15 to 17 via 16)11. Arynes are also known to participate
in hetera-ene reactions with a phenol8,12 or aniline13 derivative
serving as the ene donor. Here, we show the first examples of efficient
aromatic ene reactions. These were developed in the context of arynes
like 19, which possess suitably disposed aromatic substituents bearing
an m-alkyl substituent, and pass through isotoluene species like 20.
Isotoluenes are reactive intermediates in their own right, for which
we also report some unprecedented transformations.
3
1
H
Aromatic ene
reaction
H
CH2
H
4
H
5 6% yield
3
(and 3–6% for analogous product
from PhEt, PhiPr, or 1,3,5-Me3Ph)
Figure 1 | Structural delineation and previous example of an aromatic ene
reaction. a, The minimal structural elements for an aromatic ene reaction:
a potent enophile and an arene bearing a benzylic C–H bond as an ene
donor. This transformation is rare because it requires the energetically
demanding formation of a dearomatized isotoluene species (see 2).
b, The only reported aromatic ene reactions involve the use of the highly
energetic o-benzyne (3) in the role of enophile, which engages one of the
alkylbenzenes toluene (1), ethylbenzene, cumene or mesitylene as the ene
donor. The intermediate isotoluene 4 was invoked to account for the
formation of product 5. Yields are marginal in part because products
Results and discussion
Realization of the aromatic ene reaction has been elusive to date, arising from [4þ2] cycloaddition between 3 and the p-system in arene 1
presumably for two fundamental reasons. First, the energetics of are formed competitively.
Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, USA. e-mail: hoye@umn.edu
*
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ARTICLES
a
Reactions of arynes with alkene ene donors
c
Reactions of arynes with arene ene donors ?
O
O
O
LDA
r.t.
Br
–HBr
Me
H
H
OMe
OMe
OMe
18
6
7
8
98%
O
HDDA
O
O
97 ºC
22 h
Alder
ene
TMS
TMS
TMS
H
H
H
Heptane
(HDDA)
(fast)
H
O
O
O
19
9
10
11 83%
Aromatic
ene
This work:
b
Reactions of arynes with alkyne ene donors
H
H
KF
TfO
TMS
18-crown-6
+
H
20
THF, r.t.
H
12
3
13
14 68%
Rearomatized products
R =
Et
R
R
O
90 ºC
6 h
Alder
ene
O
O
TsN
TsN
TsN
(fast)
CH3CN
(HDDA)
H
H
O
Et
Et
Et
15
16
17 73%
Figure 2 | Arynes as enophiles reacting with various types of ene donor. a, An alkene (an Alder ene reaction)6–8. b, An alkyne (a propargylic ene
reaction)10,11. c, An arene donor bearing a suitably disposed benzylic hydrogen atom (an aromatic ene reaction, this work).
dearomatization associated with the primary ene event (see 1 to 2) bond insertion15, aryne fluorination/trifluoromethylation/trifluor-
require that the enophile be of inherently high reactivity. Second, omethylthiolation16 and dihydrogen transfer from alkanes17).
o-benzyne, the only known enophile capable of overcoming this
barrier, displays competitive [4þ2] (Diels–Alder) reactivity Substrate design: the Diels–Alder versus aromatic ene dichotomy.
toward the dienic character that is necessarily present in the In the course of considering potential aromatic ene substrates like
requisite aromatic ring of the ene donor3,4,8. We felt that both of 19 (Fig. 2c), we reasoned that it should be possible to bias the
these challenges—the issues of inherent reactivity and selectivity— reaction outcome away from an intramolecular Diels–Alder and
might be surmountable by the use of properly designed towards the aromatic ene event (that is, 19 to 20) by appropriate
aryne intermediates accessible by the hexadehydro-Diels–Alder design of the tethered substrate. We used computational methods
(HDDA) reaction.
to investigate the inherent energetic differences of reactions
The HDDA reaction generates bicyclic benzyne derivatives between o-benzyne (3) and toluene (1) (Fig. 3a). In these studies,
merely by heating suitable triyne precursors (9 to 10 (Fig. 2a), two competing modes of reactivity were examined, namely
15 to 16 (Fig. 2b) and 18 to 19 (Fig. 2c)) and comprises a aromatic ene (to 4, Figs 1b and 3a) and bimolecular Diels–Alder
general and powerful strategy for accessing these reactive inter- [4þ2] cycloaddition (to 21a and 21b, Fig. 3a). Density functional
mediates8,14. Importantly, the arynes are produced in the theory (DFT, M062X18/6-31G(d)) was used first to evaluate the
`
absence of external reagents. This feature affords them a longer relative stability of the primary products (4 and 21a/b) vis-a-vis
lifetime and an accordingly greater opportunity for entering into the o-benzyne/toluene reactant pair. Both the aromatic ene (to 4)
transformations with relatively high activation energies. Thus, and Diels–Alder (to 21a/b) reactions were found to be quite
HDDA-derived arynes also comprise a valuable platform upon exothermic (and to a similar degree), even though the toluene
which to exploit relatively rare, if not unprecedented, types of reac- moiety is dearomatized in each of these three primary products.
tivity (for example, Si–O bond insertion8, phenol ene reaction8, This largely reflects the loss of the high strain energy in an aryne
benzenoid Diels–Alder cycloaddition (26a to 28a8, Fig. 3c), C–H (ꢀ50 kcal mol21; refs 19, 20) and the net gain from the exchange
2
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ARTICLES
‡
a
b
‡
n
‡
Me
‡
n
‡
Me
Me
H
H
TS-24
18.3 (n = 2)
TS-4
18.6
TS-23
TS-21a
17.7
13.2 (n = 2)
17.5
Energies
in
kcal mol –1
Energies
in
kcal mol–1
TS-21b
Diels–Alder
(D–A) ‡
Aromatic
ene ‡
0
0
n
–40.9
-benzyne (3)
o
(n = 2)
+
–46.7
toluene (1)
–43.2
H
(n = 2)
n
–45.5
Me
22
–47.5
n
Me
Me
H
H
H
H
24
ene
D–A
–83.8
TS-23
22.0
13.2
14.4
TS-24
45.6
18.3
13.0
n
1
2
3
vs
ΔGTS
21a
23
21b
4
vs
vs
vs
= 23.6
=
5.1
Me
= –1.4
H
25
c
TMS
TMS
TMS
O
O
O
O
O
m
R
27
28
O
85 ºC
18 h
CH2
m
m
m
Me
Me
H
85%
–
a
b
c
1
0
0
–
88%
–
CHCl3
H
R
R
R
R
R
R
83%
vs.
26a–c
27a–c
Aromatic ene product
28a–c
D–A product
Figure 3 | Competition between aromatic ene and aromatic Diels–Alder pathways. a, Computed (DFT) energetics of possibilities for the bimolecular
reaction between toluene (1) and o-benzyne (3) leading to the aromatic ene product 4 (an isotoluene) versus the Diels–Alder adducts 21a and 21b.
b, Computed energetics of the analogous competitions for the tethered substrates 22 leading to the intramolecular ene product 23 versus the [4þ2] adduct
24; the potential energy surface is portrayed for the case where n ¼ 2, and the comparative values of DGTS are tabulated in the inset. c, Experimental results
for the series of related HDDA substrates 26a–c; the first and last give, exclusively, the Diels–Alder products 28a and 28c, whereas 26b gives only the
aromatic ene product 27b.
of p- for s-bonds that accompanies both the ene and Diels–Alder contains a two-atom link, to learn if the aromatic ene pathway
modes of reaction of the arene ring. We then located transition would be preferred for this structural motif. Indeed, heating triyne
structures for each of these competing reactions. A notable 26b produced only the aromatic ene-type product 27b (88%
finding is that the activation energies (DG‡) of the intermolecular yield). We presumed that the initial intramolecular aromatic ene
aromatic ene and cycloaddition processes are very similar to one adduct cleanly rearomatized (see 23 to 25 in Fig. 3b and later
another (Fig. 3a). This is well in line with the reported ratios discussion) under the reaction conditions. The complementary
among the isolated products 5, 21a and 21b (6:2:5)3,4. These substrate 26c, which lacks methyl substitution on the pendent aryl
results validated the merit of DFT analysis in this setting. We ring and is, therefore, an impotent aromatic ene substrate, was
then used the same DFT method to study three benzyne then used to establish that a Diels–Alder cycloaddition is indeed
derivatives 22 (n ¼ 1, 2 and 3), each differing only in the length feasible in this framework; product 28c was isolated in 83% yield.
of the methylene chain joining the tolyl to the benzyne moieties It is satisfying that computational study is capable of identifying
(Fig. 3b). In a previous report we described the reaction of the key structural attribute in the substrate—a two-atom linker
substrate 26a (Fig. 3c) to give the Diels–Alder product 28a (85% between the aryne and trapping arene rings—that permits it to
isolated yield) to the exclusion of any observable amount of ene undergo efficient aromatic ene reaction.
product 27a (ref. 8). In view of that previous observation, it was
reassuring to see that the computed relative transition structure Scope of the HDDA//aromatic ene reaction. To recapitulate, this
energies for 22 (n ¼ 3), which has the same tether length as 26a, unique HDDA//aromatic ene process (Table 1, top) converts a
favours the intramolecular Diels–Alder pathway. Encouragingly, triyne substrate like 29 (bearing a (meta-alkyl)aryl substituent,
computation of either of the other substrates 22 (n ¼ 1 or 2) connected through a two-atom linker) via an aryne like 30 to an
showed a decided preference for the ene rather than the Diels– isotoluene intermediate like 31, which aromatizes to a final
Alder event. The computed activation barrier for the aromatic ene tricyclic product like 32. As with all HDDA-initiated reactions8,
reaction was considerably lower for the case for n ¼ 2 than for this transformation is simply thermally induced, can be
n ¼ 1. In the meantime, we synthesized substrate 26b, which performed in a variety of non-participating solvents, and does not
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Table 1 | Examples of the HDDA-initiated aromatic ene reaction.
X
X
X
HDDA
Rearomatization
Intra-molecular
X
aromatic
ene
H
H
H
H
Me
Me
29
30
31
32
OAr
OAr
Ar = 3,5-di-MePh
O
CO2Me
O
O
MeO2C
MeO2C
O
O
O
O
O
TsN
O
PhN
32c
32e
32a
32b
32d
CHCl3, 65 °C, 20 h
90% (NMR yield)
CHCl3, 120 °C, 18 h
85%
DCB, 165 °C, 4.5 h
65%
DCE, 125 °C, 20 h
86%
DCB, 165 °C, 3.5 h
81%
O
O
O
O
TBS
O
O
O
O
O
O
N
PhN
PhN
PhN
PhN
OTBS
Br
32i
32f
CHCl3, 120 °C, 18 h
84%
32g
32j
32h
CHCl3, 120 °C, 18 h
73%
CHCl3, 120 °C, 18 h
77%
CHCl3, 95 °C, 36 h
90%
DCE, 120 °C, 18 h
88%
O
O
O
O
O
O
O
NBoc
O
O
O
O
+
PhN
PhN
OMe
32k
DCB, 165 °C, 3.5 h
85%
32l
DCB, 165 °C, 3.5 h
69%
32m
32n
32o
DCE, 120 °C, 18 h
80% (1:2 ratio)
DCB, 165 °C, 3.5 h
55%
The dotted line in each structure shows the disconnection made possible by the HDDA reaction, and the bold bond in each indicates the C–C bond formed via the aromatic ene reaction.
require particularly stringent reaction conditions (for example, the aromatic ene trapping of the aryne 34 generated by base-
oxygen- or water-free). The broad scope of the process is induced elimination of HBr from bromoarene 33 (Fig. 4a). The
demonstrated by the results summarized in Table 1. Several biaryl 35 was formed, but in only ꢀ2% yield. Products resulting
particular features can be observed. (1) Arynes with a variety of from reduction (36)17 or amine trapping (37) of the intermediate
different electronic properties, as governed by the functional aryne were predominantly formed.
groups within the triyne tether (red), are effective enophiles (see
27b and 32a–e and j). (2) The linker (blue) between the aryne Mechanistic investigations of the aromatic ene reaction. We
enophile and arene ene donor can incorporate carbon, nitrogen or performed studies relating to the mechanism of the final
oxygen atoms and can bear substitution (32h). (3) Substituents on rearomatization event (see 23 to 25 (Fig. 3b) and 31 to 32
the arene donor (for example, alkoxy (32k), silyloxy (32f) or (Table 1, top)). Thermal, suprafacial, unimolecular reorganization
halide (32g)) are well-tolerated. (4) On the other hand, minimally of isotoluene to toluene is symmetry-forbidden, and the
substituted arenes are also effective (see 32i). (5) The arene donor antarafacial variant of this 1,3-sigmatropic rearrangement is
is not restricted to benzenoid derivatives; efficient formation of geometrically unfavourable21, if not untenable. Thus, the 1,3-
the pyridine-containing product 32j bodes well for potential ene hydrogen atom migration event typically requires catalysis22. We
trapping by other heteroaromatics. (6) Secondary benzylic C–H speculated that adventitious water might be acting as a proton
bonds will participate in the ene transfer event, although at a shuttle to promote conversion of 31 to 32 in a fashion like that
slightly slower rate than that of a primary (see 1:2 ratio of known for keto-enol tautomerization23. To test this idea, we heated
products 32n:32o). (7) The ability to generate the reactive aryne triyne 38 in the presence of D2O (specifically, D2O-saturated
intermediate in the absence of other reagents (that is, by thermal chloroform). The dominant product, 32e-d1 (Fig. 4b), was
activation only) was key to the uncovering of this aromatic ene monodeuterated (ꢀ93% deuterium incorporation, see 1H NMR
reaction. This final point was reinforced by the outcome of our spectrum of 32e-d1 and Supplementary page 24 for analysis).
attempt to use the Lautens strategy (see 6 to 7 in Fig. 2a) to effect A complementary experiment was performed in which the
4
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ARTICLES
a
Attempted trapping of the classically generated aryne 34 by an aromatic ene reaction
O
O
O
O
O
Br
LiNiPr2
iPr2N
+
+
THF, r.t.
OMe
OMe
OMe
OMe
OMe
33
34
35
36
37a/b
2%
24%
61% (a:b = 2:3)
c
Stereospecificity
b
Water mediates rearomatization of the isotoluene intermediate
O
O
O
O
O
O
O
PhN
DCE
PhN
120 °C
D
H
38-d3
PhN
H
H
CHCl3
D2O
H
H
DO
D
Me
+
Me
Me
Me
120 °C
18 h
D
D
O
H
O
O
D
O
38
39
32e-d1
O
41-d3
O
O
O
A single diastereomer
(d.r. > 98:2)
O
D
PhN
O
D
D
120 °C
D
D
D
H
H
CDCl3
H2O
D
Me
HO
H
Me
Me
Me
D
H
38-d3
39-d3
32e-d2
Figure 4 | Studies giving insight into the importance of reaction conditions and the mechanism of the HDDA//aromatic ene reactions. a, Attempted
aromatic ene reaction of the aryne 34 generated by elimination of HBr from the aryl bromide 33 shows an advantage of using the reagent-free conditions of
the HDDA reaction as the method for aryne formation. b, A pair of complementary deuterium labelling experiments strongly implicate the intermediacy of
isotoluene 39. c, The cis-addition of carbon and deuterium across the maleic anhydride p-bond (see Supplementary Information for a discussion of the
1H NMR-based assignment of the structure 41-d3) provides strong mechanistic evidence for the concerted nature of the bimolecular (Alder) ene reaction.
trideuterated substrate 38-d3 was heated, this time in the presence of types of external enophiles can be used to trap the isotoluene
H2O. In this case, the dominant product was 32e-d2 (Fig. 4b; see intermediate, including electron-deficient alkenes (maleic
1H NMR spectrum of 32e-d2 and Supplementary page 24), in which anhydride and maleimides, red), a-dicarbonyl compounds
one of the three aromatic deuterium atoms in triyne 38-d3 has been (pyruvates, glyoxalate and N-methylisatin, blue) and an
lost. These results are best explained by a rearomatization process N-sulfonylimine (green). (2) The overall cascade process is
such as that portrayed in the isotoluene intermediate 39.
tolerant of a large number of inherently reactive functional
We next reasoned that because the isotoluene intermediate 39 groups, including imide, anhydride, ketone, ester, halogen,
formed via the initial aromatic ene reaction was sufficiently alcohol, aldehyde and sulfonamide, which are present in the
long-lived to encounter water, it might be possible to trap this trapping enophiles and the newly formed products, therefore
species in an even more productive manner with an added external demonstrating a considerable degree of chemoselectivity. (3) The
enophile. Indeed, when a 1,2-dichloroethane solution of the process is also compatible with a broad array of functionality in
trideuterated substrate 38-d3 was heated in the presence of maleic the aryne precursor; derivatives of isoindolone, phthalide,
anhydride24 (Fig. 4c), adduct 41-d3 was formed. Moreover, the net fluorenone and indane can all be produced in high yields. (4)
cis-addition of carbon and deuterium across the enophile p-bond The reaction can be conducted at relatively high substrate
was stereospecific (see 1H NMR spectrum of 41-d3 and (triyne) concentrations (0.2–0.3 M), which speaks to the
Supplementary page 56 for a discussion of the coupling constant inherently fast nature of the aromatic ene trapping step. (5) Only
and chemical shift analysis), providing evidence for a concerted 1.2–2 equiv. of external trapping enophiles were used, which
ene reaction between maleic anhydride and 39-d3.
suggests that the isotoluene intermediate has a relatively long
lifetime and bodes well for application to convergent coupling
Scope of the HDDA//aromatic ene//Alder ene cascade. The synthesis strategies using complex triyne substrates and complex
successful transformation of 38 to 41 via 39 (Fig. 4c) showed trapping enophiles. (6) Various steps in the cascade are
that it was possible to unite an additional (bimolecular) ene stereoselective, as indicated by the production of a 4:1 ratio of
trapping reaction with the initial (unimolecular) aromatic ene diastereomers 42i and its epimer from the corresponding
reaction. This amounts to a HDDA//aromatic ene//Alder ene (chiral) triyne. Although we do not know the exact origin of this
cascade (Table 2, top). This sequence is enabled because the selectivity, relative asymmetric induction in this case can occur
isotoluene intermediate 39 is still endowed with a considerable at either (or both) of two stages: the aromatic ene substrate 44
portion of the potential energy embodied in the three alkyne can cyclize to either of the diastereotopic re and si faces of its
units in the initial HDDA substrate 38. The scope of this three- (two equivalent) ortho-carbon atoms, and the Alder enophile
stage cascade process can be seen from the examples shown in can approach the isotoluene intermediate 43 in either an endo
Table 2, where several features can be observed. (1) A variety of or exo fashion.
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Table 2 | Examples of the HDDA//aromatic ene//Alder ene cascade.
O
O
HDDA//aromatic ene
Triyne
+
A=B
H
Me
(an enophile)
(see Table 1)
B
A
Me
A
H
B
39
40
O
O
O
O
O
O
O
O
O
O
O
O
PhN
PhN
PhN
PhN
PhN
PhN
OH
O
O
OH
CF3
NH
Ts
EtO2C
OH
EtO2C
O
N
O
N
Cl
O
Ph
O
Me
41
42a
42b
42c
42d
42e
DCE, 120 °C, 18 h
2.0 equiv.
DCE, 120 °C, 18 h
1.6 equiv.
DCE, 120 °C, 18 h
1.5 equiv.
DCE, 120 °C, 18 h
1.2 equiv.
DCE, 120 °C, 18 h
1.2 equiv.
DCE, 120 °C, 18 h
2.0 equiv.
63% (+20% 32e)
66% (+22% 32e)
67%
85%
77%
82% (+4% of 32e)
3,5-Me2PhO
Me
O
O
TMS
O
Me
OH
O
O
O
O
O
PhN
MeO2C
MeO2C
H
O
43
O
NH
Ts
N
O
N
OH
CF3
Ph
O
Cl
Me
EtO2C
Me
O
H
42f
42g
42h
42i
DCB, 165 °C, 3.5 h
1.5 equiv.
DCE, 115 °C, 24 h
1.2 equiv.
DCE, 80 °C, 18 h
2.0 equiv.
85%
DCE, 120 °C, 18 h
1.2 equiv.
X-ray structure of 42i
72% (+18% of 32d)
84%
76% (4:1 d.r.)
(major diastereoisomer)
44
In products 41 and 42a–i the moieties in red, blue and green are derived from trapping agents with C¼C (red), C¼O (blue) and C¼N (green) enophilic p-bonds, respectively.
presages additional choreographed cascades that can exploit the
high potential energy innate to alkynes. We are currently investi-
gating such possibilities.
Conclusions
In conclusion, by capitalizing on the reagent-free, aryne-generating
HDDA reaction and taking guidance from computational chem-
istry, we have designed substrates that reveal the generality of a
thus far rare and elusive type of ene reaction in which an arene
bearing a benzylic C–H bond functions as the ene donor. We
have shown that the isotoluenes generated by this HDDA-enabled
‘aromatic ene’ reaction can rearomatize either by net rearrangement
or through interception by external enophiles. Thus, two comp-
lementary overall transformations have emerged. In the first, the iso-
toluene rearomatizes to provide polycyclic products such as 32a–o
(Table 1) in a process explained by water-mediated proton shuttling.
In the second, the reactive isotoluene is further engaged by an exter-
nal enophile to give products of yet greater structural complexity
(see 41 and 42a–i, Table 2). This ene-upon-ene cascade reaction
involves the overall formation of four carbon–carbon bonds and
three rings, requires no external reagents, and generates no by-pro-
ducts. The discovery of this efficient aromatic ene reaction further
attests to the importance of a key feature of the HDDA cycloisome-
rization, namely, its ability to deliver aryne intermediates in the
absence of the potentially interfering reagents that typically accom-
Methods
Full experimental procedures for the preparation of all new compounds, complete
spectroscopic characterization data (aromatic ene substrates and products) and a
description of the computational protocols and results can be found in the
Supplementary Information.
General procedure for the HDDA//aromatic ene reaction. A solution of the triyne
precursor in the indicated solvent (ꢀ0.03 M) was placed in a vial closed with a
Teflon-lined cap and heated at the temperature indicated under each structure of the
corresponding product in Table 1 (external bath). The product was purified by
chromatography on silica gel after the indicated time.
General procedure for the HDDA//aromatic ene//Alder ene cascade. A solution of
the triyne precursor in the indicated solvent (0.2–0.3 M) and the corresponding
enophile was placed in a vial closed with a Teflon-lined cap and heated at the
temperature indicated under each structure of the corresponding product in Table 2
(external bath). Unless otherwise noted, the product was purified by
chromatography on silica gel after the indicated time.
Received 7 August 2013; accepted 11 October 2013;
pany aryne formation by classical methods25. Finally, this work published online 17 November 2013
6
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1797
ARTICLES
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Additional information
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Competing financial interests
The authors declare no competing financial interests.
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