The hexadehydro-Diels-Alder reaction

Article abstract of DOI:10.1038/nature11518

Arynes (aromatic systems containing, formally, a carbon-carbon triple bond) are among the most versatile of all reactive intermediates in organic chemistry. They can be 'trapped' to give products that are used as pharmaceuticals, agrochemicals, dyes, polymers and other fine chemicals. Here we explore a strategy that unites the de novo generation of benzynes-through a hexadehydro-Diels-Alder reaction-with their in situ elaboration into structurally complex benzenoid products. In the hexadehydro-Diels-Alder reaction, a 1,3-diyne is engaged in a [4+2] cycloisomerization with a 'diynophile' to produce the highly reactive benzyne intermediate. The reaction conditions for this simple, thermal transformation are notable for being free of metals and reagents. The subsequent and highly efficient trapping reactions increase the power of the overall process. Finally, we provide examples of how this de novo benzyne generation approach allows new modes of intrinsic reactivity to be revealed.

Full text of DOI:10.1038/nature11518

ARTICLE
doi:10.1038/nature11518
The hexadehydro-Diels–Alder reaction
Thomas R. Hoye1, Beeraiah Baire1, Dawen Niu1, Patrick H. Willoughby1 & Brian P. Woods1
Arynes (aromatic systems containing, formally, a carbon–carbon triple bond) are among the most versatile of all
reactive intermediates in organic chemistry. They can be ‘trapped’ to give products that are used as pharmaceuticals,
agrochemicals, dyes, polymers and other fine chemicals. Here we explore a strategy that unites the de novo generation of
benzynes—through a hexadehydro-Diels–Alder reaction—with their in situ elaboration into structurally complex
benzenoid products. In the hexadehydro-Diels–Alder reaction, a 1,3-diyne is engaged in a [412] cycloisomerization
with a ‘diynophile’ toproduce the highly reactive benzyne intermediate. The reaction conditions for this simple, thermal
transformation are notable for being free of metals and reagents. The subsequent and highly efficient trapping reactions
increase the powerof the overall process. Finally, we provide examples of how this de novo benzyne generation approach
allows new modes of intrinsic reactivity to be revealed.
ortho-Benzyne (1,2-didehydrobenzene, 1, Fig. 1a) is one of the oldest1,
Thevenerable Diels–Alder cycloadditionreaction11 is highly regarded
most interesting, most useful and most well-studied of all reactive in synthetic chemistry12,13. The prototypical event (Fig. 1b), found in
intermediates in chemistry. The multifaceted and often remarkably every introductory organic chemistry textbook, is the combination
efficient reactions of benzynes with suitable trapping reagents (1R3 of 1,3-butadiene (5) as the 4p-component with ethylene (4) as the
in Fig. 1a) have long been employed in the service of synthetic chemistry. dienophile to give cyclohexene (6)—a product in the tetrahydrobenzene
Even by 1967 many such reactions were known2. Nonetheless, newly oxidation state. If, instead, an alkyne like ethyne (7) is the dienophile, a
discovered benzyne reaction motifs continue to emerge, especially so 1,4-cyclohexadiene (here 1,4-dihydrobenzene (8)) results (Fig. 1c); we
within the last decade3–10. This renaissance attests to the additional ver- suggest this be viewed as a didehydro-Diels–Alder reaction. Another
satility and heralds even greater potential of this intermediate. Currently, known variant (Fig. 1d) involves engagement of a (yet more highly
all practical methods for producing benzynes involve the removal of two oxidized) 1,3-enyne (for example, 9) as the 4p-component with an
adjacent atoms or substituents (‘G’ and ‘X’; Fig. 1a) from benzenoid alkyne (for example, 7). It is interesting to note that the first example
precursors (2). These protocols typically require the use of a strong base ofthisprocess(thethermaldimerizationofphenylpropiolicacid)14 was
and/or access to a 1,2-disubstituted arene substrate. A complementary described 30 years before the initial report of Diels and Alder11. The
general method for benzyne/aryne generation would considerably intermediate cyclic allene 10 rapidly rearranges via a [1,5] hydrogen
expand the preparative utility of these remarkable intermediates.
atom shift to benzene (11). This process has until now been called,
a
o-Benzyne Generation and Trapping
b
Diels–Alder
c
Didehydro-Diels–Alder
:Nu δ–
El δ+
H
H
H
H
H
H
H
H
H
H
H
H
H
H
X
Nu
El
[4+2]
[4+2]
–G-X
H
H
H
G
H
4
5
7
5
2
1
3
6
8
d
e
Tetradehydro-Diels–Alder (TDDA)
Hexadehydro-Diels–Alder (HDDA)
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
[4+2]
Trap
[4+2]
[1,5]
H
H
H
H
H
H
7
9
7
12
1′
1
1*
10
11
Figure 1
|
Diels-Alder reactions of varying oxidation states. a, Generic
and products: classic Diels–Alder (b), didehydro-Diels–Alder
benzyne generation (2 to 1) and trapping (1 to 3). Most commonly,
(c), tetradehydro-Diels–Alder (TDDA) (d), and hexadehydro-Diels–Alder
–
G/X5 H/halogen, CO2 /N21, halogen/halogen, or TMS/OTf. b–e, Prototypes (HDDA, this work) (e) reactions. The aromatic character of benzyne is
of Diels–Alder [412] (that is, the combination of a four-atom (or 4p electron) emphasized by the resonance contributors 1 and 19 as well as by the resonance
component with a two-atom (or 2p electron) component to produce a six-
hybrid structure 1*. TMS, trimethylsilyl; OTf, trifluoromethanesulphonate;
membered ring) reactions differing in the oxidation levels of the reactant pairs Nu, nucleophile; El, electrophile.
1Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, USA.
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ARTICLE RESEARCH
generically, the dehydro-Diels–Alder (DDA) reaction15. In the light of
the generality of the results we present here, we suggest that the trans-
formation in Fig. 1d would be better named the tetradehydro-Diels–
Alder (TDDA) reaction.
The most highly oxidized Diels–Alder variant (Fig. 1e) is the cyclo-
addition between a 1,3-diyne like 12 and an alkyne diynophile like 7,
which generates o-benzyne (compare 19, 1 and 1*). This hexadehydro-
Diels–Alder (HDDA) reaction is the subject of this Article. Given the
efficiency, ease of precursor access, versatility and mild reaction condi-
tions revealed by the examples we present here, it is remarkable that this
reaction has remained essentially unexploited16–19. It is interesting to
speculate that this may be due in part to the fact that the most common
depiction of benzyne—the resonance contributor 1 (Fig. 1e)—obscures
its potential construction via a [412] cycloaddition reaction. It is the
a
TBSO
O
R2
MnO2, CH2Cl2
Room temperature
R1
OTBS
O
5 h, 53%
O
TBS
R1, R2
t
SiMe2 Bu
15
H,OH
=O
13
14
TBSO
O
TBSO
O
TBSO
O
´
alternative, but rarely encountered, Kekule depiction (19) that reveals
the opportunity for assembly via an HDDA process.
We report below the broad scope of a strategy that combines the
versatile and efficient generation of benzynes via the HDDA reaction
with various trapping reactions to yield structurally complex ben-
zenoid products. Each substrate is a readily accessible conjugated
diyne containing a remote alkynyl diynophile. These cycloisomerize
in (a highly exergonic) [412] fashion to produce the reactive aryne
intermediate. The examples demonstrate that the tandem benzyne
forming/trapping sequence can be designed to proceed with excellent
efficiency.
O
O
O
SiMe2
tBu
SiMe2
tBu
SiMe2
tBu
16′
16
17
b
H
CHO
CHO
19
TBSO
Br
The HDDA reaction revealed
Pd(0) [Sonogashira]
In the course of an otherwise unrelated study, we attempted to prepare
the ketotetrayne 14 by oxidation of the precursor alcohol 13 with
manganese dioxide (Fig. 2a). To our surprise, the major product from
this experiment, formed in about 5 hours, was the (hexasubstituted)
benzene derivative 15 (53% yield after purification). We quickly pos-
tulated that the benzyne intermediate 169/16 was being both readily
formed and efficiently trapped by the nucleophilic oxygen atom in the
fortuitously poised b-siloxyethyl group. Migration of the silyl group
from O to C within zwitterion 17, a retro-Brook rearrangement,
accounts for formation of 15. This constitutes an unprecedented
mode of benzyne trapping. Additionally, the process is attended by
a substantial increase in structural complexity. The potential power of
this transformation was immediately apparent.
We surmised that the modest yield observed in this reaction of
tetrayne 14 reflected the fact that two competitive modes of [412]
cyclization are possible. We were also keen to learn the feasibility of
cyclizationofanalogoustriynes. We thereforedesignedandsynthesized
a substrate—the ketotriyne 21 (Fig. 2b)—that could only undergo a
HDDA reaction with a single regiochemical outcome. Our efforts were
rewarded by its smooth transformation at room temperature to the
hexasubstituted, tetracyclic indenone derivative 22 in 93% yield after
chromatographic purification.
TBSO
18
20
(1) Li
TMS; (2) MnO2, 0 °C
CDCl3
26 °C
O
TMS
TBS
O
TMS
t
1/2 = 7 h
O
46 h, 93%
TBSO
21
22
Figure 2
|
Mechanistic rationale, substrate synthesis and mild conditions
for our initial two HDDA reactions. a, Serendipitous observation of the
HDDA reaction: cyclization of ketone 14 (see blue dashed lines) to putative
benzyne (red) intermediate 16/169 (via formation of the bonds indicated by the
black dashed line in each) and subsequent trapping by the pendant silyl ether
gave a hexasubstituted benzenoid (blue), the indenone 15. b, Synthesis of
21 (via convergentcoupling of 18 with19, addition of an ethynyl unit to 20, and
oxidation) and its facile, high-yielding conversion to the tetracyclic benzenoid
(blue) 22. The adjacent atoms denoted by the triangle and dot in substrate
21 map onto those of the product 22. The half-life (t1/2) for conversion of 21 to
22 was measured by in situ NMR analysis (Supplementary Fig. 1). TBS,
t-butyldimethylsilyl.
Intramolecular trapping
As the examples presented in Table 1 clearly show, the HDDA-
initiated cascade has considerable scope with respect to both the cyclizes more slowly than its N-phenyl amide analogue (entry 5),
cycloisomerization and the intramolecular trapping events. Each sub- consistent with the lower concentration of the s-cis conformation
strate is readily accessible by a convergent coupling strategy (compare required for ring closure; our observations are consistent with the
Fig. 2b). All yields of purified products were $75%, and (with the absence of radical character in both the cycloaddition and trapping
exception of entry 8) all reactions occurred between temperatures of phases of the process (for example, reactions performed in chloroform
20 and 120 uC. Highlights include: the presence of an electron with- solvent, an excellent hydrogen atom donor, have shown no evidence of
drawing substituent on the diynophile enhances substrate reactivity hydrogen atom transfer (entries 4 and 9)); the new silyl ether trapping
(compare conditions for 21 to 22 (Fig. 2b) with entry 1); the activating reaction has considerable generality (entries 1–3, 5, 6 and 8 and Fig. 2);
carbonyl group can be a distal (carboalkoxy) rather than a tethering other efficient internal benzyne traps include tethered alcohols (entries
substituent (entries 2 and 3); many classical methods of aryne gen- 4 and 7), aryl rings ([412] cycloaddition in entry 9), or alkenes (ene
eration are not compatible with electron-withdrawing groups in the reaction in entry 10); seven-membered ring formation isfeasible (entry
substrate20; carbonyl activation is not a necessity (entries 1, 4 and 7); 8), and the robust nature of the substrate and product at the high
products having nitrogen-containing heterocycles annulated to the temperature required for this slower cyclization are noteworthy; and
new arene ring can be prepared (entries 3–5); an ester tether (entry 6) finally the silyl substituents in many of the products provide handles
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RESEARCH ARTICLE
Table 1
|
Examples of intramolecular trapping of HDDA-generated for subsequent elaboration through protonative, oxidative or halo-
genative desilylation or cross-coupling reactions21.
benzynes
Entry
Substrate
Conditions
Product
Intermolecular trapping
AcO
TMS
110 ºC
72 h
AcO
TMS
We wished to validate the feasibility of bimolecular trapping of these
thermally generated benzynes. Clearly, this would add considerable ver-
satility and power to a HDDA-initiated transformation. The triyne 23
(Fig. 3) represents a substrate that bears an innocent (non-participating)
side chain. We have successfully captured the derived benzyne 24
(formed from 23 in a cyclization reaction having a half-life of ,4 h
at about 85 uC) by a variety of external reagents to give adducts 25.
Highlights include: benzene as solvent forms the Diels–Alder adduct
25a (compare entry 9 of Table 1)—although this process has
been previously documented22, because of the low reactivity of simple
aromatics, rarely have they been trapped by benzynes in high yield;
this result also indicates that many intramolecular trapping events are
faster than capture by the aromatic solvents used in earlier examples
(entries 1–3 and 5–8 of Table 1); the [212] cycloaddition of nor-
bornene gives 25b in higher yield than has been observed for trapping
of arynes formed by conventional methods2; N-phenylacetamide gives
25c, demonstrating thata nitrogenous substituentcan beconveniently
installed; acetic acid22 or phenol traps 24 to cleanly provide adducts
25d or 25e, respectively, in processes that may share a mechanistic
feature of transfer of a hydroxyl proton coincident with nucleophilic
attack; this mode of reaction with acetic acid or phenol is unique and
complementary to that seen with benzynes generated by non-reagent-
free methods23,24; and finally net trapping by hydrogen bromide was
achieved using Br(CH2)2NH2NHBr in THF/H2O (20:1) as an HBr
source to give 25f (6:1 mixture of isomers).
The sense of regioselectivity observed for formation of products
25c–f is consistent with the analyses described in refs 24 and 25, in
which the relative magnitude of the computed internal bond angles of
an unsymmetrical benzyne is correlated with the site of nucleophilic
attack. Namely, the more obtuse angle corresponds to the more elec-
tron deficient (d1) of the two benzyne carbon atoms. We computed
the geometry for 24 (R 5 CH3) using density functional theory (DFT)
at the M06-2X/6-311G(d,p)26 level to have internal angles of 135u
and 119u at atoms ‘a’ and ‘b’, respectively. We are currently inves-
tigating additional substrates that should allow us to distinguish the
relative impact of electronic versus ring-distortion effects on the site
of attack by external nucleophiles.
1
2
O
O
PhMe
96%
vvt
tBuMe2Si
CO2Et
O
BuSiMe2
CO2Et
110 ºC
20 h
O
O
d8-PhMe
TBSO
CO2 Et
86%
TBS
CO2Et
120 ºC
18 h
N
3
4
O
N
Ts
PhMe
80%
Ts
TBS
TBSO
HO
OH
65 °C
20 h
TsN
CDCl3
95%
TsN
O
O
H
O
H
H
O
120 °C
O
H
15 h
PhN
PhN
5
6
PhMe
92%
TBS
H
TBSO
TBSO
120 °C
O
O
O
H
48 h
O
PhMe
86%
O
TBS
HO
95 °C
OH
48 h
E
E
7
To gain understanding of some of the key thermodynamic features
associated with the HDDA aryne-forming step, we turned to compu-
tational analysis of the reaction of ester 26 (Fig. 4). This simple triyne
was cycloisomerized and the resulting benzyne trapped in t-butanol
(120 uC, closed tube) to produce 5-t-butoxyphthalide (28) in 68%
yield. Johnson and co-workers recently reported a DFT approach to
compute the energetics of the hypothetical HDDA reaction of 7 with
12 to produce o-benzyne (1, Fig. 1e)27. They concluded that this
benzyne-forming reaction was exothermic by 51.4 kcal mol21. Using
similar DFT methodology, we have computed the free energy of reac-
tion for the conversion of triyne 26 to the aryne 27 and found it to be
251 kcal mol21. It is remarkable that highly reactive benzyne inter-
mediates can be accessed by a thermal process that is exothermic by
,50 kcal mol21. These very favourable reaction energetics reflect the
large amount of potential energy inherent in the (albeit kinetically
protected) alkyne functional group. Finally, this point is further under-
scored by the computed free energy of reaction—namely, 273 kcal
mol21—for the trapping by t-butanol of the strained alkyne28 in 27.
Thus, the overall transformation of 26 to 28 is computed to be exo-
E
E
PhH
87%
O
HO
E = CO2Me
O
H
195 ºC
32 h
O
8
9
o-DCB
O
O
O
O
75%
TBSO
TBS
TMS
O
85 ºC
18 h
TMS
O
CHCl3
85%
O
O
TMS
TMS
97 ºC
22 h
O
O
10
O
thermic by .120 kcal mol21
.
Heptane
83%
H
H
Discussion
Our results show that the HDDA reaction is a general method for
generating benzynes under conditions amenable to a wide variety of
intra- and intermolecular trapping events. This powerful and efficient
Benzenoid (bold black bonds) synthesis via the HDDA cycloaddition has considerable substrate scope
with respect to the nature of the poly-yne tether (red) and of the intramolecular trapping moiety (blue).
Ac, acetyl; Ts, p-toluenesulphonyl; o-DCB, 1,2-dichlorobenzene.
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ARTICLE RESEARCH
TMS
a
TMS
O
O
O
R
R
TMS
AcO
CHCl3
:Nu– El
+
δ
Nu
85 °C
18 h
(or π-donor)
b
δ–
El
23
[23] = 0.01 M
24
25
= 135°
= 119°
R = (CH2)3OAc
a
b
TMS
TMS
H
TMS
O
O
O
R
H
R
R
Ac
N
Ph
H
25a
25b
25c
PhH (solvent, 14 h); 70%
Norbornene (0.1 M); 63%
Single (exo) diastereomer
PhNHAc (0.15 M); 82%
19:1 ratio of isomers
TMS
O
TMS
O
TMS
O
R
R
R
OAc
Br(H)
H(Br)
H
H
HO
25d
25e
25f
Acetic acid (0.8 M); 89%
Single isomer
Phenol (0.1 M); 85%
Single isomer
BrCH2CH2NH3+Br–(0.1 M); 72%
6:1 ratio of isomers
Solvent = THF:H2O (20:1)
Figure 3
|
Examples of intermolecular trapping of HDDA-generated
trapping agent (and amount) and yield following purification. Stereochemical
benzynes. Bimolecular trapping reactions of benzyne 24 to give adducts 25a– information is given for adduct 25b. Regiochemical information is given for
f. Under the structure of each of these adducts is given information on the adducts 25c–f. THF, tetrahydrofuran.
domino sequence comprises a fundamentally new way to synthe- have revealed themselves. These include studies of mechanistic issues
(concerted versus stepwise cycloaddition), substituent effects (electronic
versus steric), catalysis (Lewis acid or transition metal), new modes
of benzyne trapping, the use of cleavable tethers, and the feasibility
of bimolecular HDDA cycloadditions. This enabling technology is
well-suited for preparing compound libraries, for accessing aromatics
having substitution patterns that would be otherwise challenging to
prepare, and for application to target molecule synthesis (for example,
drugs, natural products9,10, heteroaromatics and polyacenes). Lessons
of how imagery (that is, 1 (versus 19) from 7 1 12) can bias our
perception are also embedded in the developments described here.
Finally, our results serve as a reminder that, even in the twenty-first
century, serendipitous discovery (‘‘in the course of an otherwise unre-
lated study’’) in science can still play a pivotal role.
size benzenoid compounds—especially those having high structural
complexity. Because HDDA-derived benzynes are produced in the
absence of by-products and external reagents, the intrinsic reactivity
of a benzyne can be more fully explored and exploited. Even at this
early stage of development, many additional lines of investigation
ΔGM06-2X
ΔGM06-2X
O
= –51
= –73
O
O
O
kcal mol–1
kcal mol–1
O
O
tBuOH
68%
δ+
OtBu
120 ºC
40 h
δ–
H
26
27
28
METHODS SUMMARY
General procedure. An oven-dried vial containing the triyne precursor in the
indicated solvent (0.05 M) was closed with a Teflon-lined cap and heated at the
indicated (external bath) temperature. After the indicated time the product was
purified by chromatography on silica gel. Full procedural details and characteri-
zation data for all new compounds (substrates and products) and a detailed
descriptionofthecomputationalprotocolsandresults areprovidedinSupplemen-
tary Information.
26
+
51
tBuOH
27
+
73
tBuOH
Received 15 May; accepted 16 August 2012.
28
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Acknowledgements P.H.W. thanks the National Science Foundation for a graduate
researchfellowship. Financialsupportfromthe NationalInstitutes ofHealth(GM65597
and CA76497) is acknowledged. This work was carried out in part using hardware and
software provided by the University of Minnesota Supercomputing Institute.
Author Contributions B.B. performed the initial experiments. All authors designed the
experiments, analysed the data and wrote the manuscript.
Author Information Reprints and permissions information is available at
www.nature.com/reprints. The authors declare no competing financial interests.
Readers are welcome to comment on the online version of the paper. Correspondence
and requests for materials should be addressed to T.R.H. (hoye@umn.edu).
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