Rates of hexadehydro-Diels-Alder (HDDA) cyclizations: Impact of the linker structure

Article abstract of DOI:10.1021/ol502131r

The rates of the hexadehydro-Diels-Alder (HDDA) reaction of substrates containing, minimally, a 1,3,8-triyne subunit are reported. Several series of related substrates, differing in the nature of the three-atom tether that links the 1,3-diyne and diynophile, were examined. Seemingly small changes in substrate structure result in large differences in cyclization rate, spanning more than 8 orders of magnitude. The reactivity trends revealed by these studies should prove useful in guiding substrate design and choice of reaction conditions in future applications.

Full text of DOI:10.1021/ol502131r

Letter
pubs.acs.org/OrgLett
Open Access on 08/25/2015
Rates of Hexadehydro-Diels−Alder (HDDA) Cyclizations: Impact of
the Linker Structure
Brian P. Woods, Beeraiah Baire,† and Thomas R. Hoye*
Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States
S
* Supporting Information
ABSTRACT: The rates of the hexadehydro-Diels−Alder (HDDA) reaction of
substrates containing, minimally, a 1,3,8-triyne subunit are reported. Several
series of related substrates, differing in the nature of the three-atom tether that
links the 1,3-diyne and diynophile, were examined. Seemingly small changes in
substrate structure result in large differences in cyclization rate, spanning more
than 8 orders of magnitude. The reactivity trends revealed by these studies
should prove useful in guiding substrate design and choice of reaction
conditions in future applications.
he thermal cycloisomerization of triynes to benzyne1
intermediates2 is a powerful process because of its
reports8 (including the first9). By contrast, the results we report
here represent the first systematic study of HDDA cyclization
rates. We have examined the reactivities of several sets of related
HDDA substrates, all of which share the common generic
structure 4 (Scheme 1b). The relative reactivities of the members
of each set provide insight about the impact of structure on the
rate of the HDDA cyclization. All substrates differ primarily, but
in a complementary fashion, in the nature of the “XYZ” atoms
that serve to link the diyne to diynophile (Table 1, various
carbonyl functional groups; Table 2, various symmetrical
tetraynes; and Tables 3 and 4, enones embedded within different
T
considerable generality.3 For example, we showed that the triyne
1 isomerized to the indenone product 3 at ambient temperature
via the reactive benzyne 2 (Scheme 1a), an overall process that we
Scheme 1. (a) Early Example of a HDDA Cascade (b) Generic
Substrates Whose Rates of Cyclization Are Reported Here
Table 1. HDDA Cycloisomerization Rates of Substrates 7−9,
Differing in the Carbonyl Functional Group in the Tether
have termed a hexadehydro-Diels−Alder (HDDA) cascade.3
This sequence comprises an initial rate-limiting benzyne
formation (1 to 2, Stage I) followed by a rapid benzyne trapping
event (2 to 3, Stage II, here with a tethered silyl ether moiety4).
Because each of the steps in the cascade is purely a thermal
process, many opportunities for using this platform for the
development of novel chemistries and/or fundamental mecha-
nistic understanding are presenting themselves.5,6
Triynes have a wide range of activation barriers for the initial
HDDA cycloisomerization event (i.e., Stage I).2c,3 The structural
features that influence the reactivity of dienes and dienophiles in
classic [4 + 2] Diels−Alder cycloaddition reactions (including
intramolecular variants7) have been delineated in manifold
a
Yields represent material following chromatographic purification
from experiments performed in o-DCB on scales of 20−40 mg of
substrate.
Received: July 19, 2014
© XXXX American Chemical Society
A
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Table 2. HDDA Cycloisomerization Rates of Substrates with
No Conjugated Electron-Withdrawing Substituents
Scheme 2. HDDA Cyclization of the Unsymmetrical
Ketotetrayne 13 Showing the Competition between Normal
(Blue) and Abnormal (Red) Modes of Reaction
a
Yields represent material following chromatographic purification.
carbocycles). The half-life for the Stage 1 cyclization, the rate-
limiting step for all of these unimolecular isomerizations, was
determined for each substrate. For the sake of consistency, the
same β-(tert-butyldimethylsilyloxy)ethyl moiety was used as the
internal trapping group4 (cf. 5 to 6) for each substrate. However,
because the intramolecular Stage II trapping event is much faster
than the Stage I HDDA reaction, it is safe to presume that the
exact choice of the nature of this benzyne trap is not particularly
relevant. The range of relative rates of the HDDA reactions
described here encompasses more than 8 orders of magnitude. In
some instances even seemingly subtle changes within the tether
structure were observed to have a relatively large impact on rate.
The triyne (or tetrayne) substrates in each table are listed in
order of decreasing reactivity. The first set of triynes is shown in
Table 1 (7−9); each cleanly gave the expected product (10−12,
respectively) upon heating. These triynes differ only in the nature
of the carbonyl functional group that is innate to the three-atom
tether in each. The reaction temperature and time for the
observed half-lives are given in the second column. The
approximate relative rates (rightmost column) for the unim-
olecular HDDA cyclization (the rate-determining step) span
more than 4 orders of magnitude (see Supporting Information
(SI) for details of how the relative rates and half-lives were
determined). The reactivity sequence is amide 7 > ester 8 ≫
ketone 9. These carbonyl functional groups affect both the
electronic character of the diynophile (in this series, the
monoyne) as well as the population of the reactive
conformation10 (cf. reactive rotamer effect11)the structure
depicted for each of 7−9. Intramolecular Diels−Alder (IMDA)
reactions have been reported for analogous pairs of classical
triene substrates in which the only difference was the presence of
an amide vs an ester10 or of an ester vs a ketone11 functionality
within the tether. Those cases also showed greater reactivity of
the amide over the ester and of the ester over the ketone,
respectively, which is similar to what we have observed for this
series of HDDA reactions.
a
Yields represent material following chromatographic purification and
are from experiments performed on scales of 20−40 mg of substrate in
1,2-DCE for 17, CDCI3 for 18,4 and o-DCB for 19.
Table 3. HDDA Cycloisomerization Rates of Substrates
Having Various Carbocycles Embedded in the Linker
We proceeded to study the unsymmetrical tetrayne 13
(Scheme 2), in which the linker is the same three-carbon ketone
subunit that is present in the triyne 9. Now two modes of HDDA
cyclization are possible. These differ in whether the 1,3-diyne
bearing the carbonyl substituent functions as the 2π (blue) or the
4π (red) HDDA component, that is, the diynophile or the diyne,
respectively. The first, which gives product 14, we call the
‘normal’ mode, and the second, leading to 15, is the ‘abnormal.’
The normal mode of cyclization is favored over the abnormal,
a
b
R = CH2CH2OTBS. Yields represent material following chromato-
graphic purification from experiments performed on scales of 20−40
mg of substrate, in various solvents, and for ca. 5 half-lives (see SI).
B
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a
This is perhaps most clearly seenby comparison of the rates of the
identically tethered tetrayne and triyne ketones 13 and 9,
respectively. The former (tetrayne) reacted nearly 5 orders of
magnitude faster than the latter (triyne) [krel(13a vs 9) = 8 × 104].
While it might be tempting to assign a significant portion of this
difference to a steric effect imposed by the trimethylsilyl group in
9 that becomes more pronounced as the transition structure
geometry is approached, we have evidence that this is not a
dominant factor. Namely, each of the substrates 23a−c (Table 2,
bottom) is a triyne analog of the tetraynes 17−19 in which one of
the two diyne units has been truncated to a simple terminal
monoyne (propargyl) moiety. Each of these triynes proved to be
much less reactive than the analogous tetrayne. When finally
heated to temperatures where starting material disappeared,16
decomposition to dark-colored, presumably oligomeric materials
was observed without any clear evidence for formation of the
product of an HDDA cascade. These observations further
emphasize the fact that an alkyne substituent enhances the
diynophilicity of the 2π-participant in HDDA cyclizations.
This type of activation of one π-component by a second of its
own kind is well-known, of course, in alkene chemistry. For
example, 1,3-butadiene enters into a [4 + 2] cycloaddition much
faster with itself than with ethylene as the dienophile, which is
consistent with the lower HOMO−LUMO gap for the former
pair of reactants. We suggest that this same type of behavior is
operative in conjugated di-, tri-, and poly-ynes. For example, neat
samples of liquid 1,3-butadiyne have been reported to detonate.17
Moreover, a report of isolation of 1,3,5-hexatriyne (produced by a
fungus) gave rise to “colorless crystals...which decomposed
slowly at −20° and explosively at room temperature.”18 In the
course of defining the boundaries for stability of progressively
longer linear conjugated poly-ynes, researchers in the Tykwinski
laboratory have established that multiynes are greatly stabilized
by the presence of extremely bulky α,ω-terminal substituents that
prevent the internal poly-yne chains from associating with one
another in parallel fashion.19 Taken together with the fact that the
HDDA cycloaddition of three alkynes to their corresponding
benzyne is computed to be exothermic by ca. 50 kcal mol−1 (!),20
we submit that the instability of unhindered, conjugated
multialkynes is due to the fact that they enter into HDDA
dimerization and, then, oligomerization with sufficiently rapid
heating to result in uncontrolled (and typically unwanted)
reactions. Moreover, we suggest that carbyne [(CC)n], the
elusive missing allotrope of carbon, will most likely never be
tamed as a tractable substance because its inherently low
HOMO−LUMO gap will necessarily result in facile cross-linking
reactions having the nature of an HDDA process.21
Table 4. Rate Effects of Changing the Location (a Series vs b
a
Series) or the Presence (a Series vs c Series) of an Electron-
Withdrawing Group (Carbonyl) within the Triyne Linker
a
Structures 1a, 24a, and 26a are identical to 1, 24, and 26 given in
Table 3. R = CH2CH2OTBS. The krel values for 24a:1a:26a are
b
c
9000:400:1 (data from Table 3).
although only by a factor of ca. 2, as judged from the 14/15
product ratio.12 For comparison we prepared the tetrayne 16, in
which the tether comprises three methylene groups and,
therefore, lacks the ketone carbonyl. It proved to be noticeably
less reactive, ultimately decomposing at higher temperatures to
mixtures that showed no evidence of formation of the expected
HDDA product 16.13 Thus, the ketone carbonyl group in 13 has a
definite activating effect3 on both the normal (blue) and
abnormal (red) pathways.
In sharp contrast to the fact that 16 is not a competent HDDA
substrate, each of the analogously symmetrical tetraynes 17−19
smoothly undergoes an HDDA cascade to give essentially a single
product, 20−22, respectively (Table 2). The only structural
difference among 16−19 is the nature of the central atom within
the three-atom linker joining the two identical 1,3-diyne moieties.
The most reactive of 17−19 is the ether-linked tetrayne 17 and
the least is the malonate 19. These three span a relative rate ratio
of ca. 200, with the sulfonamide 18 nearly as reactive as the ether
17. The more reactive ether and amide tetraynes have, perforce, a
more electronegative substituent on each of their propargylic
carbons as well as a slightly shorter carbon-to-heteroatom bond
length compared to the all-carbon linker in the nonproductive
substrate 16. Notably, the rate enhancement from the reactive
rotamer/Thorpe−Ingold effect11 imposed by the malonate
substituents in 19 apparently is sufficient to overcome the
reluctance of 16 to undergo HDDA cyclization (cf. Scheme 2).
From early reports of these types of cycloisomerization
reactions, it can be deduced that tetraynes (i.e., a linked pair of
two separated 1,3-butadiyne units) show greater reactivity than
their analogous triynes.14,15 We have now deduced the extent to
which the presence of the bystander alkyne in each of the
substrates 17−19 activates the diynophile to which it is attached.
We next examined the influence of the size and/or the nature of
the carbocycle upon which the diyne and diynophile are
templated. The series of five triyne substrates 1 and 24−27 was
studied, and their reactivities are shown in Table 3. Variation of
the carbocycle embedded within the diyne-to-ynone linker
results in HDDA-cyclization rates that, remarkably, span ca. 7
orders of magnitude. The most reactive of all HDDA substrates
we have studied to date3,4,6 is the cycloheptene-containing triyne
24, which cyclizes within hours at 0 °C. In contrast the
cyclopentene substrate 27 requires heating at 150 °C to achieve
50% conversion in 4 h.
The intraring bond angles at the alkene carbons differ across
this series of substrates. This impacts the angles at which the
diyne and ynone substituents are splayed with respect to the
cycloalkene, which, in turn, dictates the distance between the
proximal pair of terminal diyne/diynophile carbons in each
C
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pyridynes, naphthalynes, or indolynes); (ii) o-benzyne (2): the parent
1,2- or o-dehydrobenzene; (iii) a benzyne derivative (collectively,
“benzynes”): any substituted o-benzyne analog; this may or may not be
fused to an additional, nonaromatic ring. Thus, the arynes described here
from HDDA cycloisomerization of a triyne subunit are “benzynes”.
(2) (a) Bradley, A. Z.; Johnson, R. P. J. Am. Chem. Soc. 1997, 119, 9917.
(b) Miyawaki, K.; Suzuki, K.; Kawano, T.; Ueda, I. Tetrahedron Lett.
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reactant. This splay angle (and resulting distance) is largest for
the cyclopentene and smaller (and more similar) for the 6-, 7-,
and 8-membered cycloalkenes (see SI). These subtle changes in
geometry translate into the large differences in reactivity. This
acute sensitivity to small geometric changes is reminiscent of
observations made for Bergman (enediynes22) and Hopf
(dienyne23) electrocyclizations.
Finally, we studied the effect of (i) reversing the relative
orientation of the enone in a set of otherwise identical substrates
[cf. the a (“normal”) series vs the b (“abnormal”) series in Table
4] and (ii) interrupting the contiguous conjugation by
replacement of the ketone carbonyl with a reduced carbinol
derivative (cf. the a series vs the c series in Table 4). Each normal
member of the isomeric pair of enones reacted faster than the
abnormal analog, although only by a factor ranging from 30−80.
This is not dissimilar to the result presented earlier for the two
modes of reaction within ketotetrayne 13.12 Finally, each normal
enone reacted faster than its acetate analog by a considerably
larger rate factor (ca. 103 to 2 × 105), again emphasizing the
significant acceleration afforded by an electron-withdrawing
carbonyl group.
In conclusion, the results presented here provide useful insight
into both electronic and structural factors that affect the rate of
HDDA cyclization. For example, substrates having a heteroatom
within the three-atom tether joining the 1,3-diyne to the
diynophile cyclize faster than their methylene analogs (Table
2). Even minor geometric differences within the linker can have a
dramatic effect on cyclization rates (cf. cyclic enones in Table 3).
The presence of an additional bystander alkyne (cf. tetrayne
substrates) provides a rate enhancement (several orders of
magnitude) similar to that of a carbonyl substituent (cf. Table 2
with 13 vs 9). These studies should help guide the planning of
future applications of HDDA processes for the synthesis of
benzenoid target structures. These results expand the scope of
product types accessible by an HDDA strategy, especially when
considered in conjunction with the growing body of HDDA-
derived benzyne trapping reactions.3−6
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(13) When 16 was heated at 165 °C for 1 h, only a few percent of 16
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(14) (a) Miyawaki, K.; Kawano, T.; Ueda, I. Tetrahedron Lett. 1998, 39,
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, copies of 1H and
13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) Tsui, J. A.; Sterenberg, B. T. Organometallics 2009, 28, 4906.
(16) Consumption (ca. 50%) of triyne (1H NMR) was observed after
ca. 1 h at 165 °C for 23a, at 150 °C for 23b, and 200 °C for 23c.
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(21) Conjugated multi-ynes preorganized in the solid state can undergo
facile, controlled oligomerization: cf. Lauher, J. W.; Fowler, F. W.;
Goroff, N. S. Acc. Chem. Res. 2008, 41, 1215.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hoye@umn.edu.
Present Address
†Dr. Beeraiah Baire, Department of Chemistry, IIT Madras,
Chennai 600036, India.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge the General Medical Institute of the National
Institutes of Health (GM65597) for support of this research.
■
(23) Prall, M.; Kruger, A.; Schreiner, P. R.; Hopf, H. Chem.Eur. J.
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any aromatic ring containing an adjacent pair of sp-hybridized carbon
atoms (this includes any of the subfamilies of, for example, benzynes,
D
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