Reactivity and selectivity in the intermolecular alder-ene reactions of arynes with functionalized alkenes

Article abstract of DOI:10.1021/acs.orglett.7b02438

The reactivity and selectivity of functionalized alkenes in intermolecular Alder-ene reactions with arynes is described. The arynes generated from bis-1,3-diynes react with various trisubstituted and 1,1-disubstituted alkenes containing hydroxyl, amino, halo, carboxyl, boronate, and 1,3-dienyl functionalities, providing product distributions with varying degrees of selectivity between Alder-ene and addition reactions. The geometry of alkenes is another important factor for the reactivity of di- and trisubstituted alkenes where the allylic hydrogen of cis-disposed alkenyl system is reactive, which is the opposite reactivity compared to the corresponding intramolecular reaction.

Full text of DOI:10.1021/acs.orglett.7b02438

Letter
pubs.acs.org/OrgLett
Reactivity and Selectivity in the Intermolecular Alder−Ene Reactions
of Arynes with Functionalized Alkenes
Saswata Gupta,† Peipei Xie,‡ Yuanzhi Xia,*,‡ and Daesung Lee*,†
†Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, United States
‡College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, Zhejiang Province 325035, P. R. China
S
* Supporting Information
ABSTRACT: The reactivity and selectivity of functionalized
alkenes in intermolecular Alder−ene reactions with arynes is
described. The arynes generated from bis-1,3-diynes react with
various trisubstituted and 1,1-disubstituted alkenes containing
hydroxyl, amino, halo, carboxyl, boronate, and 1,3-dienyl
functionalities, providing product distributions with varying
degrees of selectivity between Alder−ene and addition
reactions. The geometry of alkenes is another important
factor for the reactivity of di- and trisubstituted alkenes where the allylic hydrogen of cis-disposed alkenyl system is reactive,
which is the opposite reactivity compared to the corresponding intramolecular reaction.
lder−ene reactions are an effective synthetic method to
functionalize allylic C−H bonds with a concomitant 1,3-
donor methyl methacrylate (Table 1). Reactions with varying
amounts of the ene donor showed that 5 equiv of methyl
methacrylate relative to the aryne precursor 1 provided the
highest yield of the ene reaction product 2a (72%); thus,
subsequent studies employed this stoichiometry unless stated
otherwise. Under this optimized condition, the Alder−ene
A
transposition of the involved alkenes.1 A wide variety of
electron-deficient π-systems have been employed as ene
acceptors for thermal and Lewis acid catalyzed Alder−ene
reactions, while alkenes can participate in the reaction if a
suitable transition-metal catalyst is used.2 Recently, Lee and
other groups took advantage of the hexadehydro Diels−Alder
reaction as an effective method for generating arynes3 and using
them in intramolecular Alder−ene reactions.4,5 To expand the
scope and utility of the green nature of the Alder−ene reaction
requiring no additional reagents other than heat for allylic C−H
bond functionalization,6 we envision an intermolecular Alder−
ene reaction of arynes with alkenes containing an additional
functional group (Scheme 1). Although the intermolecular
Table 1. Alder−Ene Reactions of Functionalized 1,1-
Disubstituted Alkenes with an Aryne
Scheme 1. Intermolecular Alder−ene Reactions of Arynes
Alder−ene reactions of hydrocarbon-based symmetrical alkenes
with structurally simple arynes are reported in the literature,7
the reactions of functionalized unsymmetrical alkenes in
intermolecular Alder−ene reactions have not been explored.
Herein, we describe the characteristic reactivity and selectivity
features of intermolecular Alder−ene reactions of function-
alized alkenes with arynes generated via hexadehydro Diels−
Alder reaction conditions.
a
b
All alkenes are used in 5 equiv amount relative to 1. Isolated yield.
c
With a larger scale (1 mmol), 2a was obtained in 68% yield.
First, we examined the Alder−ene reaction by using a
symmetrical tetrayne (1) and electronically deactivated ene-
Received: August 7, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02438
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Organic Letters
Letter
reactions of other 1,1-disubstituted alkenes bearing additional
functional groups provided the corresponding Alder−ene
products 2b−h in good yields ranging from 55% to 81%.
Next, we examined the reactivity of trisubstituted alkenes
containing a substituent, including an allylic bromide, a
conjugated carboxylate, a ketal, dimethyl malonate moiety, a
carbamate, an ester, an aldehyde, and a silyl ether (Table 2).
Scheme 2. Reactivity of 1,1-Di- and Trisubstituted Alkenes
and Geometrical Isomers of Trisubstituted Alkenes
Table 2. Alder−ene Reactions of Functionalized
Trisubstituted Alkenes with an Aryne
retained in the methyl group. The transition-state energies from
DFT calculations9 (Scheme 2) are consistent with this
conclusion. The Alder−ene reaction with a trans-disposed
methyl group leads to a transition state higher in energy by 3.4
kcal/mol than that of the cis-disposed methyl group. This is
because the trans-disposed methyl group becomes a pseudoe-
quatorial substituent at the transition state, which develops an
extra nonbonded interaction against the aryne moiety.
With the relative reactivity trend of differently substituted
alkenes in hand, we next examined the reaction profiles of
alkenyl alcohols (Table 3). In general, disubstituted alkenes
containing a hydroxyl group provide only hydrogenation10
product 4 (entries 1−4). Upon converting the hydroxyl group
to a silyl ether moiety, the cis- alkene became reactive for an ene
reaction (cyclooctadiene mono epoxide in entry 4) but the
trans-alkene was unreactive (TBS ether of crotyl alcohol in
entry 1). Trisubstituted alkenyl alcohols generated varying
degree of the Alder−ene reaction and hydrogenation depend-
ing on the disposition of allylic C−H bonds. For example,
verbenol afforded only hydrogenation product because of the
unreactive trans-disposed methyl group (entry 5), while prenyl
alcohol and 6-methylhept-5-en-2-ol provided mainly Alder−ene
products 5f and 5g along with 4 (entries 6 and 7). 1,1-
Disubstituted alkenyl 1° and 2° alcohols provided exclusively
Alder−ene products 5h−j (entries 8−10) except for an alkene
containing an allylic 2° hydroxyl group, which promotes
hydrogenation, forming 4 in significant amount (entry 11). A
notable observation from Table 3 is the lack of aryl ethers albeit
alcohols can undergo addition with arynes easily.
The overall yields of the reaction involving these trisubstituted
alkenes (entries 1−7) are slightly lower (ranging from 35 to
65%) than those of 1,1-disubstituted alkenes. It is worth noting
that the geometrical isomers show a stark difference in
reactivity such that the E-isomer generates ene reaction product
3g (entry 7), but the corresponding Z-isomer yields no ene
reaction product (entry 8).
The reactivity difference between 1,1-disubstituted and
trisubstituted alkenes and the allylic C−H bonds of cis- and
trans-disposed methyl groups were further examined8 (Scheme
2). When methallylprenyl ether was heated with 1, a mixture of
3h and 3i was obtained in 61% yield with a ratio of 1.5:1, which
suggests that 1,1-disubstituted alkenes are slightly more reactive
than trisubstituted alkenes. The reactivity of geometrical
isomers of trisubstituted alkenes was examined with geraniol
and nerol. The reaction with geraniol afforded a mixture of 3j
(60%) and 3k (27%) in a 2.2:1 ratio. On the other hand, nerol
provided only a single Alder−ene product 3l (66%) along with
a sizable amount of hydrogenation product 4 (19%). The
different product distribution indicates that the allylic C−H
bonds on the methyl group cis to the substituent on the next
carbon are reactive in the Alder−ene reaction, while the
corresponding C−H bonds on the trans methyl group are inert.
This is further confirmed by employing a deuterated nerol,
which provided product 3l-d where deuterium is completely
Recognizing the preferred Alder−ene reactivity of an aryne,
we next examined the competition between an Alder−ene and
a Diels−Alder reaction11 by employing alkenes containing a
1,3-diene moiety (Table 4). Acyclic dienes such as isoprene and
2,3-dimethylbutadiene provided only Alder−ene products 6a
and 6b in 54% and 58% yield, respectively (entries 1 and 2),
while the pivalate-substituted 2,3-dimethylbutadiene afforded a
B
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Letter
regardless of the tethered alkene, only Diels−Alder reaction
products 7d−f were obtained in good yields (entries 4−6).
Finally, we examined the regioselectivity (ortho/meta) of the
Alder−ene reaction with other unsymmetrical arynes (Table 5).
Table 3. Ene Reactions of Alkenyl Alcohols with an Aryne
Table 5. Regioselectivity in the Alder−Ene Reaction of
Arynes
The reaction of an NTs-tethered symmetrical tetrayne and
methyl methacrylate afforded isoindolines 8a−c and 2d in good
yields where the ratio of ortho/meta changes from 1.4:1 (H) to
only meta (SiEt3) depending on the steric bulk of the
substituent. On the other hand, the reaction of an ynamide-
tethered tetrayne afforded the ortho-isomer of indolines 9a−c
with Bu, H, and an aryl substituent on the aryne but generated
only the meta-isomer 9d with SiEt3 substituent. The aryne with
a fluorenone skeleton showed substituent-dependent ortho/
meta selectivity where a sterically less hindered butyl group
afforded a 1.4:1 mixture of 10-ortho and 10-meta, whereas a
bulky SiEt3 group confer an excellent control to generate only
meta product 10b. Similar selectivity was observed for meta-
isomers of 11 and 12. It is worth noting that the general
regioselectivity in the Alder−ene products 8, 10, 11, and 12 is
opposite to that of other nucleophile additions.12 Only
indolines 9a−c showed the same preference of a meta isomer
in both Alder−ene reaction and other nucleophile addition
reactions.
a
b
c
Alkene (5 equiv), toluene 90 °C, 4 h. Isolated yield. The reaction
d
led to polymerization of the aryne intermediate. The reaction
e
provided Alder−ene product 5d′ in 52% yield. Even with 5 equiv
each of MeOH and methallyl alcohol, only an Alder−ene reaction
occurred without formation of MeOH adduct.
Table 4. Selectivity between an Alder−Ene and Diels−Alder
Reaction of 1,3-Dienes Reacting with an Aryne
In summary, we have systematically investigated the
reactivity and selectivity issues of the Alder−ene reactions of
arynes reacting with a variety of alkenes containing additional
functional groups. In general, 1,1-disubstituted acyclic and
cyclic alkenes are most favorable for Alder−ene reaction over
other reactions such as hydrogenation by hydrogen transfer
from an alcohol moiety or its direct addition to form aryl
ethers. The reactivities of trisubstituted alkenes are slightly
lower than 1,1-disubstituted alkenes, and the disposition of the
reacting allylic C−H bonds is crucial for their reactivity: the
allylic C−H bonds of the carbon cis to the substituent on the
next carbon are reactive but the corresponding C−H bonds on
the trans position are inert. For acyclic 1,3-dienes containing
allylic C−H bonds, an Alder−ene reaction is more favorable
over a Diels−Alder reaction. On the other hand, alkene-
tethered cyclic dienes such as furan and pyrrole participate in
Diels−Alder reactions much more favorably over an Alder−ene
process because of the alkene moiety. High regioselectivity in
Alder−ene reactions has been demonstrated by judiciously
installing substituents with steric and electronic factors. Overall,
the aryne-mediated Alder−ene reaction is an effective and
1:1 mixture of 6c and Diels−Alder product 7c in 52% overall
yield (entry 3). From cyclic dienes such as furan and pyrrole
C
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Organic Letters
Letter
(6) Representative reports on transition-metal-catalyzed allylic C−H
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green protocol for allylic C−H functionalization that has its
own merit compared to other methods.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02438.
(7) (a) Chen, Z.; Liang, J.; Yin, J.; Yu, G. A.; Liu, S. H. Tetrahedron
Lett. 2013, 54, 5785−5787. (b) Per
́
ez, P.; Domingo, L. R. Eur. J. Org.
Chem. 2015, 2015, 2826−2834.
Detailed experimental procedures, characterization data,
(8) Stereoselectivity of Alder−ene reactions: (a) Oppolzer, W.;
Snieckus, V. Angew. Chem., Int. Ed. Engl. 1978, 17, 476−478.
(b) Tschaen, D. M.; Turos, E.; Weinreb, S. M. J. Org. Chem. 1984,
49, 5058−5064. (c) Thomas, B. E.; Houk, K. N. J. Am. Chem. Soc.
1
and H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
1993, 115, 790−792. (d) Griesbeck, A. G.; Bartoschek, A.; Neudorfl,
̈
J.; Miara, C. Photochem. Photobiol. 2006, 82, 1233−1240.
(9) All calculations were carried out with the Gaussian 09 suite using
the B3LYP-D3/6-31+G* method in the gas phase. See the details in
the Supporting Information
*E-mail: xyz@wzu.edu.cn.
*E-mail: dsunglee@uic.edu.
ORCID
(10) (a) Niu, D.; Willoughby, P. H.; Baire, B.; Woods, B. P.; Hoye, T.
R. Nature 2013, 501, 531−534. (b) Willoughby, P. H.; Niu, D.; Wang,
T.; Haj, M. K.; Cramer, C. J.; Hoye, T. R. J. Am. Chem. Soc. 2014, 136,
13657−13665.
Yuanzhi Xia: 0000-0002-7125-269X
Daesung Lee: 0000-0003-3958-5475
Notes
(11) (a) Zhang, M. X.; Shan, W.; Chen, Z.; Yin, J.; Yu, G. A.; Liu, S.
H. Tetrahedron Lett. 2015, 56, 6833−6838. (b) Pogula, V. D.; Wang,
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B.; Hoye, T. R. Tetrahedron Lett. 2015, 56, 3265−3267. (d) Bhojgude,
S. S.; Bhunia, A.; Biju, A. T. Acc. Chem. Res. 2016, 49, 1658−1670.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from NSF (1361620, D.L.) and NNSFC
(21372178 and 21572163, Y.X.) and the mass spectrometry
facility at UIUC are greatly acknowledged.
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