Diels-Alder/Ene Reactivities of 2-(1′-Cycloalkenyl)thiophenes and 2-(1′-Cycloalkenyl)benzo[ b]thiophenes with N-Phenylmaleimides: Role of Cycloalkene Ring Size on Benzothiophene and Dibenzothiophene Product Distributions

Article abstract of DOI:10.1021/acs.joc.9b03363

Scaffolds of thiophene and benzothiophene are the important class of bioactive compounds found abundant in nature. The Diels-Alder reactions of 2-(1′-cycloalkenyl)thiophenes and 2-(1′-cycloalkenyl)benzo[b]thiophenes having the alkene groups present in five-, six-, seven-, eight-, and twelve-membered rings with substituted N-phenylmaleimides are characterized. The size of the cycloalkene rings plays a critical role in dictating the product distributions of expected and isomerized Diels-Alder adducts. 2D NMR studies indicate that the isolated isomers for 2-(1′-cycloalkenyl)thiophenes having five-, six-, and seven-membered rings are aromatized benzothiophene products, whereas eight- and twelve-membered rings are un-rearranged adducts. In addition, the product of subsequent ene-reaction with the N-phenylmaleimide is isolated for the five- and six-membered ring cases. Interestingly, in the 2-(1′-cycloalkenyl)benzo[b]thiophene having five-, six-, seven-, eight-, and twelve-membered rings, the un-rearranged dibenzothiophene Diels-Alder adduct is isolated in every instance. Molecular mechanics and density functional theory (M06-2X and PBE0-D3) calculations are performed to understand the differential reactivity of the various dienes for both the initial Diels-Alder reaction and a possible, subsequent ene reaction.

Full text of DOI:10.1021/acs.joc.9b03363

Subscriber access provided by NATIONAL UNIV OF SINGAPORE
Article
Diels–Alder/Ene Reactivities of 2–(1´–Cycloalkenyl)thiophenes
and 2–(1´–Cycloalkenyl)benzo[b]thiophenes with N–
Phenylmaleimides: Role of Cycloalkene Ring Size on
Benzothiophene and Dibenzothiophene Product Distributions
Wayland E Noland, Honnaiah Vijay Kumar, Yernaidu Reddi, Christopher J. Cramer, Alexei V Novikov, Hyejin
Kim, Yumeng Zhu, Yoke Ching Chin, Yuqi Zhou, Predrag Radakovic, Anjola Uprety, Jun Xie, and Grant C Flick
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03363 • Publication Date (Web): 16 Mar 2020
Downloaded from pubs.acs.org on March 16, 2020
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Diels–Alder/Ene Reactivities of 2–(1´–Cycloalkenyl)thiophenes and
2
–(1´–Cycloalkenyl)benzo[b]thiophenes with N–Phenylmaleimides:
Role of Cycloalkene Ring Size on Benzothiophene and
Dibenzothiophene Product Distributions
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Wayland E. Noland*, Honnaiah Vijay Kumar, Yernaidu Reddi, Christopher J.
Cramer, Alexei V. Novikov, Hyejin Kim, Yumeng Zhu, Yoke Ching Chin, Yuqi
Zhou, Predrag Radakovic, Anjola Uprety, Jun Xie, and Grant C. Flick
Department of Chemistry, Chemical Theory Center, and Supercomputing Institute, University of
Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota-55455. Email– nolan001@umn.edu
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ABSTRACT:
Scaffolds of thiophene and benzothiophene are the important class of bioactive compounds found
abundant in nature. The Diels–Alder reactions of 2–(1´–cycloalkenyl)thiophenes and 2–(1´–
cycloalkenyl)benzo[b]thiophenes —having the alkene groups present in five–, six–, seven–, eight–
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and twelve–membered rings with substituted N–phenylmaleimides are characterized. The size of
the cycloalkene rings plays a critical role in dictating the product distributions of expected and
isomerized Diels–Alder adducts. 2D NMR studies indicate that the isolated isomers for 2–(1´–
cycloalkenyl)thiophenes having five–, six–, and seven–membered rings are aromatized
benzothiophene products whereas, eight– and twelve–membered rings are un–rearranged adducts.
In addition, the product of subsequent ene–reaction with the N–phenylmaleimide is isolated for
the
five–
and
six–membered
ring
cases.
Interestingly,
in
the
2–(1´–
cycloalkenyl)benzo[b]thiophene having five–, six–, seven–, eight–, and twelve–membered rings,
the un–rearranged dibenzothiophene Diels–Alder adduct is isolated in every instance. Molecular
mechanics and density functional theory (M06–2X and PBE0–D3) calculations are performed to
understand the differential reactivity of the various dienes for both the initial Diels-Alder reaction
as well as a possible, subsequent ene reaction.
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INTRODUCTION
Polycyclic thiophene and benzothiophene–based heterocycles are key intermediates and relevant
targets in the fields of synthetic, medicinal, and materials chemistry.1–12 In modern drug discovery,
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polysubstituted thiophenes are important because they constitute a bioisosteric replacement for
the phenyl ring. Thiophene containing derivatives are often characterized by reduced toxicity and
better pharmacokinetic properties.14 Several commercialized drugs containing thiophene and
benzothiophene motif have a wide range of applications in medicinal use (1-5, Figure 1). For
instance, Clopidogrel, Cymbalta(Duloxetine), Raltitrexed (Tomudex®), Arzoxifene etc.
Figure 1. Important drug molecules containing thiophene and benzothiophene core moiety.
The Diels–Alder reaction is a useful and powerful way to form two carbon–carbon bonds
and set up to four stereocenters in a single step. The Diels–Alder reaction provides a valuable
method for the regioselective and stereoselective synthesis of polycyclic compounds.15 This
method has been successfully applied to the synthesis of heterocycles using both heterodienophiles
and/or heterodienes16 and cycloaddition of vinylheterocycles.17 Vinylthiophenes as a diene
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component in the current study have been explored to a minor extent as it was initially thought
that thiophene, being exceedingly aromatic, would not contribute in Diels–Alder reactions.18,19
However, 2–vinylthiophene equivalents were first shown to undergo Diels–Alder reactions by
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Szmuszkovicz and Modest in 1950,on maleic anhydride with various 2–cycloalkenylthiophenes.20
Unsubstituted 2–vinylthiophene was first shown to give the [4+2] cycloadduct with maleic
2
1
anhydride in 1953 by Scully and Brown. Later examples include Diels–Alder reactions of 2–
2
2
23,24
p–benzoquinone,22
vinylthiophene with maleic anhydride, N–phenylmaleimide (6, Figure 2),
azo compounds,23,25–27 dimethylacetylenedicarboxylate (DMAD),23,24 methyl propiolate, singlet
28
oxygen,29 and nitrosobenzene.23 Other examples include 2–(1–trimethylsiloxyvinyl)thiophene
with a variety of dienophiles and 4–methyl–2–vinylthiophene with 1,4–naphthoquinone.30
Figure 2. Selected Diels–Alder/ene adducts of thiophene and benzothiophene with N–
phenylmaleimides.
2
–Vinylbenzo[b]thiophene was first shown to undergo a [4+2] cycloaddition reaction by
Cherry, Craig and Porter in 1979 using 3–methyl–2–vinyl–benzo[b]thiophene with 1,1,2,2–
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31
tetracyanoethylene (TCNE). In 1989 Ghosh et al. demonstrated the first Diels–Alder reaction of
unsubstituted 2–vinylbenzo[b]thiophene with DMAD, TCNE, maleic anhydride, and p–
benzoquinone.32
Later
examples
include
[4+2]
cycloadditions
of
2–
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cyclopentenylbenzo[b]thiophene with N–phenylmaleimide, 2–vinylbenzo[b]thiophene with 3–
3
4
nitro–2–cyclohexen–1–one and 2–inden–1–one under thermal and high pressure conditions, and
also an intramolecular Diels–Alder reaction.35
Interestingly, a few reports were found on Diels–Alder reaction of 2–(1´–
cycloalkenyl)thiophenes,20 or 2–(1´–cycloalkenyl)benzo[b]thiophenes33 (10, Figure 2). The
resulting Diels–Alder adducts can also undergo Michael–addition or ene–reaction with an
additional molecule of dienophile.24,26,28 In an extension of our prior work with 3–vinylindoles,36
37
38
2
– and 3–vinylpyrroles, and 5–(pyrrolidin–3–yl)thieno[3,2–e]isoindoles (8, 9; Figure 2) ; we
became interested in Diels-Alder reaction of 2–(1´–cycloalkenyl)thiophenes and 2–(1´–
cycloalkenyl)benzo[b]thiophenes with N–phenylmaleimide as the dienophile in the current study.
In this article, we focused on understanding the reactivity of 2–(1´–cycloalkenyl)thiophenes and
2
–(1´–cycloalkenyl)benzo[b]thiophenes dienes in the Diels-Alder/ene reactions and also detailed
characterization of the stereochemistry of the products. Molecular mechanics and density
functional theory (DFT) calculations are used to understanding the reactivity of these dienes
towards the product distribution of Diels-Alder/ene adducts.
RESULTS AND DISCUSSION
Our studies began with the synthesis of 2–(1´–cycloalkenyl)thiophenes 16(i–v) and 2–(1´–
cycloalkenyl)benzo[b]thiophenes 17(i–v) having the alkene groups present in five–, six–, seven–,
eight–, and twelve–membered rings in two steps (Figure 3). In the first step, lithiation of thiophene
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o
or benzo[b]thiophene at the 2–position with n–BuLi at dry ice–acetone temperature (-78 C),
followed by the slow addition of polycyclic ketones 13(i–v) and neutralization with excess NH Cl
4
39
solution affords corresponding 2–cyclothienyl and 2–cyclobenzothienyl alcohols 14-15(i–v) in
good yields (82–94%). Various commercially available cyclic ketones 13(i–v) were chosen with
respect to the cost effective was to provide a variety of substituents on the desired Diels–Alder
adducts and also to study the effect of diverse cyclic ring on Diels–Alder reaction. All the ketones
were diluted with dry diethyl ether and added dropwise to the reaction mixture to avoid aldol
condensation byproducts. In the second step, the corresponding 2–thienyl and 2–benzothienyl
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alcohols 14–15(i–v) undergo dehydration with a catalytic amount of p–toluenesulfonic acid (p–
o
TSA) at 50 C for 2h to give corresponding 2–(1´–cycloalkenyl) thiophenes 16(i–v) and 2–(1´–
cycloalkenyl)benzo[b]thiophenes 17(i–v). Among the synthesized alcohols 14–15(i–v) and diene
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6–17(i–v), compound 14v, 15iv, 15v, 16v, 17iv, and 17v are novel. The applied method proved
to be effective giving relatively high yields (79–89%). The 1H NMR’s of 2–(1´–
cycloalkenyl)thiophenes 16(i-v) and 2–(1´–cycloalkenyl)benzo[b]thiophenes 17(i-v) having
different cycloalkene rings depicts a strong triplet (some cases pentet/multiplet) at around (6.1–
6
.5) ppm confirms the formation of dienes.
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Figure 3. Schematic representation for the synthesis of polycyclic 2–(1´–cycloalkenyl) thiophenes
1
6(i-v) and 2–(1´–cycloalkenyl)benzo[b]thiophenes 17(i-v).
With the straightforward approach of dehydration affording pure 2–(1´–cycloalkenyl)
thiophenes 16(i–v) and 2–(1´–cycloalkenyl)benzo[b]thiophenes 17(i–v), 1:1 diene to maleimide
ratio of 2–(1´–cycloalkenyl)thiophenes 16(i–v) or 2–(1´–cycloalkenyl)benzo[b]thiophenes 17(i–v)
with the polycyclic rings undergoes cycloaddition reaction with substituted N–phenylmaleimides
18(a–d) in refluxing toluene for 15h (Figure 4 and 6). After the completion of reaction is indicated
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by TLC, the reaction mixture cools down; the product precipitates in the fridge overnight. The
obtained yellow solid was vacuum filtered and washed sequentially with ethyl acetate with hexanes
and dried under vacuum to get pure Diels–Alder adducts 19–21(a–d) and 23–29(a–d) as a white
solids in good yield (80–95%).
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Figure 4. Synthetic pathway for rearranged, fully aromatized Diels–alder adducts 19–21 (a–d).
N–Phenylmaleimides 18(a–d) having unsubstituted, p–OMe, m–OMe, and p–Br
functionalities were used to study the effect of substituents on the Diels–Alder reaction. N–
phenylmaleimides were synthesized using the typical procedure41 by the reaction of maleic
anhydride with the appropriate primary amines, and then heating the resulting amide–acid in an
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excess of acetic anhydride with sodium acetate. In this study, N–phenylmaleimides were chosen
as the dienophile because of their promising biological activity.36,37
To check the possibilities of oxidative aromatization, we also made an attempt to
synthesize aromatized Diels–Alder adduct using an oxidizing agent. With one example, Diels–
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Alder adduct 20c was dehydrogenated using activated manganese oxide (MnO ), giving the
2
corresponding aromatized Diels–Alder adduct 22c (Figure 5). The high–yielding (88%) results
generated from manganese(II) sulfate and potassium permanganate.42
were achieved using MnO
2
Since we were interested in the Diels–Alder adducts having stereocenters, we did not explore much
on this reactions for obtaining other cyclic ring adducts.
Figure 5. Aromatization of Diels–Alder adducts affording benzothiophene motif.
All new Diels–Alder adducts were well characterized using IR, HRMS, elemental analysis,
1H NMR, 13C NMR, 2D NMR including heteronuclear single quantum coherence (HSQC),
correlation spectroscopy (COSY), and heteronuclear multiple bond correlation (HMBC). During
the course of the HRMS study, most of the compounds ionized under electrospray ionization (ESI–
MS) and electron ionization (EI–MS)mass spectrometry except 2–(1´–cycloalkenyl)thiophenes
having 5–membered ring (16i). However, chemical ionization (CI) technique was used to obtain
the HRMS data for 16i.
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0
Figure 6. Synthesis of un–rearranged Diels–alder adducts 23–29(a–d) via endo–addition of N–
phenylmaleimides 18(a–d).
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The H and C NMR study does not provide enough evidence to determine the exact
isomer of the Diels–Alder adducts. Detailed 2D NMR studies suggest that, in the cases of
thiophene–based Diels–Alder adducts having five–, six–, and seven– membered rings the
rearranged, aromatized products 19–21(a–d) were isolated. The isolated isomers of the products
in all of these cases were assigned the cis–configuration showed in the Figure (7a) and (7b) on the
basis of the observed NOE correlations, with all four hydrogens on the same side of the ring.
Interestingly, we notice the significant correlation of a cycloalkane proton to the ortho–directed
0
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0
proton of the N–phenylmaleimides(H
e
–H ).
f
Figure 7. An indicative NOE correlation for Diels–Alder/ene adducts. (a) Rearranged, aromatized
Diels–Alder adducts 19–21(a–d); (b) rearranged, aromatized Diels–Alder adducts 19–21(a–d)
correlating with N–phenylmaleimides (H
e
–H ); (c) un–rearranged Diels–Alder adducts 23–29(a–
f
d); (d) ene–addition cascades 30–31(a–d). *Numbers indicate % enhancement.
Whereas, in the cases of thiophene–based Diels–Alder adducts having eight– and twelve–
membered ring compounds 23–24(a–d) and benzothiophene–based Diels–Alder adducts dienes
having polycyclic rings 25–29(a–d), the non–rearranged Diels–Alder products were isolated
instead. The stereochemistry of the products was assigned the cis–configuration shown in Figure
7
(c), based on NOE studies, with all hydrogens on the same side of the ring as well. Notably, H –
a
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H
d
1,4 correlation in these compounds was as large or larger than H
a
–H 1,2–correlations,
b
indicating a boat–like folded conformation of the ring.
Initially, we presumed that all the isolated Diels–Alder adducts having different ring sizes
are isolated in un–rearranged form. Instead, a spontaneous aromatization of the double bond into
the five–membered ring of thiophene to give the more stable aromatized Diels–Alder adducts 19–
1
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1(a–d) (Figure 4) was observed in the case of 2–(1´–cycloalkenyl)thiophenes with smaller rings
(five–, six–, and seven–membered). The obtained Diels–Alder intermediates were probably
protonated by residual acid, followed by aromatization.43 cis–Fusion of the cycloalkyl ring
involves less strain, but, since isomerism to the thiophene is likely irreversible, thermodynamic
equilibration may not determine the type of ring fusion. Orbital symmetry considerations forbid
suprafacial 1,3–hydride shifts and antarafacial 1,3–hydride shifts are geometrically difficult;44–45
therefore, the isomerism probably takes place through acid catalysis.
Generally, Diels–Alder reactions of vinyl–heteroaromatics occur mainly via the extra–
annular pathway, incorporating the vinylic double bond, in an endo manner. The more electron–
rich vinyl–heteroaromatics are typically more reactive as dienes due to their high energy HOMO’s.
For moderately reactive vinyl–heteroaromatics, mild reaction conditions can provide Diels–Alder
cycloadducts, whilst under more forcing conditions, rearomatization and other competing
reactions are observed. 2–(1´–cycloalkenyl)thiophenes with higher membered ring (eight and
twelve) might influence the strong ring strain could resist the feasibility of the spontaneous
aromatization to give un–rearranged Diels–Alder products 23–29(a–d) (Figure 6). Whereas, in the
case of 2–(1´–cycloalkenyl)benzo[b]thiophenes, addition to the steric, lesser aromatic stabilization
could also be a factor to get un–rearranged Diels–Alder adducts. Also, the benzene ring fused to
five membered thiophene rings might influence the secondary electronic effects to get un–
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rearranged Diels–Alder adducts 23–29(a–d) (Figure 6). Varieties of N–phenylmaleimides having
different functionalities were used to study the effect of the Diels–Alder reactions. N–
Phenylmaleimides with electron donating (–OMe) or withdrawing (–Br) groups worked well under
the reaction conditions furnishing corresponding Diels–Alder adducts smoothly. The effect of the
0
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substituents is expected to be minor. H NMR studies on entire Diels–Alder adducts confirmed
excellent diastereoselectivity (>99% de).
In order to definitively confirm the structure of 27a, crystals were grown for X–ray
crystallographic analysis by using anti–solvent crystallization method through slow diffusion from
chloroform/pentane (1:4 ratios). The structure of 27a is consistent with the Diels–Alder
cycloadduct arising from extra–annular cycloaddition, via an endo transition state. This analysis
confirmed the occurrence of un–rearranged Diels–Alder adducts having C18=C19 double bond
o
with a bond distance 1.339A . (See Supporting Information, Figure S1)
Another interesting pericyclic reaction which has expansive synthetic utility is the ene
reaction. The scope, synthetic potential and applications of the ene reaction have previously been
reviewed extensively.46–49 Despite its atom efficiency and tolerance for a range of enophiles, as
well as the importance of forming new C–C bonds and promoting C–H activation, the ene reaction
has been utilized to a much lesser extent in comparison to the Diels–Alder reaction. Watson
reported one example of a substituted 2–(1´–cycloalkenyl)thiophenes giving a 1:2 adduct with N–
phenylmaleimide, which was formed by an endo Diels–Alder reaction (lower succinimide unit),
followed by an endo ene addition of N–phenylmaleimide on the exo face (upper succinimide unit)50
(
10, Figure 2). Literature precedence51–53 would suggest that the second molecule of N–
phenylmaleimide should be incorporated via an ene reaction, to give ene–adduct. However, in the
course of study 1:2 diene to maleimide of 2–(1´–cycloalkenyl)thiophenes with different N–
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phenylmaleimide were examined for domino Diels–Alder/ene reactions. Surprisingly, ene–
cascade products were obtained only with the 2–(1´–cycloalkenyl)thiophenes having five– and
six–membered ring (Figure 8 and 9). We were not able to isolate the desired ene–addition adducts
for the larger membered ring. The rearranged Diels–Alder adduct in case of seven–membered ring
and the un–rearranged Diels–Alder adducts in the case of eight– and twelve–membered ring were
observed instead. This could be because of the cycloalkene ring steric effect where the second
addition of the N–phenylmaleimide could not participate to form ene–addition. During the course
of the study, we made an attempt to isolate ene–cascades for the larger membered rings by altering
the reaction condition. The reaction mixture was allowed to react for three days instead 15 h at
reflux condition but we were only able to isolate the un–rearranged Diels–Alder adducts for the
large ring instead ene–addition product.
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Figure 8. Domino Diels–Alder/ene reaction of 30–31(a–d).
Figure 9. Proposed mechanism for the construction of ene–adduct, via endo–ene addition of a
second molecule of N–phenylmaleimide to the endo face of the initial Diels–Alder adduct.
Encouraged by the preliminary results, we decided to study the synthesis of Diels–Alder
ene–cascades with 1:2 of 2–(1´–cycloalkenyl)benzo[b]thiophenes with different N–
phenylmaleimides. Unexpectedly, we were only able to isolate the actual Diels–Alder adducts
instead of ene adducts in the case of all dienes. We presume that this could be because of the steric
hindrance of the additional phenyl ring present in the benzothiophene moiety and also the phenyl
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ring of N–phenylmaleimide forbids the ene–addition reaction. So, we made an attempt to study the
Diels-Alder reaction with the N–methylmaleimide instead of N–phenylmaleimide. Unpredictably,
we were not able to isolate ene–addition products instead, the rearranged 1:1 Diels–Alder adducts
1
1
1
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3
3(i-v) were isolated in case of all cyclic membered ring with good yields (Figure 10). Further, we
made an attempt to alter the reaction condition by allowing the reaction mixture to react for longer
period (3 days) instead 15 h at reflux condition but still we could able to isolate only the Diels–
Alder adduct (See Supporting Information for NMR studies).
1
13
H and C NMR spectroscopy of ene–adducts were consistent with the structure, and
further analysis by COSY, HSQC, HMBC, and NOESY NMR spectroscopy revealed the presence
3
of one sp –CH
2
– environments, which would also be consistent with the ene–adduct (See
1
Supporting Information). H NMR reveals 99% diastereoselectivity for all Diels–Alder/ene
products as well.
Figure 10. Diels–Alder/ene reaction of 2–(1´–cycloalkenyl)benzo[b]thiophenes having polycyclic
rings with N–methylmaleimide.
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D gradient NOE studies depicts the correlation of H
a
and H
b
between–CH – group of the
2
succinimide ring with 5% enhancement showed in Figure 7(d) clearly indicates the endo–addition
of second molecule of N–phenylmaleimide (Figure 9). As we expected, the ene addition proceeds
0
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50
by the endo approach which have the similar prediction done by Watson. NOE experiments
indicated stereochemistry that corresponded to endo ene addition, but this counterintuitive result
merited additional evidence. The 1:2 adducts among 30–31(a–d) were obtained as microcrystalline
powders, however, we were able to prepare crystals of 30a by recrystallization from ethyl acetate
and pentane (1:4 ratios) which were suitable for X–ray diffraction. The crystallographic data
confirmed endo ene addition. (See Supporting Information, Figure S2)
Density Functional Calculations
Molecular mechanics and quantum mechanical (DFT) computations have been used to
rationalize the reactivity and selectivity of the observed Diels–Alder reactions (and possible
subsequent ene reactions) between the various dienes and dienophiles.54,55 Full methodological
details are provided in the Supporting Information. To begin, detailed conformational analysis was
undertaken for dienes (16(i-v) and 17(i-v)) in order to identify all relevant minima using first
molecular mechanics and then DFT calculations. We next employed DFT to find transition state
structures for the Diels–Alder, and subsequent cascade ene, reactions of all of the various dienes
−
1
with N–phenylmaleimide. We discuss the Gibbs free energies (kcal mol ) of all stationary points
on the potential energy surface at the SMD(toluene)/PBE0-D3/6-311++G(d,p)//SMD(toluene)/M06-
2
X/6-31+G(d,p) level of theory.56,57,58,59,60,61,62
Diels–Alder reactions. Both endo and exo transition state structures for the Diels-Alder
reactions of all dienes with N–phenylmaleimide, as well as the various conformational possibilities
associated with the dienes, were examined in detail (See the Supporting Information). In every
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case, free energies of activation were computed to be lower for endo Diels-Alder reaction than for
−
1
exo, with the difference ranging from 1.0 to 3.6 kcal mol . This result is consistent with the
selectivity observed experimentally. As an illustrative example, the endo and exo transition states
for 1´-cyclopentenylthiophene are shown in Figure 11. The endo TS structure is 1.5 kcal mol−1
lower in free energy than the exo transition state structure. The distortion/interaction-activation
strain model was carried out in order to understand the origin of the reactivity differences as well
as endo and exo selectivity in quantitatively.54,55 The difference in distortion energies of endo and
1
1
1
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1
1
1
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9
0
−
1
exo transition states of these 2–(1´–cycloalkenyl)thiophenes are very small (0.2 to 1.9 kcal mol )
−1
whereas the difference in interaction energies are in the range of 1.5 to 3.8 kcal mol . The
interaction energies play an vital role in the favor of endo transition state. Interaction energy was
further analyzed by using energy decomposition analysis (EDA), which shows that the
combination of electrostatic, orbital interaction and dispersive interactions are crucial controlling
factors that favors the endo selectivity for Diels-Alder reaction of various 2–(1´–
cycloalkenyl)thiophenes (see Supporting Information). We identify four factors contributing to the
stabilization of the endo structure, namely (i) the presence of a C−H…π interaction (3.07 Å)
between the N−phenyl group and the π cloud of the thiophene ring in the endo transition state (ii)
stronger C−H…O interactions identified in the endo transition state (iii) the presence of π…π
interaction (3.13 Å) between π cloud of carbonyl group of dienophile and π cloud of thiophene
moiety and (iv) the presence of electrostatic and secondary orbital interaction between carbonyl
carbon of dienophile and thiophene moiety in the endo transition state (Figure 11 and Figure S5 in
the Supporting Information). Interestingly, considering the forming C−C bond distances in the
Diels–Alder transition state structures, it is evident that all dienes undergo asynchronous
cycloaddition, with the asynchronicity being higher in the endo transition state structures (Figure
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1). The sense of the asynchronicity is consistent with the aromatic nature of the thiophene moiety
compared to the cycloalkene.
0
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6
7
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9
0
endo-TS1
5
(22.7)
exo-TS1
5
(24.2)
Figure 11. Optimized endo and exo transition state structures for the Diels−Alder reaction of
2
−(1´−cyclopentenyl)thiophene with N−phenylmaleimide (the subscript ‘5’ indicates the size of
the cycloalkene ring) at the SMD(toluene)/M06-2X/6-31+G(d,p) level of theory. Activation free
−
1
energies (kcal mol ) are provided in parentheses at the SMD(toluene)/PBE0-D3/6-
311++G(d,p)//SMD(toluene)/M06-2X/6-31+G(d,p) level of theory. Selected bond distances (Å) are
provided.
The free energies of activation for the preferred endo reaction of the
2−(1´−cycloalkenyl)thiophenes with N–phenylmaleimide through TS1 (X = size of cycloalkene
X
−1
ring) are computed to be 22.7, 23.7, 20.2, 20.7, and 24.1 kcal mol for X = 5, 6, 7, 8, and 12,
respectively, with respect to the separated reactants (Figure S3 in the Supporting Information). The
seven− and eight− membered-ring reactants are predicted to be more reactive than the others by
–
1
2
2
-3 kcal mol (Figures 11 and S3). The difference in energies between endo transition states of
–(1´–cycloalkenyl)thiophenes were analyzed using distortion and interaction analysis (See the
Supporting information for more details). Both distortion and interaction energies play an
important role in all these endo transition states but the distortion is the dominant factor over
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interaction which helps in stabilizing the transition state. Figure S4 shows a linear correlation (R2
=
0.92) between activation energies of endo transition states of all 2–(1´–cycloalkenyl)thiophenes
versus distortion energy. As the distortion of diene and dienophile increases, the activation energy
of the endo transition state increase.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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9
0
We also computed the analogous free energies of activation for the Diels−Alder reactions
of 2−(1´−cycloalkenyl)benzo[b]thiophenes with N−phenylmaleimide; they are 21.3, 22.1, 19.8,
−
1
1
9.7, and 22.3 kcal mol for X = 5, 6, 7, 8, and 12, respectively, with respect to the separated
reactants (Figure S4 in the Supporting Information). In every instance, the benzo[b]thiophene
–1
diene is computed to be 1–2 kcal mol more reactive than its non-benzannelated congener, which
we attribute to the lower penalty for dearomatization of the thiophene ring in the
benzo[b]thiophene case owing to the influence of the annelated benzene.
The overall reaction free energies for the formation of Diels-Alder cycloadducts derived
from the 2–(1´–cycloalkenyl)thiophenes dienes are computed to be -12.6, -10.3, -15.3, -13.3, and
−
1
-
10.9 kcal mol for X = 5, 6, 7, 8, and 12, respectively, relative to separated reactants. For the 2–
(1´–cycloalkenyl)benzo[b]thiophene, the corresponding reaction free energies are -17.9, -14.7, -
−
1
2
0.3, -18.2, and -15.4 kcal mol , respectively. The reduced penalty for dearomatization of the
thiophene in the benzannelated case is evident in the free energies of reaction as well. Once formed,
the Diels–Alder adduct can either rearomatize (possibly through trace–acid catalysis) or it can
undergo ene reaction with another molecule of dienophile. We examine these processes next.
Rearomatization. We examined free energies of activation for the direct rearomatization,
via 1,3–hydride shifts, of all of the initial Diels–Alder adducts. In all thiophene– and
−
1
benzo[b]thiophene–derived cases, values of 40 to 55 kcal mol were computed, consistent with
6
3
the well-known disfavored character of 1,3–hydride shifts. Noting the presence of some acetic
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8
9
1
1
1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
acid in the reaction mixture, we also examined acetic-acid catalyzed proton transfer as a
mechanism for rearomatization. These free energies of activation for adducts derived from the 2–
(1´–cycloalkenyl)thiophenes are computed to be substantially lower, namely, 29.6, 30.3, 31.0, 33.1,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
−1
and 33.0 kcal mol for X = 5, 6, 7, 8, and 12, respectively, relative to separated reactants (Figure
1
2). The acid–catalyzed rearomatization barrier is predicted to steadily increase with increasing
cycloalkene ring size, with a particular jump from X = 7 to X = 8 and 12, which is in good accord
with the relative reactivities observed experimentally. For adducts derived from the 2–(1´–
cycloalkenyl)benzo[b]thiophenes, the corresponding free energies of activation are computed to
−
1
be 32.2, 32.3, 33.3, 34.4, and 34.8 kcal mol , respectively (Figure S5 in the Supporting
Information). Higher predicted activation free energies for the benzannelated adducts are again
consistent with reduced aromaticity in the benzannelated thiophene ring.
TS2
5
(29.6)
TS2
6
(30.3)
TS2 (31.0)
7
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
5
5
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5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
TS2
8
(33.1)
TS212(33.0)
Figure 12. Optimized transition state structures for acetic acid-catalyzed rearomatization of the
Diels-Alder adducts of 2–(1´–cycloalkenyl)thiophenes having five−, six−, seven−, eight−, and
twelve−membered rings at the SMD(toluene)/M06−2X/6-31+G(d,p) level of theory. Activation free
−
1
energies (kcal mol ) are provided at the SMD(toluene)/PBE0-D3/6-311++G(d,p)//SMD(toluene)/M06-
X/6-31+G(d,p) level of theory. Selected bond distances (Å) and bond angles (in degrees) are also
provided.
We carefully examined the geometric details of these various transition state structures in
2
order better to understand the computed trend in free energies of activation (Figure 12). We
identify two factors that correlate with that trend, namely, (i) the valence bond angles passing
through C3 to its arriving H show an increase in θ
increases and (ii) favorable C–H…O hydrogen bonding interactions between the C−H at the (X–
) position of the cycloalkene ring and an imide carbonyl oxygen take place over increasing
1
and decreases in θ
2
and θ
3
as the ring size
1
distances with increasing ring size. These are admittedly subtle effects associated with orienting
the C3–H atom being transferred within the constraints of pyramidalization of C3 and overall ring
conformation, but they do vary consistently with ring size and theory overall is in good agreement
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1
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1
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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5
5
5
5
5
6
with experiment that rearomatization is less kinetically favorable for larger rings, and especially
for X = 8 and 12.
Ene reactions. We next examined the potential for the various Diels–Alder adducts to
undergo ene reaction with another equivalent of N–phenylmaleimide. As shown in Figure 13, this
reaction proceeds with proton transfer from C1 to N–phenylmaleimide and concomitant C−C bond
formation between C3 and C6. The computed free energies of activation for this process engaging
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
the Diels-Alder adducts of the 2–(1´–cycloalkenyl)thiophenes through TS3
X
are 22.9, 23.8, 26.3,
−
1
3
1.6, and 31.2 kcal mol , respectively, relative to separated reactants. The five− and
six−membered rings are computed to be particularly reactive, while the eight– and twelve–
membered rings are computed to be substantially less reactive, with the seven–membered ring
intermediate between these two pairs. The corresponding barriers for the reaction involving
adducts of the 2– (1´–cycloalkenyl)benzo[b]thiophenes are computed to be 25.1, 26.4, 29.2, 34.5,
−
1
and 32.4 kcal mol , respectively, relative to separated reactants (Figure S6 in the Supporting
Information). Again, the lesser aromaticity of the benzo[b]thiophene products compared to the
thiophene products is reflected in relatively higher free energies of activation for the former set of
compounds. Overall, the computed trends in free energies of activation within and across sets are
in good agreement with experimental observations of the propensity of the Diels-Alder adducts to
undergo cascade ene reaction.
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1
1
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1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
TS3
5
(22.9)
TS3
6
(23.8)
TS3 (26.3)
7
TS3
8
(31.6)
TS312(31.2)
Figure 13. Optimized transition state structures for ene reactions with N−phenylmaleimide of
Diels-Alder adducts derived from 2–(1´–cycloalkenyl)thiophenes having five−, six−, seven−,
eight−, and twelve−membered rings at the SMD(toluene)/M06-2X/6-31+G(d,p) level of theory.
−
1
Activation free energies (kcal mol ) are provided at the SMD(toluene)/PBE0-D3/6-
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5
5
5
5
5
5
6
3
11++G(d,p)//SMD(toluene)/M06-2X/6-31+G(d,p) level of theory. Selected bond distances (Å) and
bond angles (in degrees) are also provided.
As the TS3 structures are complex, it is not trivial to identify any single factor dictating
X
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
the trends in computed free energies of activation. However, some key structural parameters do
show variations that correlate with energetics (Figure 13). In particular, as the size of the
cycloalkene ring increases, the C3−C6 bond distance increases as does the breaking C1−H9 bond
distance, and there is a corresponding decrease in the forming H9−C7 bond distance. The looser
transition state structures for the larger cycloalkenes suggest that ring geometries increasingly
block the approach of the enophile as the ring size increases. Consistent with this analysis, as the
size of the cycloalkene ring increases, the valence C6–C3–C5 bond angle θ increases from 102.9°
4
to 111.3°. Another important factor appears to be C−H…O hydrogen bonding interactions both
within the Diels-Alder adduct itself as well as between adduct and the enophile, although the direct
quantification of the strength of these interactions is not practical.
CONCLUSIONS
Heteroaromatic 2–(1´–cycloalkenyl)thiophenes and 2–(1´-cycloalkenyl)benzo[b]thiophenes
characterized by five−, six−, seven−, eight− and twelve–membered rings undergo cycloaddition
reactions with substituted N–phenylmaleimides to deliver synthetically interesting rearomatized
benzo[b]thiophene and dibenzo[b,d]thiophene Diels–Alder adducts in good yield. Cycloalkene
ring sizes influence the differential reactivity of initial Diels-Alder adducts with respect to
rearomatization vs cascade ene reaction with a second equivalent of N–phenylmaleimide.
Computational studies suggest that this influence manifests through variation in stabilizing
C−H…O and C−H…π interactions as well as distortion in transition state structures driven by
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variations in cycloalkene ring conformations as a function of size. C−H…O, C−H…π, π…π,
secondary orbital interaction, and electrostatic interactions are crucial controlling factors in the
Diels-Alder addition transition states for endo selectivity. All Diels–Alder and Diels–Alder/ene
reactions are highly diastereospecific (≥ 99% de).This approach to the preparation of complex
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
annulated thiophenes and benzo[b]thiophenes is adaptable, and the starting materials are easily
prepared. Further studies of the synthetic applications are currently underway in our laboratory.
EXPERIMENTAL SECTION
I. General experimental information
Solvents and reagents were purchased and used without further purification. Thienyl and
3
9
benzothienyl
alcohols ,
2–(1´–Cycloalkenyl)thiophenes
and
2–(1´–
40
Cycloalkenyl)benzo[b]thiophenes were prepared according to literature procedures, respectively.
Melting points were recorded on a Mel-Temp and are uncorrected (Sigma Aldrich Co., St. Louis,
MO). Flash chromatography was performed using 150–Å silica gel or activated, neutral aluminum
oxide. Thin-layer chromatography analyses were performed on plastic-backed plates pre-coated
with 0.2–mm of silica with F254 indicator. Thin-layer chromatography developing solvents were
mixtures of ethyl acetate and hexane. Chemical shifts (δ, ppm) for NMR spectra were referenced
1
to the solvent (CHCl
CDCl at 77.16, CD Cl
C{ H}spectra were proton decoupled. Infrared spectra were recorded on a Thermo Scientific
3
at 7.26, CHDCl
2
at 5.32, or DMSO–d
5
at 2.50, acetone–d
6
at 2.05 for H;
1
3
3
2
2
at 53.84, or DMSO–d
6
at 39.52, acetone–d
6
at 206.68 and 29.92 for C).
1
3
1
Nicolet iS5 7200 FT–IR spectrophotometer. High–resolution mass spectra were recorded on a
Bruker BioTOF II ESITOF instrument with poly(ethylene oxide) as an internal calibrant, or a
Finnegan Mat 95 EI spectrophotometer or an Agilent 7200 GC/QTOF spectrophotometer with
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
perfluorokerosene as an internal calibrant. Elemental analyses were performed by Atlantic
Microlab, Inc., Norcross, GA.
Caution: n–BuLi was used as a 2.5M solution in hexanes and was transferred by a syringe or
cannula under nitrogen.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Method I. The preparation of thienyl alcohols 14(i-v) and 15(i-v)
Thiophene (11) or Benzothiophene (12) (5.0 g, 59.4 mmol) was placed in a 100 mL, three–neck,
round–bottom flask fixed with a condenser. The flask was flushed with nitrogen for 10 min and
placed in a dry ice/acetone bath. Anhydrous ether (30 mL) was cannulated into the flask. n–BuLi
(
2.5M in hexanes, 1 equiv) was added dropwise to the stirred solution. Upon completion of the
addition, the dry ice/acetone bath was removed, and the solution was stirred at room temperature
rt) for 2 h. The flask was placed in an ice bath; and a solution of the appropriate cyclic ketone
3(i–v), diluted with anhydrous ether (20 mL), was added dropwise. The ice bath was removed,
and the solution was stirred for 12–15 h. The resulting solution was quenched with excess saturated
NH Cl solution and extracted with ether. The combined organic portions were washed with brine
and dried over anhydrous MgSO . The solvents were removed with a rotary evaporator.
-(thiophen-2-yl)cyclopentan-1-ol (14i)
(
1
4
4
1
Compound 14i was prepared by general procedure method I (4.72g, yellow liquid, 83%). R = 0.35
f
-1
(EtOAc:Hexanes = 1:4, Al
2
O
3
); IR (film) νmax/cm 3583, 3427, 2964, 2874, 1633, 1437, 1265,
1
1
238, 1000, 833, 740, 702; H NMR (300 MHz, Chloroform-d) δ 7.20 (dd, J = 4.9, 1.2 Hz, 1H),
1
3
1
7.03 – 6.91 (m, 2H), 2.14 – 1.71 (m, 8H). C{ H}(75 MHz, CDCl
3
) δ 152.4, 126.7, 123.9, 122.3,
NH 186.0947; Found
8
1
1.6, 42.6, 23.6.; HRMS (CI) m/z: [M+NH
4
]+ Calcd for C
9
H
16
O
1
S
1
4
86.0937.
.
1-(thiophen-2-yl)cyclohexan-1-ol (14ii)
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Compound 14ii was prepared by general procedure method I (4.22 g, yellow liquid, 83%) R =
f
-1
0
.80 (EtOAc:Hexanes = 1:1, SiO
2
); IR (film) νmax/cm 3396, 2936, 2857, 1445, 1350, 1313, 1258,
1
1233, 1184, 1127, 1050, 1038, 964, 905, 845, 697; H NMR (500 MHz, Chloroform-d) δ 7.20 (d,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
J = 5.0 Hz, 1H), 6.97 (dd, J = 10.0, 5.5 Hz, 2H), 1.92 (ddd, J = 22.9, 14.8, 11.3 Hz, 4H), 1.81 –
1
3
1
1
.69 (m, 2H), 1.62 (ddt, J = 17.5, 13.0, 4.0 Hz, 3H), 1.33 (q, J = 11.6, 11.1 Hz, 1H). C{ H}(126
) δ 154.7, 126.8, 123.9, 122.1, 77.2, 40.1, 25.5, 22.5; HRMS (ESI) m/z: [M+Na]+
MHz, CDCl
Calcd for C10
-(thiophen-2-yl)cycloheptan-1-ol (14iii)
Compound 14iii was prepared by general procedure method I (4.13 g, yellow liquid, 82%). R
3
H
14
1
S Na 205.0658; Found 205.0682
1
f
=
-1
0.80 (EtOAc:Hexanes = 1:1, SiO
2
); IR (film) νmax/cm 3474, 3103, 3070, 2922, 2849, 1704, 1663,
1
6
518, 1448, 1415, 1355, 1317, 1274, 1245, 1217, 1183, 1104, 1078, 1053, 962, 937, 898, 845, 804,
1
92; H NMR (300 MHz, Chloroform-d) δ 7.19 (dd, J = 4.9, 1.3 Hz, 1H), 7.05 – 6.89 (m, 2H),
2.10 (qdd, J = 14.5, 8.5, 1.7 Hz, 5H), 1.92 (d, J = 2.5 Hz, 1H), 1.71 (dddd, J = 22.3, 11.5, 8.9, 6.8
13
1
Hz, 5H), 1.57 – 1.46 (m, 2H). C{ H}(75 MHz, CDCl
3
) δ 126.7, 123.8, 121.9, 109.8, 76.4, 44.0,
Na 219.0814; Found 219.0816
+
2
9.5, 22.4.; HRMS (ESI) m/z: [M+Na] Calcd for C11
H
S
16 1
1
-(thiophen-2-yl)cyclooctan-1-ol (14iv)
Compound 14iv was prepared by general procedure method I (4.75 g, yellow liquid, 92%). R =
f
-1
0
1
.50 (EtOAc/Hexanes = 1:2, SiO
2
); IR (film) νmax/cm 3458, 3103, 3070, 3019, 2923, 2850, 1700,
662, 1518, 1469, 1447, 1415, 1357, 1265, 1238, 1222, 1184, 1170, 1145, 1078, 1049, 970, 899,
1
843, 816, 771, 736, 692; H NMR (400 MHz, Chloroform-d) δ 7.21 (dd, J = 4.9, 1.3 Hz, 1H), 7.01
–
6.92 (m, 2H), 2.20 – 2.03 (m, 4H), 1.82 (s, 1H), 1.70 (d, J = 7.4 Hz, 5H), 1.53 (d, J = 5.7 Hz,
1
3
1
4
H). C{ H}(101 MHz, CDCl
3
) δ 154.5, 126.7, 124.0666, 122.1, 76.2, 38.5, 28.3, 24.8, 22.4.;
Na 233.0971; Found 233.0969
+
HRMS (ESI) m/z: [M+Na] Calcd for C12
H S
18 1
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