Polarization Effect on Regioselectivity of Pd-Catalyzed Cyclization of 2-Alkynylbenzaldehydes

Article abstract of DOI:10.1002/ejoc.201901203

We report a study on the relationship between the polarization of C≡C bond in a series of 2-alkynylbenzaldehydes and the regioselectivity of their Pd-catalyzed annulation reactions. The electrophilic and nucleophilic character of the triple bond carbon atoms was examined using ¹³C and HMBC NMR experiments. The direction of polarization is determined only by the formyl group and its position on an aromatic ring. On the other hand, the strength of the polarization expressed through chemical shift difference Δδ of acetylenic carbon atoms is a result of electron-withdrawing or electron-donating ability of the other substituent. Out of two possible regioisomers, the Pd-catalyzed cyclization reactions of 2-alkynylbenzaldehydes that were studied predominantly afforded 1H-isochromenes suggesting that the polarization of a triple bond is one of the contributing factors in the regioselectivity of this process.

Full text of DOI:10.1002/ejoc.201901203

DOI: 10.1002/ejoc.201901203
Full Paper
Polarization-Induced Regioselectivity
Polarization Effect on Regioselectivity of Pd-Catalyzed
Cyclization of 2-Alkynylbenzaldehydes
Nolan Nardangeli,[a] Nikola Topolovčan,[a] Razvan Simionescu,[a] and Tomáš Hudlický*[a]
Abstract: We report a study on the relationship between the through chemical shift difference Δδ of acetylenic carbon
polarization of C≡ C bond in a series of 2-alkynylbenzaldehydes atoms is a result of electron-withdrawing or electron-donating
and the regioselectivity of their Pd-catalyzed annulation reac- ability of the other substituent. Out of two possible regioiso-
tions. The electrophilic and nucleophilic character of the triple mers, the Pd-catalyzed cyclization reactions of 2-alkynylbenz-
bond carbon atoms was examined using 13C and HMBC NMR aldehydes that were studied predominantly afforded 1H-iso-
experiments. The direction of polarization is determined only chromenes suggesting that the polarization of a triple bond is
by the formyl group and its position on an aromatic ring. On one of the contributing factors in the regioselectivity of this
the other hand, the strength of the polarization expressed process.
Introduction
ways and as a result, two regioisomers can be formed. The
benzofuran product is derived from 5-exo-dig cyclization (path
a, Scheme 1), while 6-endo-dig cyclization favors the formation
of 1H-isochromene (path b, Scheme 1).
The abundance of isochromene-containing natural products
that exhibit a wide spectrum of interesting and valuable biolog-
ical properties[1] has propelled extensive effort to design syn-
thetic routes that would compete with the cost of isolation of
these heterocycles from their natural sources. We note that
intramolecular cyclization of 2-alkynylaryl aldehydes stands to-
day as one of the simplest, atom-economical and highly effec-
tive approach towards 1H-isochromenes and structurally related
cyclic ethers. A considerable amount of progress has been
achieved in the development of efficient strategies for this par-
ticular transformation. Among currently available methods, the
majority relies on using transition metal complexes, namely
those of Pd[2] and Au.[3] Reactions catalyzed by Ag,[4] Cu,[5] Pt,[6]
In,[7] and W[8] are studied and reported as well but to lesser
extent. Moreover, Pd and Au catalyzed tandem reactions in the
presence of a C-, O- or N-based nucleophile allowed synthesis
of isochromenes and structural equivalents with higher molec-
ular complexity. In a similar manner, cyclization of 2-alkynyl
benzyl alcohols catalyzed by Pd,[9] Au[10] or Ru[11] also serve as
a method for construction of cyclic alkenyl ethers. Other meth-
ods for synthesis of isochromene compounds include base pro-
moted iodocyclization of 2-alkynylbenzaldehydes[12] or 2-alk-
ynyl benzyl alcohols,[13] intramolecular Michael cyclization of
nitroalkenes,[14] intramolecular Wittig reaction,[15] and intra-
molecular oxa-Michael reaction.[16] Although highly reliable, the
above-mentioned methods often suffer from poor regioselecti-
vity. In principle, cyclization of 2-alkynylbenzaldehydes in the
presence of an external nucleophile can proceed via two path-
Scheme 1. Two possible pathways for the cyclization of 2-alkynylbenzalde-
hydes.
It is generally accepted that the regioselectivity mainly de-
pends on the basicity of a reaction medium. In the absence of
a base, the reaction is believed to proceed via domino annula-
tion/addition sequence (Scheme 2a). In the first step the metal
catalyst coordinates to the triple bond of the alkynyl aldehyde
A, thus activating it for the subsequent 6-endo-dig attack of the
carbonyl oxygen atom and the formation of the isobenzopyryl-
ium intermediate B. Next, the nucleophilic addition leads to
the intermediate C, which upon proto-demetallation gives the
isochromene product D. On the other hand, addition/annula-
tion sequence is favored in the base-promoted reaction, inde-
pendently of the metal catalyst. First, the deprotonated nucleo-
phile attacks the carbonyl carbon atom, thus forming the hemi-
acetal anion intermediate E. The following annulation and pro-
tonation of the formed alkenyl anion predominantly gives the
benzofuran product F via 5-exo-dig process (Scheme 2b).
[a] Department of Chemistry and Centre for Biotechnology, Brock University,
1812 Sir Isaac Brock Way, St. Catharines, Ontario, L2S 3A1, Canada
E-mail: thudlicky@brocku.ca
https://brocku.ca/tomas-hudlicky/
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901203.
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Scheme 2. Proposed mechanisms for the cyclization of 2-alkynylbenzaldehydes.
According to the literature, in addition to the basicity of the of these compounds, and iii) how the unequal electron distribu-
reaction medium, as stated before,[17] additional factors that tion is translated to the regioselectivity of this process.
affect the regioselectivity of this process are; i) nature of the
carbonyl group,[18] ii) nature of the metal catalyst,[5a,19] and iii)
the polarization of the acetylenic portion of the molecule.[3i]
The latter effect, that is, the correlation between the regioselec-
Results and Discussion
tivity and the polarization has not been extensively studied.[20]
In accordance with the proposed mechanisms, we believe that
the regiochemistry could be highly affected by the electron dis-
tribution (polarization) of the alkyne moiety of ortho alkynyl-
benzaldehydes. Regardless of the mechanism, the nucleophilic
carbonyl oxygen atom in the isobenzopyrilium pathway, or the
oxygen atom in the hemiacetal anion pathway should bond to
the more electrophilic acetylenic carbon atom. The presence of
an electron-withdrawing group (EWG) on the ꢀ-atom of the alk-
yne should favor the 5-exo-dig cyclization and the formation
of the benzofuran products, while the 6-endo-dig cyclization,
initiated by the presence of the electron-donating group (EDG),
would lead to 1H-isochromenes. The correlation between elec-
tron properties of the alkyne moiety and regioselectivity in cy-
clization of ortho alkynyl benzylic alcohols has been studied,[21]
but to the best of our knowledge, the same study has not been
performed for 2-alkynylbenzaldehydes. Yamamoto′s seminal
work on Pd(OAc)2-catalyzed cyclization of alkynyl aldehydes in
the presence of alcohol has shown that the regiochemistry of
the heteroannulation step is affected to some extent by the
EDG or EWG on the alkyne portion of the molecule.[2b] In the
case of carbon-tethered alkynyl aldehydes bearing an EDG on
the alkyne, a mixture of five and six-membered heterocycles
was obtained, while only the five-membered cyclic ether was
obtained in cyclization of acetylenic aldehydes bearing the
EWG. On the other hand, the cyclization of 2-alkynylbenzalde-
hydes with an EDG afforded only 1H-isochromene products,
To analyze the polarization-regioselectivity correlation, a series
of ortho substituted alkynylbenzaldehydes was prepared. The
other substitution patterns (meta and para) were intentionally
avoided to exclude any potential steric effect on the regioselec-
tivity. The electronic distribution, that is, the electrophilic and
nucleophilic character of the acetylenic carbon atoms can be
easily deduced from the chemical shift of the corresponding
signals in the 13C NMR spectra.[22] The signal that appear down-
field in the spectra would correspond to the electrophilic
carbon atom while the signal of the nucleophilic carbon atom
would have an upfield chemical shift value. Also, the strength
of the triple bond polarization can be characterized by the
chemical shift difference between the acetylenic carbon atoms.
If polarization is influenced only by the substituent on the ꢀ-
carbon atom, we assumed that 2-alkynylbenzaldehydes carry-
ing an electron-donating substituent would exert such a polari-
zation where the electron density would be higher on the α-
carbon atom. On the other hand, the ꢀ-carbon atom should be
more nucleophilic if the substituent is an electron withdrawing
group. In that manner, with the aid of 13C and HMBC NMR ex-
periments, the partial charges were assigned to the correspond-
ing carbon atoms of the triple bond.[23] The observed electron
distribution (polarization) was identical in all cases and the nu-
cleophilicity (δ–) resides mostly on the α-carbon atom (the
benzaldehyde side) while the ꢀ-carbon atom is electrophilic (δ+)
(Figure 1).
These results indicate that the electron distribution is weakly
while the same reactions with EWG on the alkyne were not affected by the substituent on the ꢀ-carbon atom of the triple
reported. As there is a lack of information on the correlation bond and that the nature of the aldehyde group plays a key
between the polarization of C≡ C bond and regioselectivity of role in its polarization. The most intriguing result was the polari-
the Pd-catalyzed cyclization of 2-alkynylbenzaldehydes in the zation in 1c. Although the cyano group is a stronger EWG com-
presence of an external oxygen-containing nucleophile, the pared to the formyl, the electron density is higher on the α-
purpose of this work is to investigate: i) how the electron- carbon atom of the triple bond. That implies that the position
donating and electron-withdrawing ability of a substituent on of the substituents might be also one of the factors that deter-
the ꢀ-carbon atom affects the polarization, ii) the additional mines the polarization. It is worth mentioning that the value
factors that influence the electron density of acetylenic portions of the chemical shift difference Δδ ranges from 1.6 ppm for
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Figure 1. Polarization of the triple bond in 2-alkynylbenzaldehydes 1a–1i.
trimethylsilyl substituent in 1a to 21.9 ppm in the case of octyl prepared and the polarization was determined on the basis of
substituent on the ꢀ-carbon atom as in 1i. The observed trend 13C NMR chemical shifts of the α- and ꢀ-carbon atoms (Fig-
shows that the polarization is stronger when the substituent ure 2).
exhibits electron-donating properties.
The observed electron distribution in 1k was the opposite
As benzaldehydes 1c–1f and 1h are essentially diphenylacet- compared to its regioisomer 1c with the value of the chemical
ylenes with an ortho-positioned formyl group on one aromatic shift difference changing from 5.0 ppm to –2.9 ppm, respec-
ring and para-positioned substituent on the other, relative to tively. The direction of polarization in 1j was reversed as well
the triple bond, we assumed that by allocating the formyl with respect to 1c but the direct “push-pull” system created by
group to para and meta positions we could directly observe its placing the aldehyde group in para position resulted in weaker
influence on the polarization. To test this assumption, the 4- polarization where the chemical shift difference dropped to
alkynylbenzaldehyde 1j and 3-alkynylbenzaldehyde 1k were only –1.2 ppm. These results suggest that the position of the
Figure 2. Polarization of the triple bond in alkynylbenzaldehydes 1c, 1k, and 1j.
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formyl group exhibits a crucial effect on the polarization of the HSQC and HMBC NMR experiments (see Supporting Informa-
triple bond and overshadows the influence of the substituents tion).
on the ꢀ-carbon atom. This phenomenon could be explained
by the effect of substituents on the electron density of carbon
atoms within an aromatic ring and how π-charges and substitu-
ent effect are transferred through highly polarizable C≡ C bond.
The π-electron population at the ortho and para positions is
depleted for the case of an EWG but not equally. The ortho
position is more affected than the para position. The cyano
group is a stronger EWG than para- and meta-positioned formyl
Driven by the above-mentioned results, which suggest the
prevalent role of the formyl group on the direction of the polar-
ization in 2-alkynylbenzaldehydes, we aimed to investigate the
extent of that effect. By placing the EDG or EWG on one or
both of the aromatic rings we might be able to influence the
polarization of the C≡ C bond that could translate to the regio-
selectivity of the cyclization reactions. For that purpose, several
2-alkynylbenzaldehydes with para substitution on the aldehyde
group and as a result it affects the polarization of the alkyne
ring relative to the alkynyl moiety were prepared. The type of
bond as expected. However, when in ortho position, formyl
substituent and the substitution pattern was selected in such a
way to create the “push-pull“ effect between the substituents
on both aromatic rings or between the substituent and the
group becomes a stronger EWG than para-positioned cyano
group and the polarization is reversed. Moreover, the study on
the transmission of electronic substituent effects through the
formyl group. Again, the partial charges were assigned to the
C≡ C bond in substituted phenylacetylenes shows that ortho- or
acetylenic carbon atoms in the same manner as previously, (Fig-
ure 3).
para-positioned π-acceptor interacts through conjugation with
the C≡ C π-bond that is orthogonal to the π-system of the aro-
The observed polarization was identical as in the previous
matic ring, thus greatly affecting its polarization.[24]
cases, even though the substituent effect was expected to be
the strongest in 1l. We assumed that the combination of elec-
tron-donating methoxy group and electron-withdrawing nitrile
would result in strong polarization of the C≡ C bond where the
negative charge would reside on the ꢀ-carbon atom. However,
in this case the observed strength of the triple bond polariza-
tion is the weakest with a chemical shift difference reduced to
only 3.5 ppm. Once again, these results provide evidence that
With 2-alkynylbenzaldehydes in hand, we proceeded with
Pd-catalyzed cyclization reactions in the presence of methanol
as the external nucleophile. If there is a correlation between
polarization of the triple bond and the regioselectivity of this
process, then the nucleophilic oxygen atom of the formyl group
in all prepared 2-alkynylbenzaldehydes should bond itself to
the electrophilic ꢀ-carbon atom, thus providing only products
with a 1H-isochromene core. In that sense, the Pd(OAc)2-cata-
the ortho positioned formyl group in 2-alkynylbenzaldehydes
has yet the greatest influence on the triple bond polarization.
lyzed cyclization reactions in THF with two equivalents of MeOH
were carried out as described previously and the results are
With respect to the observed polarization in 1l–1q, cycliza-
tion reactions should proceed in such a manner where again
the aldehyde oxygen atom would bond to the ꢀ-carbon atom
of the triple bond, thus providing the 1H-isochromene prod-
ucts. Indeed, only one regioisomer, the six-membered cyclic
ether, was obtained as a sole product upon cyclization of 2-
alkynylbenzaldehydes 1m–1n and 1p–1q (Scheme 4). Cycliza-
tion of 1o gave a complex mixture, from which it was not possi-
summarized in Scheme 3. All reactions provided the expected
six-membered cyclic alkenyl ethers while the formation of
benzofuran products was not observed indicating the close cor-
relation between the polarization and the regioselectivity. The
rather modest yields in some cases can be attributed to the
problems encountered during the isolation of the products
from the remaining Pd-catalyst and unreacted starting material.
The structures of the obtained regioisomers were confirmed by
Scheme 3. Products of cyclization of 2-alkynylbenzaldehydes 1a–1i.
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Figure 3. Polarization of the triple bond in 2-alkynylbenzaldehydes 1l–1q.
Scheme 4. Products of cyclization of 2-alkynylbenzaldehydes 1l–1q.
ble to isolate and characterize any products by 1H and 13C NMR reaction. The proposed mechanism for the cyclization of
analysis although mass spectrometry of the crude reaction mix- carbon-tethered- and 2-alkynylbenzaldehydes in the presence
ture showed a mass peak (298.1199) that matched the expected of MeOH suggests the formation of a hemiacetal as the first
product.
On the other hand, the cyclization of 1l provided a mixture
of two products: 1H-isochromene 2l and benzofuran 2l′ in a 6:1
step. Even if hemiacetal is formed during the course of the reac-
tion, the hydroxyl oxygen atom would still attack the more elec-
trophilic carbon atom of the triple bond. Nevertheless, the
ratio. This result implies either a different course of the reaction transformation of the electron-withdrawing formyl group to the
or the polarization of the triple bond being reversed during the electron-donating hemiacetal might affect the polarization it-
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Figure 4. Polarization of the triple bond in acetals 3e, 3c, 3l, and 3a.
self, thus favoring the formation of the regioisomer opposite
from the one expected with respect to the polarization in 2-
alkynylbenzaldehyde 1l. Since monitoring the change in polari-
zation using NMR would be rather difficult, to get better insight
into the polarization of the triple bond during the course of
cyclization, the stable counterparts, which would mimic the
hemiacetal formed in the first step had to be prepared. In that
sense, reactions of 1e, 1c, and 1l with trimethyl orthoformate
afforded the corresponding acetals 3e, 3c, and 3l respectively.
In addition, acetal 3a was prepared from 1a given the fact that
this substrate has the weakest polarized bond, (Figure 4). The
NMR analysis of the formed acetals 3e and 3c revealed that the
polarization is the same compared to the 2-alkynylbenzalde-
hydes 1e and 1c.
Figure 5. Possible intermediates formed during cyclization of 1a.
the course of the reaction could account for or substantially
contribute to the observed regioselectivity.
Conclusions
Without change in polarization, the cyclization would still
provide the 1H-isochromene products 2e and 2c as observed.
On the other hand, the electron distribution around the triple
bond in acetals 3l and 3a is the opposite to their aldehyde
counterparts 1l and 1a. This shows that when the polarization
of the triple bond is weak enough (Δδ = 3.5 ppm for 1l and
1.6 ppm for 1a) the formation of hemiacetals during the reac-
tion could flip the polarization thus giving a product mixture
as observed in cyclization of 1l. However, cyclization of alkynyl-
benzaldehyde 1a provided only 1H-isochromene regioisomer
2a despite the reversed polarization in acetal 3a. Formation of
only one regioisomer could be attributed to the steric effect
posed by the bulky TMS group. Regardless of the mechanism,
5-exo-dig cyclization would result in the sterically hindered
vinylpalladium intermediate 4, (Figure 5). Conversely, a pathway
towards six-membered cyclic ether would include intermediate
5 where the palladium atom bonded to the α-carbon atom
is more distant from the TMS group, thus reducing the steric
hindrance and allowing for the formation of product 2a.
Although these results are based on approximate correlation
between the formed acetals and the mechanistically proposed
We have described the factors that affect the electron distribu-
tion (polarization) around the triple bond in 2-alkynylbenzalde-
hydes and their correlation with the regioselectivity of the Pd-
catalyzed cyclization reaction. The polarization is not the direct
result of the electron-donating or electron-withdrawing ability
of the substituent on the alkynyl moiety, but rather it is a conse-
quence of the influence of a formyl group and its position on
the aromatic ring. Furthermore, the Pd-catalyzed annulation re-
actions of the compounds studied provided predominantly 1H-
isochromene heterocycles, therefore suggesting the close corre-
lation between the polarization of the triple bond and the
regioselectivity of these processes.
Experimental Section
General procedure for the cyclization of 2-alkynylbenzalde-
hydes 1: Under an argon atmosphere, a 25 mL, flame-dried Schlenk
flask was charged with 2-alkynylbenzaldehyde 1 (0.50 mmol,
1.0 equiv.) and Pd(OAc)2 (0.025 mmol, 5.0 mol-%). THF (1.0 mL)
and MeOH (1.0 mmol, 2.0 equiv.) were added sequentially and the
hemiacetals, the change in polarization that might occur during resulting reaction mixture was stirred at 25 °C. After 30 minutes,
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(1-Methoxy-1H-isochromen-3-yl)trimethylsilane (2a): Column
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˜
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Acknowledgments
The authors are grateful to the following agencies for financial
support of this work: Natural Sciences and Engineering Re-
search Council of Canada (NSERC) (Discovery Grants), Canada
Research Chair Program, Canada Foundation for Innovation
(CFI), TDC Research, Inc., TDC Research Foundation, the Ontario
Partnership for Innovation and Commercialization (OPIC), and
The Advanced Biomanufacturing Centre (Brock University).
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Keywords: Homogeneous catalysis · Cyclization ·
Isochromenes · Polarization · Regioselectivity
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Received: August 15, 2019
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Polarization-Induced
Regioselectivity
N. Nardangeli, N. Topolovčan,
R. Simionescu, T. Hudlický* ............. 1–8
Polarization Effect on Regioselecti-
vity of Pd-Catalyzed Cyclization of
2-Alkynylbenzaldehydes
The influence of C≡ C bond polariza- lyzed cyclization of 2-alkynylbenzalde-
tion on the regioselectivity of Pd-cata- hydes is described.
DOI: 10.1002/ejoc.201901203
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
8
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim