Regioselective annulation of propargyl alcohols with ambident-enols: A Ca(II)-catalyzed trisubstituted benzochromene synthesis

Article abstract of DOI:10.1016/j.tetlet.2017.10.077

Highly regioselective, 6-endo cyclization between propargyl alcohols and ambident enols such as naphthols, 4-hydroxy coumarin, cyclohexane-1,3-dione, 5,5-dimethylcyclohexane-1,3-dione is described using Ca(OTf)₂ under solvent free conditions. The reaction proceeds through a cascade annulation which involves an etherification, Claisen type rearrangement, allene formation and endocyclization. Further, we extended this method to the synthesis of iodo-derivative and demonstrated the reactivity in cross-coupling reactions.

Full text of DOI:10.1016/j.tetlet.2017.10.077

Accepted Manuscript
Regioselective Annulation of Propargyl Alcohols with Ambident-Enols: A
Ca(II)-Catalyzed trisubstituted Benzochromene Synthesis
Srinivasarao Yaragorla, Abhishek Pareek, Ravikrishna Dada
PII:
S0040-4039(17)31381-3
https://doi.org/10.1016/j.tetlet.2017.10.077
TETL 49439
DOI:
Reference:
Tetrahedron Letters
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29 October 2017
Please cite this article as: Yaragorla, S., Pareek, A., Dada, R., Regioselective Annulation of Propargyl Alcohols
with Ambident-Enols: A Ca(II)-Catalyzed trisubstituted Benzochromene Synthesis, Tetrahedron Letters (2017),
doi: https://doi.org/10.1016/j.tetlet.2017.10.077
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Regioselective Annulation of Propargyl Alcohols with Leave this area blank for abstract info.
Ambident-Enols: A Ca(II)-Catalyzed trisubstituted Benzochromene Synthesis
Srinivasarao Yaragorla,∗ Abhishek Pareek and Ravikrishna Dada
2

1
Tetrahedron Letters
journal homepage: www.els evier.com
Regioselective Annulation of Propargyl Alcohols with Ambident-Enols: A Ca(II)-
Catalyzed trisubstituted Benzochromene Synthesis
Srinivasarao Yaragorla∗a Abhishek Pareeka and Ravikrishna Dadaa
aSchool of Chemistry, University of Hyderabad, P.O. Central University, Hyderabad, 500046, Telangana, India.
ARTICLE INFO
ABSTRACT
Highly regioselective, 6-endo cyclization between propargyl alcohols and ambident enols such
as naphthols, 4-hydroxy coumarin, cyclohexane-1,3-dione, 5,5-dimethylcyclohexane-1,3-dione
is described using Ca(OTf)2 under solvent free conditions. The reaction proceeds through a
cascade annulation which involves an etherification, Claisen type rearrangement, allene
formation and endocyclization. Further, we extended this method to the synthesis of iodo-
derivative and demonstrated the reactivity in cross-coupling reactions.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
Propargyl alcohols
Ambident nucleophiles
Benzochromenes
Calcium Catalysis
Claisen rearrangement
2009 Elsevier Ltd. All rights reserved.
Ambident nucleophiles have a pair of electrons on each of two
or more atoms, or canonical forms can be drawn in which two or
more atoms bear an unshared pair of electrons. Therefore
ambident nucleophiles may attack in two or more different ways
to give different products.1 Enols are one of the most important
types of ambident nucleophiles, used extensively as reagents in
organic synthesis.2 Enols can react through hard oxygen or soft
carbon with the ambident substrates based on the conditions. As
depicted in the Scheme 1, the ambident enol (2) can react with
the ambident propargyl alcohol (1) to give two possible
regioisomeric benzopyrans 3a or 3Ia. Indeed, propargyl alcohol
reacts with the Lewis acid to produce the propargyl cation (3o-
carbocation) which is a hard acid, then ambident enol reacts with
this hard acid (3o-carbocation) through its hard base (oxygen,-
OH) to furnish more stable regioisomer 3a through a hard-hard
interactions. Alternatively, ambident enol may react with this
hard acid ((3o-carbocation) through its soft base (carbon) to
furnish less stable 3Ia through a hard-soft interactions.
Therefore, it can be understood that, under thermodynamic
conditions 3a can be the major or exclusive product. Owing to
the biological importance3 and natural abundance4 of the
benzeochromene derivatives (pyran derivatives) several synthetic
methods were reported5,6. In continuation of our research aimed
to develop the regioselective methods for the synthesis of
privileged molecules using propargyl alcohols as synthons,7 here
in we are reporting a highly facile, regioselective, solvent free
reaction between propargyl alcohols and enols.
We commenced our investigation by using easily available
propargyl alcohol 1a and 2-naphthol 2a in the presence of 10
mol% of Ca(OTf)2, 10 mol% of Bu4NPF6 in 1,2-dichloroethane
at rt (25 oC). To our delight product 3a was formed in 50% after
5 h (single product), however, there was no significant progress
in the reaction till 12 h (Table 1, entry 1). When refluxed in DCE
at 90 oC, the reaction yielded 3a in 74% after 5 h (entry 2). The
yield of 3a was raised to 81% after 90 minutes, when a mixture
of 1a, 2a and 10 mol% of Ca(OTf)2/Bu4NPF6 was heated to 110
oC, in the absence of solvent (entry 3). Attempts to minimize the
catalyst loadings were moderately successful to get the maximum
yield of 3a (entries 4, 5). However, in the absence of the additive,
———
∗ Corresponding author. Tel.: +91-40-23133800; fax: +91-463-238722; e-mail: srinivas.yaragorla@uohyd.ac.in and ysriict@gmail.com
1

2
Tetrahedron
the reaction yielded only 20% of 3a (entry 6), therefore the
Having the optimal conditions in hand, we next examined the
generality of our regioselective transformation as showed in
Table 2. Propargyl alcohol 1a (ethyl 4-hydroxy-4-phenylpent-2-
ynoate) was treated with a variety of phenolic compounds under
standard conditions and gratifyingly the products 3a-3d were
isolated as single isomers in excellent yields. Propargyl alcohol
1b (ethyl 4-hydroxy-4,4-diphenylbut-2-ynoate) was also reacting
well with the phenols bearing (Br, Cl, Me) different substitutions
and yielded the products 3e-3h (Table 2). Products 3i-3l were
synthesized in excellent yields from propargyl alcohol 1c (methyl
4-hydroxy-4,4-diphenylbut-2-ynoate) with phenolic compounds.
After the successful demonstration of scope of ambident phenols
in the annulation reaction, next we moved to the check the
reactivity of another ambident enol, 4-hydroxycoumarin and
synthesized the products 3m, 3n and 3o by treating 4-hydroxy
coumarin with 1a, 1b and 1c respectively. So far the scope of
propargyl alcohols bearing ester group was demonstrated hence
we further planned to replace the ester group with aryl moiety.
For example 1d (1,1,3-triphenylprop-2-yn-1-ol) was treated with
naphthols in presence of 2 mol% Ca(OTf)2/10 mol% Bu4NPF6 at
presence of additive is necessary, so that a ligand metathesis
takes place between Ca(OTf)2 and Bu4NPF6 to furnish
Ca[(OTf)(PF6)] with increased Lewis acidity. Other additives
such as, KPF6, NH4BF4, and Bu4NF gave moderate yields with
Ca(OTf)2 (entries 7-9). Metal catalysts, such as Mg(OTf)2 and
FeCl3 were employed, but moderate yield of 3a was obtained
(entries 10,11). The reaction did not occur in water (entry 12) and
another protic-solvent, ethanol gave only 20% of the product and
rest of the propargyl alcohol converted into corresponding ether
(entry 13). The reaction gave 45% product in an aprotic nonpolar
solvent, toluene (entry 14).
Table 1. Optimization of reaction conditionsa
Entry Catalyst (mol%)
Conditionsb
Yield (%)c
o
110 C under neat conditions gave the naphthopyrans 3p-3r in
1
Ca(OTf)2/Bu4NPF6 (10/10)
1,2-DCE, rt, 5 h
50
74
81
81
75
20
65
55
62
61
53
nr
good yields. Similarly, other triaryl propargyl alcohols (Table 2)
reacted with naphthols and 4-hydroxy coumarin and yielded the
pyran derivatives 3s-3x in good yields. 1,3-diketones, such as
5,5-dimethylcyclohexane-1,3-dione and cyclohexane-1,3-dione
exists in keto-enol tautomersim and hence considered as
ambident enols and treated with propargyl alcohols to get the
pyrans 3y and 3z in good yields. 1-(phenylethynyl)cyclohexan-1-
ol gave the spirocyclic pyrans 3aa-3ac with naphthols. Another
spiro compound 3ad was synthesized from 4-hydroxy coumarin
and 9-(phenylethynyl)-9H-fluoren-9-ol. 2-methyl-4-phenylbut-3-
yn-2-ol gave the pyran derivatives 3ae-3ag in excellent yields.
Finally, 2-methyl-4-(trimethylsilyl)but-3-yn-2-ol was treated
with 4-methoxynaphthalen-1-ol under standard conditions and
obtained 74% of 3ah, which resembles the Lapachenole natural
product (depicted in the box, Table 2).
2
Ca(OTf)2/Bu4NPF6 (10/10)
Ca(OTf)2/Bu4NPF6 (10/10)
Ca(OTf)2/Bu4NPF6 (05/10)
Ca(OTf)2/Bu4NPF6 (05/05)
Ca(OTf)2 (10)
1,2-DCE, 90 oC, 5 h
Neat, 110 oC, 1.5 h
Neat, 110 oC, 1.5 h
Neat, 110 oC, 5 h
Neat, 110 oC, 10 h
Neat, 110 oC, 3 h
Neat, 110 oC, 6 h
Neat, 110 oC, 3 h
Neat, 110 oC, 6 h
Neat, 110 oC, 10 h
Water, 110 oC, 12 h
Ethanol, 90 oC, 10 h
3
4d
5
6
7
Ca(OTf)2/KPF6 (10/10)
Ca(OTf)2/NH4BF4 (10/10)
Ca(OTf)2/Bu4NF (10/10)
Mg(OTf)2/Bu4NPF6 (10/10)
FeCl3 (10)
8
9
10
11
12
13
14
Ca(OTf)2/Bu4NPF6 (10/10)
Ca(OTf)2/Bu4NPF6 (10/10)
Ca(OTf)2/Bu4NPF6 (10/10)
20e
Toluene, 110 oC, 6 h
45
b
c
a1 equiv of 1a and 1.2 equib of 2a were used. Oil bath temperature. Isolated
yields. dOptimum conditions. eremaining compound was found as propargyl
ether. rt=room temp (25 oC)
Though our hypothesis in the Scheme 1 suggests the possible
formation of two regioisomeric benzopyrans, the rationale
suggested (HSAB theory) a thermodynamically stable single
isomer and the experimental result also confirmed the single
regioisomer (Table 1). To confirm the structure of the product,
The scalability of this solvent free method for the synthesis of
1,3,3-triphenyl-3H-benzo[f]chromene 3p (1150 mg, 80% yield)
from 2-naphthol and propargyl alcohol 1d was demonstrated in
the Scheme 4.
o
After the successful development of a regioselective method for
the solvent free synthesis of benzo/naphthochromens, we planned
the synthesis of 2-iodo-derivatives.5c Therefore 1d and 2a were
treated with 2 mol% Ca(OTf)2/10 mol% Bu4NPF6, iodine (2
equiv) in toluene at rt for 1.5 h and found that the reaction
yielded a mixture (4:1) of 4a and 3p in 88% yield (Scheme 5).
Encouraged by these observations, we then decided to see the
reactivity of this 2-iodo pyran derivative in cross-coupling
reactions. Since 4a and 3p were formed as an inseparable
mixture, we treated the mixture with ethyl acrylate under Heck
we subjected the compound 3f to ozonlysis (O3, DCM, -78 C)
and obtained the product 3fa in 85% yield (Scheme 3). Further
the structure of compound 3f was unambiguously endorsed by X-
ray crystallograpgic data (Scheme 3).
o
conditions87d (Pd(OAc)2, Bu4NBr, K2CO3, DMF, 80 C, 22 h), to
obtain 5 in 66% yield (the product 3p was also separated). The
iodide mixture (4a+3p) was also subjected to the Sonogashira
cross coupling reaction9,7d with acetylene (Pd(OAc)2, DABCO,
CH3CN, rt, 12 h) and obtained the product 6 in 61% yield
(Scheme 5).
2

3
Table 2
. Substrate scope of Calcium catalyzed regioselective annulation of propargyl alcohols with ambident enols
R3
R1 OH
Ca(OTf)/Bu4NPF6
H
R2
+
R2
Neat, 110 o
C
OH
O
3
R1
R3
2
1
Br
COOEt
COOEt
COOEt
COOEt
COOEt
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Ph
Ph
Me
O
O
O
O
O
3ba
3ca
3da
3ea
3aa
86%, 2 h
75%, 4 h
72 % , 4.5 h
COOMe
Ph
76%, 3 h
81%, 1.5 h
Br
COOEt
COOEt
Br
COOMe
COOEt
Cl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
Me
O
O
O
O
Ph
3ha
3ia
3ga
3fa
(
3ja
CCDC:1561470)
63%, 6 h
4 h
5%,
7
81%, 2 h
86%, 2 h
77%, 2 h
COOMe
COOMe
O
COOEt
O
COOEt
O
COOMe
Cl
O
O
O
Ph
Ph
Ph
Ph
Me
Ph
Ph
Ph
Ph
Ph
O
Me
O
O
O
3na
O
3ma
3ka
3la
3oa
76%, 3 h
Ph
72%, 3 h
69%, 5 h
79%,3.5 h
81%, 3 h
Br
Br
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
Ph
Ph
O
Me
Ph
O
O
O
O
3pb
3qb
3rb
3sb
84%, 45 min
3tb
76%, 45 min
88%, 30 min
87%, 45 min
Ph
81%, 1h
Ph
Ph
O
Ph
O
Ph
O
Me
Ph
Ph
Ph
Me
Me
Ph
Ph
O
O
O
O
O
Me
Me
Me
Br
3xb
3yb
3wb
3ub
3vb
75%, 2.5 h
77%, 2 h
70%, 2h
77%, 1 h
82%, 50 min
Br
Ph
O
Ph
O
O
Ph
Ph
Ph
O
Me
O
O
O
O
3aab
3abb
3acb
76%, 1 h
3zb
75%, 1.5 h
3adb
77%, 2 h
86%, 50 min
84%, 45 min
Br
Ph
TMS
Ph
MeO
Ph
MeO
Me
Me
O
Me
Me
Me
Me
Me
Me
Me
Me
O
O
O
O
Lapachenole
3aeb
3afb
3agb
3ahb
(natural product)
91%, 30 min
83%, 50 min
89%, 40 min
74%, 3 h
Reaction conditions: a1eq. of , 1.2 eq. of , 5 mol% of Ca(OTf)2 and 10 mol% Bu4NPF6 were heated at 110 oC (oil bath temperature) for
1
2
specified time; b.1eq. of , 1.2 eq. of , 2 mol% of Ca(OTf)2 and 10 mol% Bu4NPF6 were heated at 110 oC (oil bath temperature) for
1
2
specified time;
3

4
Tetrahedron
Ph
Ph
O
References
Ca(OTf)2/Bu4NPF6
2/10 mol%, toluene
OH
+
I
+
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Ph
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Pd(OAc)2, DABCO
CH3CN, rt, 12 h
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K2CO3, DMF, 80 oC, 22 h
Ph
Ph
Ph
COOEt
Ph
Ph
Ph
Ph
O
O
6, 61%
5, 66%
Scheme 5. Synthesis of Iodo-nephthopyrans and their cross-coupling reactions
We proposed the possible reaction mechanism for the synthesis
of 3 from 1 and 2 in the Scheme 6. Initially the oxophilic calcium
promotes the formation of vinyl-propargyl ether I1 from 2 and 1
3.
4.
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(hard-hard), which then undergoes
a thermodynamic-[3,3]
rearrangement5e to furnish the allene I2. Allene I2 can readily
form the enol I3 (path-a), which then undergo a regioselective, 6-
endo cyclization to yield the desired product 3. Alternatively
(path-b), allene I2 can rearrange to a diene and then cyclize to
give the product 3.
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In summary, we developed a regioselective annulation reaction
between propargyl alcohols and ambident enols using calcium
triflate as the sustainable lewis acid catalyst, under solvent free
conditions. Through this approach, we introduced the carboxylate
derivatives of benzochromenes as new chemical entities.
Ozonolysis and X-ray data supported the structure of the
products. We extended this method for the synthesis of iodo-
pyrans, further the synthetic utlity is demonstrated through cross
coupling reactions.
6.
7.
Selected
methods
for
synthesis
of
2,4,4-trisubstituted
naphthopyran(or 1,1,3-trisubstituted bezochromene); (a) Li HJ, Deng
K, Luo DH, Liu DH, Wang JL, Lin CH, Wu YC. RSC Adv.
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1
All compounds were fully characterized by H, 13C NMR, IR,
Mass, melting point and X ray data as required.10
Acknowledgements
8.
9.
Sonogashira K, Tohda Y, Hagihara N. Tetrahedron Lett.
1975;16:4467
SY thankful to UPE, AP and RD thank School of Chemistry, University of
Hyderabad for the facilities and Central University of Rajasthan for the
fellowship.
10.
Refer to the supporting information for complete details of
experimental procedures, spectral data and copies of the spectra.
4

5
Highlights of the Work
Regioselective Annulation of Propargyl Alcohols
with Ambident-Enols: A Ca(II)-Catalyzed
trisubstituted Benzochromene Synthesis
•
Highly regioselective Synthesis
Involves a Cascade Process of
•
etherification, [3,3] rearrangement, allene
formation and endocyclization
Solvent-Free Synthesis
•
•
•
Large Substrate Scope with High Yields
Extended to iodo-derivatives and
demonstrated the cross-couplings
5