Base-induced cyclization of derivatives of bispropargylated acetic acid to m -toluic acid

Article abstract of DOI:10.1055/s-0034-1380513

A base-induced cyclization reaction of 1,1-bispropargyls has been examined. Alkali treatment of 2,2-bispropynyl acetic acid derivatives in aqueous ethanol mostly provided 3-methylbenzoic acid. Investigations on substituent effects indicate the requirement of an electron-withdrawing group causing CH acidity and the center of the dipropargylic structure. Besides, an intramolecular hydrogen transfer causing the rearrangement of one terminal alkyne into a corresponding allene appears to be essential. Despite an unsatisfying conversion yield of below 40%, the reaction is interesting due to the mild cyclization conditions.

Full text of DOI:10.1055/s-0034-1380513

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, A–D
letter
A
T. H. Ali et al.
Letter
Synlett
Base-Induced Cyclization of Derivatives of Bispropargylated Acetic
Acid to m-Toluic Acid
O
Tammar Hussein Ali*
O
NaOH
Thorsten Heidelberg*
Rusnah Syahila Duali Hussen
X
H
HO
H2O–EtOH
Chemistry Department, Faculty of Science, University of Malaya,
Lembah Pantai, 50603, Kuala Lumpur
tammar86@gmail.com
H
– H+
heidelberg@um.edu.my
X
HX
O
O
Received: 21.01.2015
Accepted after revision: 05.03.2015
Published online: 30.03.2015
isomerization of 1,6-heptadiyne-4-carboxylic acid 1d un-
der similar conditions.7 Other reports indicate an identical
isomerization of 1d upon treatment with acid without
heating.8 However, the latter record has been previously
rated as nonreproducible.7 Despite the low reaction yield of
below 40% for the transformation of methyl 2,2-dipropargyl
acetate 1a to 3-methylbenzoic acid (2), the process is inter-
esting because of the unexpected reaction product and re-
lated mechanistic implications.
DOI: 10.1055/s-0034-1380513; Art ID: st-2015-b0045-l
Abstract A base-induced cyclization reaction of 1,1-bispropargyls has
been examined. Alkali treatment of 2,2-bispropynyl acetic acid deriva-
tives in aqueous ethanol mostly provided 3-methylbenzoic acid. Investi-
gations on substituent effects indicate the requirement of an electron-
withdrawing group causing CH acidity and the center of the dipropar-
gylic structure. Besides, an intramolecular hydrogen transfer causing
the rearrangement of one terminal alkyne into a corresponding allene
appears to be essential. Despite an unsatisfying conversion yield of be-
low 40%, the reaction is interesting due to the mild cyclization condi-
tions.
O
HO
O
NaOH, Δ
1d
Key words alkyne–allene isomerization, vinylogous enolate, 6-endo-
dig cyclization, bispropargyl, intramolecular proton transfer
EtOH (aq)
MeO
O
1a
The equilibrium of alkynes and allenes gives rise to var-
ious cyclizations, frequently involving aldol-type reactions.
Many reactions are initiated by coordinating metals; this
fits both intra-1–4 and intermolecular reactions.5 However,
initiation can also apply basic conditions, if resonance ef-
fects drive the reaction.6
HO
2
Scheme 1 Base-catalyzed cyclization of methyl 1,6-heptadiyne-4-car-
boxylate
Based on a targeted synthesis of dendrimers by ex-
ploitation of ‘click’ chemistry, we synthesized various
dipropargylic building blocks. The purification of some of
these led to unexpected problems, due to the presence of
aromatic compounds despite exclusive use of aliphatic re-
agents and solvents. This led to an investigation of the
source of the aromatics, revealing an unexpected intrinsic
reactivity for 1,6-heptadiynes with an electron-withdraw-
ing substituent (EWG) on the central carbon.
Dipropargyl acetates, like 1a, formed 3-methylbenzoic
acid (2) upon treatment with strong base in aqueous alco-
hol at elevated temperature instead of the expected saponi-
fication product 1d. The reaction is depicted in Scheme 1.
This result is in line with a previous report on the aromatic
It indicates an intrinsic reactivity of the 1,6-heptadiyne
core for aromatic cyclization under moderate reaction con-
ditions. The reaction is believed to pass through an initial
alkyne–allene isomerization as shown in Scheme 2, proba-
bly driven by resonance stabilization of the enolate. Base-
induced isomerizations of alkynes and allenes have been
reported previously.9–11 However, for these reactions stron-
ger bases are normally applied.6,11 Reaction mechanisms in-
volving a cyclic proton transfer mediated by a deprotonated
diamine10,11 or an alkali amide11 have been proposed. Both
mechanisms propose a push–pull concept. The same may
apply in water.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–D

B
T. H. Ali et al.
Letter
Synlett
Table 1 Attempted Cyclization of 1,1-Dipropargyls
O
O
Entry
Compd
EWG
CO2Me
R
Y
Yield (%)a
HO
RO
1
2
1a
1b
1c
1d
1e
1ec
1f
3
H
C
C
C
C
C
C
C
C
C
C
C
N
37b
1
2
CO2Et
CO2tBu
CO2H
CN
H
25b
O
3
H
n.r.
30b
RO
4
H
5
H
45b
Scheme 2 Reaction pathway for cyclization of 1,6-heptadiyne-4-car-
6
CN
H
n.r.
boxylates
7
CONC4H8O
COMe
COMe
CO2Me
CH2OH
N/A
H
>35d,e
ca. 60d,f
completef
n.r.g
8
H
Based on the distance of the carbons for the proton
transfer, a transition state involving a hydrated hydroxide is
favored over an isolated hydroxide ion. Scheme 3 displays
the isomerization of dialkyne 1 into the corresponding
alkynyl allene. This reaction is likely driven by the conjuga-
tion of the enolate. Subsequent reaction of the allene with
the second triple bond provides the aromatic ring. The con-
cept of isomerization of alkenes and allenes through eno-
lates with subsequent cyclization has been reported previ-
ously.6
9
3c
4
H
10
11
12
CO2Me
H
5
traceh
n.r.
6
C12H25
a n.r. = no reaction.
b Sole product: 2.13
c Modified reaction conditions: anhydrous MeOH, NaOMe.
d No detection of leftover starting material, but diverse degradation prod-
ucts. Yield estimation based on integration of 1H NMR (aromatic CH vs.
propargylic CH).
e Instead of acid 2 the corresponding ethyl amide14 was obtained.
f NMR indicates complex mixture of products.
H
O
g No detection of aromatic compounds, but saponification of ester.
h NMR indicates no single product but mixture of aromatic products.
H
O
H
H
H
H
Scheme 5. Aromatic products were also observed for the
base treatment of ketone 3. The olefinic NMR signals in the
range of aromatics for the latter may partially originate
from aldol-type reactions. However, the simultaneous dis-
appearance of propargylic signals strongly suggests a par-
ticipation of the alkynes in the formation of aromatic com-
pounds. On the other hand, substrates without a central hy-
drogen atom, referring to entries 4 and 6 (Table 1), did not
form any aromatic products. The minor cyclization of alco-
hol 5, despite missing CH acidity at the central carbon, is
surprising. The NMR of the crude product indicated the
presence of more than one aromatic product. It is assumed
that an initial oxidation of the alcohol led to an aldehyde,
which cyclized according to Scheme 5. Subsequent Canniz-
zaro reaction of the intermediate benzaldehyde gave rise to
a mixture of aromatic compounds.
A more detailed analysis of reactions for dipropargylat-
ed acetic acid derivatives provided a surprising result:
While esters with high sensitivity towards alkaline hydro-
lysis, like 1a and 1b, led to practically identical cyclization
yields than those obtained for the corresponding carboxylic
acid 1d the tert-butyl ester 1c failed to form aromatic prod-
ucts. Since tert-butyl esters commonly do not inhibit the α-
CH acidity of carboxylic acids, it was concluded that the re-
action starts with the saponification of the ester. This con-
clusion is in line with a solvent-dependent reactivity of ni-
trile 1e, leading to benzoic acid 2 in the presence of water,
whereas no reaction was observed under anhydrous condi-
MeO
O
H
MeO
O
Scheme 3 Solvent-mediated alkyne–allene isomerization
Although the isomerization of various diacetylenes to
aromatics has been previously proposed as generic con-
cept,7 the reaction typically requires high temperatures
(>160 °C), while the current reaction already enables the
aromatization at temperatures below 100 °C. In order to ra-
tionalize the unexpected reactivity, a comparative study on
various dipropargylic systems reflecting different substitu-
ent effects was performed.12 The generic reaction scheme is
displayed in Scheme 4, while specifications of the sub-
strates and their respective reaction outputs are summa-
rized in Table 1.
NaOH
R
Y
HOOC
EWG
EtOH (aq)
Scheme 4 Variation of substrates for attempted cyclization of 1,1-diprop-
argyls
Table 1 illustrates the importance of an acidic hydrogen
atom at the central carbon of the starting material. Various
dipropargyl acetic acid derived substrates (Table 1, entries
1a,b,d,f) provided aromatic products in accordance with
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–D

C
T. H. Ali et al.
Letter
Synlett
While most derivatives of 1,6-heptadiyne-4-carboxylic
acid furnished 3-methylbenzoic acid (2) upon treatment
with base, a different output was observed for morpholide
1f. Instead of the carboxylic acid its ethyl amide was ob-
tained. The different behavior may be understood based on
an enhanced basicity of the morpholine nitrogen atom,
which may enable the initial proton transfer on stage of the
amide enolate, as shown in Scheme 7. While the conversion
of the morpholide into an ethyl amide is not completely un-
derstood, an explanation may involve a thermoinduced
elimination process of the protonated morpholide enolate.
Unlike the morpholide 1f, nitrile 1e did not furnish an am-
ide product based on a partial hydrolysis, but provided the
carboxylic acid 2 instead. The reason for different reaction
pathways for the morpholide and a primary amide can be
found in the amide protons, which prevent the formation of
an amide enolate owing to higher acidity of the nitrogen-
bonded protons.
EWG
– H+
EWG
CH2
CH2
EWG
EWG
Me
CH2
EWG
EWG
H
H
H
H
Scheme 5 Mechanism for base-induced cyclization of 1,6-heptadiynes
with EWG at the central carbon
O
O
O
X
NaOH
tions. As a consequence of these results, the basic mecha-
nistic explanation in Scheme 5 requires adjustments.
An intramolecular hydrogen transfer to initiate the
alkyne–allene isomerization may explain the requirement
for the saponification of carboxylic esters in 1 prior to the
cyclization process. A possible mechanism is shown in
Scheme 6. A cyclic proton transfer from the propargylic
methylene group to a basic center at the carboxylic enolate
replaces the previously suggested solvent-mediated push–
pull mechanism displayed in Scheme 3. The five-mem-
bered-ring transition state, displayed in Scheme 6, cannot
be achieved on stage of an ester, owing to the low basicity
of both the enolate and the ester oxygen atoms. On the oth-
er hand, the enolate of a carboxylic acid, which requires
double deprotonation, would be sufficiently alkaline to ini-
tiate the reaction. However, the formation of multiple an-
ions is rather unfavored. Therefore, usually very strong bas-
es are applied to produce enolates of carboxylic acid an-
ions.15,16 This requirement for strong basic conditions may
explain why a substantial reduction of either base (12
equiv) or reaction temperature (ca. 90 °C) failed to induce
the cyclization and rationalize the reaction time of several
hours.
1
– H
H
HO
O
O
O
H
HO
O
CH2
HO
O
CH2
CH2
CH2
HO
O
HO
O
H
H
H
H
Following the initial alkyne–allene isomerization, the
reaction continues as intramolecular nucleophilic addition
of an allene enolate to an alkyne. It follows a 6-endo-dig
route, which commonly is less favored compared to the
competing 5-exo-dig cyclization.17 However, Vasilevsky et
al. reported a similar 6-endo-dig cyclization for an alkyne
without enhanced electrophilicity.18 Tautomeric rearrange-
ment of the resulting vinyl anion through a formal 1,2-hy-
drogen shift provides a resonance-stabilized anion, which
upon protonation readily leads to the substituted toluene
derivative.
H
Me
H
HO
O
H
2
Scheme 6 Detailed mechanism for cyclization of 1,6-heptadiyne-4-
carboxylates
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–D

D
T. H. Ali et al.
Letter
Synlett
(3) Brummond, K. M.; Davis, M. M.; Huang, C. J. Org. Chem. 2009, 74,
8314.
O
O
H
(4) Lu, S.; Jin, T.; Bao, M.; Yamamoto, Y. Org. Lett. 2010, 12, 864.
(5) Shibata, Y.; Noguchi, K.; Tanaka, K. Org. Lett. 2010, 12, 5596.
(6) Kitagaki, S.; Teramoto, S.; Mukai, C. Org. Lett. 2007, 9, 2549.
(7) (a) Eglinton, G.; Raphael, R. A.; Willis, R. G. Proc. Chem. Soc.
1960, 247. (b) Eglinton, G.; Raphael, R. A.; Willis, R. G.;
Zabliewicz, J. A. J. Chem. Soc. 1964, 2597.
N
O
N
O
– H+
1f
H
(8) Perkin, W. H. Jr.; Simonson, J. L. J. Chem. Soc. 1907, 91, 840.
(9) Spence, J. D.; Wyatt, J. K.; Bender, D. M.; Moss, D. K.; Nantz,
M. H. J. Org. Chem. 1996, 61, 4014.
(10) Abrams, S. R.; Shaw, A. C. J. Org. Chem. 1987, 52, 1835.
(11) Wotiz, J. H.; Barelski, P. M.; Koster, D. F. J. Org. Chem. 1973, 38,
489.
O
NH
CH2
O
Scheme 7 Base-induced alkyne–allene-tautomerization of tertiary
(12) General Cyclization Procedure
1,6-heptadiyne-4-carboxamides
The dipropargylic substrate (ca. 6.5 mmol) was dissolved in aq
EtOH (24 mL, 75% v/v) and NaOH (12 equiv) was added, after
which the reaction was heated to reflux overnight. The cooled
reaction mixture was acidified with aq HCl and extracted three
times with CH2Cl2. The combined organic layers were washed
with brine, dried over MgSO4, and the solvent was evaporated in
vacuum to leave the respective product (mass recovery 85% and
above). The conversion rate was determined based on relative
1H NMR integrations of the aromatic product and remaining
starting material. Details on the synthesis of starting materials
are provided in the Supporting Information.
We have rationalized the aromatization of 1,6-hepta-
diynes with electron-withdrawing groups at the central
carbon based on a new reaction mechanism. The previously
reported generic aromatization of diacetylenes7 suggested a
conjugated diene–allene intermediate. The current mecha-
nism explains why certain derivatives of 1,6-heptadiyne-4-
carboxylic acid exhibit a significant higher reactivity for the
cyclization. The reaction starts with an intramolecular pro-
ton transfer initiating the alkyne–allene isomerization. The
resulting allene enolate led to a nucleophilic addition fol-
lowing a 6-endo-dig cyclization, which finalized in a proton
rearrangement resulting in benzene ring.
(13) 3-Methylbenzoic Acid (2)
Purification applied chromatography using hexane–EtOAc (4:1)
followed by crystallization. The conversion of 1a (0.98 g, 6.5
mmol) provided 2 in 37% yield (0.33 g) as colorless solid. 1H
NMR (400 MHz, CDCl3): δ = 10.3 (br s, OH), 7.94 (s), 7.93 (d),
7.42 (d), 7.42 (d), 7.36 (t), 2.42 (s, 3 H). 13C NMR (100 MHz,
CDCl3): δ = 172.5, 138.3, 129.2, 134.6, 130.7, 128.4, 127.4, 21.2.
(14) N-Ethyl-3-methylbenzamide
Acknowledgment
Purification applied repeated (2×) column chromatography
using hexane–EtOAc (3:1). The isolation of the conversion
product of 1f (200 mg, 1 mmol) only provided an analytical
sample (ca. 30 mg, ca. 18%) as yellowisch oil. IR (ATR): 3304
Financial support of this work by the University of Malaya under re-
search grants RG201-11AFR, RG273-14AFR and PV055-2012A is
gratefully acknowledged.
(NH), 2923, 2852 (CH), 1644 (C=O), 1550 (C=C) cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 7.52 (s), 7.46 (t), 7.22 (m, 2H), 6.13 (br s,
NH), 3.42/3.41 (2 q, 2 H, Et-CH2), 2.31 (s, 3 H, CH3), 1.17 (t, 3 H,
Et-CH3). 13C NMR (100 MHz, CDCl3): δ = 167.7, 138.38, 134.5,
132.1, 128.4, 123.6, 34.9, 21.3, 14.9. MS: 163, 162, 119, 91, in
accordance with previously reported data.19
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380513.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(15) Lion, C.; Dubois, J. E. J. Chem. Res., Synop. 1980, 44.
(16) Pohmakotr, M.; Winotai, C. Synth. Commun. 1988, 18, 2141.
(17) Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 111, 6513.
(18) Vasilevsky, S. F.; Baranoc, D. S.; Mamatyuk, V. L.; Gatilov, Y. V.;
Alabugin, L. V. J. Org. Chem. 2009, 74, 6143.
References and Notes
(1) Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2002, 124, 4178.
(2) Brummond, K. M.; Lu, J. J. Am Chem. Soc. 1999, 121, 5087.
(19) Tay, K. S.; Rahman, N. A.; Abas, M. R. B. Chemosphere 2009, 76,
1296.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–D