Dichotomous control of E/Z-geometry in intramolecular cyclization of o-alkynylbenzamide derivatives catalyzed by organic superbase P4-tBu in the presence/absence of water

Article abstract of DOI:10.1002/asia.200900342

E/Z does it! An intramolecular cycli-zation reaction of o-alkynylbenzamides that allows dichotomous control of E/Z-geometry has been developed using an organic superbase, P4-tBu, as a catalyst. The presence/absence of water along with the use of an organi

Full text of DOI:10.1002/asia.200900342

COMMUNICATION
DOI: 10.1002/asia.200900342
Dichotomous Control of E/Z-Geometry in Intramolecular Cyclization of
o-Alkynylbenzamide Derivatives Catalyzed by Organic Superbase P4-tBu
in the Presence/Absence of Water
Chikashi Kanazawa and Masahiro Terada*[a]
Synthetic studies on heterocyclic compounds have been a
continuous theme in organic chemistry and hence a consid-
erable number of synthetic methods have been reported to
date. Among these methodologies, intramolecular cycliza-
tion of alkynylbenzene derivatives having a nucleophilic
substituent at the ortho-position is a simple and powerful
strategy to construct a variety of heterocyclic compounds.
Intramolecular cyclization of o-alkynylbenzoic acid[1] and o-
alkynylbenzamide,[2,3] as well as their derivatives,[4] repre-
sents one of the most efficient and well-investigated meth-
odologies for constructing oxygen and nitrogen heterocycles,
respectively (Figure 1). In particular, palladium-catalyzed[2]
or iodine-promoted[3e] intramolecular cyclization of o-alky-
nylbenzamides, which proceeds through electrophilic activa-
tion of an alkyne moiety via 5-exo or 6-endo cyclization, is a
well documented method to provide five- or six-membered
nitrogen heterocycles, many of which are potentially useful
as pharmaceuticals or other biologically active compounds.
Figure 1. Intramolecular cyclization of o-alkynylbenzene derivatives.
An alternative strategy to electrophilic activation is intramo-
lecular cyclization via activation of a nucleophilic site
through the addition of a catalytic or stoichiometric amount
of a base (Figure 1). However, such base-catalyzed intramo-
lecular reactions have not been well exploited.[2c,e,3c,d] Herein
we report the organic base-catalyzed intramolecular cycliza-
tion of o-alkynylbenzamide (1) to provide efficient access to
isoindolinone derivatives (2), in which dichotomous control
of the geometry at the exo-vinylidene moiety was estab-
lished using the organic superbase P4-tBu (3), a member of
the phosphazene family.[5,6] The presence/absence of water
along with the use of P4-tBu (3) was found to provide the
necessary control of the E/Z-geometry at the double bond.
The use of water as a controlling element in the final ge-
ometry obtained at the double bond was inspired by the re-
sults of an initial screening for organic bases under water-
free conditions.[7] The base-catalyzed intramolecular cycliza-
tion reactions of the parent compound o-alkynylbenzamide
(1a) were performed using a catalytic amount (10 mol%) of
a common organic base, DBU (1,8-diazabicycloACTHNURTGNEU[GN 5.4.0]undec-
7-ene), or a phosphazene superbase, P4-tBu (3), in acetoni-
trile or DMSO under an argon atmosphere. As shown in
Table 1, the reaction of o-alkynylbenzamide (1a) proceeded
smoothly and E/Z-geometrical mixtures of the isoindolinone
derivative (2a) were obtained in excellent chemical yield in
all cases. It is noteworthy that the E/Z-selectivity of 2a was
markedly dependent not only on the solvents and organic
bases employed, but also on the concentration of the reac-
tants. When acetonitrile was employed as a solvent, higher
Z-selectivity was observed than that in DMSO (Table 1,
[a] Dr. C. Kanazawa, Prof. Dr. M. Terada
Department of Chemistry
Graduate School of Science
Tohoku University
Sendai 980-8578 (Japan)
Fax : (+81)22-795-6602
E-mail: mterada@mail.tains.tohoku.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.200900342.
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Chem. Asian J. 2009, 4, 1668 – 1672

Table 1. Screening of catalysts, solvents, and concentration of intramolec-
we proposed that an intermediary carbanion (5’) was effec-
tively quenched by the acidic proton delivered from the car-
boxylic acid fragment of 4.[10,11] In contrast to the cyclization
of the carboxylic acid system, the acidity of the amide
proton is presumed to be insufficient to enable it to be an
effective proton source in the present system. Therefore, it
seems likely that the intriguing dependence of the E/Z-se-
lectivity on the concentration and properties of the organic
bases can be ascribed to the absence or presence of an effi-
cient proton source for quenching of the intermediary carb-
anion species (2’). If a more acidic proton source existed in
the reaction media, the intermediary carbanion (2’) could be
protonated immediately, and hence it is anticipated that
(Z)-2 would be formed predominantly as in the case of the
carboxylic acid system. In order to validate this hypothesis,
we therefore attempted the reaction using water as the
facile proton source coupled with the more basic P4-tBu (3)
as the catalyst.[12]
ular cyclization of 1a.[a]
Entry
Organic base
Solvent
t [h]
Yield [%][b]
E/Z[c]
1
2
3
4
DBU
DBU
3
3
MeCN (0.25m)
DMSO (0.25m)
DMSO (0.25m)
DMSO (0.125m)
6
6
2
2
99
99
99
99
10:90
50:50
70:30
81:19
The proposed Z-selective cyclization of 1a was performed
in a DMSO/H2O (v/v=9:1) co-solvent system in the pres-
ence of P4-tBu (3) (10 mol%). The representative results
are summarized in Table 2. As expected, the Z-isomer was
[a] Unless otherwise noted, all reactions were carried out using 0.2 mmol
of 1a and 20 mmol of an organic base (10 mol%) in the indicated solvent
(0.8 mL: 0.25m or 1.6 mL: 0.125m) at 808C. [b] 1H NMR yield. [c] E/Z
1
ratio was detemined by H NMR.
Table 2. Z-Selective cyclization reaction catalyzed by P4-tBu in DMSO/
entry 2 vs 1).[8,9] The use of the much stronger base P4-tBu
(3), instead of DBU, was found to provide the opposite geo-
metrical isomer, (E)-2a, as the major product, albeit in mod-
erate selectivity (Table 1, entry 3). Further screening of the
reaction conditions while changing the concentration
(Table 1, entry 4) revealed a considerable concentration
effect in the catalysis by P4-tBu (3) (Table 1, entry 4 vs 3);
H2O co-solvent system.[a]
Entry
1
R1
R2
R3
Yield [%][b]
E/Z
at
a lower concentration, the E-selectivity increased
1[c]
2[c]
3[c]
4[c]
5[c]
6
7
8
9
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Ph
Bn
allyl
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
87
96
99
95
97
99
99
91
97
61
92
<2:>98
<2:>98
<2:>98
<2:>98
<2:>98
24:76
(Table 1, entry 4), reaching 81% E for a 0.125m solution of
1a.
Recently we reported the analogous intramolecular cycli-
zation of o-alkynylbenzoic acids (4) catalyzed by organic
bases to afford phthalide derivatives (5) in excellent Z-selec-
tivity (Figure 2).[1b,10] In the previous carboxylic acid system,
MPM
MPM
MPM
MPM
MPM
MPM
MPM
MPM
p-MeOC6H4
p-CF3C6H4
1-naphthyl
TMS
nPr
Ph
11:89
[d]
–
H
Ac
MeO
53:47
67:33
<2:>98
10
1j
1k
11[c]
Ph
[a] Unless otherwise noted, all reactions were carried out using 0.2 mmol
of 1 and 20 mmol of 3 (10 mol%) in 1.8 mL of DMSO and 0.2 mL of H2O
at 408C for 30 min. [b] Isolated yield. [c] Only trace amount of (E)-2 was
obtained in crude 1H NMR or was not obtained. [d] Desilylated product
(2r) was obtained.
obtained as the major product in the DMSO/H2O co-solvent
system in most cases. It is noteworthy that a catalytic
amount of P4-tBu (3) worked very well even in the presence
of water and gave the corresponding isoindolinone deriva-
tives (2) in excellent yield, albeit at a lower reaction temper-
ature (408C).[13] A variety of substituents (R1) at the nitro-
gen atom, including phenyl, benzyl, allyl, and p-methoxy-
phenylmethyl (MPM) groups, were applicable to the present
DMSO/H2O system, providing the Z-isomers exclusively in
excellent yield (Table 2, entries 1–4). We further investigated
Figure 2. Intramolecular cyclization of o-alkynylbenzoic acids and o-alky-
nylbenzamides catalyzed by organic base.
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M. Terada and C. Kanazawa
COMMUNICATION
the scope and limitations of the Z-selective cyclization using
a series of o-alkynylbenzamide derivatives (1) bearing a
MPM moiety at the nitrogen atom (Table 2, entries 5–11).
The introduction of an electron-donating methoxy group to
either the terminal or backbone aromatic ring provided ex-
cellent Z-selectivities (Table 2, entries 5 and 11). In contrast,
the introduction of an electron-withdrawing group on either
ring led to a decrease in the Z-selectivity (Table 2, entries 6
and 10). In particular, introduction of an acetyl group to the
backbone aromatic ring provided the opposite E-isomer as
the major product (Table 2, entry 10). Further screening of
sterically demanding substituents at the alkynyl terminus re-
vealed that the 1-naphthyl substituent was able to provide a
high level of Z-selectivity (Table 2, entry 7), while the cycli-
zation of 1h, having a trimethylsilyl (TMS) group, afforded
the desilylated product (2r), although in high yield (Table 2,
entry 8). The aliphatic substituent was also applicable but
compromised the selective formation of Z-isomers (Table 2,
entry 9).
most sterically hindered substituents, TMS and 1-naphthyl,
exhibited high E-selectivities (Table 3, entries 7 and 8). In-
troduction of an aliphatic group at the alkynyl terminus led
to a decrease in chemical yield, but gave rise to the E-
isomer in a highly selective manner (Table 3, entry 9).
A plausible mechanism for the dichotomous control of E/
Z-geometry is depicted in Figure 3. An anionic intermediate
We next turned our attention to developing E-selective
cyclization reactions using the same catalyst, P4-tBu (3), but
under water-free conditions. As shown in Table 3, E/Z-selec-
Table 3. E-Selective cyclization reaction catalyzed by P4-tBu under
water-free conditions.[a]
Figure 3. Plausible mechanism of dichotomous control of E/Z-geometry
in intramolecular cyclization reaction catalyzed by P4-tBu.
Entry
1
R1
R2
R3
Yield [%][b]
E/Z
1[c]
2[c]
3[c]
4
5
6
7
8
9
10
11
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Ph
Bn
allyl
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
98
70
72
99
99
90
93
58
62
30
92
80:20
91:9
53:47
87:13
51:49
89:11
94:6
>98:<2
94:6
87:13
28:72
1’ generated by deprotonation of 1 undergoes intramolecu-
lar cyclization to form a vinyl anion intermediate, (Z)-2’. In
the presence of water, the intermediary (Z)-2’ would be pro-
tonated immediately by water to provide (Z)-2 as the kineti-
cally favored product with high selectivity. After protona-
tion, a hydroxide is also formed, which serves as a base to
reproduce 1’ for subsequent catalytic cycles. In contrast, in
the absence of water, an efficient proton source is not pres-
ent during the course of the reaction, because the conjugate
acid of P4-tBu, that is, [P4-tBu·H]+, and the amide proton
of 1 are less acidic.[12] Hence a repulsive interaction between
R1 and R2 would enforce the geometrical isomerization
from anion (Z)-2’ to the thermodynamically favored (E)-2’
before protonation occurs.[15] After isomerization to (E)-2’
as the major geometrical isomer, the intermediary anion (2’)
would be protonated by the less acidic 1, accompanied by
the generation of anion (1’) for further catalytic cycles.
Finally we attempted to increase the E-selectivity under
water-free conditions on the basis of the above mechanistic
considerations. If the repulsive interaction between R1 and
R2 were critical for determining the relative stability be-
tween E/Z-geometrical isomers of the anions (2’), it can be
anticipated that the E-selectivity would be enhanced by in-
troduction of a more sterically congested substituent at the
R1 group. As expected, substitution by the bulky benzhydryl
or tert-butyl moiety at the nitrogen atom gave rise to a
higher E-selectivity (Table 4, entries 1 and 2). The tert-butyl
substituent is particularly effective[16] and applicable to a
series of o-alkynylbenzamide derivatives (1), providing the
MPM
MPM
MPM
MPM
MPM
MPM
MPM
MPM
p-MeOC6H4
p-CF3C6H4
1-naphthyl
TMS
nPr
Ph
H
Ac
MeO
1j
1k
Ph
[a] Unless otherwise noted, all reactions were carried out using 0.2 mmol
of 1 and 20 mmol of 3 (10 mol%) in dried DMSO (1.6 mL) at 408C for
1–2 h. [b] Isolated yield. [c] Reactions were carried out at 608C.
tivities were substantially dependent on the substituents
(R1) introduced at the nitrogen atom (Table 3, entries 1–4).
Among the substituents examined, the MPM group was
found to be the best with respect to both reactivity and se-
lectivity (Table 3, entry 4), with the cyclization product ob-
tained quantitatively in high E-selectivity.[14] We further in-
vestigated the scope and limitations of the present E-selec-
tive cyclization under the P4-tBu/DMSO system in the ab-
sence of water. In summary, it was found that the electronic
properties and steric demand of the substituents (R2 and R3)
had a marked impact on the E/Z-selectivities. Substitution
by an electron-donating group at the terminal or backbone
phenyl ring compromised the formation of E-isomers
(Table 3, entries 5 and 11), while substitution of an electron-
withdrawing group afforded the E-isomers predominantly
(Table 3, entries 6 and 10), albeit in low yield for the acetyl
substituent owing to side reactions (Table 3, entry 10). The
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Chem. Asian J. 2009, 4, 1668 – 1672

Dichotomous Control of E/Z-Geometry in Intramolecular Cyclization
Table 4. E-Selective cyclization of 1 having bulky R1 substituents under
eluent) to give (Z)-3-benzylidene-N-(p-methoxyphenylmethyl)-isoindo-
lin-1-one [(Z)-2d, yellow oil] in 95% yield.
water-free conditions.[a]
Typical procedure for E-selective cyclization: To
a DMSO solution
(1.6 mL) of N-(p-methoxyphenylmethyl)-2-(2’-phenylethynyl)benzamide
(1d) (68.3 mg, 0.2 mmol) was added phosphazene base P4-tBu (1m solu-
tion in hexane, 20 mL, 20 mmol) under an Ar atmosphere. The solution
was stirred at 408C for 1.5 h. After the consumption of 1d, the reaction
mixture was extracted with AcOEt. The combined organic layers were
washed with water and brine, and dried over MgSO4. After the solvent
was removed by rotary evaporator, the residue was purified by silica gel
column chromatography (n-hexane/AcOEt 10:1—1:1 as eluent) to give
(Z)-3-benzylidene-N-(p-methoxyphenylmethyl)-isoindolin-1-one [(Z)-2d,
yellow oil] and (E)-3-benzylidene-N-(p-methoxyphenylmethyl)-isoindo-
lin-1-one [(E)-2d, yellow solid] in 13% and 87% yield, respectively.
Entry
1
R1
R2
Yield [%][b]
E/Z
1
2
3
4
5
6
1l
Ph2CH-
tBu
tBu
tBu
tBu
Ph
Ph
93
93
93
91
90
11
92:8
1m
1n
1o
1p
1q
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
p-MeOC6H4
p-CF3C6H4
1-naphthyl
nPr
tBu
[a] Unless otherwise noted, all reactions were carried out using 0.2 mmol
of 1 and 20 mmol of 3 (10 mol%) in DMSO (1.6 mL) at 408C for 1 h.
[b] Isolated yield.
Acknowledgements
We thank for Research Fellowships of the Japan Society for the Promo-
tion of Science for Young Scientists.
E-isomers exclusively (Table 4, entries 3–6), even in the re-
action of 1n, which has a p-methoxyphenyl substituent at
the alkynyl terminus (Table 4, entry 3). The excellent E-se-
lectivity achieved in the reaction of 1n deserves attention,
because the MPM-substituted 1e, which also has a p-me-
thoxyphenyl terminus, yielded a 1:1 mixture of E/Z-isomers
under water-free conditions (see Table 3, entry 5). The com-
pound 1q, bearing an aliphatic substituent, afforded the E-
product exclusively, albeit in low chemical yield owing to
the formation of byproducts (Table 4, entry 6).
In conclusion, we have developed an intramolecular cycli-
zation reaction of o-alkynylbenzamides that allows dichoto-
mous control of the E/Z-geometry when catalyzed by an or-
ganic superbase, P4-tBu. The presence/absence of water
along with the use of P4-tBu was found to be crucial in con-
trolling the geometry at the double bond. In the presence of
water, the kinetically favoured Z-isomers were formed in a
highly selective manner in most cases, while in the absence
of water, the steric interaction of the substituents introduced
at the alkynyl terminus and the nitrogen atom were respon-
sible for the high E-selectivity. These methods provide effi-
cient access to isoindolinone derivatives, an important class
of biologically active molecules, without the need for a
metal catalyst. Further studies on the applicability of the
present method, which combines the use of an organic su-
perbase and water, are underway in our laboratory to select-
ed organic syntheses.
Keywords: intramolecular cyclization
phosphazenes · superbase
· organocatalysis ·
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Experimental Section
Typical procedure for Z-selective cyclization: To water (0.2 mL) and N-
(4-methoxyphenylmethyl)-2-(2’-phenylethynyl)benzamide (1d) (68.3 mg,
0.2 mmol) was added DMSO (1.8 mL), and then phosphazene base P4-
tBu (1m solution in hexane, 20 mL, 20 mmol) under an Ar atmosphere.
The solution was stirred at 408C for 1 h. After the consumption of 1d,
the reaction mixture was extracted with AcOEt. The combined organic
layers were washed with water and brine, and dried over MgSO4. After
the solvent was removed by rotary evaporation, the residue was purified
by silica gel column chromatography (n-hexane/AcOEt 40:1—3:1 as
Chem. Asian J. 2009, 4, 1668 – 1672
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. Terada and C. Kanazawa
COMMUNICATION
schenthaler, I. Kaljurand, A. Kꢂtt, I. Koppel, V. Mꢁemets, I. Leito,
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formation of the Z-isomer. See, Ref. [10].
ˇ
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providing (Z)-2a predominantly (Table 1, entries 1–3). To prove our
hypothesis, we performed the reaction using P4-tBu (3), because this
stronger base generates a much less acidic conjugate acid, [P4-
tBu·H]+.
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[7] Acetonitrile and DMSO were dried over 3 ꢃ molecular sieves.
[8] Other solvents, such as DMF, toluene, 1,4-dioxane were investigated
using 10 mol% of DBU as the catalyst, however these solvents were
less effective in terms of either E/Z-selectivities or chemical yields;
DMF: 96% yield, 47% Z; toluene: 19% yield, >98% Z; 1,4-diox-
ane: 16% yield, >98% Z.
[13] The reaction of 1a (R1 =R2 =Ph, R3 =H) in a DMSO/H2O co-sol-
vent system provided a trace amount of 2a at 608C for 3 h when
DBU was employed as the catalyst. An elevated temperature and
prolonged reaction time were required to obtain the desired product
in good yield (at 808C for 1 h: 89% yield, >98% Z).
[14] The structure of the major isomer of 2d was determined to be E by
X-ray crystallographic analysis. See the Supporting Information for
details.
[15] Neither (Z)-2d nor (E)-2d isomerized to opposite geometrical ste-
reoisomer in the presence of 10 mol% P4-tBu in dried DMSO
(0.125m) at 408C for 2 h.
[16] The reaction of 1m (R1 =tBu, R2 =Ph, R3 =H) in a DMSO/H2O co-
solvent system gave a 1:1 mixture of E/Z-isomers in 95% yield. This
result strongly suggests that the tBu substituent effectively acceler-
ates the isomerization of (Z)-2’ into (E)-2’ (see Table 2, entries 1–4).
[9] The structure of the major isomer of 2a was determined to be Z by
X-ray crystallographic analysis. See the Supporting Information for
details.
[10] M. Terada, C. Kanazawa, M. Yamanaka, Heterocycles 2007, 74, 819–
825.
Received: August 5, 2009
Published online: September 8, 2009
[11] Theoretical studies on the carboxylic acid system revealed that the
participation of the carboxylic acid fragment reduced the activation
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Chem. Asian J. 2009, 4, 1668 – 1672