Phosphazene-base-catalyzed tandem addition-cyclization reaction of o-alkynylbenzaldehyde with oxygen and nitrogen nucleophiles

Article abstract of DOI:10.1055/s-0028-1087909

The tandem addition-cyclization reaction between o-alkynylbenzaldehyde and nucleophile catalyzed by P4-^tBu, a phosphazene base, is demonstrated. The nucleophilic cyclization is efficiently triggered not only by alcohols, including sterically de

Full text of DOI:10.1055/s-0028-1087909

638
LETTER
Phosphazene-Base-Catalyzed Tandem Addition–Cyclization Reaction of
o-Alkynylbenzaldehyde with Oxygen and Nitrogen Nucleophiles
A
ddition–Cycliza
h
tion Reactio
i
n of
o
-A
k
lkynylbenz
a
aldehyde
w
s
ithOxyge
h
n
andNitrog
i
enNucleoph
K
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Fax +81(22)7956602; E-mail: mterada@mail.tains.tohoku.ac.jp
Received 4 October 2008
starting o-alkynyl-substituted arene carbonyl compounds
Abstract: The tandem addition–cyclization reaction between o-
alkynylbenzaldehyde and nucleophile catalyzed by P4-tBu, a phos-
phazene base, is demonstrated. The nucleophilic cyclization is effi-
ciently triggered not only by alcohols, including sterically
demanding ones, but also by nitrogen nucleophiles, such as amide
and pyrrole, under the influence of a catalytic amount of P4-tBu.
The method enables efficient access to isobenzofuran derivatives
under mild conditions.
and activating agents.1,2
The analogous cyclization of heteroaromatic aldehydes
having an o-alkynyl substituent was recently reported by
Belmont and co-workers3a and Cikotiene et al.3b using
K2CO3 or alkoxide as base promoter to activate nucleo-
philic components. However, this type of nucleophilic cy-
clization, namely, the base-mediated tandem addition–
cyclization reaction, remains largely unexplored despite
exclusive formation of a furan ring via the 5-exo-dig cy-
clization mode (Scheme 1, b).3 Alcohols are the only nu-
cleophiles reported to date and neither secondary nor
tertiary alcohols promote the nucleophilic cyclization ef-
fectively. Primary alcohols are the sole nucleophile that
triggers the cyclization efficiently. In addition, a large ex-
cess of alcohol (generally used as solvent) is required to
obtain the corresponding heterocycles in good yields.
Key words: phosphazene, tandem reaction, cyclization, isobenzo-
furan, o-alkynylbenzaldehyde
The intramolecular cyclization reaction of o-alkynyl-sub-
stituted arene carbonyl compounds with nucleophilic
components is a powerful and atom-efficient strategy for
the construction of substituted oxygen heterocycles.1–3
A
variety of activating agents, such as metallic catalysts1
and iodine or related electrophiles,2 have been extensively
investigated for their potential to promote the cyclization
via electrophilic activation of alkynes (Scheme 1, a). Un-
der electrophilic conditions, various nucleophiles, such as
alcohol and carbon-centered ones, have been employed to
afford densely functionalized oxygen heterocycles, and it
was shown that the predominance of the cyclization
mode, 6-endo-dig or 5-exo-dig, is highly dependent on the
Recently, we demonstrated the intramolecular cyclization
of o-alkynylbenzoic acid catalyzed by organic bases to af-
ford isobenzofuranone derivatives via the 5-exo-dig
cyclization mode.4 In our continuing effort to develop
base-catalyzed intramolecular cyclization reactions of o-
alkynyl-substituted arene carbonyl compounds, we have
aimed to expand the synthetic utility of the tandem addi-
(a) Transition metal- or electrophile-promoted
R
(El)H
H(El)
O
R
R
transition metal
or
and/or
O
CHO
electrophile
Nu
+
Nu
Nu-H
5-exo-dig
6-endo-dig
(b) Base-promoted
R
H
R
R
base
O
O–
CHO
1
Nu
Nu
2
+
Nu-H
A
5-exo-dig
Scheme 1 Tandem addition–cyclization reaction of o-alkynyl-substituted arene carbonyl compounds with nucleophiles
SYNLETT 2009, No. 4, pp 0638–0642
x
x.
x
x.
2
0
0
9
Advanced online publication: 16.02.2009
DOI: 10.1055/s-0028-1087909; Art ID: U10708ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Addition–Cyclization Reaction of o-Alkynylbenzaldehyde with Oxygen and Nitrogen Nucleophiles
639
Table 1 Screening of Bases and Optimization of Reaction Conditionsa
tBu
N
H
NMe2
N
P
N
P
NMe2
Ph
Ph
organic
base
(cat.)
Me2N
P
N
P
NMe2
iPrOH
NMe2
Me2N
NMe2
+
O
NMe2
CHO
1a
OiPr
NMe2
2a
P4-tBu
Entry
Base (mol%)
DBU (10)
i-PrOH (equiv)
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
i-PrOH
toluene
MeCN
THF
Conditions
80 °C, 3 h
80 °C, 3 h
40 °C, 1 h
30 °C, 3 h
30 °C, 0.5 h
30 °C, 1 h
30 °C, 1 h
30 °C, 1 h
30 °C, 1 h
Yield (%)b
1
2
3
4
5
6
7
8
9
2
0c
TMG (10)
2
0c
P4-tBu (20)
P4-tBu (10)
P4-tBu (10)
P4-tBu (10)
P4-tBu (10)
P4-tBu (10)
P4-tBu (10)
2
77
1.5
4
60
88
–
23
4
57
4
trace
(90)
4
a All reactions were carried out using 0.2 mmol of 1a, the indicated equivalent of i-PrOH, and catalyst in 0.4 mL of solvent (0.5 M) under argon
atmosphere for the time indicated.
b NMR yield. Isolated yield is in parentheses.
c Compound 1a was recovered.
tion–cyclization sequence triggered by nucleophiles. was conducted in the presence of 20 mol% P4-tBu at
Herein we report the organic-base-catalyzed 5-exo-dig 40 °C (entry 3). Delightfully, the reaction proceeded
cyclization of o-alkynylbenzaldehyde derivatives 1 with smoothly and corresponding product 2a was obtained in
not only oxygen but also nitrogen nucleophiles, yielding an acceptable yield within one hour. Optimization of the
isobenzofuran derivatives 2. The proposed nucleophilic reaction conditions allowed us to reduce the catalyst load
cyclization was found to proceed smoothly under mild to 10 mol% and to decrease the reaction temperature to
conditions using a catalytic amount of phosphazene base 30 °C (entry 5), even though 4 equivalents i-PrOH was
P4-tBu.5
necessary to achieve a high chemical yield. Further
screening for solvents revealed that the catalytic efficien-
cy is markedly dependent on the solvent employed (en-
tries 6–9). Interestingly, a significant reduction in
chemical yield was observed when i-PrOH was used as
solvent (entry 6). A less polar solvent, toluene, was also
useful for the present reaction albeit the moderate yield
(entry 7), while in the presence of more polar acetonitrile,
1a was recovered in a nearly quantitative manner (entry
8). Among the solvents tested, THF was found to be the
best in terms of chemical yield (entry 9). Desired product
2a was isolated in 90% yield.
An initial experiment was performed using o-alkynylbenz-
aldehyde 1a with i-PrOH as the nucleophilic component
(2 equiv), a catalytic amount of organic base {10 mol%
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)}, and DMSO
as solvent, at 80 °C under argon atmosphere. As shown in
Table 1, despite using DBU, a relatively strong organic
base, and following reaction conditions similar to those
used in the base-catalyzed cyclization of o-alkynylbenzo-
ic acids,4 no desired product was obtained (entry 1). Tetra-
methylguanidine (TMG) was also ineffective and 1a was
recovered in a nearly quantitative manner (entry 2). We
hence turned our attention to using much stronger organic With the optimal conditions in hand, a series of nucleo-
bases, such as phosphazene bases. The organic base P4- philes including nitrogen ones were investigated for their
tBu, a member of the phosphazene family, is known as one suitability in the tandem addition–cyclization reaction. As
of the strongest metal-free bases.5 Taking advantage of its shown in Table 2, the present catalytic method is applica-
unique properties, intriguing transformations using a cat- ble not only to oxygen nucleophiles but also to nitrogen
alytic amount of P4-tBu have been accomplished.6 We ones. The reactions of primary alcohols, n-BuOH, BnOH,
therefore attempted to employ P4-tBu in the present tan- and allyl alcohol, proceeded smoothly to give correspond-
dem reaction. The reaction of 1a with i-PrOH (2 equiv) ing products 2b–d in high yields (entries 1–3).
Synlett 2009, No. 4, 638–642 © Thieme Stuttgart · New York

640
C. Kanazawa et al.
LETTER
Table 2 Tandem Addition–Cyclization Reaction of 1a with Various Nucleophilesa
Entry
1
Nucleophile
Conditions
30 °C, 2 h
2
Yield (%)b
H
H
H
H
H
H
Ph
n-BuOH
90
O
OnBu
2b
2c
2d
2e
2f
Ph
2
BnOH
60 °C, 3 h
60 °C, 3 h
30 °C, 1 h
80 °C, 18 h
93
91
99
70
O
OBn
Ph
3
OH
O
O
Ph
4
O
OH
OcHex
Ph
5c
t-BuOH
O
OtBu
Ph
O
N
6
2-pyrrolidinone
30 °C, 1 h
90
O
2g
2h
2i
H
Ph
H
N
7
8
30 °C, 1 h
90
O
N
Me
CHO
Me
CHO
Ph
H
H
80 °C, 12 h
O
67d
N
Me
COPh
N
Me
COPh
Synlett 2009, No. 4, 638–642 © Thieme Stuttgart · New York

LETTER
Addition–Cyclization Reaction of o-Alkynylbenzaldehyde with Oxygen and Nitrogen Nucleophiles
641
Table 2 Tandem Addition–Cyclization Reaction of 1a with Various Nucleophilesa (continued)
Entry
Nucleophile
pyrrole
Conditions
30 °C, 1 h
2
Yield (%)b
H
Ph
O
9
95
N
2j
–
10
11
phthalimide
benzamide
100 °C, 8 h
100 °C, 8 h
n.r.e
n.r.e
–
a The reaction of 1a (0.2 mmol) with nucleophile (4 equiv) was conducted in THF (0.5 M) in the presence of P4-tBu (20 mmol, 20 mL of 1 M
solution in hexane) under argon atmosphere for the time indicated.
b Isolated yield.
c The amount of 15 mol% of P4-tBu was used.
d Recovery of 1a in 20%.
e n.r. = no reaction.
A cyclic secondary alcohol, cyclohexanol, is also applica-
ble giving the corresponding product 2e in a nearly quan-
titative yield (entry 4). It is noteworthy that the sterically
demanding tertiary alcohol, t-BuOH, could be utilized as
an effective trigger for the present reaction; desired prod-
uct 2f was obtained in satisfactory yield when catalyst
load was increased to 15 mol% and the reaction tempera-
ture elevated to 80 °C (entry 5). It markedly contrasts the
trace or limited amounts of desired products formed in
previous methods reported so far.3 Nitrogen nucleophiles
as well as alcohols functioned as an effective trigger for
the present tandem addition–cyclization sequence. 2-Pyr-
rolidinone, N-methylformamide, N-methylbenzamide,
and 1-H pyrrole provided corresponding products 2g–j in
good to excellent yields (entries 6–9). However, neither
phthalimide nor benzamide gave the product (entries 10
and 11), presumably due to the instability of anionic inter-
mediate A (Scheme 1).7
Table 3 Scope of Substituents on Alkynyl Terminusa
Entry
1 (R)
Time (h)
2
Yield (%)b
83
1
2
3
4
5
6
7
1b 4-MeOC6H4
1c 4-MeC6H4
1d 4-F3CC6H4
1e CO2Et
1f n-Bu
3
2
1
1
4
5
3
2l
2m
2n
2o
–
78
65c
75d
dec.
dec.
dec.
1g TMS
–
1h H
–
a The reaction of 1 (0.2 mmol) with i-PrOH (4 equiv) was conducted
in THF (0.5 M) in the presence of P4-tBu (20 mmol, 20 mL of 1 M so-
lution in hexane) under argon atmosphere for the time indicated.
b Isolated yield.
c Trace amount of (E)-2n was obtained.
The tandem addition–cyclization reaction afforded prod-
uct 2 as the sole geometrical isomer. The geometry of the
newly generated double bond was determined to be Z after
comparing with stereochemically known compound (Z)-
2k.1f Thus, the reaction of o-alkynylbenzaldehyde 1b with
MeOH was conducted under modified optimum condi-
tions (Equation 1). Product 2k was obtained as the sole
geometrical isomer in 92% yield and its 1H NMR and 13C
NMR data were consistent with those reported by Wu et
al.1f
d Combined yield of (Z)- and (E)-2o; Z/E = 72:28.
Finally, the scope of substituents on the alkynyl terminus
was investigated using i-PrOH as the nucleophilic compo-
nent (Table 3). Although the introduction of electron-
donating groups to the terminal benzene ring prolonged
the reaction time (entries 1 and 2), products 2l and 2m
were obtained in good yields. The reaction of 1d having
an electron-withdrawing substituent, trifluoromethyl moi-
ety, gave (Z)-2n in an acceptable yield, accompanied by a
trace amount of the geometrical isomer, (E)-2n (entry 3).
The formation of the geometrical isomer was detected
markedly in the reaction of 1e in which electron-with-
drawing ethoxycarbonyl was directly introduced to the
alkynyl terminus (entry 4). The isomerization at the dou-
ble bond could be attributed to the fact that vinylic anion
intermediates, generated at the cyclization step, were
stabilized by these electron-withdrawing groups. Further
investigation of terminal substituents, such as alkyl, tri-
methylsilyl, and hydrogen, showed that decomposition of
H
R
R
P4-tBu
(10 mol%)
+
MeOH
O
THF (0.5 M)
60 °C, 4 h
CHO
OMe
1b: R = 4-MeOC6H4
(Z)-2k
92% yield
Equation 1
Synlett 2009, No. 4, 638–642 © Thieme Stuttgart · New York

642
C. Kanazawa et al.
LETTER
ESI-HRMS: m/z calcd for C19H15NO [M+ + Na]: 296.1046; found:
296.1045.
the starting o-alkynylbenzaldehyde occurred and no de-
sired product was obtained (entries 5–7).
In conclusion, we have demonstrated the organic-base-
catalyzed tandem addition–cyclization reaction of o-alky-
nylbenzaldehyde with various nucleophiles. The organic
base P4-tBu was found to be an efficient catalyst for the
tandem reaction. Most notably is the fact that sterically
demanding alcohols are capable of triggering the nucleo-
philic cyclization efficiently under the influence of a cat-
alytic amount of P4-tBu. We showed for the first time that
nitrogen nucleophiles, such as amide and pyrrole, are ap-
plicable to the nucleophilic cyclization. The method en-
ables efficient access to isobenzofuran derivatives under
mild conditions. Further studies on base-catalyzed nu-
cleophilic cyclization are under way in our laboratory.
Acknowledgment
We thank the Japan Society for the Promotion of Sciences for the
JSPS Research Fellowship for Young Scientists (C.K.).
References
(1) (a) Iwasawa, N.; Shindo, M.; Kusama, H. J. Am. Chem. Soc.
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Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 764.
(c) Nakamura, H.; Ohtaka, M.; Yamamoto, Y. Tetrahedron
Lett. 2002, 43, 7631. (d) Mondal, S.; Nogami, T.; Asao, N.;
Yamamoto, Y. J. Org. Chem. 2003, 68, 9496. (e) Bacchi,
A.; Costa, M.; Cà, N. D.; Fabbricatore, M.; Fazio, A.;
Gabriele, B.; Nasi, C.; Salerno, G. Eur. J. Org. Chem. 2004,
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Typical Procedure for P4-tBu-Catalyzed Tandem Addition–
Cyclization Reaction between o-Alkynylbenzaldehyde 1a and
i-PrOH
To a THF solution (0.4 mL, 0.5 M) of o-(2-phenylethynyl)benzal-
dehyde 1a (41.2 mg, 0.2 mmol) and i-PrOH (61 mL, 0.8 mmol) was
added P4-tBu (20 mL, 20 mmol; 1.0 M solution in hexane) at 30 °C
under argon atmosphere. After the consumption of 1a, the reaction
mixture was filtered through a short Florisil pad and concentrated
under reduced pressure. The residue was purified by column chro-
matography (SiO2, n-hexane–EtOAc, 50:1 to 15:1) to afford prod-
uct 2a in 90% yield (37.1 mg).
(2) (a) Barluenga, J.; Vázquez-Villa, H.; Ballesteros, A.;
González, J. M. J. Am. Chem. Soc. 2003, 125, 9028.
(b) Yue, D.; Cà, N. D.; Larock, R. C. Org. Lett. 2004, 6,
1581. (c) Yue, D.; Cà, N. D.; Larock, R. C. J. Org. Chem.
2006, 71, 3381. (d) Barluenga, J.; Vázquez-Villa, H.;
Merino, I.; Ballesteros, A.; González, J. M. Chem. Eur. J.
2006, 12, 5790.
(3) (a) Godet, T.; Bosson, J.; Belmont, P. Synlett 2005, 2786.
(b) Cikotiene, I.; Morkunas, M.; Motiejaitis, D.; Rudys, S.;
Brukstus, A. Synlett 2008, 1693; also see ref. 1f.
Analytical Data of 2a
White solid. 1H NMR (270 MHz, CDCl3): d = 1.36 (6 H, d, J = 6.0
Hz), 4.22 (1 H, sept, J = 6.0 Hz), 5.98 (1 H, s), 6.67 (1 H, s), 7.17 (1
H, tt, J = 7.0, 1.0 Hz), 7.32–7.46 (5 H, m), 7.55–7.59 (1 H, m), 7.75–
7.80 (2 H, m). 13C NMR (68 MHz, CDCl3): d = 22.69, 23.61, 71.85,
97.81, 106.21, 119.74, 123.05, 125.68, 128.15, 128.33, 128.88,
129.67, 135.41, 136.02, 137.89, 153.04. IR (neat): 3053, 2972,
2927, 1658, 1489, 1463, 1365, 1084, 1033, 1014, 942, 904, 822 cm–1.
ESI-HRMS: m/z calcd for C18H18O2 [M+ + Na]: 289.1199; found:
289.1197.
(4) (a) Kanazawa, C.; Terada, M. Tetrahedron Lett. 2007, 48,
933. (b) Terada, M.; Kanazawa, C.; Yamanaka, M.
Heterocycles 2007, 74, 819.
Analytical Data of 2g
White solid. 1H NMR (500 MHz, CDCl3): d = 1.88–2.60 (2 H, m),
2.54 (2 H, m), 2.83–2.88 (1 H, m) 3.18 (1 H, tt, J = 7.0, 11.0 Hz),
5.98 (1 H, s), 7.18 (1 H, dd, J = 6.0 Hz), 7.26–7.48 (6 H, m), 7.61 (1
H, d, J = 8.0 Hz), 7.74 (2 H, d, J = 7.0 Hz). 13C NMR (125 MHz,
CDCl3): d = 17.65, 31.40, 41.50, 85.99, 97.68, 119.95, 122.36,
125.85, 128.26, 128.35, 129.13, 129.66, 135.54, 135.64, 136.01,
153.16, 176.04. IR (neat): 3726, 3707, 3624, 3599, 2891, 1695,
1665, 1491, 1411, 1359, 1271, 1226, 1038, 942 cm–1. ESI-HRMS:
m/z calcd for C19H17NO2 [M+ + Na]: 314.1151; found: 314.1150.
(5) For a review on phosphazene base, see: (a) Schweisinger,
R.; Schlemper, H.; Hasenfratz, C.; Willaredt, J.; Dambacher,
T.; Breuer, T.; Ottaway, C.; Fletschinger, M.; Boele, J.;
Fritz, H.; Putzas, D.; Rotter, H. W.; Bordwell, F. G.; Satish,
A. V.; Ji, G.-Z.; Peters, E.-M.; Peters, K.; Schnering, H. G.;
Walz, L. Liebigs Ann. 1996, 1055. (b) For a pioneering
study on phosphazene base, see: Schwesinger, R.;
Schlemper, H. Angew. Chem., Int. Ed. Engl. 1987, 26, 1167.
(6) For recent studies on the catalytic use of P4-tBu, see:
(a) Imahori, T.; Hori, C.; Kondo, Y. Adv. Synth. Catal. 2004,
346, 1090. (b) Ueno, M.; Yonemoto, M.; Hashimoto, M.;
Wheatley, A. E. H.; Naka, H.; Kondo, Y. Chem. Commun.
2007, 2264. (c) Ebisawa, M.; Ueno, M.; Oshima, Y.; Kondo,
Y. Tetrahedron Lett. 2007, 48, 8918; and references cited
therein.
Analytical Data of 2j
White solid. 1H NMR (500 MHz, CDCl3): d = 6.05 (1 H, s), 6.25 (2
H, s), 6.74 (2 H, s), 7.17 (1 H, dd, J = 7.0 Hz), 7.26–7.35 (3 H, m),
7.41 (1 H, dd, J = 7.0 Hz), 7.52 (1 H, dd, J = 7.0 Hz), 7.67 (1 H, d,
J = 7.0 Hz), 7.71 (3 H, d, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3):
d = 91.78, 98.45, 109.86, 119.90, 119.91, 123.17, 126.01, 128.33,
128.35, 129.23, 130.06, 135.32, 135.52, 136.60, 152.61. IR (neat):
2923, 1689, 1596, 1487, 1307, 1082, 1033, 1016, 960, 760 cm–1.
(7) Other nucleophiles, such as phenol, 1-butanethiol, dimethyl
malonate, and phenylacetylene did not give desired product.
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