Tandem addition/cyclization reaction of organozinc reagents to 2-alkynyl aldehydes: Highly efficient regio- and enantioselective synthesis of 1,3-dihydroisobenzofurans and tetrasubstituted furans

Article abstract of DOI:10.1021/jo800029m

(Chemical Equation Presented) The enantioselective addition of organozinc reagents to some 2-alkynyl benzaldehydes and the subsequent regioselective cyclization step was performed in one pot to form chiral 1,3- dihydroisobenzofurans with good product yields and excellent regio- and enantioselectivities. In the case of 2-alkynylcycloalkene aldehydes, tetrasubstituted furans were obtained in good product yields through a 1, 5-hydride shift of the preformed cyclization product.

Full text of DOI:10.1021/jo800029m

from the corresponding 2-alkynylbenzaldehydes have been
realized utilizing a series of metal catalysts2 or various bases.3
Such cyclization reactions are particularly challenging because
both the 6-endo-dig and the 5-exo-dig cyclization of 2-alky-
nylbenzyl alcohols must be well-controlled to avoid formation
of intractable mixtures of regioisomeric five- and six-membered
rings; anti- and syn-addition to the triple bond should also be
controlled to avoid formation of a mixture of Z- and E-isomeric
isobenzofurans in the case of the 5-exo-dig process.2,3 Mean-
while, to the best of our knowledge, there has been no report
concerning the enantioselective formation of chiral 1,3-dihy-
droisobenzofurans.
Recently, Nakamura and co-workers4 have pioneered the use
of diethylzinc for the cyclization reactions of 2-alkynylphenols.
Inspired by this work, our group5 has also realized the Et2Zn-
catalyzed intramolecular hydroamination reaction of alkynyl
sulfonamides to form indole derivatives. On the other hand, the
enantioselective addition reactions of organozinc reagents to
aldehydes are well developed.6 On the basis of these studies,
we conceived a one-pot procedure involving a tandem addition/
cyclization process of organozinc reagents to 2-alkynylbenzal-
dehydes for the regio- and enantioselective synthesis of 1,3-
dihydroisobenzofurans. Thus, the present work presented a novel
tandem addition/cyclization of 2-alkynylbenzaldehydes with
organozinc reagents in the presence of chiral 2-pyrrolidinyl-
methanol derivatives to exclusively afford optically active (S,Z)-
1, 3-dihydroisobenzofurans in good yields and excellent enan-
tioselectivities with virtually complete Z-selectivities via a highly
regiospecific 5-exo-dig process involving stereoselective anti
addition to the triple bond (Scheme 1). Herein, we report our
results with this strategy.
Tandem Addition/Cyclization Reaction of
Organozinc Reagents to 2-Alkynyl Aldehydes:
Highly Efficient Regio- and Enantioselective
Synthesis of 1,3-Dihydroisobenzofurans and
Tetrasubstituted Furans
Zhuo Chai,† Zheng-Feng Xie,‡ Xin-Yuan Liu,†
Gang Zhao,*,† and Ji-De Wang*,‡
Laboratory of Modern Synthetic Organic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China, and Education
Ministry Key Laboratory of Oil and Gas Fine Chemicals,
XinJiang UniVersity, 14 Shengli Lu, Urumqi 830046, China
zhaog@mail.sioc.ac.cn; awangjdl@xju.edu.cn
ReceiVed January 5, 2008
The enantioselective addition of organozinc reagents to some
2-alkynyl benzaldehydes and the subsequent regioselective
cyclization step was performed in one pot to form chiral 1,3-
dihydroisobenzofurans with good product yields and excel-
lent regio- and enantioselectivities. In the case of 2-alkynyl-
cycloalkene aldehydes, tetrasubstituted furans were obtained
in good product yields through a 1, 5-hydride shift of the
preformed cyclization product.
Our study began with the use of 2-phenylethynylbenzaldehyde
(1a) as the probe substrate. In the presence of DPMPM (2a) or
the dendritic ligand (2b) developed by us previously,7a we were
pleased to find that the asymmetric addition of Et2Zn to 1a and
the subsequent regiospecific 5-exo-dig cyclization to form 3a
could be done in a one-pot fashion in toluene (Table 1). The
addition step was performed at room temperature; after disap-
pearance of the aldehyde monitored by TLC on silica gel plates,
Annulation processes involving the addition of heteroatoms
to multiple C-C bonds represent an important method for the
synthesis of heterocyclic compounds.1 Usually, such processes
are advantageous in terms of atom-economy, operational
simplicity, and variability for the design of tandem processes.1
In the synthesis of 1,3-dihydroisobenzofurans, the cyclization
reactions of 2-alkynylbenzyl alcohols which are usually prepared
(2) (a) Gabriele, B.; Salerno, G.; Fazio, A. Tetrahedron 2003, 59, 6251.
(b) Hashmi, A. S. K.; Scha¨fer, S.; Wo¨lfle, M.; Gil, C. D.; Fischer, P.;
Laguna, A.; Blanco, M. C.; Gimeno, M. C. Angew. Chem., Int. Ed. 2007,
46, 6184.
(3) (a) Padwa, A.; Krumpe, K. E.; Weingarten, M. D. J. Org. Chem.
1995, 60, 5595. (b) Hiroya, K.; Jouka, R.; Kameda, M.; Yasuhara, A.;
Sakamoto, T. Tetrahedron 2001, 57, 9697.
(4) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. Angew. Chem.,
Int. Ed. 2006, 45, 944.
(5) Yin, Y.; Ma, W.-Y.; Chai, Z.; Zhao, G. J. Org. Chem. 2007, 72,
5731.
* Corresponding author. Fax: 0086-21-64166128.
† Shanghai Institute of Organic Chemistry.
‡ XinJiang University.
(6) For reviews, see: (a) Noyori, R.; Kitamura, M. Angew. Chem., Int.
Ed. Engl. 1991, 30, 49-69. (b) Soai, K.; Niwa, S. Chem. ReV. 1992, 92,
833-856. (c) Soai, K.; Shibata, T. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin,
1999; Vol. 2, pp 911-922. (d) Pu, L.; Yu, H. B. Chem. ReV. 2001, 101,
757-824. (e) Pu, L. Tetrahedron 2003, 59, 9873-9886. For works from
our group in this field, see: (f) Zhao, G.; Li, X.-G.; Wang, X.-R.
Tetrahedron: Asymmetry 2001, 12, 399-403. (g) Wu, X.-Y.; Liu, X.-Y.;
Zhao, G. Tetrahedron: Asymmetry 2005, 16, 2299-2305. (h) Chai, Z.;
Liu, X.-Y.; Wu, X.-Y.; Zhao, G. Tetrahedron: Asymmetry 2006, 17, 2442-
2447 and ref. 7.
(1) For recent reviews, see: (a) Chemler, S. R.; Fuller, P. H. Chem. Soc.
ReV. 2007, 36, 1153. (b) Molteni, V.; Ellis, D. A. Curr. Org. Synth. 2005,
2, 333. (c) Wolfe, J. P.; Thomas, J. S. Curr. Org. Chem. 2005, 9, 625. For
recent examples, see: (d) Waldo, J. P.; Larock, R. C. J. Org. Chem. 2007,
72, 9643. (e) Gao, K.; Wu, J. J. Org. Chem. 2007, 72, 8611. (f) Arimitsu,
S.; Hammond, G. J. Org. Chem. 2007, 72, 8559. (g) Barange, D. K.; Nishad,
T. C.; Swamy, N. K.; Bandameedi, V.; Kumar, D.; Sreekanth, B. R.; Vyas,
K.; Pal, M. J. Org. Chem. 2007, 72, 8547. (h) Ding, Q.; Wu, J. Org. Lett.
2007, 9, 4959. (i) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. Org.
Lett. 2006, 8, 2803. (j) Tsuji, H.; Mitsui, C.; Llies, L.; Sato, Y.; Nakamura,
E. J. Am. Chem. Soc. 2007, 129, 11902. (k) Liang, Z.; Ma, S.; Yu, J.; Xu,
R. Tetrahedron 2007, 63, 12877. (l) Zhang, H.; Larock, R. C. J. Org. Chem.
2003, 68, 5132.
(7) (a) Liu, X.-Y.; Wu, X.-Y.; Chai, Z.; Wu, Y.-Y.; Zhao, G.; Zhu, S.-
Z. J. Org. Chem. 2005, 70, 7432. (b) Chai, Z.; Liu, X.-Y.; Zhang, J.-K.;
Zhao, G. Tetrahedron: Asymmetry 2007, 18, 724.
10.1021/jo800029m CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/04/2008
J. Org. Chem. 2008, 73, 2947-2950
2947

TABLE 1. Eantioselective Addition and Cyclization Reaction of
Et2Zn to 2-Alkynylbenzaldehydesa
SCHEME 1. Addition and Cyclization Reaction of
Organozinc Reagents to 2-Alkynyl Benzaldehydes
the reaction system was brought to reflux for the next cyclization
step. The geometry of the double bond of 3a was proved to be
Z by NOE experiments (see the Supporting Information). Both
ligands provided similar product yields, while a slightly higher
ee value was obtained with the dendritic ligand 2b (Table 1,
entries 1-3).8 Changing the solvent to Et2O, CH2Cl2, or THF
all only led to the ethylation product (S)-1-(2-(phenylethynyl)-
phenyl)propan-1-ol 3a′ rather than the desired cyclization
product, which may be due to the low boiling points of these
solvents that fail to effect the cyclization step (Table 1, entries
4-6). Moreover, the dendritic ligand 2b could be recovered
almost quantitatively with the precipitation method by addition
of methanol and could be reused at least twice without
considerable loss of catalytic activity (Table 1, entries 7 and
8). Subsequent investigation of the scope of this reaction
revealed that the reaction could proceed smoothly with a
decreased cyclization reaction time when 1b with the electron-
withdrawing group CF3 was used (Table 1, entry 9). With
compounds 1c and 1d, slightly less successful results were
observed (Table 1, entries 10, 11). Unfortunately, when R1 was
an aliphatic group 1f, only the ethylation product was isolated
(Table 1, entry 13). In addition, a linear substrate 1g was also
prepared and tested under the same reaction conditions, but again
only the ethyl adduct was isolated (Table 1, entry 14).
The absolute configuration of the product 3a was determined
to be S by conversion into the known (S)-3-ethylisobenzofuran-
1(3H)-one (Scheme 2), which belongs to an important class of
compounds with good biological and pharmaceutical activities,11
followed by comparison of the specific rotation value with
literature data (see Experimental Section for details).
We next turned our attention to the scope of several other
organozinc reagents. They were reacted with 1a under similar
reaction conditions, and the results are summarized in Table 2.
Both the aryl and alkenyl organozinc reagents gave the
cyclization products with good yields and high regio- and
(8) An equilibrium has been proposed between a compound of 3a’s type
and its tautomer 2-benzylisobenzofuran; see: Smith, J. G.; Wikman, R. T.
J. Org. Chem. 1974, 39, 3648. However, in view of the enantioselectivity’s
retention during the cyclization step, such an equilibrium may be ruled out
in our case.
(9) Treatment of the isolated intermediate alkynyl alcohol with Et2Zn in
toluene at 60 °C or with NaOH in THF at room temperature led to its
decomposition.
a Et2Zn/1 ) 2:1, 10 mol % of 2b, toluene/hexane ) 7:1. b Reaction time
for the cyclization step. c Isolated yields. d Determined by chiral HPLC, see
text for the determination of the absolute configuration of 3a. For the other
compounds 3b-e, that determination was done by assuming that a similar
catalytic mechanism was taken. e Ligand 2a (10 mol %) was used. f 5 mol
% of 2b was used. g Et2O used as the cosolvent, and only the ethyl adduct
3a′ was isolated. h CH2Cl2 used as the cosolvent, and only the ethyl adduct
3a′ was isolated. i THF used as the cosolvent, and only the ethyl adduct
3a′ was isolated. j Second use of 2b (10 mol %). k Third use of 2b (10 mol
%). l The ee value was determined by converting 3d into the known
corresponding phthalide compound 3d′11followed by chiral HPLC analysis.
m Only the ethyl adduct was isolated.
(10) For a recent review on the synthesis and uses of polysubstituted
furans, see: (a) Kirsch, S. F. Org. Biomol. Chem. 2006, 4, 2076; For very
recent examples see: (b) Badudri, F.; Cicco, S. R.; Farinola, G. M.; Lopez,
L. C.; Naso, F.; Pinto, V. Chem. Commun. 2007, 3756. (c) Liu, Z.; Yu,
W.; Yang, L.; Liu, Z.-L. Tetrahedron Lett. 2007, 48, 5321. (d) William, D.
R.; Lee, M.-R.; Song, Y.-A.; Ko, S.-K.; Kim, G.-H.; Shin, I. J. Am. Chem.
Soc. 2007, 129, 9258. (e) Zhan, Z.-P.; Cai, X.-B.; Wang, S.-P.; Yu, J.-L.;
Liu, H.-J.; Cui, Y.-Y. J. Org. Chem. 2007, 72, 9838.
(11) (a) Takahashi, H.; Tsubuki, T.; Higashiyama, K. Chem. Pharm. Bull.
1991, 39, 3136. (b) Watanabe, M.; Hashimoto, N.; Araki, S.; Butsugan, Y.
J. Org. Chem. 1992, 57, 742. (c) Ramachandran, P. V.; Chen, G.-M.; Brown,
H. C. Tetrahedron Lett. 1996, 37, 2205. (d) Yang, H.; Hu, G.-Y.; Chen, J.;
Wang, Y.; Wang, Z.-H. Bioorg. Med. Chem. Lett. 2007, 17, 5210.
2948 J. Org. Chem., Vol. 73, No. 7, 2008

TABLE 3. Reaction of Several Cycloalkenyl Substrates 1h-j
SCHEME 2. Conversion and Determination of the Absolute
Configuration of 3a
entry
substrate
RR′Zna
product
yieldb (%)
eec (%)
1
2
3
4
5
6
1h
1h
1i
1i
1j
1j
Et2Zn
PhZnEt
Et2Zn
PhZnEt
Et2Zn
PhZnEt
3k
3k′
3l
3l′
3m
3m′
53
65
75
70
70
72
85
39
TABLE 2. Reaction of Several Different Organozinc Reagents
with 1a
a RR′Zn/1 ) 2:1. b Isolated yields. c Determined by chiral HPLC. The
absolute configuration of 3k and 3k′ was assigned by assuming that a
catalytic mechanism similar to that of the aromatic substrates was taken.
Experimental Section
General Procedure for the Tandem Addition/Cyclization
Reaction of Organozinc Reagents with 2-Alkynylbenzaldehydes
(Tables 1-3). A Schlenk tube was charged with ligand 2b7 (0.025
mmol, 10 mol %), and the system was purged three times with
argon. Then 2.5 mL of freshly distilled toluene was added followed
by diethylzinc (0.5 mmol, 1.0 M in hexanes); after being stirred
for 10 min at room temperature, the substrate aldehyde (0.25 mmol
in 1 mL of toluene) was added in one portion. After disappearance
of the substrate aldehyde (monitored by TLC on silica gel plates),
the system was brought to reflux for the indicated times before
being quenched with 8 mL of dry methanol, thus precipitating the
dendritic ligand 2b. After filtration, the filtrate was concentrated,
and the residue was purified by chromatography to give the desired
products. The dendritic ligand was recovered by extraction of the
filtering cake with CH2Cl2 followed by removal of the solvent.
(S,Z)-1-Benzylidene-3-ethyl-1,3-dihydroisobenzofuran (3a,
Table 1, Entry 1). Compound 3a was prepared from 2-(phenyl-
ethynyl)benzaldehyde according to the general procedure as a
colorless oil (50 mg, 70% yield; 94% ee) after chromatography
(silica gel, 2.5% ether in petroleum): [R]26D ) 98.2 (c 1.25, CHCl3)
for 94% ee; IR (CH2Cl2, film) 2967, 2926, 1655, 1464, 1052, 961,
a RR′Zn/1 ) 2:1, 10 mol % of 2b. b Reaction temperature for the addition
step. c Isolated yields. d Determined by chiral HPLC. The absolute config-
uration of the products 3h-j was assigned by assuming that the catalytic
mechanism was similar to the one when Et2Zn was used. e See the
Supporting Information for experimental details. f 15 mol % of 2b was used.
enantioselectivities (Table 2, entries 2 and 3). However,
enantioselectivity was poor when Me2Zn was used (Table 2,
entry 1). The alkynylzinc reagent obtained via treatment of
phenylacetylene with Et2Zn failed to give the corresponding
product (Table 2, entry 4), which results could be attributed to
the instability of the intermediate product alkynyl alcohol under
basic conditions at high temperatures. Control experiments on
the separately isolated intermediate alkynyl alcohol revealed that
this compound would decompose under basic conditions even
at room temperature.9
1
762, 694 cm-1; H NMR (300 MHz, CDCl3) δ 7.75 (d, J ) 7.5
Hz, 2H), 7.55 (m, 1H), 7.36-7.16 (m, 5H), 7.11(m, 1H), 5.90 (s,
1H), 5.63 (m, 1H), 2.07 (m, 1H), 1.84 (m, 1H), 1.06 (m, 3H); 13
C
NMR (100 MHz, CDCl3) 155.5, 142.3, 136.6, 135.1, 128.5, 128.2,
128.0, 127.7, 125.0, 121.1, 119.8, 95.6, 86.9, 28.8, 8.9; MS (EI)
(m/z) 236 (M+), 207 (base); HRMS calcd for C17H16O 236.1201,
found 236.1194; HPLC Daicel CHIRALCEL OJ column, hexane/
IPA ) 9:1, 0.75 mL/min, λ 254 nm, tR(R) ) 26.2 min, tR(S) )
28.5 min. The absolute configuration of 3a was determined by
converting it into the known compound 3-ethylisobenzofuran-1(3H)-
one. Procedure with KMnO4: To a solution of 3a (47.2 mg, 0.2
mmol) in 5 mL of acetone were added solid KMnO4 (1.1 equiv)
and 0.5 mL of 1 N HCl; after being stirred for 1 h at room
temperature, the mixture was filtered through Celite and concen-
trated, and column chromatography (silica gel, 5% ether in
petroleum) gave the desired product as colorless oil. Procedure with
PCC: To a solution of 3a (47.2 mg, 0.2 mmol) in 4 mL of CH2Cl2
was added PCC (1.2 equiv), and after being stirred for 2 h at room
temperature, the mixture was filtered through Celite and concen-
trated. Column chromatography (silica gel, 5% ether in petroleum)
gave the desired product as a colorless oil. The spectrocopic values
were in good agreement with those reported in literature:11a IR (neat)
2972, 2937, 1762, 1466, 1059, 960, 738, 695 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.90 (d, J ) 8.0 Hz, 1H), 7.67 (m, 1H), 7.53 (m,
Subsequently, several 2-alkynylcycloalkene aldehydes were
prepared and reacted with organozinc reagents to expand the
scope of this reaction (Table 3). Unlike their aromatic coun-
terparts, it was found that the products of this reaction were
highly dependent on the size of the alkyl cycles of the
substrates: for the five-membered cycle, only the intermediate
alcohol adduct was isolated; for six- and seven-membered ones,
only the tetrasubstituted furan compounds10 were obtained as a
single product, which may result from the 1,5-hydride shift of
the corresponding cyclization products.
In conclusion, we have reported a novel tandem addition/
cyclization reaction of organozinc reagents to 2-alkynyl aromatic
and cycloalkene aldehydes. Using this method, chiral 1,3-
dihydroisobenzofurans could be obtained in high ee values and
moderate to good yields with virtually complete Z-selectivities
from aromatic substrates and some tetrasubstitued furan com-
pounds could also be obtained in good yields from cycloalkene
substrates.
J. Org. Chem, Vol. 73, No. 7, 2008 2949

1H), 7.44(d, J ) 7.6 Hz, 1H), 5.46 (m, 1H), 2.10 (m, 1H), 1.84
(m, 1H), 1.01 (t, J ) 7.0 Hz, 3H); [R]26D ) -68.7 (c 1.20, CHCl3)
[lit.11a [R]D ) -73.5 (c 3.60, CHCl3) for 96% ee (S)].
Acknowledgment. The generous financial support from the
National Natural Science Foundation of China, QT Program,
Shanghai Natural Science Council, and Excellent Young
Scholars Foundation of NNSF is gratefully acknowledged.
1-Benzyl-3-ethyl-4,5,6,7-tetrahydroisobenzofuran (3l, Table
3, Entry 3). This compound was prepared according to the general
procedure as a colorless oil (45 mg, 75% yield) after chromatog-
raphy (silica gel, 2.5% ether in petroleum): IR (CH2Cl2, film) 2931,
2856, 1593, 1494, 1453, 703 cm-1; 1H NMR (300 MHz, CDCl3) δ
7.30-7.18 (m, 5H), 3.85 (s, 2H), 2.50 (q, J ) 7.6 Hz, 2H), 2.39
(m, 4H), 1.64 (m, 4H), 1.15 (t, J ) 7.6 Hz, 3H); 13C NMR (75
MHz, CDCl3) 148.9, 144.7, 139.2, 128.5, 128.3, 126.0, 117.2, 115.4,
32.8, 23.5, 20.6, 20.5, 19.8, 12.7; MS (EI) (m/z) 240 (M+), 225
(base); HRMS calcd for C17H20O 240.1514, found 240.1512.
Supporting Information Available: Experimental procedures
and characterization data for all new compounds and copies of 1H
NMR, 13C NMR, and HPLC spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO800029M
2950 J. Org. Chem., Vol. 73, No. 7, 2008