Reductive coupling of phthalic anhydrides with aliphatic ketones by low-valent titanium: Unusual two-to-one coupling for preparation of 3,3-disubstituted phthalides

Article abstract of DOI:10.1016/j.tet.2019.130820

The reductive coupling of phthalic anhydrides with acetone by Zn-TiCl₄ in THF gave two-to-one and one-to-one coupled products. The coupled products were transformed to 3,3-diisopropyl-, 3-isopropylidene-, and 3-isopropylphthalides. In addition, the reductive coupling of phthalic anhydrides with acetonylacetone by Zn-TiCl₄ in THF gave 3-spirocyclopentanylphtalides stereoselectively.

Full text of DOI:10.1016/j.tet.2019.130820

Journal Pre-proof
Reductive coupling of phthalic anhydrides with aliphatic ketones by low-valent
titanium: Unusual two-to-one coupling for preparation of 3,3-disubstituted phthalides
Naoki Kise, Shota Yamamoto, Toshihiko Sakurai
PII:
S0040-4020(19)31228-1
https://doi.org/10.1016/j.tet.2019.130820
TET 130820
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 October 2019
Revised Date: 21 November 2019
Accepted Date: 22 November 2019
Please cite this article as: Kise N, Yamamoto S, Sakurai T, Reductive coupling of phthalic anhydrides
with aliphatic ketones by low-valent titanium: Unusual two-to-one coupling for preparation of 3,3-
disubstituted phthalides, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.130820.
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Graphical abstract

Reductive coupling of phthalic anhydrides with aliphatic ketones by low-valent
titanium: Unusual two-to-one coupling for preparation of 3,3-disubstituted phthalides
Naoki Kise,*1,2 Shota Yamamoto,1 Toshihiko Sakurai1,2
1Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori
University, 4-101, Koyama-Minami, Tottori 680-8552, Japan
2Center for Research on Green Sustainable Chemistry, Graduate School of Engineering,
Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan
*Corresponding author. E-mail address: kise@bio.tottori-u.ac.jp (N. Kise)
ABSTRACT:
The reductive coupling of phthalic anhydrides with acetone by Zn-TiCl4 in THF gave
two-to-one and one-to-one coupled products. The coupled products were transformed to
3,3-diisopropyl-, 3-isopropylidene-, and 3-isopropylphthalides. In addition, the reductive
coupling of phthalic anhydrides with acetonylacetone by Zn-TiCl4 in THF gave
3-spirocyclopentanylphtalides stereoselectively.
Keywords: Reductive coupling; Low-valent titanium; Phthalic anhydrides; 3,3-disubstituted
phthalides; 3-isopropylidenephthalides; 3-spirocyclopentanylphtalides.
- 1 -

1. Introduction
Phthalides (isobenzofuran-1(3H)-ones) are found in many biologically active naturally
occurring compounds (Figure 1).1
Therefore, the synthesis of 3-substituted,2
3,3-disubstituted,3 and 3-alkylidenephthalides4 has attracted much attention from organic
chemists.
On the other hand, we have reported that the reductive coupling of phthalimides
with ketones and aldehydes by low-valent titanium (Zn-TiCl4)5a or electroreduction5b is a
promising method for the synthesis of 3-substituted and 3-alkylideneisoindolones (Scheme 1).
From these results, we examined the reductive coupling of phthalic anhydrides with ketones,
since 3-substituted phthalides and 3-alkylidenephthalides might be synthesized by this
reaction. As far as we know, this type of reductive coupling has not so far been reported at
all. In this paper, we report our study on the reductive coupling of phthalic anhydrides with
acetone and acetonylacetone by Zn-TiCl4 (Scheme 2). Unlike our expectation, two-to-one
coupled products were formed mainly from the reaction of 4,7-unsubstituted phthalic
anhydrides with acetone. In particular, 3-spirocyclopentanylphthalides were obtained
stereoselectively from the reaction with acetonylacetone. Reaction mechanism of the
reductive coupling was also discussed.
Figure 1. Examples of biologically active natural phthalides.
- 2 -

5a
Scheme 2. Reductive coupling of phthalimides with aldehydes and ketones by Zn-TiCl4 or
electroreduction5b (our previous works).
Scheme 2. Reductive coupling of phthalic anhydride with acetone and acetonylacetone by
Zn-TiCl4 (this work).
- 3 -

2. Results and discussion
2.1. Reductive coupling of phthalic anhydrides with acetone by Zn-TiCl4
The reductive coupling of phthalic anhydride (1a) with acetone (2a) was carried out with
the molar ratio of 1a/2a/TiCl4 as 1/3/3 (run 1) or 1/5/5 (run 2) at 30 °C (Table 1). The molar
ratio of Zn/TiCl4 was fixed as 2/1. The two-to-one coupled product 3a was obtained in 29%
and 38% yields, respectively, together with a small amount (7% and 10% yields) of
one-to-one coupled product 4a. Other than these cross-coupled products, homo-coupled
product of 2a, 2,3-dimethylbutane-2,3-diol, was also formed as by-product. The reaction
with the ratio of 1a/2a/TiCl4 as 1/10/5 at 30 °C (run 3) brought about some improvement in
the yield of 3a (41% yield). It gave almost the same result to double the quantity of 2a in
run 3 (run 4). The reaction at 50 °C with the same ratio as run 3 somewhat lowered the yield
of 3a (run 5). To obtain one-to-one coupled product 4a as the major product, the reaction
was carried out with the molar ratio of 1a/2a/TiCl4 as 1/10/2 at 0 °C (run 6). Although 3a
was not formed, one-to-one products were isolated as a 1:1 mixture of 4a and 5a in 60% total
yield. The mixture of 4a and 5a was subjected to the reductive coupling with 2a under the
same conditions in run 3 to give 3a (66% yield) with some recovered 4a (Scheme 3). This
result shows that 3a was formed from 4a and 5a by the reductive coupling with 2a. The
two-to-one coupled product 3a was transformed to 3,3-diisopropylphthalide (7a) by
dehydration in refluxing PTSA/toluene and subsequent hydrogenation of resultant 6a
(Scheme 4). In a similar manner, the mixture of 4a and 5a was converted to
3-isopropylidenephthalide (8a)4c and 3-isopropylphthalide (9a).
- 4 -

Table 1
Reductive coupling of 1a with 2a by Zn-TiCl4.
run
2a
TiCl4
Zn
Temp.
(°C)
30
Time
% Yielda
(h)
2
(mmol)
3a
29
38
41
41
37
-
4a
7
5a
-
1
2
3
4
5
6
3
3
5
5
5
5
2
6
5
10
10
10
10
4
30
2
10
13
15
10
-
10
20
10
10
30
2
-
30
2
-
50
1
-
0
1
60 (1:1)
aIsolated yields.
Scheme 3. Reductive coupling of 4a and 5a with 2a by Zn-TiCl4.
Scheme 4. Dehydration and subsequent hydrogenation of 3a and 1:1 mixture of 4a and 5a.
- 5 -

Next, the reductive coupling of 1a with other ketones such as 3-pentanone, acetophenone,
and benzophenone was examined using the same conditions as run 3 in Table 1. However,
cross-coupled products of 1a with ketones could not be obtained from these ketones.
Although the yield was low, two-to-one coupling product 3b was formed from 1a and
cyclohexanone (2b) (Scheme 5). Since 3b could not be purified, the product was isolated as
6b in 26% overall yield after dehydration of 3b. From these results, it is suggested that the
reductive coupling of 1a with ketones strongly inhibited by the steric bulkiness of ketones.
O
O
TiCl4 (5 mmol)
Zn (10 mmol)
OH
+
O
O
THF
30 °C, 2 h
O
O
2b
1a (1 mmol)
3b not purified
(5 mmol)
PTSA
O
toluene
reflux, 2 h
O
6b 26% (2 steps)
Scheme 5. Reductive coupling of 1a with 2b by Zn-TiCl4 and subsequent dehydration to
6b.
On the other hand, the reductive coupling of 5,6-dimethoxyphthalic anhydride (1b) with 2a
gave two-to-one coupled product 3c in 62% yield (Scheme 6). In this case, a small amount
(11% yield) of one-to-one coupled product was formed as 3-isopropylphthalide 9c. The
dehydration of 3c and following hydrogenation of resultant 6c afforded
3,3-diisopropylphthalide (7c).
It is noted that the reductive coupling of
4,5-dimethoxyphthalic anhydride (1c) with 2a gave two-to-one coupled product 3d (39%
- 6 -

yield) and one-to-one coupled product 5d (25% yield) (Scheme 7). This result shows that
two-to-one coupled product was not formed by the reaction at the 3-position of 1c probably
due to steric hindrance of 4-methoxy group but formed by the reaction at the 1-position of 1c.
The products 3d and 5d were transformed to 7d and 9d through 6d and 8d in a similar
manner as above. The regio-chemistry of 3d was determined by 2D-NMR (NOESY)
analysis and that of 5d was confirmed by X-ray crystallography of 8d. In addition, the
reductive coupling of 4,5,6,7-tetrachlorophthalic anhydride (1d) with 2a gave one-to-one
coupled product 5e as a sole product (41% yield) and 5e was dehydrated to 8e4c (Scheme 8).
Similarly, the one-to-one coupled product of 4,5,6,7-tetrafluorophthalic anhydride (1e) with
2a was isolated as 8f (34% overall yield) after dehydration, since 5f could not be purified.
These results suggest that two-to-one coupled products are not formed from 4- and
7-disubstituted phthalic anhydrides owing to the steric hindrance of 4- and 7-substituents.
Scheme 6. Reductive coupling of 1b with 2a by Zn-TiCl4 and transformation of 3c to 7c.
- 7 -

Scheme 7. Reductive coupling of 1c with 2a by Zn-TiCl4 and transformation of 3d and 5d
to 7d and 9d.
Scheme 8. Reductive coupling of 1d,e with 2a by Zn-TiCl4 and dehydration of 5e,f to 8e,f.
- 8 -

2.2. Reductive coupling of phthalic anhydrides with acetonylacetone by Zn-TiCl4
Expecting the synthesis of spiro compounds by the two-to-one reductive coupling, the
reductive coupling of 1a with acetonylacetone (2c) was examined. As shown in Table 2,
3-spirocyclopentanylphthalides 10a (exo-cis) and 11a (exo-cis) were obtained
stereoselectively. The reaction at 30 °C gave diol 10a as the major product (run 1), while
11a was the major product by the reaction at 50 °C (run 2). The reaction at 0 °C, however,
decreased the total yield of 10a and 11a (run 3). In all cases, no one-to-one coupled product
could
be
isolated
and
intramolecular
homo-coupled
product
of
2c,
1,2-dimethylcyclobutane-1,2-diol, was formed as by-product. The stereochemistries of 10a
and 11a were both determined to be exo-cis by X-ray crystallographic analysis (Figure 2).
Similarly, the reductive coupling of 1b and 1c with 2c afforded 10b, 11b, and 10c
stereoselectively (Scheme 9). It is assumed that the stereostructures of 10b,c and 11b are the
same as those of 10a and 11a, respectively. In the latter case, 10c was formed from the
reaction at the 1-position of 1c and no coupled product at the 3-position of 1c could be
detected. The regio-chemistry of 10c was determined by 2D-NMR (NOESY) analysis.
Table 2. Reductive coupling of 1a with 2c by Zn-TiCl4.
run
Temp.
(°C)
30
Time
% Yielda
10a 11a
(h)
1
1
2
3
37
16
24
19
30
9
50
1
0
6
aIsolated yields.
- 9 -

11a
10a
Figure 2. X-ray crystal structures of 10a and 11a.
Scheme 9. Reductive coupling of 1b,c with 2c by Zn-TiCl4.
2.3. Reaction mechanism of reductive coupling of phthalic anhydrides with ketones
The cyclic voltammogram of 1a in 0.03 M Bu4NClO4 on a platinum cathode showed a
first reduction peak at −1.30 V versus SCE, although that of 2a did not show a reduction peak
to −2.50 V under the same conditions. This result shows that 1a is much more reducible
than 2a. Therefore, the presumed reaction mechanism of the reductive coupling of 1a with
2a can be illustrated in Scheme 10. First, 1a is reduced by low-valent titanium to dianion
intermediate A. The nucleophilic addition of A to 2a and subsequent further reduction of
adduct B give dianions C1 and C2. When the reaction was conducted and quenched with
water at 0 °C, one-to-one coupled products 4a and 5a are formed from C1 and C2,
respectively. At 30 °C, further reduction of C1 and C2 proceeds to give D and following
- 10 -

nucleophilic addition of D to 2a produces adduct E. From the results in Table 1 and Scheme
3, it is supposed that the reduction of C2 is much faster than that of C1 with low-valent
titanium at this temperature and, therefore, C2 is immediately reduced to D. Finally,
two-to-one coupled product 3a is formed from E after workup with water. At first, we
expected that 3-alkylidenephthalide 8a was formed as an one-to-one coupled product like the
previously reported coupling of phthalimides.5a However, mono-alcohols 4a and 5a were
formed as four-electron reduced products in this reaction. Although the reason is not clear at
present, we have found that the similar reductive C-O bond cleavage occurred in the reductive
coupling of isatins6a and hydantoins.6b
Incidentally, the presumed reaction mechanism of reductive coupling of 4a and 5a with
2a (Scheme 3) is shown in Scheme 11. Mono-alcohols 4a and 5a are reduced by low-valent
titanium to anion intermediates D1’ and D2’, respectively. Unstable anion D1’ is
immediately isolated to more stable benzylic anion D2’. The nucleophilic addition of D2’ to
2a and following workup of resultant E’ give 3a.
Similarly to Scheme 10, the presumed reaction mechanism of the reductive coupling of
1a with 1c is depicted in Scheme 12. The nucleophilic addition of A to 2c and following
reduction of adduct F afford dianions G1 and G2. Even at 0 °C, intramolecular nucleophilic
addition of G1 proceeds to give adduct H. At the same time, G1 and G2 are subjected
further reduction and subsequent intramolecular addition of resultant I gives adduct J.
Similarly to dianion C2 in Scheme 10, it seems that dianion G2 is immediately reduced to I.
Finally, coupled products 10a and 11a are obtained from H and J by workup with water.
Since the titanium ions in dianions H and J are located in less hindered side (exo side),
exo-diol 10a and exo-alcohol 11a are produced stereoselectively. In addition, protonation to
C-anion of J occurs from the opposite side of the titanium ion (endo side) to give
exo-cis-alcohol 11a selectively.
- 11 -

Scheme 10. Presumed reaction mechanism of reductive coupling of 1a with 2a.
Scheme 11. Presumed reaction mechanism of reductive coupling of 4a and 5a with 2a.
- 12 -

Scheme 12. Presumed reaction mechanism of reductive coupling of 1a with 2c.
3. Conclusion
The reduction of phthalic anhydrides 1a-c and acetone (2a) with Zn-TiCl4 in THF at 30 °C
gave unusual two-to-one coupled products 3a,c,d with small amounts of one-to-one coupled
products 4a and 5d. On the contrary, the reduction of 4,5,6,7-tetrahalophthalic anhydrides
1d,e and 2a under the same conditions afforded one-to-one coupled products 5e,f. The
two-to-one coupled products 3a,c,d were transformed to 3,3-diisopropylphthalides 7a,c,d by
dehydration and subsequent hydrogenation. The dehydration of one-to-one coupled
products 4a and 5d-f produced 3-isopropylidenephthalides 8a,d-f. In addition, the reductive
coupling of phthalic anhydrides 1a-c and acetonylacetone (2c) with Zn-TiCl4 in THF at 30 °C
gave 3-spirocyclopentanylphthalides 10a-c and 11a-b. These products were obtained as
exo-cis isomers with complete stereoselectivity.
- 13 -

4. Experimental section
4.1. General
Column chromatography was performed on silica gel 60. THF was freshly distilled from
1
sodium benzophenone ketyl. H NMR (500 MHz) and 13C NMR (125 MHz) spectra were
measured on a JEOL JNM-ECP500 spectrometer with tetramethylsilane (TMS) as an internal
standard. IR spectra were recorded on a Shimadzu IRAffinity-1 infrared spectrometer. HRMS
were measured on a Thermo Scientific Exactive FTMS spectrometer. Melting points were
uncorrected.
4.2. Starting materials
5,6- and 4,5-Dimethoxyisobenzofuran-1,3-diones (1b and 1c) were prepared by the
reported methods.7,8 4,5,6,7-Tetrachloro- and tetrafluoroisobenzofuran-1,3-diones (1d and
1e) are commercially available.
4.2.1. 5,6-Dimethoxyisobenzofuran-1,3-dione (1b)7
1
White solid; mp 175 ; Rf 0.5 (hexanes-ethyl acetate, 2:1); H NMR (CDCl3) δ 4.05 (s,
6H), 7.37 (s, 2H); 13C NMR (CDCl3) δ 56.9 (q), 106.1 (d), 124.9 (s), 155.7 (s), 163.1 (s).
4.2.2. 4,5-Dimethoxyisobenzofuran-1,3-dione (1c)8
1
White solid; mp 166-167 ; Rf 0.35 (hexanes-ethyl acetate, 2:1); H NMR (CDCl3) δ
4.01 (s, 3H), 4.22 (s, 3H), 7.28 (d, 1H, J = 8.3 Hz), 7.68 (d, 1H, J = 8.3 Hz); 13C NMR
(CDCl3) δ 56.9 (q), 62.6 (q), 118.2 (d), 120.5 (s), 121.5 (d), 122.9 (s), 148.5 (s), 158.6 (s),
160.6 (s), 162.4 (s).
4.3. Typical procedure for the reductive coupling of 1a with 2a (Table 1, run 3)
- 14 -

To a solution of 1a (148 mg, 1 mmol), 2a (0.75 mL, 10 mmol), and zinc powder (0.65 g,
10 mmol) in THF (10 mL) was added TiCl4 (0.55 mL, 5 mmol) dropwise at 0 ºC and then the
dark blue suspension was stirred for 2 h at 30 ºC. To the mixture was added 1 M HCl (20 mL)
and the mixture was stirred for 15 min at 25 ºC. The clear solution was extracted with ethyl
acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4.
After the solvent was removed in vacuo, the residue was purified by column chromatography
on silica gel to give 3a (96 mg, 41%) and 4a (25 mg, 13%).
4.3.1. 3-(2-Hydroxypropan-2-yl)-3-isopropylisobenzofuran-1(3H)-one (3a)
White solid (CCDC 1958789); Rf 0.55 (hexanes-ethyl acetate, 2:1); mp 125-126 °C; IR
(ATR) 3466 (br), 1736 cm−1; 1H NMR (CDCl3) δ 0.91 (d, 3H, J = 6.6 Hz), 0.93 (d, 3H, J = 6.9
Hz), 1.18 (s, 3H), 1.23 (s, 3H), 1.97 (brs, 1H), 2.59-2.68 (m, 1H), 7.51-7.57 (m, 2H),
7.63-7.67 (m, 1H), 7.86-7.90 (m, 1H); 13C NMR (CDCl3) δ 18.50 (q), 18.52 (q), 25.5 (q), 26.5
(q), 32.4 (d), 75.2 (s), 94.7 (s), 123.4 (d), 125.5 (d), 127.5 (s), 129.0 (d), 133.6 (d), 149.9 (s),
170.7 (s); HRMS (ESI, ion trap) calcd for C14H19O3 (M + H+) 235.1334, found 235.1324.
4.3.2. 3-(2-Hydroxypropan-2-yl)isobenzofuran-1(3H)-one (4a)
1
Colorless paste; Rf 0.5 (hexanes-ethyl acetate, 1:1); IR (ATR) 3424 (br), 1743 cm−1; H
NMR (CDCl3) δ 1.18 (s, 3H), 1.35 (s, 3H), 2.19 (brs, 1H), 5.29 (s, 1H), 7.54-7.58(m, 1H),
13
7.65-7.71 (m, 2H), 7.90-7.93 (m, 1H); C NMR (CDCl3) δ 24.0 (q), 26.3 (q), 72.5 (s), 86.6
(d), 123.7 (d) 125.7 (d), 126.6 (s), 129.4 (d), 133.9 (d), 146.9 (s), 170.5 (s); HRMS (ESI, ion
trap) calcd for C11H13O3 (M + H+) 193.0865, found 193.0863.
4.3.3. 3-(2-Hydroxypropan-2-yl)-3-isopropyl-5,6-dimethoxyisobenzofuran-1(3H)-one (3c)
Colorless paste; Rf 0.4 (hexanes-ethyl acetate 1:1); IR (ATR) 3428 (br), 1749, 1713, 1597
cm−1; 1H NMR (CDCl3) δ 0.89 (d, 3H, J = 6.8 Hz), 0.97 (d, 3H, J = 7.0 Hz), 1.20 (s, 3H), 1.22
(s, 3H), 1.98 (brs, 1H), 2.56-2.64 (m, 1H), 3.95 (s, 3H), 3.99 (s, 3H), 6.95 (s, 1H), 7.26 (s,
13
1H); C NMR (CDCl3) δ 18.38 (q), 18.44 (q), 25.6 (q), 26.4 (q), 32.3 (d), 56.0 (q), 56.3 (q),
- 15 -

75.2 (s), 93.7 (s), 105.1 (d), 105.7 (d), 119.4 (s), 144.4 (s), 150.1 (s), 154.0 (s), 170.9 (s);
HRMS (ESI, ion trap) calcd for C16H23O5 (M + H+) 295.1545, found 295.1540.
4.3.4. 3-Isopropyl-5,6-dimethoxyisobenzofuran-1(3H)-one (9c)
Colorless paste; Rf 0.55 (hexanes-ethyl acetate 1:1); IR (ATR) 1742, 1601, 1503 cm−1; 1H
NMR (CDCl3) δ 0.79 (d, 3H, J = 6.8 Hz), 1.14 (d, 3H, J = 7.0 Hz), 2.22-2.28 (m, 1H), 3.94 (s,
13
3H), 3.98 (s, 3H), 5.28 (d, 1H, J =3.4 Hz), 6.83 (s, 1H), 7.29 (s, 1H); C NMR (CDCl3) δ
15.3 (q), 18.8 (q), 32.3 (d), 56.2 (q), 56.3 (q), 85.0 (d), 103.3 (d), 106.0 (d), 118.6 (s), 143.4
(s), 150.3 (s), 154.6 (s), 171.1 (s); HRMS (ESI, ion trap) calcd for C13H17O4 (M + H+)
237.1127, found 237.1122.
4.3.5. 3-(2-Hydroxypropan-2-yl)-3-isopropyl-6,7-dimethoxyisobenzofuran-1(3H)-one (3d)
Colorless paste; Rf 0.55 (hexanes-ethyl acetate 1:1); IR (ATR) 3476 (br), 1736, 1593
cm−1; 1H NMR (CDCl3) δ 0.92 (d, 6H, J = 6.8 Hz), 1.17 (s, 3H), 1.23 (s, 3H), 1.64 (brs, 1H),
2.51-2.60 (m, 1H), 3.92 (s, 3H), 4.09 (s, 3H), 7.12-7.15 (m, 1H), 7.17-7.20 (m, 1H); 13C NMR
(CDCl3) δ 18.5 (q), 18.6 (q), 25.5 (q), 26.5 (q), 32.7 (d), 56.7 (q), 62.3 (q), 75.4 (s), 93.0 (s),
117.7 (d), 118.7 (d), 119.9 (s), 143.0 (s), 148.2 (s), 152.5 (s), 168.0 (s); HRMS (ESI, ion trap)
calcd for C16H23O5 (M + H+) 295.1545, found 295.1539.
4.3.6. 3-(2-Hydroxypropan-2-yl)-4,5-dimethoxyisobenzofuran-1(3H)-one (5d)
Colorless paste; Rf 0.4 (hexanes-ethyl acetate 1:2); IR (ATR) 3389 (br), 1736, 1706 1597
1574 cm−1; 1H NMR (CDCl3) δ 1.11-1.33 (m, 6H), 2.64-2.84 (brs, 1H), 3.89 (brs, 3H), 3.96 (s,
13
3H), 4.55 (brs, 1H), 6.98-7.10 (m, 1H), 7.48-7.69 (m, 1H); C NMR (CDCl3) δ 15.5 (brq),
17.2 (brs), 34.6 (brd), 56.2 (brq), 61.4 (brq), 109.0 (brs), 114.5 (brd), 119.7 (brs), 121.9 (brd),
141.0 (brs), 143.6 (brs), 157.8 (brs), 168.7 (brs); HRMS (ESI, ion trap) calcd for C13H17O6 (M
+ H+) 253.1076, found 253.1068.
4.3.7. 4,5,6,7-Tetrachloro-3-hydroxy-3-isopropylisobenzofuran-1(3H)-one (5e)
White solid; Rf 0.4 (hexanes-ethyl acetate 2:1); mp 215 ; IR (ATR) 3443 (br), 1751,
- 16 -

1
1744, 1560 cm−1; H NMR (CDCl3) δ 0.67 (d, 3H, J = 6.9 Hz), 1.30 (d, 3H, J = 6.9 Hz),
2.87-2.96 (m, 1H), 3.83 (brs, 1H); 13C NMR (CDCl3) δ 15.2 (q), 16.9 (q), 33.5 (d), 107.7 (s),
124.1 (s), 127.6 (s), 131.3 (s), 136.9 (s), 140.3 (s), 145.5 (s), 163.0 (s); HRMS (ESI, ion trap)
calcd for C11H7Cl4O2 (M + H+ − H2O) 310.9200, found 310.9195.
4.3.8.
(1s*,2R*,5S*)-2,5-Dihydroxy-2,5-dimethyl-3'H-spiro[cyclopentane-1,1'-isobenzofuran]-3'-on
e (10a)
White solid (CCDC 1958792); Rf 0.4 (hexanes-ethyl acetate, 1:1); mp 160 ; IR (ATR)
1
3391, 1759 cm−1; H NMR (CDCl3) δ 0.90 (s, 6H), 2.13-2.19 (m, 2H), 2.38-2.43 (m, 2H),
4.19 (brs, 2H), 7.29 (d, 1H, J = 8.0 Hz), 7.56 (t, 1H, J = 7.5 Hz), 7.67-7.72 (m, 1H), 7.93 (d,
1H, J = 7.5 Hz); 13C NMR (CDCl3) δ 22.9 (q), 34.9 (t), 82.1 (s), 96.9 (s), 122.3 (d), 125.7 (s),
126.3 (d), 129.5 (d), 134.5 (d), 147.9 (s), 169.8 (s); HRMS (ESI, ion trap) calcd for C14H17O4
(M + H+) 249.1127, found 249.1123.
4.3.9.
(1R*,2R*,5S*)-2-Hydroxy-2,5-dimethyl-3'H-spiro[cyclopentane-1,1'-isobenzofuran]-3'-one
(11a)
White solid (CCDC 1958793); Rf 0.6 (hexanes-ethyl acetate, 1:1); mp 172-173 ; IR
(ATR) 3445, 1738 cm−1; 1H NMR (CDCl3) δ 0.77 (d, 3H, J = 6.9 Hz), 1.43 (s, 3H), 1.64-1.74
(m, 1H), 2.02-2.16 (m, 3H), 2.17 (brs, 1H), 2.58-2.68 (m, 1H), 7.38-7.41 (m, 1H), 7.52-7.56
13
(m, 1H), 7.65-7.69 (m, 1H), 7.89-7.92 (m, 1H); C NMR (CDCl3) δ 13.4 (q), 24.3 (q), 27.5
(t), 39.5 (t), 39.7 (d), 81.3 (s), 98.4 (s), 123.0 (d), 125.6 (d), 127.8 (s), 129.2 (d), 133.6 (d),
147.2 (s), 170.0 (s); HRMS (ESI, ion trap) calcd for C14H17O3 (M + H+) 233.1178, found
233.1172.
4.3.10.
(1s*,2R*,5S*)-2,5-Dihydroxy-5',6'-dimethoxy-2,5-dimethyl-3'H-spiro[cyclopentane-1,1'-isobe
- 17 -

nzofuran]-3'-one (10b)
Colorless paste; Rf 0.25 (hexanes-ethyl acetate 1:2); IR (ATR) 3393 (br), 1748, 1597,
1
1503 cm−1; H NMR (CDCl3) δ 0.93 (s, 6H), 2.09-2.14 (m, 2H), 2.38-2.43 (m, 2H), 3.96 (s,
3H), 3.97 (s, 3H), 4.29 (s, 2H), 6.61 (s, 1H), 7.29 (s, 1H); 13C NMR (CDCl3) δ 22.8 (q), 35.0
(t), 56.2 (q), 56.4 (q), 81.9 (s), 96.3 (s), 103.6 (d), 106.3 (d), 118.0 (s), 142.2 (s), 150.6 (s),
155.0 (s), 170.1 (s); HRMS (ESI, ion trap) calcd for C18H21O6 (M + H+) 309.1338, found
309.1337.
4.3.11.
(1R*,2R*,5S*)-2-Hydroxy-5',6'-dimethoxy-2,5-dimethyl-3'H-spiro[cyclopentane-1,1'-isobenzo
furan]-3'-one (11b)
colorless paste; Rf 0.4 (hexanes-ethyl acetate 1:2); IR (ATR) 3451 (br), 1736, 1599, 1503
cm−1; 1H NMR (CDCl3) δ 0.78 (d, 3H, J = 6.9 Hz), 1.44 (s, 3H), 1.63-1.70 (m, 1H), 2.02-2.15
(m, 3H), 2.20 (brs, 1H), 2.53-2.62 (m,1H), 3.94 (s, 3H), 3.98 (s, 3H), 6.75 (s, 1H), 7.30 (s,
13
1H); C NMR (CDCl3) δ 13.4 (q), 24.3 (q), 27.4 (t), 39.46 (t), 39.54 (d), 56.2 (q), 56.4 (q),
81.1 (s), 97.6 (s), 104.5 (d), 106.1 (d), 120.0 (s), 141.5 (s), 150.6 (s), 154.3 (s), 170.1 (s);
HRMS (ESI, ion trap) calcd for C16H21O5 (M + H+) 293.1389, found 293.1387.
4.3.12.
(1s*,2R*,5S*)-2,5-Dihydroxy-4',5'-dimethoxy-2,5-dimethyl-3'H-spiro[cyclopentane-1,1'-isobe
nzofuran]-3'-one (10c)
Pale yellow solid; Rf 0.3 (hexanes-ethyl acetate 1:1 ); mp 130-131 ; IR (ATR) 3285 (br),
1
1753, 1593 cm−1; H NMR (CDCl3) δ 0.95 (s, 6H), 2.08-2.14 (m, 2H), 2.38-2.44 (m, 2H),
3.92 (s, 3H), 4.11 (s, 3H), 4.49 (brs, 2H), 6.87 (d, 1H, J = 8.5 Hz), 7.22 (d, 1H, J = 8.5 Hz);
13C NMR (CDCl3) δ 22.7 (q), 34.7 (t), 56.7 (q), 62.4 (q), 82.6 (s), 95.5 (s), 116.8 (d), 118.0 (s),
119.5 (d), 140.6 (s), 148.4 (s), 152.7 (s), 167.5 (s); HRMS (ESI, ion trap) calcd for C16H21O6
(M + H+) 309.1338, found 309.1331.
- 18 -

4.4. Typical procedure for the dehydration of 3 to 6
A solution of 3a (117 mg, 0.5 mmol) in toluene (10 mL) was refluxed in the presence of
cat. p-TsOH for 1 h using Dean-Stark apparatus. After the solvent was removed in vacuo,
the residue was purified by column chromatography on silica gel to give 6a (82 mg, 76%).
4.4.1. 3-Isopropyl-3-(prop-1-en-2-yl)isobenzofuran-1(3H)-one (6a)
1
Colorless paste; Rf 0.45 (hexanes-ethyl acetate, 10:1); IR (ATR) 1757 cm−1; H NMR
(CDCl3) δ 0.67 (d, 3H, J = 6.9 Hz), 1.00 (d, 3H, J = 6.9 Hz), 1.88 (s, 3H), 2.52-2.61 (m, 1H),
4.97 (s, 1H), 5.19 (s, 1H), 7.45-7.48 (m, 1H), 7.49-7.53 (m, 1H), 7.63-7.67 (m, 1H), 7.86-7.89
13
(m, 1H); C NMR (CDCl3) δ 16.1 (q), 16.9 (q), 19.2 (q), 33.0 (d), 94.0 (s), 113.2 (t), 122.2
(d), 125.7 (d), 126.2 (s), 128.9 (d), 133.6 (d), 143.1 (s), 151.1 (s), 170.4 (s); HRMS (ESI, ion
trap) calcd for C14H17O2 (M + H+) 217.1229, found 217.1223.
4.4.2 3-(Propan-2-ylidene)isobenzofuran-1(3H)-one (8a)4c
Colorless paste; Rf 0.45 (hexanes-ethyl acetate, 5:1); IR (ATR) 1755, 1717, 1674, 1603,
1586 cm−1; 1H NMR (CDCl3) δ 2.12 (s, 3H), 2.20 (s, 3H), 7.48 (t, 1H, J = 7.5 Hz), 7.67-7.71
(m, 1H), 7.80 (d, 1H, J = 8.0 Hz), 7.93 (d, 1H, J = 7.8 Hz); 13C NMR (CDCl3) δ 18.7 (q), 20.2
(q), 119.5 (s), 122.5 (d), 125.4 (d), 125.5 (s), 128.3 (d), 134.1 (d), 138.8 (s), 141.4 (s), 167.1
(s); HRMS (ESI, ion trap) calcd for C11H11O2 (M + H+) 175.0759, found 175.0756.
4.4.3. 3-(Cyclohex-1-en-1-yl)-3-cyclohexylisobenzofuran-1(3H)-one (6b)
Colorless paste; Rf 0.5 (hexanes-ethyl acetate, 5:1); IR (ATR) 1757, 1717 cm−1; 1H NMR
(CDCl3) δ 0.86-1.28 (m, 6H), 1.43-1.78 (m, 8H), 1.97-2.20 (m, 5H), 5.82-5.85 (m, 1H),
7.41-7.46 (m, 1H), 7.46-7.51 (m, 1H), 7.60-7.64 (m, 1H), 7.84-7.87 (m, 1H); 13C NMR
(CDCl3) δ 21.9 (t), 22.7 (t), 24.6 (t), 25.1 (t), 26.0 (t), 26.3 (t), 26.35 (t), 26.39 (t), 26.9 (t)
42.6 (d), 94.4 (s), 122.6 (d), 124.4 (d), 125.6 (d), 126.5 (s), 128.6 (d), 133.2 (d), 135.1 (s),
151.1 (s), 170.5 (s); HRMS (ESI, ion trap) calcd for C20H25O2 (M + H+) 297.1855, found
- 19 -

297.1849.
4.4.4. 3-Isopropyl-5,6-dimethoxy-3-(prop-1-en-2-yl)isobenzofuran-1(3H)-one (6c)
Colorless paste; Rf 0.65 (hexanes-ethyl acetate 1:1) IR (ATR) 1748, 1705, 1599 cm−1; 1H
NMR (CDCl3) δ 0.68 (d, 3H, J = 6.7 Hz), 1.01 (d, 3H, J = 6.7 Hz), 1.85 (s, 3H), 2.48-2.57 (m,
1H), 3.94 (s, 3H), 3.98 (s, 3H), 4.98 (s, 1H), 5.18 (s, 1H), 6.80 (s, 1H), 7.26 (s, 1H); 13C NMR
(CDCl3) δ 16.1 (q), 16.9 (q), 19.2 (q), 32.8 (d), 56.1 (q), 56.3 (q), 93.2 (s), 103.6 (d), 105.9 (d),
112.9 (t), 118.1 (s), 143.4 (s), 145.6 (s), 150.2 (s), 154.3 (s), 170.6 (s); HRMS (ESI, ion trap)
calcd for C16H21O4 (M + H+) 277.1440, found 277.1434.
4.4.5. 3-Isopropyl-6,7-dimethoxy-3-(prop-1-en-2-yl)isobenzofuran-1(3H)-one (6d)
Colorless paste; Rf 0.5 (hexanes-ethyl acetate 2:1); IR (ATR) 1751, 1595 cm−1; 1H NMR
(CDCl3) δ 0.68 (d, 3H, J = 6.7 Hz), 0.98 (d, 3H, J = 6.7 Hz), 1.86 (s, 3H), 2.44-2.52 (m, 1H),
3.91 (s, 3H), 4.10 (s, 3H), 4.94 (s, 1H), 5.18 (s, 1H), 7.05 (d. 1H, J = 8.2 Hz), 7.19 (d, 1H, J =
8.2 Hz); 13C NMR (CDCl3) δ 16.0 (q), 16.9 (q), 19.1 (q), 33.0 (d), 56.7 (q), 62.2 (q), 92.3 (s),
112.7 (t), 116.7 (d), 118.3 (s), 118.7 (d), 143.4 (s), 144.1 (s), 148.1 (s), 152.3 (s), 167.7 (s);
HRMS (ESI, ion trap) calcd for C16H21O4 (M + H+) 277.1440, found 277.1435.
4.4.6. 4,5-Dimethoxy-3-(propan-2-ylidene)isobenzofuran-1(3H)-one (8d)
White solid (CCDC 1958790); Rf 0.5 (hexanes-ethyl acetate 2:1); mp 89-90 ; IR (ATR)
1
1749, 1659, 1612, 1578 cm−1; H NMR (CDCl3) δ 2.12 (s, 3H), 2.35 (s, 3H), 3.82 (s, 3H),
3.99 (s, 3H), 7.08 (d, 1H, J = 8.2 Hz), 7.68 (d, 1H, J = 8.2 Hz); 13C NMR (CDCl3) δ 19.3 (q),
21.4 (q), 56.5 (q), 61.1 (q), 113.4 (d), 119.8 (s), 122.2 (s), 122.3 (d), 131.6 (s), 140.1 (s), 142.2
(s), 158.3 (s), 166.5 (s); HRMS (ESI, ion trap) calcd for C13H15O4 (M + H+) 235.0970, found
235.0965.
4.4.7. 4,5,6,7-Tetrachloro-3-(propan-2-ylidene)isobenzofuran-1(3H)-one (8e) 4c
Pale yellow solid; Rf 0.55 (hexanes-ethyl acetate 10:1); mp 117 ; IR (ATR) 1757, 1636,
13
1570 cm−1; 1H NMR (CDCl3) δ 2.18 (s, 3H), 2.31(s, 3H); C NMR (CDCl3) δ 22.6 (q), 23.3
- 20 -

(q), 123.2 (s), 125.3 (s), 126.3 (s), 131.2 (s), 134.8 (s), 137.2 (s), 138.4 (s), 140.4 (s), 161.3
(s); HRMS (ESI, ion trap) calcd for C11H7Cl4O2 (M + H+) 310.9200, found 310.9195.
4.4.8. 4,5,6,7-Tetrafluoro-3-(propan-2-ylidene)isobenzofuran-1(3H)-one (8f)
Yellow solid (CCDC 1958791); Rf 0.5 (hexanes-ethyl acetate 10:1); mp 92 ; IR (ATR)
1
13
1761, 1670, 1518 cm−1; H NMR (CDCl3) δ 2.15 (s, 3H), 2.23 (s, 1.5H), 2.24 (s, 1.5H); C
NMR δ 19.1 (q), 19.3 (q), 21.4 (q), 109.7 (s, JCCF = 12.0 Hz), 121.4 (s, JCCF = 15.6 Hz), 126.1
(s), 137.3 (s), 139.0 (s, JCF = 257.3 Hz, JCCF = 13.8 Hz, JCCCF = 4.8 Hz), 140.4 (s, JCF = 258.5
Hz, JCCF = 14.4 Hz), 144.1 (s, JCF = 265.1 Hz, JCCF = 11.4 Hz, JCCCF = 3.6 Hz), 145.6 (s, JCF
=
261.5 Hz, JCCF = 13.8 Hz, JCCCF = 2.4 Hz); HRMS (ESI, ion trap) calcd for C11H7F2O2 (M +
H+) 247.0382, found 247.0375.
4.5. Typical procedure for the hydrogenation of 6 to 7
A solution of 6a (54 mg, 0.25 mmol) in ethyl acetate (10 mL) was stirred in the presence
of cat. Pd/C (10%) under H2 (1 atm) for 2 h. After the solution was filtered, the solvent was
removed in vacuo. The residue was purified by column chromatography on silica gel to give
7a (52 mg, 95%).
4.5.1. 3,3-Diisopropylisobenzofuran-1(3H)-one (7a)
1
Colorless paste; Rf 0.45 (hexanes-ethyl acetate, 10:1); IR (ATR) 1751 cm−1; H NMR
(CDCl3) δ 0.83 (d, 6H, J = 6.9 Hz), 0.84 (d, 6H, J = 6.9 Hz), 2.45-2.54 (m, 2H), 7.34-7.39 (m,
13
1H), 7.48-7.53 (m, 1H), 7.61-7.66 (m, 1H) 7.85-7.89 (m, 1H); C NMR (CDCl3) δ 16.6 (q),
16.8 (q), 32.4 (d), 94.9 (s), 121.9 (d), 125.5 (d), 127.9 (s), 128.7 (d), 133.4 (d), 150.6 (s),
170.9 (s); HRMS (ESI, ion trap) calcd for C14H19O2 (M + H+) 219.1385, found 219.1380.
4.5.2. 3-Isopropylisobenzofuran-1(3H)-one (9a)
1
Colorless paste; Rf 0.4 (hexanes-ethyl acetate, 5:1); IR (ATR) 1757 cm−1; H NMR
(CDCl3) δ 0.81 (d, 3H, J = 6.9 Hz), 1.13 (d, 3H, J = 6.9Hz), 2.25-2.32 (m, 1H), 5.37 (d, 1H, J
- 21 -

= 3.9 Hz), 7.45 (d, 1H, J = 7.7 Hz), 7.53 (t, 1H, J = 7.7 Hz), 7.65-7.69 (m, 1H), 7.90 (d, 1H, J
= 7.7 Hz); 13C NMR (CDCl3) δ 15.6 (q), 18.6 (q), 32.3 (d), 85.6 (d) 122.1 (d), 125.6 (d), 126.7
(s), 129.0 (d), 133.8 (d), 148.8 (s), 170.8 (s); HRMS (ESI, ion trap) calcd for C11H13O2 (M +
H+) 177.0916, found 177.0912.
4.5.3. 3,3-Diisopropyl-5,6-dimethoxyisobenzofuran-1(3H)-one (7c)
Colorless paste; Rf 0.55 (hexanes-ethyl acetate 2:1), IR (ATR) 1736, 1597 cm−1; 1H NMR
(CDCl3) δ 0.84 (d, 6H, J = 6.6 Hz), 0.85 (d, 6H, J = 6.3 Hz), 2.41-2.50 (m, 2H), 3.94 (s, 3H),
3.98 (s, 3H), 6.72 (s, 1H), 7.27 (s, 1H); 13C NMR (CDCl3) δ 16.5 (q), 16.8 (q), 32.3 (d), 56.1
(q), 56.3 (q), 94.1 (s), 103.4 (d), 105.9 (d), 119.9 (s), 144.9 (s), 150.0 (s), 154.2 (s), 171.1 (s);
HRMS (ESI, ion trap) calcd for C16H23O4 (M + H+) 279.1596, found 279.1587.
4.5.4. 3,3-Diisopropyl-6,7-dimethoxyisobenzofuran-1(3H)-one (7d)
Colorless paste; Rf 0.6 (hexanes-ethyl acetate 2:1), IR (ATR) 1749, 1593 cm−1; 1H NMR
(CDCl3) δ 0.83 (d, 6H, J = 7.2 Hz), 0.84 (d, 6H, J = 6.9 Hz), 2.38-2.46 (m, 2H), 3.91 (s, 3H),
4.10 (s, 3H), 6.95 (d, 1H, J = 8.2 Hz), 7.18 (d, 1H, J = 8.2 Hz); 13C NMR (CDCl3) δ 16.5 (q),
16.7 (q), 32.5 (d), 56.6 (q), 62.3 (q), 93.2 (s), 116.3 (d), 118.5 (d), 120.1 (s), 143.6 (s), 148.0
(s), 152.1 (s), 168.2 (s); HRMS (ESI, ion trap) calcd for C16H23O4 (M + H+) 279.1596, found
279.1594.
4.5.5. 3-Isopropyl-4,5-dimethoxyisobenzofuran-1(3H)-one (9d)
1
Colorless paste; Rf 0.5 (hexane-ethyl acetate 2:1); IR (ATR) 1751, 1612, 1599 cm−1; H
NMR (CDCl3) δ 0.59 (d, 3H, J = 7.0 Hz), 1.26 (d, 3H, J = 7.0 Hz), 2.50-2.59 (m, 1H), 3.91 (s,
3H), 3.97 (s, 3H), 5.46 (d, 1H, J = 2.3 Hz), 7.08 (d, 1H, J = 8.4 Hz), 7.61 (d, 1H, J = 8.4 Hz);
13C NMR (CDCl3) δ 13.9 (q), 20.1 (q), 30.6 (d), 56.3 (q), 60.4 (q), 84.1 (d), 113.8 (d), 119.8
(s), 121.8 (d), 141.4 (s), 142.8 (s), 157.0 (s), 170.5 (s); HRMS (ESI, ion trap) calcd for
C13H17O4 (M + H+) 237.1127, found 237.1123.
- 22 -

4.6. X-ray crystallographic analysis
All measurements were made on a Rigaku RAXIS imaging plate area detector with
graphite monochromated Mo Kα radiation. The structure was solved by direct methods with
SIR-97 and refined with SHELXL-97. The non-hydrogen atoms were refined anisotropically.
Hydrogen atoms were refined isotropically. All calculations were performed using the
YADOKARI-XG software package. Crystal data of 3a, 8d, 8f, 10a, and 11a are deposited into
CCDC 1958789-1958793, respectively. These data can be obtained free of charge from The
Cambridge Crystallographic Data Center via www.ccdc.ac.uk/data/cif.
Appendix A. Supplementary data
Supplementary
data
to
this
article
can
be
found
online
at
https://doi.org/10.1016/j.tet.XXXX.
References
1. For reviews, see: (a) Xioang, M.-J.; Li, Z.-H. Curr. Org. Chem. 2007, 11, 833−844. (b)
Beck, J. J.; Chou, S.-C. J. Nat. Prod. 2007, 70, 891−900. (c) Karmakar, R.; Pahari, P.; Mal,
D. Chem. Rev. 2014, 114, 6213−6284.
2. For recent reports, see: (a) Petrignet, J.; Ngi, S. I.; Abarbri, M.; Thibonnet, J. Tetrahedron
Lett. 2014, 55, 982−984. (b) Krätzschmar F.; Kaßel M.; Delony, D.; Breder, A. Chem. Eur.
J. 2015, 21, 7030−7034. (c) Sueki, S.; Wang, Z.; Kuninobu, Y. Org. Lett. 2016, 18,
304−307. (d) Shcherbinin, V. A.; Shpuntov, P. M.; Konshin, V. V.; Butin, A. V.
Tetrahedron Lett. 2016, 57, 1473−1475. (e) Nguyen, T. V. Q.; Rodríguez-Santamaría, J.
A.; Yoo, W.-J.; Kobayashi, S. Green Chem. 2017, 19, 2501−2505.
3. For recent reports, see: (a) Egami, H.; Asada, J.; Sato, K.; Hashizume, D.; Kawato, Y.;
Hamashima, Y. J. Am. Chem. Soc. 2015, 137, 10132−10135. (b) Santos, H.; Distiller, A.;
- 23 -

D’Souza, A. M.; Arnoux, Q.; White, J. M.; Meyer, A. G.; Ryan, J. H. Org. Chem. Front.
2015, 2, 705−712. (c) Mahendar, L.; Satyanarayana, G. J. Org. Chem. 2016, 81,
7685−7691.
4. For recent reports, see: (a) Liu, Y.; Yang, Y.; Shi, Y.; Wang, X.; Zhang, L.; Cheng, Y.; You,
J. Organometallics 2016, 35, 1350−1353. (b) Dragan, A.; Jones, D. H.; Kennedy, A. R.;
Tomkinson, N. C. O. Org. Lett. 2016, 18, 3086−3089. (c) Dussart, N.; Trinh, H. V.;
Gueyrard D. Org. Lett. 2016, 18, 4790−4793. (d) Mancuso, R.; Pomelli, C. S.; Chiappetta,
P.; Gioia, K. F.; Maner, A.; Marino, N.; Veltri, L.; Chiappe, C.; Gabriele, B. J. Org. Chem.
2018, 83, 6673−6680. (e) Zheng, Y.; Liu, M.; Qiu, G.; Xie, W.; Wu, J. Tetrahedron 2019,
75, 1663−1668.
5. (a) Kise, N.; Kawano, Y.; Sakurai, T. J. Org. Chem. 2013, 78, 12453−12459. (b) Kise, N.;
Isemoto, S.; Sakurai, T. Tetrahedron 2012, 68, 8805−8816.
6. (a) Kise, N.; Sasaki, K.; Sakurai, T. Tetrahedron 2014, 70, 9668−9675. (b) Kise, N.; Goi,
S.; Sakurai, T. Tetrahedron 2018, 74, 992−1001.
7. Wasserman, H. H.; Amici, R.; Frechette, R.; van Duzer, J. H. Tetrahedron Lett. 1989, 30,
869−872.
8. Zhang, J.; Li, Y.; Xu, R.; Chen, Y. Angew. Chem. Int. Ed. 2017, 56, 12619−12623.
- 24 -

Highlights
► Reductive coupling of phthalic anhydrides with acetone and acetonylacetone by ZnꢀTiCl4.
► Unusual twoꢀtoꢀone coupled products for preparation of 3,3ꢀdisubstituted phthalides. ►
Stereoselective synthesis of 3ꢀspirocyclopentanylphtalides. ► Oneꢀtoꢀone coupled products for
preparation of 3ꢀisopropylideneꢀ and 3ꢀisopropylphthalides.

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: