Polycyclic N-heterocyclic compounds. Part 631 improved synthesis of 5-amino-1,2-dihydrofuro[2,3-c]isoquinolines via truce-smiles rearrangement and subsequent formation to furo[2,3-c]isoquinoline

Article abstract of DOI:10.1248/cpb.58.363

An improved synthesis of 5-amino-1,2-dihydrofuro[2,3-c]isoquinoline has been achieved using a slight modification of reaction conditions for the Truce-Smiles rearrangement. Acid treatment of the obtained 5-amino-1,2- dihydrofuro[2,3-c]isoquinolines gave unexpected ring-opened spiro ring compounds. The previously unreported parent compound, furo[2,3-c]isoquinoline, was also synthesized.

Full text of DOI:10.1248/cpb.58.363

March 2010
Chem. Pharm. Bull. 58(3) 363—368 (2010)
363
Polycyclic N-Heterocyclic Compounds. Part 631) Improved Synthesis of
5-Amino-1,2-dihydrofuro[2,3-c]isoquinolines via Truce–Smiles
Rearrangement and Subsequent Formation to Furo[2,3-c]isoquinoline
,a
b
b
,b
*
*
Kensuke OKUDA, Masahiko YOSHIDA, Takashi HIROTA, and Kenji SASAKI
a Gifu Pharmaceutical University; 1–25–4 Daigaku-nishi, Gifu 501–1196, Japan: and b Faculty of Pharmaceutical
Sciences, Okayama University; 1–1–1 Tsushima-naka, Kita-ku, Okayama 700–8530, Japan.
Received October 29, 2009; accepted December 15, 2009; published online December 22, 2009
An improved synthesis of 5-amino-1,2-dihydrofuro[2,3-c]isoquinoline has been achieved using a slight modi-
fication of reaction conditions for the Truce–Smiles rearrangement. Acid treatment of the obtained 5-amino-1,2-
dihydrofuro[2,3-c]isoquinolines gave unexpected ring-opened spiro ring compounds. The previously unreported
parent compound, furo[2,3-c]isoquinoline, was also synthesized.
Key words Truce–Smiles rearrangement; furo[2,3-c]isoquinoline; furo[2,3-b]pyridine; heterocycle; spiro[cyclopropane-(1,4ꢀ)-
isoquinoline]
Formation of carbon–carbon (C–C) bonds is a central 2-(3-cyanopropoxy)benzonitriles (3a—c) as substrates.
issue in synthetic organic chemistry. In this regard, the
Truce–Smiles rearrangement is among those useful re- Results and Discussion
arrangement reactions that provide access to complex struc-
tures from simple precursors through formation of new C–C in Chart 2. First, 5-chloro-2-hydroxybenzoic and 5-nitro-2-
bonds.2—6)
hydroxybenzoic acid (5b, 5c) were transformed to 5-chloro-
Substrate compounds 3b and 3c were prepared as shown
We have previously reported the application of the Truce– 2-(3-cyanopropoxy)benzoic acid and 2-(3-cyanopropoxy)-5-
Smiles rearrangement for the synthesis of many aromatic nitro-benzoic acid (8b, 8c), respectively. Next, 8b and 8c
fused dihydrothieno (or dihydrofuro)naphthyridines (1) in were activated with phosphoryl chloride and then treated
one step from cyanopyridines having a 3-cyanopropoxy with liquid ammonia to give the carboxamide derivatives (9b,
group adjacent to cyano group (2). Thus, base-mediated 9c). Dehydration of 9b and 9c with phosphoryl chloride gave
Truce–Smiles rearrangement of 2 followed by intramolecular the desired dinitriles (3b, 3c).
cyclization (Chart 1) produces 1 in moderate to good
The initial reaction of 3a with potassium tert-butoxide in
yields.7—10) Some of these products and their chemically N,N-dimethylformamide (DMF) at room temperature pro-
modified derivatives showed promising bronchodilatory ac- duced 4a, albeit in only 14% yield (Table 1, run 1).12) Chang-
tivity in a primary in vitro assay (relaxation of tracheal con- ing the solvent from DMF to dioxane did not significantly
traction induced by carbamylcholine chloride).11) As an ex- improve the product yield (17%, run 2). However, addition of
tension of this work, we sought to expand this rearrangement potassium tert-butoxide around 95 °C in one portion to the
reaction system to 2-(3-cyanopropoxy)benzonitrile (3a) as reaction solution and raising the reaction temperature to re-
a route to 5-amino-1,2-dihydrofuro[2,3-c]isoquinoline (4a). flux for 1 h increased the yield of 4a to 60% (run 3). Using
This transformation was successful but the product yield was NaH as base gave no further improvement in yield compared
low (14%)12) because 3a is not activated for nucleophilic re- to potassium tert-butoxide (runs 4 and 5). We then turned our
action compared to 2. As is well established, the key step of attention to reactions of 3b which has a Cl substituent, a rela-
the Truce–Smiles rearrangement is the ipso attack of an in- tively weak electron withdrawing group. As with 3a, the re-
coming nucleophile.13) In order to apply this reaction for fur- action at room temperature in dioxane for 3b gave a poor re-
ther syntheses of heterocycles with potential pharmaceutical sult (run 6). However, under reflux 4b was formed in 83%
applications, including bronchodilatory activity, we initiated yield (run 7). From these results, we expected that 3c would
a study of conditions designed to improve this reaction step. be a more favorable substrate under these reaction conditions
Here we report the optimization of reaction conditions and because the Truce–Smiles rearrangement is known to occur
the successful application of this reaction using 5-substituted
Chart 1. Substrates (2, 3) and Their Rearranged Products (1, 4)
Chart 2. Preparation of 3b and 3c
© 2010 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: okuda@gifu-pu.ac.jp

364
Vol. 58, No. 3
Table 1. Reaction of Dinitriles 3 with Bases to Give 4
Run
Compd.
Basea)
Solvent
Temperature
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
3a
3a
3a
3a
3a
3b
3b
3c
3c
3c
3c
3c
3c
tert-BuOK
tert-BuOK
tert-BuOK
NaH
DMF
r.t.
r.t.
4
24
1
1412)
17
60
N.R.
42
18
83
17
24
Trace
N.R.
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DMF
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Refluxb)
r.t.
24
72
22
0.1
0.5
0.5
0.1
24
24
2
NaH
Refluxc)
r.t.
tert-BuOK
tert-BuOK
tert-BuOK
tert-BuOK
tert-BuOK
NaH
Refluxb)
r.t.
r.t.
Refluxb)
r.t.
NaH
NaOEt
Refluxc)
r.t.
N.R.
d)
a) 2 eq base was used except for run 13 (1.2 eq base). b) Base was added around 95 °C in one portion to the reaction solution then refluxed. c) Base was added at room temper-
ature to the reaction solution then refluxed. d) 2-Ethoxy-5-nitrobenzonitrile (10) was obtained (51%). r.t.: room temperature. N.R.: no reaction.
readily on reactants having the strong electron withdrawing
nitro group.13) However, reaction of 3c with potassium tert-
butoxide in dioxane under reflux condition was unsuccessful.
Many spots on TLC analysis indicated that these reaction
conditions were too harsh for an activated substrate such
as 3c (run 10). Reaction under milder conditions (room tem-
perature) either in DMF or in dioxane gave 4c, but in rela-
tively low yield (17 and 24%, runs 8 and 9). When 3c was
allowed to react with sodium ethoxide as the base, the 3-
cyanopropoxy group was displaced by ethoxide to give 2-
ethoxy-5-nitrobenzonitrile (10, 51%, run 13). This shows
that the bulky tert-butoxide is a better base for this reaction.
Although several derivatives containing the furo[2,3-c]iso-
quinoline ring system have been already synthesized,14—17)
the parent ring skeleton, unsubstituted furo[2,3-c]isoquino-
Chart 3. Reaction of 4 with Acid
line (11), has not been reported. We therefore attempted to
execute sequential deamination and aromatization of 4a to
give 11. Our initial synthetic strategy appeared to be quite in Chart 4. We have previously observed this sort of rear-
straightforward. Thus, we expected that 11 could be prepared rangement in our laboratory,10) in that a similar spiro com-
by the following sequence of reactions; 1) acid hydrolysis of pound spiro[cyclopropane-1,5ꢀ(6ꢀH)-[1,7]naphthyridine]-
the amino group of 4a to the corresponding lactam, 2) chlori- 6ꢀ,8ꢀ(7ꢀH)-dione was obtained from 5-amino-1,2-dihydro-
nation of the lactam carbonyl group with phosphoryl chlo- furo[3,2-f ][1,7]naphthyridine on treatment with conc. hy-
ride, 3) dechlorination by catalytic hydrogenation, and 4) drochloric acid.
aromatization with 2,3-dichloro-5,6-dicyano-p-benzoquinone
(DDQ).
To explore the generality of this reaction, compounds 4b
and 4c were subjected to the same reaction conditions. The
We encountered immediate problems with this approach. corresponding spiro derivatives 13b and 13c were produced
When 4a was heated with conc. hydrochloric acid, an un- in moderate yield.
expected furan ring opening occurred to yield 4-(2-
Since we were unable to hydrolyze the amino group of 4 to
chloroethyl)-1,2,3,4-tetrahydroisoquinoline-1,3-dione (12) in produce the desired lactam, we next tried to access the corre-
73% yield (Chart 3).18) We then tried hydrolysis of 10a under sponding chloro derivative by a diazotization reaction of 4
milder condition using conc. hydrochloric acid and acetic with sodium nitrite in conc. hydrochloric acid (Chart 5). This
acid in 2-methoxyethanol. Under these conditions the furan in fact produced the desired 5-chloro derivative 14a, but in
ring opened again and a rearranged product, spiro[cyclo- only 8% yield. Low yields were also obtained in similar reac-
propane-1,4ꢀ(1ꢀH)-isoquinoline]-1ꢀ,3ꢀ(2ꢀH)-dione (13a)19) tions with 14b and 14c (5% and 15% yield, respectively). It
was obtained. The presence of the cyclopropane ring is is possible that the poor yields were due to low solubility of 4
shown by a 1.66 and 2.16 ppm upfield shift of the aliphatic in conc. hydrochloric acid. Unacceptably low yields for 14a
1
protons in the H-NMR spectrum of 13a. A possible pro- and 14b prompted us to examine another diazotization proce-
posed reaction mechanism of 4 to 12 and 13a is shown dure. Somewhat better results were obtained in the reaction

March 2010
365
Chart 4. Mechanistic Proposal for Formation of 12 and 13
currently exploring the biological properties of the products
with the goal of developing new pharmaceutical agents.
Experimental
General All melting points were determined on a Yanagimoto micro-
melting point apparatus, and are uncorrected. Elemental analyses were per-
formed on a Yanagimoto MT-5 CHN Corder elemental analyzer. The FAB-
mass and EI-mass spectra were obtained on a VG 70 mass spectrometer and
m-nitrobenzyl alcohol or glycerol was used as the matrix. The IR spectra
were recorded on a Japan Spectroscopic diffraction grating A-102 or FT/IR-
200 spectrophotometer with KBr and frequencies are expressed in cmꢁ1
.
The 1H-NMR spectra were recorded on a Varian VXR-200 instrument oper-
ating at 200 MHz or Hitachi R-1500 instrument operating at 60 MHz with
tetramethylsilane as an internal standard. Chemical shifts are given in ppm
(d) and J values in Hz, and the signals are designated as follows: s, singlet;
d, doublet; dd, double doublet; t, triplet; q, quartet; quin, quintet; br, broad;
m, multiplet. Column chromatography was performed on silica gel (IR-60-
63-210-W, Daiso). TLC was carried out on Kieselgel 60F254 (Merck) or
silica gel 70FM (Wako).
Chart 5. Deaminochlorination of 4
Methyl 5-Chloro-2-hydroxybenzoate (6) To a solution of 5-chloro-2-
hydroxybenzoic acid (5b, 1.00 g, 5.79 mmol) in dry methanol (1.0 ml) was
added conc. H2SO4 (600 mg, 6.12 mmol) and the mixture was refluxed for
4 h. After addition of water, the mixture was extracted with diethyl ether
(10 ml). The combined organic layer was washed with water (10 mlꢂ3), sat-
urated KHCO3 aq. solution, and saturated brine, dried over Na2SO4, and then
evaporated in vacuo. The residue was recrystallized from n-hexane to give 6
1
(900 mg, 83%) as colorless needles, mp 46—47 °C (lit.22) 44—46 °C). H-
NMR (60 MHz, CDCl3) d: 3.96 (3H, s, OCH3), 6.93 (1H, d, Jꢃ9.1 Hz, H-3),
7.41 (1H, dd, Jꢃ9.1, 2.6 Hz, H-4), 7.81 (1H, d, Jꢃ2.6 Hz, H-6), 10.66 (1H,
br s, D2O exchangeable OH). IR (KBr) cmꢁ1: 3130, (OH), 1660 (CO). EI-
MS m/z: 186 (Mꢄ), 188 (Mꢄꢄ2). Anal. Calcd for C8H7ClO3: C, 51.49; H,
3.78. Found: C, 51.60; H, 3.77.
Methyl 5-Chloro-2-(3-cyanopropoxy)benzoate (7) To a solution of 6
(330 mg, 1.77 mmol) in dry DMF (1.0 ml) were added 4-chlorobutyronitrile
(274 mg, 2.66 mmol) and K2CO3 (366 mg, 2.66 mmol) and the mixture was
refluxed for 5 h. After addition of ice water (90 ml), the mixture was ex-
tracted with ethyl acetate (100 mlꢂ3). The combined organic layer was
washed with saturated brine, dried over Na2SO4, and then evaporated in
vacuo. The residue was chromatographed on silica gel. The eluate of ben-
zene was evaporated and the residue was recrystallized from ethyl acetate–
Chart 6. Synthesis of Furo[2,3-c]isoquinoline (11)
of 4a with n-amyl nitrite in chloroform.20,21) This gave two
products, 5-chloro derivative 14a and the product of its dehy-
drogenation 15a in 24% and 13% yield, respectively. Reac-
tion of 4b under these conditions gave 14b and 15b in 18%
and 10% yield, respectively.
Finally, the parent skeleton, furo[2,3-c]isoquinoline 11 was
synthesized by using the above two products 14a and 15a, as
shown in Chart 6. Catalytic hydrogenation of 14a gave
dechlorinated compound 16 in 55% yield. This was treated
with DDQ to give desired parent skeleton 11 in 93% yield.
Dechlorination of 15a with catalytic hydrogenation also gave
11 in 53% yield.
In summary, we have developed an improved method for
the synthesis of 5-amino-1,2-dihydrofuro[2,3-c]isoquinoline
(4) based on the Truce–Smiles rearrangement. Acid treat-
ment of 4 gave unexpected ring-opened spiro ring com-
pounds. The previously unreported parent compound,
1
n-hexane to give 7 (368 mg, 82%) as colorless needles, mp 56—57 °C. H-
NMR (60 MHz, CDCl3) d: 2.23 (2H, br quin, Jꢃ6.0 Hz, H-2ꢀ), 2.72 (2H, t,
Jꢃ6.0 Hz, H-3ꢀ), 3.88 (3H, s, OCH3), 4.14 (2H, t, Jꢃ6.0 Hz, H-1ꢀ), 6.90
(1H, d, Jꢃ8.9 Hz, H-3), 7.41 (1H, dd, Jꢃ8.9, 2.6 Hz, H-4), 7.80 (1H, d,
Jꢃ2.6 Hz, H-6). IR (KBr) cmꢁ1: 2235 (CN), 1705 (CO). FAB-MS m/z: 254
(MHꢄ), 256 (MHꢄꢄ2). Anal. Calcd for C12H12ClNO3: C, 56.81; H, 4.77; N,
5.52. Found: C, 56.65; H, 4.78; N, 5.48.
5-Chloro-2-(3-cyanopropoxy)benzoic Acid (8b) To a solution of 7
(1.00 g, 3.94 mmol) in dioxane (20 ml) was added 1 N NaOH (20 ml) and the
solution was stirred at room temperature for 2 h. The reaction mixture was
acidified with 1 N HCl and then extracted with ethyl acetate (20 mlꢂ3). The
combined organic layer was washed with saturated brine, dried over Na2SO4,
and then evaporated in vacuo. The residue was recrystallized from ethyl
acetate–n-hexane to give 8b (900 mg, 95%) as colorless needles, mp 94—
1
95 °C. H-NMR (60 MHz, CDCl3) d: 2.28 (2H,, br quin, Jꢃ6.0 Hz, H-2ꢀ),
2.70 (2H, t, Jꢃ6.0 Hz, H-3ꢀ), 4.24 (2H, t, Jꢃ6.0 Hz, H-1ꢀ), 6.96 (1H, d,
Jꢃ8.8 Hz, H-3), 7.51 (1H, dd, Jꢃ8.8, 2.6 Hz, H-4), 8.02 (1H, d, Jꢃ2.6 Hz,
furo[2,3-c]isoquinoline (11), was also synthesized. We are H-6), 9.92 (1H, br s, D2O exchangeable, OH). IR (KBr) cmꢁ1: 3430 (OH),

366
Vol. 58, No. 3
2245 (CN), 1700 (CO). FAB-MS m/z: 240 (MHꢄ), 242 (MHꢄꢄ2). Anal.
(2H, t, Jꢃ6.5 Hz, H-1ꢀ), 7.50 (1H, d, Jꢃ9.3 Hz, H-3), 8.52 (1H, dd, Jꢃ9.3,
Calcd for C11H10ClNO3: C, 55.13; H, 4.21; N, 5.84. Found: C, 55.07; H, 2.8 Hz, H-4), 8.71 (1H, d, Jꢃ2.8 Hz, H-6). IR (KBr) cmꢁ1: 2270, 2260
4.36; N, 5.77.
2-(3-Cyanopropoxy)-5-nitrobenzoic Acid (8c) To a solution of 2-hy- C, 57.14; H, 3.92; N, 18.17. Found: C, 57.21; H, 4.10; N, 17.90.
(CN), 1525, 1345 (NO2). EI-MS m/z: 231 (Mꢄ). Anal. Calcd for C11H9N3O3:
droxy-5-nitrobenzoic acid (5c, 200 mg, 1.09 mmol) in dry DMF (5.0 ml)
were added 4-chlorobutyronitrile (451 mg, 4.36 mmol) and K2CO3 (300 mg,
2.18 mmol), and the reaction mixture was refluxed for 1.5 h. After cooling of
the reaction mixture to room temperature, ice water (25 ml) and 1 N NaOH
5-Amino-1,2-dihydrofuro[2,3-c]isoquinoline (4a) To a solution of
3a12) (1.00 g, 5.37 mmol) in dry dioxane (30 ml) around 95 °C was added
tert-BuOK (1.20 g, 10.8 mmol) in one portion under stirring. Solid precipi-
tated during the reaction after about 1 h, at which time the mixture was
(10 ml) were added and the mixture was stirred at room temperature for 1 h. cooled to room temperature. After evaporation of solvent, the residue was
The resulting solution was acidified with 1 N HCl and extracted with ethyl washed with ice water (300 ml) and then filtered. The mother liquid was ex-
acetate (10 mlꢂ3). The combined organic layer was washed with saturated tracted with ethyl acetate (100 mlꢂ3). The combined organic layer was
brine, dried over Na2SO4, and then evaporated in vacuo. The residue was re- washed with saturated brine, dried over Na2SO4, and then evaporated in
crystallized from ethanol to give 8c (193 mg, 71%) as colorless needles, mp
vacuo. The residue and the above precipitate were combined and recrystal-
135—137 °C. 1H-NMR (200 MHz, CDCl3) d: 2.24 (2H, quin, Jꢃ6.3 Hz, H-
lized from acetone to give 4a (600 mg, 60%) as pale brown prisms. All ana-
1
2ꢀ), 2.61 (2H, t, Jꢃ6.3 Hz, H-3ꢀ), 4.58 (2H, t, Jꢃ6.3 Hz, H-1ꢀ), 7.10 (1H, d, lytical data (mp, IR, H-NMR, MS, and EA) were in good agreement with
Jꢃ9.2 Hz, H-3), 8.36 (1H, dd, Jꢃ9.2, 2.7 Hz, H-4), 8.77 (1H, d, Jꢃ2.7 Hz, literature values.12)
H-6), 11.33 (1H, br s, D2O exchangeable, OH). IR (KBr) cmꢁ1: 3430 (OH),
5-Amino-7-chlorofuro[2,3-c]isoquinoline (4b) To a solution of 3b
(300 mg, 1.36 mmol) in dry dioxane (3.0 ml) around 95 °C was added tert-
2260 (CN), 1675 (CO), 1515, 1340 (NO2). FAB-MS m/z: 251 (MHꢄ). Anal.
Calcd for C11H10N2O5: C, 52.80; H, 4.03; N, 11.20. Found: C, 52.75; H, BuOK (305 mg, 2.72 mmol) in one portion under stirring. Solid precipitated
4.17; N, 11.43.
during the reaction after about 0.1 h, at which time the mixture was cooled to
room temperature. After evaporation of solvent, the residue was washed
5-Chloro-2-(3-cyanopropoxy)benzamide (9b) Compound 8b (1.00 g,
4.17 mmol) in POCl3 (6.40 g, 41.8 mmol) was refluxed for 4 h. After evapo- with ice water (30 ml) and then filtered. The mother liquid was extracted
ration of excess POCl3, dry toluene (10 ml) was added to the residue then
evaporated again in vacuo twice. The residue was cooled with dry ice–ace-
with ethyl acetate (10 mlꢂ3). The combined organic layer was washed with
saturated brine, dried over Na2SO4, and then evaporated in vacuo. The
tone and liq. NH3 (ca. 50 ml) was added. The mixture was allowed to stand residue and the above precipitate were combined and recrystallized from
for one night and saturated brine was added to the mixture. The resulting ethyl acetate to give 4b (250 mg, 83%) as pale brown needles, mp 254—
1
solid was washed with water. The precipitate was filtered in vacuo and then
255 °C. H-NMR (200 MHz, CDCl3) d: 3.32 (2H, t, Jꢃ8.8 Hz, H-1), 4.72
(2H, t, Jꢃ8.8 Hz, H-2), 5.16 (2H, br s, D2O exchangeable, NH2), 7.36 (1H,
recrystallized from ethanol–n-hexane to give 9b (900 mg, 90%) as colorless
1
needles, mp 120—121 °C. H-NMR (60 MHz, CDCl3) d: 2.10—2.71 (4H, d, Jꢃ8.9 Hz, H-9), 7.46 (1H, dd, Jꢃ8.9, 2.0 Hz, H-8), 7.70 (1H, d,
m, H-2ꢀ, 3ꢀ), 4.26 (2H, t, Jꢃ5.6 Hz, H-1ꢀ), 6.46 (2H, br s, D2O exchange- Jꢃ2.0 Hz, H-6). IR (KBr) cmꢁ1: 3490, 3395 (NH). FAB-MS m/z: 221
able, NH2), 6.92 (1H, d, Jꢃ8.8 Hz, H-3), 7.42 (1H, dd, Jꢃ8.8, 2.6 Hz, H-4),
(MHꢄ), 223 (MHꢄꢄ2). Anal. Calcd for C11H9ClN2O: C, 59.88; H, 4.11; N,
8.11 (1H, d, Jꢃ2.6 Hz, H-6). IR (KBr) cmꢁ1: 3385, 3190 (NH), 2250 (CN), 12.70. Found: C, 59.90; H, 4.28; N, 12.79.
1635 (CO). FAB-MS m/z: 239 (MHꢄ), 241 (MHꢄꢄ2). Anal. Calcd for
5-Amino-7-nitrofuro[2,3-c]isoquinoline (4c) To a solution of 3c (3.01
C11H11ClN2O2: C, 55.36; H, 4.65; N, 11.74. Found: C, 55.30; H, 4.64; N, g, 13.0 mmol) in dry dioxane (50 ml) was added tert-BuOK (2.91 g,
11.74.
2-(3-Cyanopropoxy)-5-nitrobenzamide (9c) To a solution of 8c (5.00
g, 20.0 mmol) in dry dioxane (50 ml) was added POCl3 (9.18 g, 60.0 mmol)
25.9 mmol) and the mixture was stirred for 0.5 h at room temperature. After
evaporation of solvent in vacuo, the residue was treated with hot acetone.
The combined acetone extracts were evaporated. The resulting residue was
and the mixture was then refluxed for 4 h. After evaporation of excess recrystallized from acetone to give 4c (720 mg, 24%) as deep red needles,
POCl3, dry toluene (20 ml) was added to the residue then evaporated again mp 271—273 °C. 1H-NMR (200 MHz, CDCl3) d: 3.24 (2H, t, Jꢃ8.6 Hz, H-
in vacuo three times. The residue was cooled with dry ice–acetone and liq.
1), 4.66 (2H, t, Jꢃ8.6 Hz, H-2), 7.44 (1H, d, Jꢃ9.2 Hz, H-9) 7.69 (2H, br s,
NH3 (ca. 200 ml) was added. The mixture was allowed to stand for one night D2O exchangeable, NH2), 8.19 (1H, dd, Jꢃ9.2, 2.2 Hz, H-8), 9.21 (1H, d,
and saturated brine was added to the mixture. The resulting solid was Jꢃ2.2 Hz, H-6). IR (KBr) cmꢁ1: 3470, 3300 (NH), 1480, 1310 (NO2). FAB-
washed with water. The precipitate was filtered in vacuo and extracted with MS m/z: 232 (MHꢄ). Anal. Calcd for C11H9N3O3: C, 57.14; H, 3.92; N,
acetone. The combined acetone extracts were evaporated. The resulting 18.17. Found: C, 57.01; H, 3.90; N, 18.02.
residue was recrystallized from ethyl acetate to give 9c (4.98 g, 100%) as
2-Ethoxy-5-nitrobenzonitrile (10) To a solution of 3c (200 mg, 0.865
1
pale brown scales, mp 170—172 °C. H-NMR (200 MHz, CDCl3) d: 2.15 mmol) in dry dioxane (5.0 ml) was added EtONa (70.0 mg, 1.03 mmol) and
(2H, quin, Jꢃ6.3 Hz, H-2ꢀ), 2.69 (2H, t, Jꢃ6.3 Hz, H-3ꢀ), 4.30 (2H, t, the mixture was stirred for 2 h at room temperature After evaporation of sol-
Jꢃ6.3 Hz, H-1ꢀ), 7.38 (1H, d, Jꢃ9.2 Hz, H-3), 7.82 (2H, br s, D2O ex- vent, water (25 ml) was added to the residue and the aqueous solution was
changeable, NH2), 8.34 (1H, dd, Jꢃ9.2, 2.7 Hz, H-4), 8.47 (1H, d, Jꢃ2.7 Hz,
then extracted with ethyl acetate (10 mlꢂ3). The combined organic layer
H-6). IR (KBr) cmꢁ1: 3485, 3190 (NH), 2260 (CN), 1670 (CO), 1510, 1345 was washed with saturated brine, dried over Na2SO4, and then evaporated in
(NO2). FAB-MS m/z: 250 (MHꢄ). Anal. Calcd for C11H11N3O4: C, 53.01; H, vacuo. The residue was chromatographed on silica gel, and the eluate of
4.45; N, 16.86. Found: C, 53.09; H, 4.51; N, 16.83.
5-Chloro-2-(3-cyanopropoxy)benzonitrile (3b) To a solution of 9b vacuo. The residue was recrystallized from ethyl acetate to give 10 (84.0 mg,
(200 mg, 0.838 mmol) in dry CHCl3 (2.0 ml) was added POCl3 (1.29 g,
51%) as colorless needles, mp 101—102 °C (lit.23) 94 °C). 1H-NMR
cyclohexane–ethyl acetate (9 : 1 to 4 : 1) was collected and evaporated in
8.41 mmol) and the mixture was then refluxed for 2 h. After evaporation of (200 MHz, CDCl3) d: 1.56 (3H, t, Jꢃ7.0 Hz, CH3), 4.30 (2H, q, Jꢃ7.0 Hz,
CHCl3 and excess POCl3, ice water (15 ml) was added to the residue. The re- OCH2), 7.07 (1H, d, Jꢃ9.2 Hz, H-3), 8.43 (1H, dd, Jꢃ9.2, 2.7 Hz, H-4), 8.49
sulting precipitate was filtered, washed with water, and the residue was re- (1H, d, Jꢃ2.7 Hz, H-6). IR (KBr) cmꢁ1: 2245 (CN), 1515, 1340 (NO2).
crystallized from diethyl ether to give 3b (185 mg, 100%) as colorless nee-
FAB-MS m/z: 193 (MHꢄ). Anal. Calcd for C9H8N2O3: C, 56.25; H, 4.20; N,
1
dles, mp 57—58 °C. H-NMR (60 MHz, CDCl3) d: 2.17—2.42 (2H, m, H- 14.58. Found: C, 56.19; H, 4.26; N, 14.57.
2ꢀ), 2.70 (2H, t, Jꢃ5.6 Hz, H-3ꢀ), 4.21 (2H, t, Jꢃ5.6 Hz, H-1ꢀ), 6.95 (1H, d,
4-(2-Chloroethyl)-1,2,3,4-tetrahydroisoquinoline-1,3-dione (12)
A
Jꢃ9.7 Hz, H-3), 7.42—7.63 (2H, m, H-4, H-6). IR (KBr) cmꢁ1: 2245, 2235 solution of 4a (500 mg, 2.69 mmol) in conc. HCl (50 ml) was refluxed for
(CN). FAB-MS m/z: 221 (MHꢄ), 223 (MHꢄꢄ2). Anal. Calcd for 4 h. After cooling the reaction mixture to room temperature, it was made
C11H9ClN2O: C, 59.88; H, 4.11; N, 12.70. Found: C, 59.76; H, 4.23; N, basic with NaHCO3. The precipitated solid was filtered off and the mother
12.81.
2-(3-Cyanopropoxy)-5-nitrobenzonitrile (3c) To
liquid was extracted with ethyl acetate (50 mlꢂ3). The combined organic
solution of 9c layer was washed with saturated brine, dried over Na2SO4, and then evapo-
a
(1.05 g, 4.21 mol) in dry dioxane (20 ml) was added POCl3 (6.46 g,
rated in vacuo. The residue and the above solid were combined then recrys-
42.1 mmol) and the mixture was then refluxed for 1 h. After evaporation of tallized from ethyl acetate to give 12 (440 mg, 73%) as colorless prisms, mp
1
dioxane and excess POCl3, ice water (500 ml) was added to the residue. The 168—170 °C. H-NMR (200 MHz, CDCl3) d: 2.50 (2H, td, Jꢃ6.4, 6.4 Hz,
resulting mixture was neutralized with NaHCO3 (pH 7). The solution was H-1ꢀ), 3.50—3.77 (2H, m, H-2ꢀ), 4.11 (1H, t, Jꢃ6.4 Hz, H-4), 7.41 (1H, d,
extracted with ethyl acetate (100 mlꢂ3) and the combined organic layer was Jꢃ7.5 Hz, H-5), 7.50 (1H, m, H-7), 7.69 (1H, m, H-6), 8.24 (1H, dd, Jꢃ7.5,
washed with saturated brine, dried over anhydrous Na2SO4, and then evapo- 1.4 Hz, H-8), 8.13—8.40 (1H, br s, D2O exchangeable, NH). IR (KBr) cmꢁ1
:
rated in vacuo. The residue was recrystallized from ethanol to give 3c 3180, 3085 (NH), 1690, 1675, (CO). FAB-MS m/z: 224 (MHꢄ), 226
1
(860 mg, 88%) as pale yellow needles, mp 84—86 °C. H-NMR (200 MHz,
(MHꢄꢄ2). Anal. Calcd for C11H10ClNO2: C, 59.07; H, 4.51; N, 6.26. Found:
CDCl3) d: 2.09—2.17 (2H, m, H-2ꢀ), 2.69 (2H, t, Jꢃ6.5 Hz, H-3ꢀ), 4.38 C, 59.18; H, 4.64; N, 6.26.

March 2010
367
General Procedure for Preparation of 13 To a solution of 4 (200 mg) 11.26.
in 2-methoxyethanol (10 ml) were added acetic acid (4.0 ml) and conc. HCl
5-Chloro-1,2-dihydrofuro[2,3-c]isoquinoline (14a) and 5-Chlorofuro-
(2.0 ml) and the reaction mixture was refluxed for the appropriate time. After [2,3-c]isoquinoline (15a) To a solution of 4a (180 mg, 0.97 mmol) in dry
cooling, NaHCO3 was added to the reaction mixture and the aqueous solu- CHCl3 (50 ml) was added n-amyl nitrite (446 mg, 3.88 mmol) and the mix-
tion was extracted with ethyl acetate (30 mlꢂ3). The combined organic layer ture was then refluxed for 0.5 h. After cooling, the solution was evaporated
was washed with saturated brine, dried over Na2SO4, and then evaporated in in vacuo and the residue was chromatographed on silica gel. An early frac-
vacuo. The residue was recrystallized from ethyl acetate to give 13.
tion eluted with petroleum ether–diethyl ether (9 : 1) was evaporated and the
Spiro[cyclopropane-1,4ꢀ(1ꢀH)-isoquinoline]-1ꢀ,3ꢀ(2ꢀH)-dione (13a)
residue was recrystallized from petroleum ether to give 15a (26.0 mg, 13%)
1
Refluxed for 8 h. Colorless prisms 13a (103 mg, 51%), mp 215—217 °C as pale red feathers, mp 109—111 °C. H-NMR (200 MHz, CDCl3) d: 7.23
(lit.19) 206—207 °C). 1H-NMR (200 MHz, CDCl3) d: 1.63—1.69 and 2.13— (1H, d, Jꢃ2.3 Hz, H-1), 7.67 (1H, m, H-7), 7.81 (1H, Jꢃ2.3 Hz, H-2), 7.85
2.19 (each 2H, each m, H-cyclopropane), 6.84 (1H, br d, Jꢃ8.0 Hz, H-5ꢀ), (1H, m, H-8), 8.15 (1H, dd, Jꢃ8.6, 1.4 Hz, H-9), 8.48 (1H, br d, Jꢃ8.6 Hz,
7.41 (1H, br t, Jꢃ8.0 Hz, H-7ꢀ), 7.61 (1H, td, Jꢃ8.0, 1.4 Hz, H-6ꢀ), 8.26 H-6). FAB-MS m/z: 204 (MHꢄ), 206 (MHꢄꢄ2). Anal. Calcd for
(1H, dd, Jꢃ8.0, 1.4 Hz, H-8ꢀ), 8.42 (1H, br s, D2O exchangeable, NH). IR C11H6ClNO: C, 64.88; H, 2.97; N, 6.88. Found: C, 65.12; H, 3.21; N, 6.99.
(KBr) cmꢁ1: 3180, 3080 (NH), 1710, 1670 (CO). FAB-MS m/z: 188 (MHꢄ). A later fraction eluted with the same solvent system on chromatography was
Anal. Calcd for C11H9NO2: C, 70.58; H, 4.85; N, 7.48. Found: C, 70.33; H, evaporated and the residue was recrystallized from petroleum ether to give
4.94; N, 7.32.
14a (48.0 mg, 24%) as pale yellow feathers. The spectroscopic properties
7ꢀ-Chlorospiro[cyclopropane-1,4ꢀ(1ꢀH)-isoquinoline]-1ꢀ,3ꢀ(2ꢀH)-dione were identical to those described for 14a.
(13b) Refluxed for 6 h. Colorless needles 13b (90.0 mg, 45%), mp 232—
5,7-Dichloro-1,2-dihydrofuro[2,3-c]isoquinoline (14b) and 5,7-Dichlo-
233 °C. 1H-NMR (200 MHz, DMSO-d6) d: 1.68—1.74 and 1.88—1.94 rofuro[2,3-c]isoquinoline (15b) To a solution of 4b (1.00 g, 4.53 mmol) in
(each 2H, each m, H-cyclopropane), 7.12 (1H, d, Jꢃ8.5 Hz, H-5ꢀ), 7.69 (1H, dry CHCl3 (250 ml) was added n-amyl nitrite (2.12 g, 18.2 mmol) and the re-
dd, Jꢃ8.5, 2.4 Hz, H-6ꢀ), 7.98 (1H, d, Jꢃ2.4 Hz, H-8ꢀ), 11.65 (1H, br s, D2O action mixture was then refluxed for 0.5 h. After cooling, the solution was
exchangeable, NH). IR (KBr) cmꢁ1: 3195, 3075 (NH), 1700 (CO). FAB-MS evaporated in vacuo and the residue was chromatographed on silica gel. An
m/z: 222 (MHꢄ), 224 (MHꢄꢄ2). Anal. Calcd for C11H8ClNO2: C, 59.61; H, early fraction eluated with petroleum ether–diethyl ether (9 : 1) was evapo-
3.64; N, 6.32. Found: C, 59.61; H, 3.83; N, 6.23.
7ꢀ-Nitrospiro[cyclopropane-1,4ꢀ(1ꢀH)-isoquinoline]-1ꢀ,3ꢀ(2ꢀH)-dione
rated and the residue was recrystallized from ethanol to give 15b (110 mg,
10%) as pale yellow feathers, mp 174—175 °C. 1H-NMR (200 MHz, CDCl3)
(13c) Refluxed for 23 h. Pale red prisms 13c (106 mg, 53%), mp ꢅ300 °C. d: 7.21 (1H, d, Jꢃ2.3 Hz, H-1), 7.78 (1H, dd, Jꢃ8.8, 2.0 Hz, H-8), 7.82 (1H,
1H-NMR (200 MHz, DMSO-d6) d: 1.84—1.90, 2.02—2.08 (each 2H, each d, Jꢃ2.3 Hz, H-2), 8.09 (1H, d, Jꢃ8.8 Hz, H-9), 8.46 (1H, d, Jꢃ2.0 Hz, H-
m, H-cyclopropane), 7.36 (1H, d, Jꢃ8.8 Hz, H-5ꢀ), 8.40 (1H, Jꢃ8.8, 2.6 Hz,
6). FAB-MS m/z: 238 (MHꢄ), 240 (MHꢄꢄ2). Anal. Calcd for C11H5Cl2NO:
H-6ꢀ), 8.70 (1H, d, Jꢃ2.6 Hz, H-8ꢀ), 11.88 (1H, br s, D2O exchangeable, C, 55.50; H, 2.12; N, 5.88. Found: C, 55.51; H, 2.35; N, 5.83. A later chro-
NH). IR (KBr) cmꢁ1: 3200, 3090 (NH), 1710, 1690 (CO), 1530, 1345 matographic fraction eluted with the same solvent system was recrystallized
(NO2). FAB-MS m/z: 233 (MHꢄ). Anal. Calcd for C11H8N2O4: C, 56.90; H, from ethanol to give 14b (200 mg, 18%) as pale yellow feathers. The spec-
3.47; N, 12.06. Found: C, 56.81; H, 3.52; N, 12.06.
troscopic properties were identical to those described for 14b.
5-Chloro-1,2-dihydrofuro[2,3-c]isoquinoline (14a) To a suspension of
1,2-Dihydrofuro[2,3-c]isoquinoline (16) To a solution of 14a (490 mg,
4a (500 mg, 2.69 mmol) in conc. HCl (100 ml) under ice water cooling was 2.38 mmol) in benzene–methanol (1 : 1, 100 ml) were added 10% palladium
added a solution of NaNO2 (740 mg, 10.8 mmol, 1.8 ml of water) dropwise carbon (1.00 g) and KOH (134 mg, 2.40 mmol) and the mixture was then
with stirring. The end point of the reaction was confirmed with KI-starch
paper at which time the solution was basified with NaHCO3. The mixture
stirred under an atmosphere of H2 for 24 h. After filtration of the reaction
mixture, the mother liquid was evaporated in vacuo. The residue was recrys-
was extracted with ethyl acetate (100 mlꢂ3). The combined organic layer tallized from benzene to give 16 (226 mg, 55%) as colorless prisms, mp
was washed with saturated brine, dried over Na2SO4, and then evaporated in 125—127 °C (dec.). 1H-NMR (200 MHz, DMSO-d6) d: 3.50 (2H, t,
vacuo. The residue was chromatographed on silica gel and the eluate of pe- Jꢃ9.0 Hz, H-1), 4.73 (2H, t, Jꢃ9.0 Hz, H-2), 7.36—7.46 (1H, m, H-7),
troleum ether–diethyl ether (9 : 1) was evaporated. The residue was recrys- 7.65—7.72 (2H, m, H-8, 9), 8.04 (1H, br d, Jꢃ8.4 Hz, H-6), 8.62 (1H, s, H-
tallized from petroleum ether to give 14a (45.0 mg, 8%) as pale yellow 5). FAB-MS m/z: 172 (MHꢄ). FAB-HR-MS m/z: 172.0794 (Calcd for
feathers, mp 111—113 °C. 1H-NMR (200 MHz, CDCl3) d: 3.50 (2H, t, C11H10NO: 172.0762).
Jꢃ9.0 Hz, H-1), 4.83 (2H, t, Jꢃ 9.0 Hz, H-2), 7.43 (1H, m, H-7), 7.54—
Furo[2,3-c]isoquinoline (11) Run 1: To a solution of 16 (70.0 mg,
7.71 (2H, m, H-8, 9), 8.26 (1H, br d, Jꢃ8.7 Hz, H-6). FAB-MS m/z: 206 0.409 mmol) in chlorobenzene (25 ml) was added DDQ (280 mg, 1.23
(MHꢄ), 208 (MHꢄꢄ2). Anal. Calcd for C11H8ClNO: C, 64.25; H, 3.92; N, mmol) and the reaction mixture was then refluxed for 1 h. After evaporation
6.81. Found: C, 64.22; H, 4.01; N, 6.72.
of solvent, the residue was chromatographed on silica gel. The eluate of
5,7-Dichloro-1,2-dihydrofuro[2,3-c]isoquinoline (14b) To a suspen- CHCl3 was recrystallized from n-hexane to give 11 (64.0 mg, 93%) as color-
1
sion of 4b (200 mg, 0.906 mmol) in conc. HCl (100 ml) under ice water
cooling was added a solution of NaNO2 (251 mg, 3.64 mmol, 0.9 ml of
water) dropwise with stirring. The end point of the reaction was confirmed
less prisms, mp 131—132 °C. H-NMR (200 MHz, CDCl3) d: 7.25 (1H, d,
Jꢃ2.3 Hz, H-1), 7.60 (1H, m, H-7), 7.80 (1H, m, H-8), 7.83 (1H, d,
Jꢃ2.3 Hz, H-2), 8.08—8.18 (2H, m, H-6, 9), 8.99 (1H, s, H-5). FAB-MS
with KI-starch paper at which time the solution was basified with NaHCO3. m/z: 170 (MHꢄ). FAB-HR-MS m/z: 170.0615 (Calcd for C11H8NO:
The mixture was extracted with ethyl acetate (30 mlꢂ3). The combined or-
170.0606).
ganic layer was washed with saturated brine, dried over Na2SO4, and then
Run 2: To a solution of 15a (68.0 mg, 0.334 mmol) in benzene–methanol
evaporated in vacuo. The residue was chromatographed on silica gel. The (1 : 1, 5.0 ml) were added 10% palladium carbon (100 mg) and KOH
eluate of petroleum ether–diethyl ether (9 : 1) was evaporated and the residue (18.0 mg, 0.34 mmol) and the reaction mixture was then stirred under an
was recrystallized from ethanol to give 14b (11.0 mg, 5%) as pale yellow atmosphere of H2 for 24 h. After filtration of the reaction mixture, the
feathers, mp 182—183 °C. 1H-NMR (200 MHz, CDCl3) d: 3.49 (2H, t, mother liquid was evaporated in vacuo. The residue was chromatographed
Jꢃ8.9 Hz, H-1), 4.83 (2H, t, Jꢃ8.9 Hz, H-2), 7.51 (1H, d, Jꢃ8.7 Hz, H-9),
on silica gel. The eluate of petroleum ether–diethyl ether (9 : 1) was evapo-
7.60 (1H, dd, Jꢃ8.7, 1.4 Hz, H-8), 8.24 (1H, d, Jꢃ1.4 Hz, H-6). FAB-MS rated and the residue was recrystallized from n-hexane to give desired 11
m/z: 240 (MHꢄ), 242 (MHꢄꢄ2), 244 (MHꢄꢄ4). Anal. Calcd for (30.0 mg, 53%) as colorless prisms. The spectroscopic properties were iden-
C11H7Cl2NO: C, 55.03; H, 2.94; N, 5.83. Found: C, 55.04; H, 3.07; N, 5.80.
5-Chloro-7-nitro-1,2-dihydrofuro[2,3-c]isoquinoline (14c) To a sus-
pension of 4c (1.81 g, 7.83 mmol) in conc. HCl (300 ml) under ice water
cooling was added a solution of NaNO2 (2.53 g, 36.7 mmol, 9.0 ml of water)
dropwise. The workup of the reaction was carried out as described in 14a,
and the obtained residue was chromatographed on silica gel. The eluate of
tical to those for 11 described above.
Acknowledgements We are grateful to the SC-NMR Laboratory of
1
Okayama University for 200 MHz H-NMR experiments. We also thank Dr.
K. L. Kirk (NIDDK, NIH) for helpful suggestions.
cyclohexane–ethyl acetate (4 : 1) was evaporated and the residue was recrys- References and Notes
tallized from benzene to give 14c (290 mg, 15%) as yellow feathers, mp
243—244 °C. H-NMR (200 MHz, CDCl3) d: 3.54 (2H, t, Jꢃ9.0 Hz, H-1),
4.88 (2H, t, Jꢃ9.0 Hz, H-2), 7.97 (1H, d, Jꢃ9.0 Hz, H-9), 8.45 (1H, dd,
Jꢃ9.0, 2.0 Hz, H-8), 8.97 (1H, d, Jꢃ2.0 Hz, H-6). IR (KBr) cmꢁ1: 1500,
1335 (NO2). FAB-MS m/z: 251 (MHꢄ), 253 (MHꢄꢄ2). Anal. Calcd for
C11H7ClN2O3: C, 52.71; H, 2.82; N, 11.18. Found: C, 52.84; H, 2.91; N,
1) Part 62: Okuda K., Zhang Y.-X., Ohtomo H., Hirota T., Sasaki K.,
1
Chem. Pharm. Bull., 58, 369—374 (2010).
2) For a leading review, see: Snape T. J., Chem. Soc. Rev., 37, 2452—
2458 (2008).
3) For recent reports on Truce–Smiles rearrangement, see: Erickson W.
R., McKennon M. J., Tetrahedron Lett., 41, 4541—4544 (2000).

368
4) For recent reports on Truce–Smiles rearrangement, see: Kimbaris A.,
Cobb J., Tsakonas G., Varvounis G., Tetrahedron, 60, 8807—8815
(2004).
5) For recent reports on Truce–Smiles rearrangement, see: Mitchell L.
H., Barvian N. C., Tetrahedron Lett., 45, 5669—5671 (2004).
6) For recent reports on Truce–Smiles rearrangement, see: Snape T. J.,
Synlett, 2689—2691 (2008).
7) Sasaki K., Rouf A. S. S., Kashino S., Hirota T., J. Chem. Soc., Chem.
Commun., 1767—1768 (1994).
8) Sasaki K., Rouf A. S. S., Kashino S., Hirota T., Heterocycles, 41,
1307—1318 (1995).
9) Sasaki K., Rouf A. S. S., Hirota T., J. Heterocycl. Chem., 33, 49—52
(1996).
10) Hirota T., Matsushita T., Sasaki K., Kashino S., Heterocycles, 41,
2565—2574 (1995).
Vol. 58, No. 3
13) Plesniak K., Zarecki A., Wicha J., Top. Curr. Chem., 275, 163—250
(2007).
14) Bailey A. S., Swallow D. L., J. Chem. Soc., 2477—2482 (1956).
15) Yakushijin K., Yakugaku Zasshi, 100, 313—318 (1980).
16) Ito K., Yakushijin K., Yoshina S., Tanaka A., Yamamoto K., J. Hetero-
cycl. Chem., 15, 301—305 (1978).
17) Harigaya Y., Takamatsu S., Yamaguchi H., Kusano T., Onda M.,
Chem. Pharm. Bull., 28, 2029—2034 (1980).
18) Ring opening of 1,2-dihydrofuro[2,3-b]pyridine derivatives to 3-(2-
chloroethyl)pyridin-2-ones with refluxing 20% hydrochloric acid has
been reported. See: Lipin´ska T., Branowska D., Rykowski A., Chem.
Heterocycl. Compd., 35, 334—342 (1999).
19) Horning D. E., Lacasse G., Muchowski J. M., Can. J. Chem., 49,
246—254 (1971).
20) Nair V., Richardson S. G., Synthesis, 670—672 (1982).
21) Nair V., Richardson S. G., J. Org. Chem., 45, 3969—3974 (1980).
22) Lednicer D., Sun J. H., Eur. Pat. Appl., 234872 (1987).
23) George T., Tahilramani R., J. Org. Chem., 36, 2190—2192 (1971).
11) Sasaki K., Rouf A. S. S., Hirota T., Nakaya N., J. Heterocycl. Chem.,
36, 461—465 (1999).
12) Hirota T., Tomita K., Sasaki K., Okuda K., Yoshida M., Kashino S.,
Heterocycles, 55, 741—752 (2001).