Synthesis of 7-substituted-(2,3-dihydro-1,4-benzodioxin-5-yl)-piperazine

Article abstract of DOI:10.1080/00397910802219148

A simple and versatile method for the synthesis of 7-substituted (2,3-dihydro-1,4-benzodioxin-5-yl)-piperazines starting from easy available class of derivatives has been developed. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802219148

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Synthesis of 7-Substituted-(2,3-
dihydro-1,4-benzodioxin-5-yl)-
piperazine
Fabio Rancati a , Steven M. Bromidge b , Simone
Del Sordo c , Salvatore La Rosa a , Carlo Parini a &
Stefania Gagliardi a
a NiKem Research Baranzate (MI) , Italy
b Psychiatry Center of Excellence for Drug Discovery,
GlaxoSmithKline, Medicinal Research Centre ,
Verona, Italy
c NiKem Research Centre
Published online: 09 Sep 2008.
To cite this article: Fabio Rancati , Steven M. Bromidge , Simone Del Sordo ,
Salvatore La Rosa , Carlo Parini & Stefania Gagliardi (2008) Synthesis of 7-Substituted-
(2,3-dihydro-1,4-benzodioxin-5-yl)-piperazine, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:15,
2507-2520, DOI: 10.1080/00397910802219148
To link to this article: http://dx.doi.org/10.1080/00397910802219148
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Synthetic Communications1, 38: 2507–2520, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802219148
Synthesis of 7-Substituted-(2,3-dihydro-1,
4-benzodioxin-5-yl)-piperazine
Fabio Rancati,1 Steven M. Bromidge,2 Simone Del Sordo,3
Salvatore La Rosa,1 Carlo Parini,1 and Stefania Gagliardi1
1NiKem Research Baranzate (MI), Italy
2Psychiatry Center of Excellence for Drug Discovery, GlaxoSmithKline,
Medicinal Research Centre, Verona, Italy
3NiKem Research Centre
Abstract: A simple and versatile method for the synthesis of 7-substituted
(2,3-dihydro-1,4-benzodioxin-5-yl)-piperazines starting from easy available class
of derivatives has been developed.
Keywords: Baeyer-Villiger, oxidation, piperazine, rearrangements, ring closure
A great number of scientific publications and patents have described the
synthesis of arylpiperazines as part of more complex molecules possessing
biological activity (e.g., binding to serotoninergic receptors or to the
dopamine D2-D4 binding site).[1] Typically, this class of compounds has
been obtained by ring closure of the appropriately substituted
arylamine and bis(2-chloroethyl)amine hydrochloride[2] in presence of a
base. Long reaction time and low yields are the main drawbacks of this
synthetic procedure. In a different approach, arylpiperazines can be
synthesized via palladium-catalyzed aromatic amination between pipera-
zine and bromoarenes, using the methodology developed by Buchwald.[3]
In this article, we describe different and generally applicable syn-
thetic pathways for the preparation of 7-substituted-(2,3-dihydro-1,4-
benzodioxin-5-yl)-piperazines where R is chloro,[1d] bromo, cyano, and
fluoro (Fig. 1) with some interesting findings on their unexpected
chemical behavior.
Received in the U.K. August 3, 2007
Address correspondence to Fabio Rancati, NiKem Research, via Zambeletti,
25, 20021 Baranzate, MI, Italy. E-mail: fabio.rancati@nikemresearch.com
2507

2508
F. Rancati et al.
Figure 1. Target compounds.
Figure 2. Retrosynthetic approach.
Simple retrosynthetic analysis showed that, in our case, the last step
would involve piperazine construction from an amino group in position 5
(Fig. 2), obtained by nitro reduction or acyl azide decomposition.
Diazotation of 5-aminobenzodioxane with halogen exchange
followed by nitro insertion at position 8 were chosen at the beginning.
Scheme 1. Nitration of 2,3-dihydrobenzo[1,4]dioxine-6-carbonitrile.

Synthesis of 1,4-benzodioxin-5-yl-piperazine
2509
Scheme 2. Synthesis of target compound 1.
The first attempt to introduce the fluorine atom via thermal decompo-
sition of the tetrafluoroborate diazonium salt[4] 5a was unsuccessful
(Scheme 1).
On the other hand, the same reaction in the presence of CuCN
and NaCN gave the correct cyano derivative 6. Unfortunately, this
intermediate was not a valid building block for the synthesis of the
desired cyano derivative 21, because nitration using nitric acid in acetic
anhydride confirmed that the nitro group was inserted adjacent to the
cyano residue (7).[5]
Many publications have discussed the synthesis of (2,3-dihydro-7-
chloro-1,4-benzodioxin-5-yl)-piperazine starting from the commercially
available 1,4-benzodioxin-5-carboxylic acid.[1]
To test the effectiveness of the published methods, 1,4-benzodioxin-
5-carboxylic acid was nitrated in position 7, using a standard procedure,
with 30% yield after crystallization: hydrogenation of 8 produced quanti-
tatively the desired amino derivative 9.
The Sandmeyer reaction using hydrochloric acid in the presence of
CuCl produced the desired compound 10b in good yield. The acid was
converted into the corresponding acylazide and then decomposed to give
the 5-amino derivative 17b, which was treated with bis(2-chloroethyl)amine
hydrocloride supported on basic alumina[2b] to build the piperazine ring
Scheme 3. Sandmeyer reaction on intermediate 9.

2510
F. Rancati et al.
Scheme 4. Failed nitration of 4-fluoro-2-methoxyphenol.
(Scheme 2). N-Boc protection allowed an easier workup and purification
of the desired compound 1.
Surprisingly, the Sandmeyer reaction using CuBr (Scheme 3)
produced the desired substituted 1,4-benzodioxin-5-carboxylic acid 10c
with very low yield (less than 10%).
When the Sandmeyer reaction was performed on 9 using NaCN and
CuCN, only the chloro derivative 10 was obtained in very low yield
(Scheme 3). This result was probably determined by the low propensity
of CNꢀ to enter on the aromatic ring after the decomposition of the dia-
zonium salt, allowing the low amount of Clꢀ present (derived from hydro-
chloric acid used during diazonium salt preparation) to react with the
active species.
The work done indicates that the reported route, involving several
steps including a nonregioselective nitration and acyl azide demolition,
cannot be considered a general route for the synthesis of 7-substituted-
(2,3-dihydro-1,4-benzodioxin-5-yl)-piperazines but useful only for the
preparation of 7-chloro derivative.
Focusing attention on the preparation of 7-fluoro derivative 2, our
first approach involved the nitration of 4-fluoro-2-methoxy-phenol: only
the oxidized product 11 (Scheme 4) was obtained, even at low tempera-
ture or using a milder nitration protocol.[6]
An alternative synthetic approach was devised starting from the
commercially available 4-fluorophenol.
Scheme 5. Synthesis of target compound 2.

Synthesis of 1,4-benzodioxin-5-yl-piperazine
2511
Scheme 6. Overall yield of target compounds through Baeyer-Villiger approach.
The crucial reaction step involved Baeyer–Villiger rearrangement of
2-hydroxy-3-nitro-5-fluoroacetophenone 14a.[7] Because the acetylation
of 2-nitro-4-fluorophenol proved to be unsuccessful, it was then decided
to perform acetylation first and Fries rearrangement, leaving the
nitration as the last step (Scheme 5). This sequence turned out to be
the most appropriate for the synthesis of 14a. An accurate setup of both
reaction and workup conditions for the nitration of 2-hydroxy-5-fluoro-
acetophenone 13 was crucial to obtain good overall quantity of the
desired product. The overall yield for the preparation of the fluoro
derivative 2 was good.
The same procedure was also used for the preparation of 2-hydroxy-
5-chloro-3-nitro-acetophenone 14b and 2-hydroxy-5-bromo-3-nitro-
acetophenone 14c. The reactions proceeded smoothly (in a similar
way), and the corresponding products were isolated in good yields
(Scheme 6). Compared with the previously described procedure, the
approach presented in this article, clearly shows some important advan-
tages. First of all, the starting building blocks that are commercially
available contain all the functional groups in the correct positions, and
through a short and atom-conservative synthetic sequence produce the
desired arylpiperazines with good overall yield.
The easy availability of the bromine derivative 17c encouraged us to take
into consideration the palladium-catalyzed cyanation of 4-(2,3-ethylen-
dioxy-5-bromo)-piperazine as a valid methodology to access compound 4
(Scheme 7). NaCN supported on alumina in the presence of Pd Tetrakis
and CuCN in N,N-dimethylformamide (DMF) did not give the desired
compound. Also cyanation of 7-bromo-5-nitro-2,3-dihydro-benzo[1,4]diox-
ine was ineffective in providing the corresponding cyano derivative.
All these unsuccessful attempts forced us to take into consideration
an alternative pathway, involving the conversion of an aldehyde into a

2512
F. Rancati et al.
Scheme 7. Failed cyanation of 7-bromo-2,3-dihydrobenzo[1,4]dioxin-5-amine.
cyano group as described in literature (Scheme 8).[8] The methoxy group
of nitrovanillin was hydrolyzed using BBr3, and subsequent conversion of
aldheyde 19 to product 20 was performed using hydroxylamine and for-
mic acid with low yield. The benzodioxine ring was built by treating 20
with dibromoethane, and then the nitro group was reduced (H2, Pd=C),
affording 7-cyano-2,3-dihydro-benzo[1,4]dioxin-5-ylamine 22. Other
reported methods[9] using NH4 OH and CAN were unsuccessful in
providing the desired derivative 21. From intermediate 22, the synthesis
was completed using the same pathway used for compound 2, involving
Scheme 8. Synthesis of target compound 4.

Synthesis of 1,4-benzodioxin-5-yl-piperazine
2513
piperazine ring reconstruction on basic alumina and N-Boc protection.
The desired compound 4 was obtained with an overall yield of 12%.
In conclusion, we have developed simple and versatile methods for
the synthesis of 7-substituted (2,3-dihydro-1,4-benzodioxin-5-yl)-pipera-
zines starting from commercially available compounds.
GENERAL PROCEDURE
1H NMR were recordered on a Bruker ARX 300 spectrometer at 300MHz
using the solvent peak as internal reference. The solvents are indicated in the
parentheses before the chemical shift value (d relative to TMS). Mass spectra
were performed with an AQA Thermo Finnigan single quadrupole coupled
with Agilent 1100 LC system (positive electrospray ionization (ESI POS);
spray 3.5 KV=source 30V=probe 250 ꢁC) or TSQ 700 Thermo Finnigan Tri-
ple quadrupole (EI: source 180 ꢁC; 70 V; 200 mA). Hydrogenations were per-
formed in a Parr apparatus. All reagents were standard-grade commercial
products. Petroleum ether had a bp of 40–60 ꢁC.
Method A
7-Nitro-2,3-dihydro-benzo[1,4]dioxine-5-carboxylic Acid (8)
A solution of fuming nitric acid (4 ml) in acetic acid (4 ml) was added
dropwise to a suspension of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic
acid (3.9 g, 21.6 mmol) in acetic acid (20 ml) and acetic anhydride (20 ml)
at room temperature. The internal temperature was maintained at less than
65 ꢁC during the addition. The reaction was stirred at room temperature
for 1 h. The solid formed was filtered, washed with water, and dried to give
1.4 g of the title compound (yield ¼ 30%) as a yellow powder.
1H NMR (DMSO-d6 ): d ¼ 13.33 (s br, 1H); 8.09 (d, 1H); 7.85
(d, 1H); 4.46 (m, 2H); 4.38 (m, 2H). MS (ESI POS): 226 [M þ H]þ.
7-Amino-2,3-dihydro-benzo[1,4]dioxine-5-carboxylic Acid
Hydrochloride (9)
7-Nitro-2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid 8 (5.5 g, 24.4) mmol
was dissolved in 0.5M NaOH (50 ml). This solution was hydrogenated over
10% Pd=C (0.9 g) for 16h at 40 psi. The reaction was filtered and acidified
with 20% HCl. The precipitate was filtered and dried under vacuum to yield
5.65 g of the title compound (yield 100%) as a white solid.
1H NMR (DMSO-d6): d ¼ 10.40 (s br, 3H); 7.25 (d, 1H); 7.07 (d,
1H); 4.30 (s br, 4H). MS (ESI POS): 196 [M þ H]þ.

2514
F. Rancati et al.
7-Chloro-2,3-dihydro-benzo[1,4]dioxine-5-carboxylic Acid (10b)
To a solution of 9 (3.4 g, 14.69 mmol) in H2O (15 ml) and concentrated
HCl (4 ml) cooled to–5 ꢁC, a solution of NaNO2 (1.09 g, 15.77 mmol) in
H2O (7 mL) was added dropwise. The brown solution of the diazionium
salt was then added dropwise to a solution of CuCl (1.48 g, 14.69 mmol)
in concentrated HCl (5 ml), maintaining the internal temperature around
10 ꢁC. The mixture was then diluted with H2O (120 ml), and the solution
was stirred for an additional 1 h at room temperature. The mixture was
filtered; the residue washed with water and dried under vacuum to obtain
3.2 g of the title compound as a yellow solid (yield 100%).
1HNMR (CDCl3): d ¼ 7.65 (d, 1H); 7.10 (d, 1H); 4.48 (m, 2H); 4.36
(m, 2H). MS (ESI POS): 215.2 [M þ H]þ.
7-Chloro-2,3-dihydro-benzo[1,4]dioxine-5-amine (17b)
To a solution of 10 (3.2 g, 14.9 mmol) in trifluoroacetic acid (40 ml) and
trifluoroacetic anhydride (15 ml), NaN3 (1.94 g, 29.8 mmol) was added at
0 ꢁC. The reaction was stirred 5 h at room temperature. The organic phase
was removed under vacuum, and the residue was dissolved in EtOAc,
washed with saturated solution of NaHCO3, dried over Na2SO4, filtered,
and concentrated to dryness to obtain 4 g of crude N-(7-chloro-2,3-
dihydro-benzo[1,4]dioxin-5-yl)-2,2,2-trifluoro-acetamide, which was used
in the next step without further purification.
N-(7-Chloro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-2,2,2-trifluoro-acetamide
(4 g) dissolved in MeOH (40 ml) and 2N NaOH (20 ml) was refluxed for 5 h.
The organic solvent was removed under vacuum, and the residue was
dissolved in EtOAc, washed with brine, dried over Na2SO4, filtered, and
concentrated to dryness. The residue was dissolved in 2N HCl and washed
with Et2O. The aqueous phase was basified with 2N NaOH, extracted with
EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated to
dryness to obtain 0.6 g of the title compound as a brown oil (yield 22%),
which was used for the next step without further purification.
1H NMR (CDCl3): d ¼ 6.32 (d, 1H); 6.29 (d, 1H); 4.28–4.21 (m, 4H).
MS (ESI POS): 186 [M þ H]þ.
Method B
1-Nitro-2,3-dihydroxy-5-chlorobenzene (15b)
Concentrated H2SO4 (6.4 ml) was added to a solution of 35% hydrogen per-
oxide (307 mmol), in dioxane (110 ml), and the obtained mixture was heated

Synthesis of 1,4-benzodioxin-5-yl-piperazine
2515
at 40 ꢁC for 1 h. Compound 14b (8 g, 371 mmol) was added in one portion.
Stirring was continued for 15 min before adding H3BO3 (18.9 g, 307mmol)
in one portion. The temperature rose to 80 ꢁC and was maintained for 8 h.
The solvent was removed under vacuum, and the residue was treated with
water (150ml) and filtered. The solid was washed with water and dried under
vacuum. It was then redissolved in diethyl ether, and the insoluble part was
filtered off. The solvent was removed under vacuum to give 5.4 g of the title
compound as an orange powder (yield 77%).
1H NMR (CDCl3): d ¼ 10.52 (s, 1H); 7.65 (d, 1 h); 7.23 (d, 1H); 5.97
(s br, 1H); 3.70 (s, 4H). MS (ESI POS): 190 [M þ H]þ.
5-Nitro7-chloro-2,3-dihydro-benzo[1,4]dioxine (16b)
A mixture of 15b (5.4 g, 28.5 mmol), anhydrous K2CO3 (115.7 mmol),
DMF (50 ml), and 1,2-dibromoethane (13.4 g, 6.15 ml, 71.27 mmol) was
heated to 80 ꢁC for 5 h. After cooling to room temperature, water
(200 ml) was added, and the solution was extracted with ethyl acetate.
The organic layer was washed with brine, dried over Na2SO4, filtered,
and evaporated under vacuum to yield 4.35 g of the title compound as
a light brown powder (yield 71%).
1H NMR (CDCl3): d ¼ 7.49 (d, 1H); 7.10 (d, 1H); 4.42–4.33 (m, 4H).
MS (ESI POS): 216 [M þ H]þ.
7-Chloro-2,3-dihydro-benzo[1,4]dioxin-5-ylamine (17b)
Iron powder (0.85 g, 15.2 mmol) was added to a mixture of 16b (0.8 g,
3.72 mmol) in 96% EtOH (15 ml) and glacial acetic acid (8 ml). The reac-
tion was stirred for 6 h at room temperature. The reaction mixture was
neutralized with a saturated solution of NaHCO3 and then extracted with
ethyl acetate. The organic layer was washed with brine, dried over
Na2SO4, and evaporated to dryness. The residue was treated with 10%
HCl, and the solution was washed with Et2O, basified with 2N NaOH,
extracted with ethyl acetate, dried, and evaporated under vacuum to give
0.35 g of the title compound as a brown oil (yield 51%).
1H NMR (CDCl3): d ¼ 6.32 (d, 1H); 6.29 (d, 1H); 4.28–4.21 (m, 4H).
MS (ESI POS): 186 [M þ H]þ.
1-(7-Chloro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-
tertbutoxycarbonylpiperazine (1)
To a solution of 17b (0.85 g, 4.58 mmol) in AcOEt (30 ml), finely grinded
bis-(2-chloroethyl)-amine hydrochloride (1.8 g, 10 mmol) was added,

2516
F. Rancati et al.
followed by basic alumina (13 g). This suspension was cautiously evapo-
rated on a rotary evaporator, and the obtained dry powder was heated in
a glass oven at 160 ꢁC for 2 h. After cooling, the reaction mixture was
suspended in methanol (50 mL), filtered on a sintered funnel, and exten-
sively washed with methanol. The filtrate was evaporated, and the crude
18b was suspended in THF (40 mL). To this suspension, an excess of
(BOC)2O was added (2 g), followed by NaOH 1 M (30 mL). After vigorous
stirring (15 min), the two phases were separated, the aqueous layer was
washed with AcOEt, and the organic phase was dried and evaporated.
The residue was purified by silica chromatography, eluting with a gradient
of petroleum ether=AcOEt, 9=1!8=2. The corresponding BOC-protected
compound (1.06 g) was obtained as a colorless solid (yield 62%).
1H NMR (CDCl3): d ¼ 6.59 (dd, 1H); 6.49 (dd, 1H); 4.29–4.23 (m, 4H);
3.54 (m, 4H); 2.97(m, 4H); 1.48(s, 9H). MS (ESI POS): 355.2 [Mþ H]þ.
1-Nitro-2,3-dihydroxy-5-fluorobenzene (15a)
The title compound was prepared as described for 15b starting from 14a
(1.1 g, 5.5 mmol) in 89% yield.
1H NMR (CDCl3): d ¼ 10.41 (s, 1H); 7.35 (dd, 1H); 7.03 (dd, 1H);
6.27 (s br, 1H). MS (EI, 70 eV): m=z ¼ 173 [M]þ.
5-Nitro7-fluoro-2,3-dihydro-benzo[1,4]dioxine (16a)
The title compound was prepared as described for 16b starting from 15a
(0.85 g, 4.7 mmol), in 72% yield.
1H NMR (CDCl3): d ¼ 7.24 (dd, 1H); 6.88 (dd, 1H); 4.41–4.34
(m, 4H). MS (ESI POS): 200.2 [M þ H]þ.
7-Fluoro-2,3-dihydro-benzo[1,4]dioxin-5-ylamine (17a)
A solution of 16a (0.6 g, 3 mmol) in MeOH (50 mL) was hydrogenated
over 10% Pd=C (60 mg) at 45 psi for 24 h. The suspension was filtered
and the solvent was evaporated to dryness to yield 0.5 g of the title
compound as a brown oil (yield 100%), which was used for the next step
without furthur purification.
MS (ESI POS): 170.2 [M þ H]þ.
1-(7-Fluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-
terbutoxycarbonylpiperazine (2)
The title compound was prepared as described for 2 starting from 17a
(0.5 g, 2.95 mmol) in 50% yield.

Synthesis of 1,4-benzodioxin-5-yl-piperazine
2517
1H NMR (CDCl3): d ¼ 6.32 (dd, 1H); 6.23 (dd, 1H); 4.31–4.22
(m, 4H); 3.58 (m, 4H); 2.97 (m, 4H); 1.48 (s, 9H). MS (ESI POS):
339.3 [M þ H]þ.
1-Nitro-2,3-dihydroxy-5-bromobenzene (15c)
The title compound was prepared as described for 15b starting from
5-bromo-2-hydroxy-3-nitroacetophenone 14c (5 g, 19.2 mmol) in 71.2%
yield, mp: 102–105 ꢁC.
1H NMR (CDCl3): d ¼ 10.54 (s, 1H); 7.80 (d, 1H); 7.36 (d, 1H); 5.94
(s br, 1H). MS (ESI POS): 233.9 [M þ H]þ.
5-Nitro7-bromo-2,3-dihydro-benzo[1,4]dioxine (16c)
The title compound was prepared as described for 16b starting from 15c
(3.4 g, 13.67 mmol) in 94.6% yield.
1H NMR (CDCl3): d ¼ 7.62 (d, 1H); 7.25 (d, 1H); 4.41–4.33 (m, 4H).
MS (EI, 70 eV): m=z ¼ 259 [M]þ.
7-Bromo-2,3-dihydro-benzo[1,4]dioxin-5-ylamine (17c)
The title compound was prepared as described for 17b starting from
16c (3.2 g, 12.3 mmol) in 42.4% yield, and it was used without further
purification.
MS (ESI POS): 230.1 [M þ H]þ.
1-(7-Bromo-2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-
terbutoxycarbonylpiperazine (3)
The title compound was prepared as described for 2 starting from 17c
(1.2 g, 5.2 mmol) in 65% yield.
1H NMR (CDCl3): d ¼ 6.76 (d, 1H); 6.60 (d, 1H); 4.29 (m, 2H); 4.23
(m, 2H); 3.58 (m, 4H); 2.97 (m, 4H); 1.48 (s, 9H). MS (ESI POS): 399.1
[M þ H]þ.
3,4-Dihydroxy-5-nitrobenzaldehyde (19)
To a solution of nitrovanilline (4.0 g 20.29 mmol) in DCM, BBr3 (12.8 ml,
135.33 mmol) was added at 0 ꢁC over 30 min. The solution was left to heat
at rt and then stirred for 6 h. Water (60 ml) and NH4 Cl (40 ml) were
added, and the pH of the solution was made acid with conc. HCl and

2518
F. Rancati et al.
extracted with AcOEt. The organic phase was separated, filtered on a
Celite1 pad, dried over sodium sulfate, and then concentrated. The crude
19 obtained (4.0 g) was used for the next step without further purification.
1H NMR (DMSO-d6): d 9.69 (s, 1 H), 7.94 (d, 1 H), 7.27 (d, 1 H). MS
(EI, 70 eV): m=z ¼ 183 [M]þ.
3,4-Dihydroxy-5-nitro-benzonitrile (20)
Compound 19 (3.3 g, 18.6 mmol), hydroxylamine hydrochloride (1.8 g,
26 mmol), and formic acid (24 ml) were refluxed for 4 h. The solvent
was removed under vacuum. The residue was dissolved in AcOEt,
washed with water and brine, dried over sodium sulfate, and concen-
trated. The crude 20 obtained (2.9 g) was used for the next step without
further purification.
1H NMR (CDCl3): d 8.00 (d, 1 H), 7.39 (d, 1 H). MS (ESI POS): 181
[M þ H]þ.
8-Nitro-2,3-dihydro-benzo[1,4]dioxine-6-carbonitrile (21)
The title compound was prepared as described for 16b starting from 20
(0.2 g, 1.11 mmol) in 87% yield.
1H NMR (CDCl3): d ¼ 7.79 (d, 1H); 7.34 (d, 1H); 4.50 (m, 2H); 4.40
(m, 2H). MS (ESI POS): 207.1 [M þ H]þ.
8-Amino-2,3-dihydro-benzo[1,4]dioxine-6-carbonitrile (22)
The title compound was prepared as described for 17b starting from 21
(0.2 g, 0.97 mmol) in 58% yield.
1H NMR (CDCl3): d ¼ 6.61 (d, 1H); 6.55 (d, 1H); 4.33 (m, 2H); 4.25
(m, 2H). MS (ESI POS): 177.1 [M þ H]þ.
4-(7-Cyano-2,3-dihydro-benzo[1,4]dioxin-5-yl)-terbutoxycarbonyl
Piperazine (4)
The title compound was prepared as described for 2 starting from 22
(0.1 g, 0.57 mmol) in 51% yield.
1H NMR (CDCl3): d ¼ 6.87 (dd, 1H); 6.72 (dd, 1H); 4.35–4.25
(m, 4H); 3.50 (m, 4H); 2.93 (m, 4H); 1.48 (s, 9H). MS (ESI POS):
346.31 [M þ H]þ.

Synthesis of 1,4-benzodioxin-5-yl-piperazine
REFERENCES
2519
1. Van Steen, B. J.; van Wijngaarden, I.; Ronken, E.; Soudijn, W. Functional
characteristics of a series of N4-substituted 1-(2,3-dihydro-1,4-benzodioxin-
5-yl)piperazines as 5-HT1A receptor ligands structure–activity relationships.
Biorg. Med Chem Lett. 1998, 8, 2457; (b) Van Steen, B. J.; van Wijngaarden,
I.; Tulp, M. T. M.; Soudijn, W. A series of N4-imidoethyl derivatives of 1-(2,3-
dihydro-1,4-benzodioxin-5-yl)piperazine as 5-HT1A receptor ligands:
Synthesis and structure–affinity relationships. J. Med. Chem. 1995, 38, 4303;
(c) Gaster, L. M.; Blaney, F. E.; Davies, S.; Duckworth, D. M.; Ham, P.;
Jenkins, S.; Jennings, A. J.; Joiner, G. F.; King, F. D.; Mulholland, K. R.;
Wyman, P. A.; Hagan, J. J.; Hatcher, J.; Jones, B. J.; Middlemiss, D. N.; Price,
G. W.; Riley, G.; Roberts, C.; Routledge, C.; Selkirk, J.; Slade, P. D. The
selective 5-HT1B receptor inverse agonist 10-methyl-5-[[20-methyl-40-(5-
methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydro-spiro-
[furo[2,3-f]indole-3,40-piperidine] (SB-224289) potently blocks terminal 5-HT
autoreceptor function both in vitro and in vivo. J. Med. Chem. 1998, 41,
1218; (d) Peglion, J.; Goument, B.; Despaux, N.; Charlot, V.; Giraud, H.;
Nisole, C.; Newman-Tancredi, A.; Dekeyne, A.; Bertrand, M.; Genissel, P.;
Millan, M. Improvement in the selectivity and metabolic stability of the sero-
tonin 5-HT1A ligand, S 15535: A series of cis- and trans-2-(arylcycloalkyla-
mine) 1-indanols J. J. Med. Chem. 2002, 45, 165; (e) Reitz, A. B.; Baxter, E.
W.; Codd, E. E.; Davis, C. B.; Jordan, A. D. All orally active benzamide
antipsychotic agents with affinity for dopamine D2, serotonin 5-HT1A, and
adrenergic a1 receptors. J. Med. Chem. 1998, 41, 1997.
´
2. Oru´s, L.; Martınez, J.; Perez, S.; Oficialdegui, A. M.; Del Castillo, J.-C.;
Mourelle, M.; Lasheras, B.; del Rıo, J.; Monge, A. New 3-[4-(3-substituted
´
´
phenyl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propanol derivatives with
dual action at 5-HT1A serotonin receptors and serotonin transporter as a
new class of antidepressants. Pharmazie 2002, 57, 515; (b) Mishani, E.; Dence,
C. S.; McCarthy, T. J.; Welch, M. J. Formation of phenylpiperazines by a
novel alumina supported bis-alkylation. Tetrahedron. Lett., 1996, 37, 319.
3. Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Copper-catalyzed coupling of
alkylamines and aryl iodides: An efficient system even in an air atmosphere.
Org. Lett. 2002, 4, 581; (b) Kerrigan, F.; Martin, C.; Thomas, G. H. Synthesis
of arylpiperazines via palladium-catalysed aromatic amination reactions of
bromoarenes with N-tert-butoxycarbonylpiperazine. Tetrahedron Lett. 1998,
39, 2219.
4. Furlano, D. C.; Kink, K. An improved synthesis of 4-fluoroveratrole. Efficient
route to 6-fluoroveratraldehyde and 6-fluoro-D,L-DOPA. J. Org. Chem. 1986,
51, 4073; (b) Daukshas, V. K.; Martinkus, R. S.; Kuleshyus, V. A. Synthesis of
2,3-dimethoxy-5-fluoro and 4,5-dimethoxy-2-fluoro substituted phenylacetic
and phenylacetoxyhydroxamic acids. J. Org. Chem. USSR (Engl. Trans.)
1984, 20, 465.
´
5. Daukshas, V. K.; Balyavichyus, L. Z.; Udrenaite, E. B.; Purvanetskas, G. V.;
Urba, V. A.; Dembinskene, I. A.; Gineitite, V. L.; Rukshenas, A. Y.;

2520
F. Rancati et al.
Bal’sis, S. Y. Electrophilic substitution of 5- and 6-substituted benzo-1,4-
dioxanes. Chem. Heterocycl. Comp. 1978, 14, 1188; Khimiya Geterotsiklicheskikh
Soedinenii 1978, 11, 1465.
6. Zolfigol, M. A.; Ghaemi, E.; Madrakian, E. Trichloroisocyanuric acid=
NaNO2 as a novel heterogeneous system for the selective mononitration of
phenols under mild conditions. Synlett 2003, 2, 191.
7. Roy, A.; Reddy, K. R.; Mohanta, P. K.; Ila, H.; Junjappa, H. Hydrogen
peroxide=boric acid: An efficient system for oxidation of aromatic aldehydes
and ketones to phenols. Synth. Commun. 1999, 29, 3781.
8. Backstrom, R.; Honkanen, E.; Pippuri, A.; Kairisalo, P.; Pystynen, J.;
Heinola, K.; Nissinen, E.; Linden, I. B.; Mannisto, P. T.; Kaallola, S.; Pohto,
P. Synthesis of some novel potent and selective catechol O-methyltransferase
inhibitors. J. Med. Chem. 1989, 32(4), 841.
9. Bandgar, B. P.; Makone, S. S. Organic reactions in water: Highly rapid CAN
mediated one-pot synthesis of nitriles from aldehydes under mild conditions.
Synlett 2003, 2, 262.