A novel synthesis of spiro[(2,2-dimethyl-[1,3]-dioxane)-5,2′- (2′,3′-dihydroindole)] using SRN1 reaction conditions

Article abstract of DOI:10.1016/j.tetlet.2003.12.092

A concise synthesis of the spiro[(2,2-dimethyl-[1,3]-dioxane)-5,2′- (2′,3′-dihydroindole)] nucleus from substituted benzyl chlorides and 5-(hydroxymethyl)-2,2-dimethyl-5-nitro-1,3-dioxane 5 as starting materials is reported. The nitro intermediates 6 and 7 were prepared under S _RN1 reaction conditions.

Full text of DOI:10.1016/j.tetlet.2003.12.092

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1737–1740
A novel synthesis of spiro[(2,2-dimethyl-[1,3]-dioxane)-5,20-
(20,30-dihydroindole)] using SRN1 reaction conditions
*
ꢀ
I. Sanchez, M. Sobrino and M. D. Pujol
Laboratori de Quꢀımica Farmacꢁeutica, Unitat Associada al CSIC, Facultat de Farmꢁacia,
Universitat de Barcelona, Av. Diagonal 643, 08028 Barcelona, Spain
Received 1 December 2003; accepted 15 December 2003
Abstract—A concise synthesis of the spiro[(2,2-dimethyl-[1,3]-dioxane)-5,20-(20,30-dihydroindole)] nucleus from substituted benzyl
chlorides and 5-(hydroxymethyl)-2,2-dimethyl-5-nitro-1,3-dioxane 5 as starting materials is reported. The nitro intermediates 6 and
7 were prepared under SRN1 reaction conditions.
ꢀ 2003 Elsevier Ltd. All rights reserved.
The indoline (2,3-dihydroindole) framework is included
in a wide range of natural alkaloids and synthetic
compounds. Each of these structural groups has pro-
vided molecules possessing interesting, and clinically
useful, pharmaceutical profiles (Fig. 1).1
reactions used to obtain the objective of our study is
illustrated in Schemes 1 and 2.
Initially we attempted the reaction of 2-nitrobenzyl
chloride 1 with the nitronate anion derived from 5-
(hydroxymethyl)-2,2-dimethyl-5-nitro-1,3-dioxane
5
Due to their biological activity, significant effort has
gone into the development of efficient methods for their
preparation.2 The preparation of 3-spiroindolines B has
been described, but several methods reported for the
synthesis of 3-spiroindolines3 and other substituted
indolines failed with 2-spiroindolines A. This report
describes our preliminary studies on the preparation of
2-spiroindolines using a novel strategy. The sequence of
under SRN1 reaction conditions.4 This reaction has been
studied and extended to the preparation of several het-
erocyclic compounds such as 5-nitroimidazole deriva-
tives,5 imidazo[1,2-a]pyridines6 and 5-nitrothiophenes,7
as well as to the synthesis of chlorambucil analogues.8
Several bases can be used for the formation of the
nitronate anion in situ, e.g. NaOH,4b tetrabutylammo-
nium hydroxide,9 LDA, LiOCH3,5c;8;10 and NaOCH3. A
number of these bases were tried for the reaction of 1
with 5, and the results are shown in Table 1. When an
aqueous solution of 2 M NaOH was used only the
benzyl alcohol 12 was obtained as the major product
(Table 1, entry 2). The utilization of lithium derivatives
gave the expected compound in lower yields (entries 4
and 5).
X
Y
3
3
( )n
X
2
2
N
R
Y
N
( )n
1
1
R
A
B
Treatment of 5-(hydroxymethyl)-2,2-dimethyl-5-nitro-
1,3-dioxane 5 with tetrabutylammonium hydroxide gave
the desired dinitro compound 6 in moderate yield, and
the olefin 10 was also obtained in 8% yield (entry 3). As
shown in Table 1, when freshly prepared sodium
methoxide was used the dinitro compound 6 was
obtained in better yield, and NaOCH3 proved to be the
best out of a large number of bases tested for the for-
mation of the nitronate (entry 1). It appears from these
Figure 1. 2- or 3-Spiroindoline structures. R ¼ CH3, benzyl, acetyl;
X ¼ NH, N-alkyl, N-aryl, CH2; Y ¼ NH, N-alkyl, N-aryl, CH2; n ¼ 0,
1, 2, 3.
Keywords: Spiroindolines; Cyclization; SRN1 reaction conditions; 1,3-
Dioxane; Nitronate anion.
* Corresponding author. Fax: +34-93-4035941; e-mail: mdpujol@
farmacia.far.ub.es
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.092

1738
I. Sꢀanchez et al. / Tetrahedron Letters 45 (2004) 1737–1740
R
R
CH3
CH3
i
R
CH3
CH3
O2N
HO
CH3
CH3
O
+
+
O
O
O
Cl
O
O
O2N
10 R = NO2
11 R = F
6 R = NO2 (83%)
7 R = F (31%)
8 R = Br (8%)
9 R = H (2%)
1 R = NO2
2 R = F
5
+
3 R = Br
4 R = H
R
ii
OH
12 R = NO2
13 R = F
R
CH3
O
CH3
O
NH2
14 R = NH2 (95%)
15 R = F (91%)
Scheme 1. Reagents and conditions: (i) NaOCH3, MeOH, hm, 16 h; (ii) H2/Raney-Ni, MeOH, rt.
24 h. Radical trapping experiments concerning the reac-
tion between 2 and 5 have been carried out using nitr-
oxides, and in this study only products resulting from
radical scavenging or degradation were detected.12
CH3
CH3
NH2
O
CH3
CH3
i
O
O
N
H
O
NH2
14
16
Both the aliphatic and aromatic nitro groups of 6 were
reduced to amines in good yield by catalytic hydroge-
nation using Raney-Ni.13 The reduction of 7 under the
aforementioned conditions afforded the corresponding
amine 15. Cyclization of the diamine 14 was accom-
plished using a mixture of trifluoroacetic anhydride/tri-
fluoroacetic acid 1:1 at reflux in 65% yield. Our prior
experience of intramolecular aromatic fluoride dis-
placement14 suggested a facile method to construct the
indoline system by using the same concept applied to the
fluoroamine 15, and in this way the spiroindoline 16 was
obtained in 62% yield.15
ii
F
CH3
CH3
O
O
NH2
15
Scheme 2. Reagents and conditions: (i) (CF3CO)2O/CF3COOH 1:1,
reflux, 12 h, 65% yield; (ii) DMF/K2CO3, 120–130 ꢁC, 12 h, 62% yield.
Table 1. Results of the SRN1 reaction between 2-nitrobenzyl chloride 1
and 1,3-dioxane 5 using different bases
Entry
Base
Reaction time (h) 6 yield (%)
In summary, we have described an operationally simple
and efficient method for the preparation of 2-spiroind-
olines16 based on the cyclization of amino compounds
obtained as intermediates from 2-nitro or 2-fluorobenzyl
chloride in two steps. Further work is under way
to examine the introduction of other substituents at the
2-position of the indoline system.
1
2
3
4
5
NaOMe
NaOH
Bu4NOH
LDA
12
24
12
24
12
83
––a
60b
21c
5c
LiOMe
a Compound 12 isolated in 82% yield.
b Compound 10 isolated in 8% yield.
c Other by-products formed.
Acknowledgements
results that the choice of base is crucial to achieve the
expected compounds with good yields.
Financial support for this work was provided by the
ꢀ
Ministerio de Ciencia y Tecnologıa (MCYT, BQU 2002-
These conditions11 have been extended to other benzyl
chlorides. 2-Fluorobenzyl chloride afforded the desired
nitro compound 7 in 31% yield, and 2-bromobenzyl
chloride gave 8 in 8% yield, unreacted starting material
being recovered in both cases. Benzyl chloride gave the
expected compound in only 2% yield. It is noteworthy
that the best results were obtained with 2-nitrobenzyl
chloride, from which it may be concluded that an elec-
tron-withdrawing group at the ortho or para position of
the benzyl chloride favored the SRN1 reaction.10a More-
over, it is noteworthy that irradiation of the reaction is
required; reaction under the same conditions but without
irradiation led to recovery of the starting material after
00148), and the Comissionat per a Universitats i
Recerca of the Generalitat de Catalunya, Spain (2001-
SGR-00085). We also thank Lluc Sotelo Prats for his
contribution.
References and notes
1. (a) Ong, H. H.; Profitt, J. A. Patent Application: US 78-
936185 19780823; Chem. Abstr. 1982, 96, 122653; (b) Gao,
Y.-D.; Macneil, D. J.; Yang, L.; Morin, N. R.; Fukami,
T.; Kanatani, A.; Fukurada, T.; Ishii, Y.; Morin, M.

I. Sꢀanchez et al. / Tetrahedron Letters 45 (2004) 1737–1740
1739
Application: WO 0027845 A1 20000518; Chem. Abstr.
2000, 132, 334474.
(20 mL) was added and the residue was extracted with
dichloromethane (3 · 30 mL). The organic layer was
washed with 2 M NaOH solution, dried over Na2SO4,
filtered, and the solvent removed under vacuum. Purifica-
tion of the residue by column chromatography (silica gel,
hexane/ethyl acetate) gave the indoline 16 in 65% yield. (b)
To a stirred solution of 15 (0.3 mmol) in freshly distilled
DMF (2 mL), K2CO3 (0.6 mmol) was added at rt under
argon. The mixture was stirred for 12 h at 130 ꢁC. Then,
water (10 mL) and ether (10 mL) were added, and the
organic extracts were washed with water (3 · 20 mL), dried
(Na2SO4), and concentrated under reduced pressure to
give a residue which was purified by silica gel chromato-
graphy (hexane/ethyl acetate as eluent). The indoline 16
was obtained in 62% yield as a yellow oil.14
2. (a) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger,
A.; Daeniker, H. V.; Schelenker, K. J. Am. Chem. Soc.
1954, 76, 4749–4751; (b) Woodward, R. B.; Cava, M. P.;
Ollis, W. D.; Hunger, A.; Daeniker, H. V.; Schelenker, K.
Tetrahedron 1963, 19, 247–288.
3. (a) Aramaki, S.; Atkinson, G. H. J. Am. Chem. Soc. 1992,
114, 438–444; (b) Meyers, C.; Carreira, E. M. Angew.
Chem., Int. Ed. 2003, 42, 694–696.
4. (a) Kinden, G. B.; Gold, M. H. J. Org. Chem. 1956, 21,
1175–1176; (b) Piotrowska, H.; Urbanski, T.; Kmiotek, I.
Roczmiki Chemii, Ann. Soc. Chim. Polonorum 1973, 47,
409–413; Chem. Abstr. 1973, 79, 66264.
5. (a) Crozet, M. P.; Surzur, J. M.; Vanelle, P.; Ghiglione, C.;
Maldonado, J. Tetrahedron Lett. 1985, 26, 1023–1026; (b)
Vanelle, P.; Crozet, M. P.; Maldonado, J.; Barreau, M.
Eur. J. Med. Chem. 1991, 26, 167–178; (c) Jentzer, O.;
Vanelle, P.; Crozet, M. P.; Maldonado, J.; Barreau, M.
Eur. J. Med. Chem. 1991, 26, 687–697.
6. Vanelle, P.; Madadi, N.; Roubaud, C.; Maldonado, J.;
Crozet, M. P. Tetrahedron 1991, 47, 5173–5184.
7. Vanelle, P.; Ghezali, S.; Maldonado, J.; Crozet, M. P.;
Delmas, F.; Gasquet, M.; Timon-David, P. Eur. J. Med.
Chem. 1994, 29, 41–44.
8. Benakli, K.; Terme, T.; Vanelle, P. Synth. Commun. 2002,
32, 1859–1865.
9. Burt, B. L.; Freemen, D. J.; Gray, P. G.; Norris, R. K.;
Randles, D. Tetrahedron Lett. 1977, 3063–3066.
16. Analytical data of some representative compounds synthe-
sized: 2,2-Dimethyl-5-nitro-5-(nitrobenzyl)-[1,3]-dioxane
(6). Mp 122–124 ꢁC (hexane/ethyl acetate). IR (KBr): m
(cmꢀ1) 1607 (N@O); 1544 (C@C); 1360 (N–O); 1199 (C–
O). 1H NMR (CDCl3, 200 MHz): d (ppm) 1.37 (s, 3H,
CH3); 1.48 (s, 3H, CH3); 3.63 (s, 2H, CH2); 4.05 (d,
J ¼ 13 Hz, 2H, CH2–O); 4.34 (d, J ¼ 13 Hz, 2H, CH2–O);
7.18 (dd, J1 ¼ 8 Hz, J2 ¼ 2 Hz, 1H, H-6); 7.53 (m, 2H, H-4,
H-5); 7.98 (dd, J1 ¼ 8 Hz, J2 ¼ 2 Hz, 1H, H-3). 13C NMR
(CDCl3, 50.3 MHz): d (ppm) 21.2 (CH3, A); 23.8 (CH3, B);
25.3 (CH3, C); 34.9 (CH2); 60.0 (CH2–O, A); 63.4 (CH2–
O, B); 64.1 (CH2–O, C); 88.8 (C, C-2); 99.0 (C, C-5, A);
99.3 (C, C-5, B); 118.8 (CH, C-50); 124.7 (CH, C-30); 127.5
(C, C-10); 128.1 (CH, C-60); 132.5 (CH, C-40); 137.8 (C, C-
20). Anal. Calcd for C13H16N2O6: C, 52.70; H, 5.44; N,
9.46. Found: C, 52.93; H, 5.69; N, 9.17.
10. (a) Kerber, R. C.; Urry, G. W.; Kornblum, N. J. Am.
Chem. Soc. 1965, 87, 4520; (b) Kornblum, N. Angew.
Chem., Int. Ed. 1975, 14, 744–755.
2,2-Dimethyl-5-(2-fluorobenzyl)-5-nitro-[1,3]-dioxane (7).
Yellow oil. IR (KBr): m (cmꢀ1) 1623 (N@O); 1589 (C@C);
11. Preparation of nitro compounds. General procedure. To a
stirred solution of the nitroacetal (200 mg, 1.05 mmol) in
methanol (10 mL) was added sodium methoxide (97.2 mg,
1.8 mmol). The reaction mixture was stirred for 30 min at
room temperature under an inert atmosphere. After
30 min, the corresponding benzyl chloride (1.05 mmol)
was added and the mixture was heated to reflux, and
irradiated with a 100 W lamp for 24 h. The solvent was
removed, water (15 mL) was added, and the residue was
extracted with CH2Cl2 (3 · 15 mL). The combined organic
extracts were washed with H2O (15 mL), dried over
Na2SO4, the solvent removed on a rotary evaporator
and silica gel column chromatography of the residue
(SiO2, 70–230 mesh, hexane/ethyl acetate) gave the prod-
ucts. Solids were purified by column chromatography,
followed by crystallization (hexane/ethyl acetate). The
yields of the pure compounds are indicated in Scheme 1.
12. (a) Busfield, W. K.; Jenkins, I. D.; Thang, S. H.; Rizzardo,
E.; Solomon, D. H.; Thang, S. H. J. Chem. Soc., Perkin
1
1378 (N–O); 1098 (C–O). H NMR (CDCl3, 200 MHz): d
(ppm) 1.40 (s, 6H, CH3); 4.25 (s, 2H, CH2–O); 4.55 (s, 2H,
CH2–O); 5.12 (s, 2H, CH2–Ar); 7.18 (m, 3H, Ar); 7.28 (m,
1H, Ar). 13C NMR (CDCl3, 50.3 MHz): d (ppm) 24.0
(CH3); 58.1 (CH2, CH2–O); 59.6 (CH2, CH2–O); 69.6
(CH2); 100.3 (C, C-2); 115.1 (CH, J ¼ 21 Hz, C-30); 123.8
(CH, J ¼ 3.6 Hz, C-50); 129.7 (CH, J ¼ 8.2 Hz, C-40); 130.4
(CH, J ¼ 4 Hz, C-60); 156.1 (C, C-10); 161.4 (C, J ¼ 254 Hz,
C-20). Anal. Calcd for C13H16FNO4: C, 57.98; H, 5.98; N,
5.20. Found: C, 58.23; H, 6.21; N, 5.72.
5-(2-bromobenzyl)-2,2-dimethyl-5-nitro-[1,3]-dioxane (8).
Red oil. IR (KBr): m (cmꢀ1) 1643 (N@O); 1578 (C@C);
1
1356 (N–O); 1102 (C–O). H NMR (CDCl3, 200 MHz): d
(ppm) 1.40 (s, 6H, CH3); 3.46 (s, 2H, CH2–Ar); 4.26 (s, 2H,
CH2–O); 4.58 (s, 2H, CH2–O); 7.44 (m, 4H, Ar).
5-Benzyl-2,2-dimethyl-5-nitro-[1,3]-dioxane (9). Yellow
oil. IR (KBr): m (cmꢀ1) 1605 (N@O); 1551 (C@C); 1090
(C–O). 1H NMR (CDCl3, 200 MHz): d (ppm) 1.39 (s, 6H,
CH3); 3.39 (s, 2H, CH2); 4.23 (s, 2H, CH2–O); 4.46 (s, 2H,
CH2–O); 4.55 (s, 2H, CH2–O); 5.06 (s, 2H, CH2–O); 7.34
(m, 5H, Ar); Anal. Calcd for C13H17NO4: C, 62.15; H, 6.82;
N, 5.57. Found: C, 61.95; H, 6.53; N, 5.89.
ꢀ
Trans. 1 1991, 1351–1354; (b) Gimenez-Arnau, E.; Hab-
erkorn, L.; Grossi, L.; Lepoittevin, J.-P. Tetrahedron 2002,
58, 5535–5545.
13. Reduction. To a solution of the nitro compound (2 mmol)
in methanol (20 mL) was added Raney-Ni (50% slurry in
water) (3 mmol). The mixture was stirred at room
temperature under H2 until the starting material had been
consumed or no further reaction was evident (according to
TLC analysis). The catalyst was separated by filtration,
the solvent was removed under reduced pressure and the
residue was subjected to column chromatography (silica
gel, hexane/ethyl acetate) to afford the corresponding
amine.
14. Harrak, Y.; Guillaumet, G.; Pujol, M. D. Synlett 2003,
813–816.
15. Cyclization. (a) A stirred solution of 14 (2 mmol) in a
mixture of trifluoroacetic anhydride/trifluoroacetic acid
1:1 (5 mL) was heated with stirring for 12 h. 2 M NaOH
2,2-Dimethyl-5-(2-nitrobenzylidene)[1,3]-dioxane (10).
Colorless oil. IR (KBr): m (cmꢀ1) 1589 (N@O); 1372 (N–
O); 1098 (C–O). 1H NMR (CDCl3, 200 MHz): d (ppm) 1.44
(s, 6H, CH3); 4.49 (m, 2H, CH2); 5.11 (m, 2H, CH2); 7.17 (t,
J1 ¼ 1.5 Hz, 1H, olefin); 7.54 (m, 3H, Ar); 7.93 (m, 1H, H-
3). 13C NMR (CDCl3, 50.3 MHz): d (ppm) 28.9 (CH3); 32.2
(CH3); 60.2 (CH2–O); 67.8 (CH2–O); 98.7 (C, C-2); 120.2
(CH, C-30); 123.4 (C, C-5); 126.2 (CH, C-40); 127.5 (C, C-
10); 128.5 (CH, C-60); 135.5 (CH, C-50); 140.3 (C, C-20).
Anal. Calcd for C13H15NO4: C, 62.64; H, 6.07; N, 5.62.
Found: C, 62.31; H, 6.34; N, 5.89.
5-Amino-5-(2-aminobenzyl)-2,2-dimethyl-[1,3]-dioxane
(14). Yellow oil. IR (KBr): m (cmꢀ1) 3357 (N–H); 1197

1740
I. Sꢀanchez et al. / Tetrahedron Letters 45 (2004) 1737–1740
(C–O). 1H NMR (CDCl3, 200 MHz): d (ppm) 1.45 (s, 3H,
69.2 (CH2, CH2–O); 101.3 (C, C-2); 115.8 (CH,
J ¼ 21 Hz, C-30); 122.9 (CH, J ¼ 4 Hz, C-50); 129.9
(CH, J ¼ 8, C-40); 131.4 (CH, J ¼ 4 Hz, C-60); 155.0 (C,
C-10); 160.9 (C, J ¼ 249 Hz, C-20). Anal. Calcd for
C13H18FNO2: C, 65.25; H, 7.58; N, 5.85. Found: C,
65.55; H, 7.42; N, 5.76.
Spiro[(2,2-Dimethyl-[1,3]-dioxane)-5,20-(20,30-dihydroin-
dole)] (16). Yellow oil. IR (KBr): m (cmꢀ1) 3290 (N–H);
1158 (C–O). 1H NMR (CDCl3, 200 MHz): d (ppm) 1.24 (s,
3H, CH3); 1.25 (s, 3H, CH3); 3.02 (m, 2H, CH2); 3.45 (m,
4H, CH2–O); 5.80 (bs, 1H, NH); 7.24 (m, 3H, H-40, H-50,
H-60); 7.83 (d, J ¼ 8 Hz, 1H, H-7). 13C NMR (CDCl3,
50.3 MHz): d (ppm) 29.7 (CH3); 31.7 (CH3); 61.7 (CH2,
CH2–O); 63.9 (CH2, CH2–O); 69.2 (C); 69.9 (C); 125.1
(CH, C-7); 126.5 (CH, C-6); 128.3 (CH, C-4); 131.2 (C, C-
3a); 136.2 (C, C-7a); 132.3 (CH, C-5). Anal. Calcd for
C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found: C, 71.08;
H, 7.52; N, 6.45.
CH3); 1.46 (s, 3H, CH3); 2.81 (s, 2H, CH2); 3.47 (m, 4H,
NH2); 3.60 (d, J ¼ 12 Hz, 2H, CH2–O); 3.73 (d, J ¼ 12 Hz,
2H, CH2–O); 6.72 (m, 2H, H-30, H-50); 7.04 (m, 2H, H-40,
H-60). 13C NMR (CDCl3, 50.3 MHz): d (ppm) 23.1 (CH3);
23.7 (CH3); 36.0 (CH2); 50.4 (C-5); 68.1 (CH2, 2 ꢁ CH2–O);
98.4 (C, C-2); 116.5 (CH, C-30); 118.4 (CH, C-50); 120.2 (C,
C-10); 128.0 (CH, C-60); 132.0 (CH, C-40); 145.8 (C, C-20).
Anal. Calcd for C13H20N2O2: C, 66.07; H, 8.53; N, 11.85.
Found: C, 66.34; H, 8.86; N, 11.59.
5-Amino-5-(2-fluorobenzyl)-2,2-dimethyl-[1,3]-dioxane
(15). Colorless oil. IR (KBr): m (cmꢀ1) 3386 (N–H); 1122
(C–O). 1H NMR (CDCl3, 200 MHz): d (ppm) 1.40 (s,
3H, CH3); 1.42 (s, 3H, CH3); 2.78 (s, 2H, CH2); 3.20 (bs,
2H, NH2); 3.86 (d, J ¼ 10 Hz, 2H, CH2–O); 3.96 (d,
J ¼ 10 Hz, 2H, CH2–O); 6.88–7.12 (m, 4H, Ar). 13C
NMR (CDCl3, 50.3 MHz): d (ppm) 24.9 (CH3); 34.5
(CH2, CH2–Ar); 56.8 (C, C-5); 68.9 (CH2, 2 ꢁ CH2–O);