Synthesis of medium-sized rings, spiro-annulated oxazacycles and 1- amino-3-siloxy dienes based on regioselective reactions of ambident dianions

Article abstract of DOI:10.1055/s-1999-2537

Ambident dianions react as dinucleophiles with various electrophiles to form six- to nine-membered heterocycles, spirocyclic compounds and 1-amino- 3-siloxy dienes.

Full text of DOI:10.1055/s-1999-2537

LETTER
135
Synthesis of Medium-Sized Rings, Spiro-annulated Oxazacycles and 1-Amino-
3-Siloxy Dienes Based on Regioselective Reactions of Ambident Dianions1
Peter Langer,*,a Manfred Döringb and Dietmar Seyferthc
aInstitut für Organische Chemie der Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany
bInstitut für Anorganische und Analytische Chemie der Universität Jena, August-Bebel-Strasse 2, 07743 Jena, Germany
cDepartment of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Received 1 June 1998
Abstract: Ambident dianions react as dinucleophiles with various
electrophiles to form six- to nine-membered heterocycles, spirocy-
clic compounds and 1-amino-3-siloxy dienes.
Keywords: ambident dianions, medium-sized rings, spiro com-
pounds, l-amino-3-siloxy dienes, regioselectivity
Delocalized dianions are versatile reagents in organic syn-
thesis.2 Attention has been directed mainly at reactions of
such dianions with one equivalent of monofunctional
electrophiles and subsequent aqueous quench of the
monoanion thus formed. Much less interest has been fo-
cused on the synthetic scope of such dianions reacting as
dinucleophiles.3 In the course of our program directed at
cyclization reactions of dianions we have reported recent-
ly the synthesis of five-membered N-heterocycles based
on reactions of amide and nitrile derived dianions.4 Here-
in, we report the reaction of acetone-derived and related
dianions as dinucleophiles with chlorosilanes and carbox-
ylic acid dichlorides to form novel six- to nine-membered
zo[1,2-c][1,3]oxazin-1-one 8 (46%). Reaction of 7 with
heterocycles, spirocyclic compounds or functionalized
benzophenone and subsequent aqueous quench gave the
dienes.
alcohol 9 (85%) which was reacted with diethylmalonyl
chloride to give the eight-membered ring 10. Reaction of
The dianion of 1,1-diphenylacetone 1 was generated5 and
condensed in situ with one equivalent of benzophenone
giving a dianionic intermediate by attack of the CH2 ter-
minus of 1 at the carbonyl group. This condensation pro-
ceeds in high yield as shown by the addition of Me3SiCl
which gave Ph2C=C(OSiMe3)CH2C(OSiMe3)Ph2 2 in
86% yield. Treatment of 1 with benzophenone and subse-
quent reaction with dielectrophiles, in principle, can result
in formation of 1:1 cyclization products (two regioiso-
mers), macrocyclization and polymerization. In fact, reac-
7 with benzophenone and phthaloyl chloride afforded a
2:1 mixture (72%) of the spirocyclic amino orthoester 11
(which could be isolated in 32% yield) and the nine-mem-
bered ring 12, respectively. The structure of 11 was con-
firmed by an X-ray structure analysis.10
According to MM+ calculations, the spiro heterocycles 6
and 11 are more stable than the respective isomeric medi-
um-sized rings and may be formed by reaction of the di-
anions with unsymmetric iso-phthaloyl chloride.
However, initial formation of a medium-sized ring and
subsequent base-mediated rearrangement of the latter to
the spiro compounds is also possible.11
tion
with
diethylmalonyl
chloride
afforded
[1,5]dioxocane-2,4-dione 3, an eight-membered ring, in
62% yield (Scheme 1). Similarly, treatment with oxalyl
chloride and diphenyl dichlorosilane gave [1,4]diox-
epane-2,3-dione 4 (36%) and [1,3,2]dioxasilinane 5
(76%), respectively. Interestingly, addition of phthaloyl
chloride afforded spiro-annulated ([1,3]dioxane-2,1′-
isobenzofuran)-3′-one 6 in excellent yield (89%),6,7 rather
than the isomeric nine-membered ring.
Reaction of dianion 1 with benzonitrile or 2-cyanopyri-
dine and subsequent treatment with two equivalents of tri-
methylchlorosilane afforded the 1-amino-3-siloxy-
substituted dienes 14 (85%) and 15 (74%), respectively
(Scheme 3). Similarly, reaction of the parent acetone di-
anion 13 with benzonitrile and Me3SiCl gave diene 16
(56%). 1-Amino-3-siloxy substituted dienes have, to the
best of our knowledge, not been previously reported and
could be useful electronically favored 4π components in
cycloaddition reactions.
The dianion of 2-methylbenzimidazole 7 (which is an
azaanalogue of 1)8 also was reacted with benzophenone
and subsequently treated with dielectrophiles (Scheme 2).
In the course of the reaction with oxalyl chloride expul-
sion of CO occurred9 to give 3,4-dihydrobenzo[4,5]imida-
Synlett 1999, No. 1, 135–137 ISSN 0936-5214 © Thieme Stuttgart · New York

136
P. Langer et al.
LETTER
Treatment of 17 with benzophenone followed by addition
of CEt2(COCl)2 resulted in a complex reaction mixture
from which 1,3,5-triketooctene 21 could be isolated
(18%) (Scheme 5). Interestingly, 21 contained an eight-
membered ring annulated in positions 3 and 4 to the indole
moiety. As an excess of LDA was used, regeneration of an
enolate anion appears to be possible after condensation of
17 with benzophenone. The carbon center of the enolate
reacts with the dielectrophile and subsequent ring closure
involves attack on carbon C-4 of the indole system as at-
tack on the nitrogen would lead to a highly strained prod-
uct. The exocyclic double bond C=CPh2 is formed by
elimination of water during the aqueous work-up. Biolog-
ically significant 3,4-annulated indoles are found in sever-
al agonists for serotonin receptors such as lysergic acid
diethylamide (LSD).13
The novel dianion of 3-acetylindole 17 was generated by
means of three molar equivalents of n-BuLi or LDA
(Scheme 4). External quench of the resulting red solution
with Me3SiCl gave silyl enol ether 18 (64%) rather than
the isomeric benzofulvene 19 (which should be less stable
for electronic reasons).12 In contrast to dianion 1 (which
reacts with chlorosilanes as a C,O-dinucleophile),4e silyla-
tion of 17 occurs at the oxygen and at the nitrogen atom
which suggests that the negative charges of the enolate
and of the indole system do not correspond. This is also
supported by the fact that, in spite of the oxophilicity of
silicon, silylation of the monoanion of 3-acetylindole gave
N-silylated derivative 20 (78%). Similar to 14-16, indole
18 contains a 1-amino-3-siloxy diene unit.
Scheme 5
The dianion of 2-acetylpyrrole behaved similarly to the
dianion 17. Addition of Me3SiCl gave 2-vinylpyrrole 22
(56%)14 containing a 2-amino-3-siloxy diene unit.
Synlett 1999, No. 1, 135–137 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Regioselective Reactions of Ambident Dianions
137
(7) Procedure for the prepartion of 6. To a THF suspension (50
mL) of potassium hydride (0.5 g, 12.5 mmol) was added a
THF solution (10 mL) of 1,1-diphenylacetone (2.62 g, 12.5
mmol). Evolution of hydrogen was observed. After stirring for
20 min at 20 °C, n-BuLi (17.5 mL, 28 mmol, 1.6 M solution
in hexane) was added by syringe at 0 °C. After stirring for 8
min, a red suspension was formed. A THF solution (30 mL) of
benzophenone (2.3 g, 12.5 mmol) was added within 10 min at
0 °C. The color of the solution became deep blue. After stir-
ring for 2 h at 20 °C a THF solution (20 mL) of phthaloyl chlo-
ride (2.54 g, 12.5 mmol) was added at 0 °C using a metal
cannula. A colorless precipitate formed immediately which
was filtered and washed with water and with ether to give 6
(5.8 g, 89 %) as colorless solid, mp 190 °C. 1H NMR (200
MHz, CDCl3): 3.45, 3.91 (2 x d, J = 16 Hz, 2 x 1 H, CH2), 6.90
-7.90 (m, 24 H, Ph). 13C NMR (50 MHz, CDCl3): 36.95 (CH2),
83.20 (C, OCPh2), 117.29 (spiro atom), 121.66 (Ph2C=),
123.06, 125.23, 126.30, 126.55, 127.22, 127.55, 127.78,
128.18, 128.44, 129.79, 130.52, 131.61, 134.87 (CH, Ph),
138.05, 139.50, 142.00, 143.04, 144.21 (C, Ar, =C-O), 166.21
(CO). IR (KBr, cm-1): 3058 (w), 3052 (w), 2926 (w), 1781 (s,
CO), 1597 (w), 1494 (m), 1449 (m), 1355 (s), 1313 (s), 1281
(s), 1220 (m), 1130 (s), 1108 (s), 1084 (m), 1065 (m). MS (CI,
MeOH): 523 (M+ + 1), 375 (M+ - C8H4O3), 357 (M+ - C8H4O3,
- H2O), 149 (C8H4O3 + H+). Anal. Calcd. for C36H26O4: C,
82.74; H, 5.01. Found: C, 82.42; H, 5.13.
In summary, we have shown that 1,3-dianions react as di-
nucleophiles with chlorosilanes to form amino-siloxy
dienes 14-16, 18 and 22 which should be useful synthetic
building blocks. Cyclization reactions with dielectro-
philes afforded spiro-annulated ring systems which are of
interest in view of possible photochromic properties15 or
medium-sized rings which are of biological interest.13,16
Our current work is directed towards exploring the prepar-
ative scope of the cyclization reactions presented.
Acknowledgement
P. L. thanks Professor A. de Meijere and Professor H. M. R. Hoff-
mann for their support. Financial support from the Fonds der Che-
mischen Industrie e. V. (award of a fellowship to P. L.) is gratefully
acknowledged.
(8) Hay, J. V.; Portlock, D. E.; Wolfe, J. F. J. Org. Chem. 1973,
38, 4379.
(9) In the NEt3-mediated reaction of 1,2-diols with oxalyl chlori-
de decarbonylation has been reported to be stereocontrolled:
Iida, T.; Itaya, T. Tetrahedron 1993, 49, 10511.
References and Notes
(1) Regioselective Reactions of Ambident Dianions, part 6. For
part 5, see reference 4(f).
(2) For a review on carbon-based polylithio compounds, see:
Maercker, A. in Methoden Org. Chem. (Houben-Weyl) 4th ed.,
vol. E19d, 1993, 448. See also: Thompson, C. M.; Green, D.
Tetrahedron 1991, 47, 4223.
(10) Langer, P.; Döring, M.; Görls, H.; Seyferth, D., unpublished
results.
(11) For the rearrangement of a cyclic phthalate to an orthoester in
the presence of base, see: (a) Zupancic, J. J.; Horn, K. A.;
Schuster, G. B. J. Am. Chem. Soc. 1980, 102, 5279.
(b) Greene, F. D. J. Am. Chem. Soc. 1956, 78, 2250.
(12) Pindur, U; Rogge, M. Heterocycles 1995, 41, 2785.
(13) Carr, M. A.; Creviston, P. E.; Hutchison, D. R.; Kennedy, J.
H.; Khau, V. V.; Kress, T. J.; Leanna, M. R.; Marshall, J. D.;
Martinelli, M. J.; Peterson, B. C.; Varie, D. L.; Wepsiec, J. P.
J. Org. Chem. 1997, 62, 8640.
(3) (a) Seebach, D.; Pohmakotr, M. Tetrahedron 1981, 37, 4047.
(b) Vollhardt, J.; Gais, H.-J.; Lukas, L. Angew. Chem., Int. Ed.
Engl. 1985, 24, 608. (c) Maercker, A.; Theis, M. Topics Curr.
Chem. 1987, 138, 1. (d) Maercker, A.; Groos, A. Angew.
Chem. 1996, 108, 216; Angew. Chem., Int. Ed. Engl. 1996, 35,
210. (e) Katritzky, A. R.; Fali, C. N.; Li, J. J. Org. Chem.
1997, 62, 4148.
(4) For recent work from our laboratory on cyclization reactions
of ambident dianions, see: (a) Langer, P; Döring, M; Görls,
H.; Beckert, R., Liebigs Ann./Recueil 1997, 2553. (b) Langer,
P.; Döring, M. Synlett 1998, 396. (c) Langer, P.; Döring, M.
Synlett 1998, 399. (d) Langer, P; Wuckelt, J.; Döring, M;
Beckert, R. Eur. J. Org. Chem. 1998, 1467. (e) Seyferth, D.;
Wang, T.; Langer, P.; Ostrander, R. L.; Rheingold, A. L.
Organometallics 1997, 16, 2413. (f) Langer, P.; Döring, M.
Chem. Comm. 1998, in print.
(14) Ohno, M.; Shimizu, S.; Eguchi, S. Tetrahedron Lett. 1990,
4613.
(15) (a) Malatesta, V.; Millini, R.; Montanari, L. J. Am. Chem. Soc.
1995, 117, 6258. (b) Delbaere, S.; Bochu, C.; Azaroual, N.;
Buntinx, G.; Vermeersch, G. J. Chem. Soc., Perkin Trans. 2
1997, 1499. (c) Fabian, J.; Nakazumi, H.; Matsuoka, M.
Chem. Rev. 1992, 92, 1197. (d) Dorweiler, C.; Holderbaum,
M.; Münzmay, T.; Spang, P.; Dürr, H.; Krüger, C.; Raabe, E.
Chem. Ber. 1988, 121, 843.
(16) Bartra, M.; Urpi, F.; Vilarrasa, J. Methods Related to the Syn-
thesis of Macrolide Antibiotics; in: Lukacs, G.; Ohno, M.
(Eds.), Recent Progress in the Chemical Synthesis of Antibio-
tics, Springer: Berlin, 1993.
(5) Trimitsis, G. B.; Hinkley, J. M.; TenBrink, R.; Faburada, A.
L.; Anderson, M.; Poli, M.; Christian, B.; Gustafson, G.;
Erdman, J.; Rop, D. J. Org. Chem. 1983, 48, 2957.
(6) For spiro-acetals, see: (a) Ley, S. V.; Priepke, H. W. M. An-
gew. Chem. 1994, 33, 2292; Ley, S. V.; Priepke, H. W. M.;
Warriner, S. L. Angew. Chem., Int. Ed. Engl. 1994, 33, 2290.
(b) Ley, S. V.; Downham, R.; Edwards, P. J.; Innes, J. E.;
Woods, M. Contemporary Organic Synthesis 1995, 2, 365 and
literature cited herein. (c) Kirby, A. J.; in: The Anomeric Effect
and Related Stereochemical Effects at Oxygen, Springer: Ber-
lin, 1983.
Synlett 1999, No. 1, 135–137 ISSN 0936-5214 © Thieme Stuttgart · New York