Synthesis of succinimido[3,4-b]indane and 1,2,3,4,5,6-hexahydro-1,5-methano-3-benzazocine-2,4-dione by sequential alkylation and intramolecular arylation of enolates derived from N,N,N'N'-tetramethylbutanediamides and N,N,N'N'-tetramethylpentanediamides

Article abstract of DOI:10.1021/jo982000b

The tricyclic title compounds, 4 and 5, were synthesized by initial alkylation of the lithium monoenolates of N,N,N',N'-tetramethylbutanediamide (6) and N,N,N',N'-tetramethylpentanediamide (19) with 2-iodobenzyl chloride in liquid NH₃ at -60°C to afford 2-(2-iodobenzyl)-N,N,N',N'-tetramethylbutanediamide (9) and 2-(2-iodobenzyl)-N,N,N',N'-tetramethylpentanediamide (20) in yields of 88 and 87%, respectively. Treatment of 9 with KNH₂ in liquid NH₃ resulted in formation and intramolecular arylation of the less-substituted α-enolate to produce trans-1,2-bis(N,N-dimethylcarboxamido)indane (10a) in 60% yield. Selective hydrolysis of 10a with aqueous Na₂O₂ gave trans-1-(N,N-dimethylcarboxamido)indane-2-carboxylic acid (17), which was then converted to bridged succinimide 4 by transformation to trans-1-(N,N-dimethylcarboxamido)indane-2-carboxamide (10c) followed by cyclization of this mixed primary/tertiary amide by means of NaH in refluxing THF. Treatment of 20 with KNH₂ in liquid NH₃ led to intramolecular arylation and accompanying ammonolysis to afford trans-1-(N,N-dimethylcarboxamido)-1,2,3,4-tetrahydronaphthalene-3-carboxamide (21b). Conversion of 21b to 5 was similarly effected by means of NaH. Experiments designed to test the mechanistic aspects of the intramolecular arylations provided evidence for competing aryne and SET pathways.

Full text of DOI:10.1021/jo982000b

J . Org. Chem. 1999, 64, 1543-1553
1543
Syn th esis of Su ccin im id o[3,4-b]in d a n e a n d
1,2,3,4,5,6-Hexa h yd r o-1,5-m eth a n o-3-ben za zocin e-2,4-d ion e by
Sequ en tia l Alk yla tion a n d In tr a m olecu la r Ar yla tion of En ola tes
Der ived fr om N,N,N′N′-Tetr a m eth ylbu ta n ed ia m id es a n d
N,N,N′N′-Tetr a m eth ylp en ta n ed ia m id es
Sushama A. Dandekar, Stacey N. Greenwood, Thomas D. Greenwood, Ste´phane Mabic,
J oseph S. Merola, J ames M. Tanko, and J ames F. Wolfe*
Department of Chemistry and the Harvey W. Peters Research Center for the Study of Parkinson’s Disease
and Disorders of the Central Nervous System, Virginia Polytechnic Institute and State University,
Blacksburg, Virginia 24061-0212
Received October 5, 1998
The tricyclic title compounds, 4 and 5, were synthesized by initial alkylation of the lithium
monoenolates of N,N,N′,N′-tetramethylbutanediamide (6) and N,N,N′,N′-tetramethylpentanedi-
amide (19) with 2-iodobenzyl chloride in liquid NH3 at -60 °C to afford 2-(2-iodobenzyl)-N,N,N′,N′-
tetramethylbutanediamide (9) and 2-(2-iodobenzyl)-N,N,N′,N′-tetramethylpentanediamide (20) in
yields of 88 and 87%, respectively. Treatment of 9 with KNH2 in liquid NH3 resulted in formation
and intramolecular arylation of the less-substituted R-enolate to produce trans-1,2-bis(N,N-
dimethylcarboxamido)indane (10a ) in 60% yield. Selective hydrolysis of 10a with aqueous Na2O2
gave trans-1-(N,N-dimethylcarboxamido)indane-2-carboxylic acid (17), which was then converted
to bridged succinimide 4 by transformation to trans-1-(N,N-dimethylcarboxamido)indane-2-
carboxamide (10c) followed by cyclization of this mixed primary/tertiary amide by means of NaH
in refluxing THF. Treatment of 20 with KNH2 in liquid NH3 led to intramolecular arylation and
accompanying ammonolysis to afford trans-1-(N,N-dimethylcarboxamido)-1,2,3,4-tetrahydronaph-
thalene-3-carboxamide (21b ). Conversion of 21b to 5 was similarly effected by means of NaH.
Experiments designed to test the mechanistic aspects of the intramolecular arylations provided
evidence for competing aryne and SET pathways.
In tr od u ction
We recently reported on the preparation and anticon-
vulsant activity of a series of 2-benzylsuccinimides (1a )1
and 2-benzylglutarimides (1b ),2 which blocked penty-
lenetetrazol-induced seizures in murine models. As part
of a study of structural features which might contribute
to and enhance this activity, we performed molecular
mechanics calculations on 1a (R ) H) and 1b (R ) H).3
These calculations revealed that there are two important
(nearly degenerate) conformations associated with these
molecules, one in which the relatively bulky phenyl and
cyclic imide moieties assumed a nearly face-to-face,
gauche type conformation (Figure 1) and the other where
F igu r e 1.
these groups were anti. The face-to-face orientation of
the phenyl and imidyl groups in the gauche conformation
is reminiscent of π-stacking. It is conceivable that donor-
acceptor interactions might be important in this confor-
mation and thus that the orientation of these groups (i.e,
the conformation) may affect the biological activity of
these compounds. To address this issue, higher level,
semiempirical MO calculations (AM1)4 were performed
and revealed that the gauche conformation was preferred
for both compounds by ca. 1-2 kcal mol-1. These calcula-
* Corresponding author. Phone: (540) 231-8200. Fax: (540) 231-
8890. E-mail: jwolfe@chemserver.chem.vt.edu.
(1) Goehring, R. R.; Greenwood, T. D.; Pisipati, J . S.; Wolfe, J . F. J .
Pharm. Sci. 1991, 80, 790.
(2) Goehring, R. R.; Greenwood, T. D.; Nwokogu, G. C.; Pisipati, J .
S.; Rogers, T. G.; Wolfe, J . F. J . Med. Chem. 1990, 33, 926.
(3) PCModel, v. 4.0, Serena Software, Box 3076, Bloomington, IN
47402. See Gajewski, J . J .; Gilbert, K. W. In Advances in Molecular
Modeling; Liotta, D., Ed.; J AI Press Inc.: Greenwich, CT, 1990; Vol.
2, pp 65-92.
10.1021/jo982000b CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/09/1999

1544 J . Org. Chem., Vol. 64, No. 5, 1999
Dandekar et al.
Sch em e 1
tions also suggested a slight shift distortion in electron
density from the phenyl group into the imidyl, consistent
with the notion that this donor-acceptor interaction
stabilizes the gauche conformation.
If these conformational preferences are important to
anticonvulsant activity, it seemed that establishment of
a bond between the R′ position of the imide ring of 1a ,b
(R ) H) and the ortho-position of their phenyl substitu-
ents might enhance antiseizure efficacy in the resulting
fused compounds, succinimido[3,4-b]indane (4) and
1,2,3,4,5,6-hexahydro-1,5-methano-3-benzazocine-2,4-di-
one (5), respectively (Figure 1). We were further encour-
aged to investigate the synthesis of these conformation-
ally constrained analogues of 1a ,b (R ) H) by an earlier
report that several benzo-fused succinimides of type 2
exhibited anticonvulsant activity,5 and by the fact that
5 had not been reported in the literature, while 4 had
been reported once6 but without complete structure
elucidation or biological test data.
Sch em e 2
Resu lts a n d Discu ssion
Initially we anticipated that 4 and 5 might be conve-
niently accessible by photoinduced intramolecular SRN17
cyclization of the N,C(R′)-dianions of 2-iodobenzylimides
3a -b (eq 1). Although the SRN1 reactivity of N, C(R′)-
dianions of imides had not been investigated, the par-
dehalogenation of 3a . Similar treatment of glutarimide
3b led only to slow production of 2-benzylglutarimide (1b,
R ) H) with no accompanying formation of the desired
tricyclic product 5. Attempts to induce possible aryne cy-
clization of 3a with excess KNH2 in liquid NH3 without
irradiation gave results essentially identical with those
obtained under photostimulation (3:2 mixture of 4:1a (R
) H).
P r ep a r a tion of Su ccin im id o[3,4-b]in d a n e (4). A
report by Snieckus and co-workers,10 describing the
sequential R,R′-dialkylation of the dilithium salt, 7, of
N,N,N′,N′-tetramethylbutanediamide (6) (Scheme 1) ap-
peared promising as a starting point for an alternative
synthesis of 4.
ticipation of carboxamide monoenolates in both inter-8
and intramolecular9 photoassisted radical-chain aromatic
substitution reactions encouraged us to test this ap-
proach.
Irradiation of 3a with near-UV light in the presence
of 3 equiv of KNH2 in liquid NH3 resulted in rapid con-
sumption of starting material to afford an inseparable
3:2 mixture of the desired cyclization product 4 and
2-benzylsuccinimide (1a , R ) H), formed by reductive
The success of this mixed dialkylation reaction is likely
attributable to the greater reactivity of dianion 7 com-
pared with the monoalkylated enolate 8, which allows
introduction of the first alkyl group without significant
dialkylation until the second alkyl halide is added.
Although the Snieckus group did not attempt to obtain
monoalkylated products, it seemed possible that mon-
alkylation might be achieved by treating dianion 7 with
1 equiv of an alkylating agent. Thus, our alternative
synthetic strategy as outlined in Scheme 2 was based on
monoalkylation of dianion 7 with 2-iodobenzyl chloride
to give 9, followed by cyclization, hydrolysis, and imi-
dization. Although Rathke and Long11 have accomplished
the successful generation and monoalkylation of the
lithium dienolate of diethyl succinate, we chose to use
diamide 6, anticipating that it would be less vulnerable
(4) Dewar, M. J . S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J . J . P.
J . Am. Chem. Soc. 1985, 107, 3902.
(5) (a) Campaigne, E.; Roelofs, W.; Weddleton, R. F. J . Med Chem.
1968, 11, 395. (b) Campaigne, E.; Yodice, R. J . Heterocycl. Chem. 1980,
17, 661. (c) Campaigne, E.; Yodice, R. J . Heterocycl. Chem. 1981, 18,
79. (d) Despite good anticonvulsant activity in clinical trials, 2 (X )
carbonyl) caused undesirable psychological side effects see: Angrist,
B. M., Gershon, S., Floyd, A. Curr. Ther. Res. 1968, 10, 237.
(6) Pathak, K. L.; Pathak, K. B. J . Indian Chem. Soc. 1961, 38, 253.
(7) For reviews on SRN1 reactions see: (a) Rossi, R. A.; de Rossi, R.
H. Aromatic Substitution by the SRN1 Mechanism; ACS Monograph
178; American Chemical Society: Washington D. C., 1983. (b) Bowman,
W. R. Chem. Soc. Rev. 1988, 17, 283. (c) Rossi, R. A.; Pierini, A. B.;
Palacios, S. M. In Advances in Free Radical Chemistry; Tanner, D. D.,
Ed.; J AI Press: Greenwich, CT, 1990; Chapter 5, p 193. J . Chem. Educ.
1989, 66, 720. (d) Norris, R. K. In Comprehensive Organic Synthesis;
Trost, B. M., Ed.; Pergammon: New York, 1991; Vol. 4, p 451. (e)
Save´ant, J .-M. Tetrahedron 1994, 50, 10117. (f) Rossi, R. A.; Pierini,
A. B.; Penenory, A. B. In The Chemistry of Functional Groups, Suppl.
D, The Chemistry of Halides, Pseudo-halides and Azides; Patai S.,
Rappoport, Z., Eds.; Wiley: New York, 1995; Chapter 24, p 1395.
(8) (a) Rossi, R. A.; Alonso, R. A. J . Org. Chem. 1980, 45, 1239. (b)
Alonso, R. A.; Rodriguez, C. H.; Rossi, R. A. J . Org. Chem. 1989, 54,
5983. (c) Palacios, S. M.; Asis, S. E.; Rossi, R. A. Bull. Soc. Chim. Fr.
1993, 130, 111. (d) van Leeuwen, M.; McKillop, A. J . Chem. Soc., Perkin
Trans. 1 1993, 2433. (e) Wong, J .-W.; Natalie, K. J ., J r.; Nwokogu, G.
C.; Pisipati, J . S.; Flaherty, P. T.; Greenwood, T. D.; Wolfe, J . F. J .
Org. Chem. 1997, 62, 6152.
(9) (a) Wolfe, J . F.; Sleevi, M. C.; Goehring, R. R. J . Am. Chem. Soc.
1980, 102, 3646. (b) Goehring, R. R.; Sachdeva, Y. P.; Pisipati, J . S.;
Sleevi, M. C.; Wolfe, J . F. J . Am. Chem. Soc. 1985, 107, 435. (c)
Goehring, R. R. Tetrahedron Lett. 1992, 33, 6045.
(10) Mahalanabis, K. K.; Mumtaz, M.; Snieckus, V. Tetrahedron Lett.
1982, 23, 3971.
(11) Long, N. R.; Rathke, M. W. Synth. Commun. 1981, 11, 687.

Synthesis of Succinimido[3,4-b]indane
J . Org. Chem., Vol. 64, No. 5, 1999 1545
than the diester to side reactions during the subsequent
cyclization step, which we planned to effect with an alkali
metal amide in liquid NH3.9b
When dianion 7, generated from diamide 6 as described
previously10 (2.2 equiv of LDA in THF at -78 °C), was
alkylated using 1 equiv of 2-iodobenzyl chloride at 0 °C,
mostly dibenzylated threo product 11 (68%) was obtained
along with lesser amounts of the desired 9 (12%) and
stilbene derivative 12 (8%) (eq 2). By adding a cooled (-78
This regiospecificity implies selective formation of the
less-substituted enolate.
Having established the efficacy of KNH2 as a base for
the generation of the required enolate, diamide 9 was
treated with 3 equiv of KNH2 in liquid NH3 under pho-
tostimulation (eq 4). After 30 min of irradiation, 9 was
completely consumed and the desired trans-cyclized
°C), dilute (6% w/v) THF solution of the halide slowly
(30 min) to the dianion at -78 °C, the yield of 9 was
improved to 34%, but dialkylation product 11 was still
formed in 47% yield. When 6 was treated with 1 equiv of
LDA in THF at -78 °C in an attempt to generate
exclusively the monoenolate, subsequent alkylation af-
forded a mixture of 9 (38%), 11 (10%), and recovered
halide (36%). Apparently, even under these conditions,
proton exchange between the original monoenolate and
newly formed 9 occurs competitively with alkylation of
the original monoenolate. Owing to the chronic problem
of dialkylation, the use of LDA as a base in the prepara-
tion of 9 was abandoned.
We then shifted our attention to finding a more satis-
factory base/solvent system for the alkylation of diamide
6. Since alkali metal amides in liquid NH3 have been used
successfully to generate the requisite enolates in alky-
lation reactions of certain N,N-disubstituted carbox-
amides,12 we decided to investigate the feasibility of
generating and alkylating the monoanion of 6 in this
reaction system using LiNH2 to suppress polyalkylation.13
Thus, treatment of diamide 6 with 1.1 equiv of LiNH2 in
liquid NH3 at -33 °C for 30 min, followed by the addition
of 2-iodobenzyl chloride, afforded a mixture consisting of
the desired 9 (46%), monoalkylated ammonolysis product
1314 (22%) and unreacted 6 (14%) (eq 3). When the
deprotonation-alkylation sequence was carried out at
lower temperature (-60 °C), an 88% yield of 9 was
obtained virtually free of ammonolysis product 13.15
product 10a was isolated in 60% yield by MPLC. Also
obtained were minor amounts of the corresponding cis-
cyclized product 10b (7%), trans-cyclized ammonolysis
product 10c (2%), hydrogenolysis compound 15a (9%) and
N-cyclized compound 16 (9%). Surprisingly, the cycliza-
tion reaction proceeded equally well with 3 equiv of KNH2
in the absence of photostimulation to afford a 70% yield
of indanes 10a ,b along with minor amounts of 10c (3%),
15a (2%), and 16 (13%) after only 5 min. Employment of
as much as 8 equiv of KNH2 had a negligible effect on
the product distribution in either photostimulated or dark
reactions. Attempts to avoid amide ion-derived products
10c and 16 through the use of other bases were unsuc-
cessful. Thus, attempted photocyclization of 9 with 3
equiv of t-BuOK in liquid NH3 failed, presumably due to
the inability of t-BuOK to generate the required enolate.8a
The photostimulated reaction of 9 in the presence of 4
equiv of LDA in THF at -30 °C gave mostly unreacted 9
(72%) and only 10% of 10a after 3 h of irradiation.
The next step in the synthetic sequence leading to
succinimide 4, involved the hydrolysis of 10a . By utilizing
the mild procedure developed by Vaughn and Robbins,19
and through careful choice of reaction conditions (1.1
equiv of Na2O2, 50 °C, 12 h), selective hydrolysis of the
less-hindered carboxamido group of 10a was achieved to
afford a 77% yield of monoacid 1720 along with 5% of
(12) (a) Gassman, P. G.; Fox, B. L. J . Org. Chem. 1966, 31, 982. (b)
Needles, H. L.; Whitfield, R. E. J . Org. Chem. 1966, 31, 989.
(13) Hampton, K. G.; Harris, T. M.; Hauser, C. R. J . Org. Chem.
1965, 30, 61.
With a satisfactory synthesis of 9 in hand, we next
investigated its conversion to indane 10 (eq 4), which we
(14) The regiochemistry for 13 was established from its 1H NMR
spectrum, mass spectral fragmentation pattern, and by X-ray crystal-
lographic structure determination.
anticipated might occur via an intramolecular SRN
1
reaction involving enolate 14, formed by means of KNH2
in liquid NH3. To determine if synthetically useful
concentrations of the required enolate 1416 could be
prepared from 9 in this reaction system, preliminary
methylation studies were carried out using 2-benzylbu-
tanediamide 15a as a model substrate.17 When 15a was
treated with 1.1 equiv of KNH2 in liquid NH3 and the
resulting solution quenched with methyl iodide, a mix-
ture of threo and erythro methylation products 15b18 were
obtained in 76% yield along with 23% of recovered 15a .
(15) In contrast, attempted alkylation of the monoanion of dimethyl
succinate under identical conditions gave only Claisen condensation
products and unreacted starting materials.
(16) The enolate structure is shown in the preferred Z-configuration
based on stability studies of lithium N,N-dialkylcarboxamide enolates
see: Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M. C.;
Sohn, J . E.; Lampe, J . J . Org. Chem. 1980, 45, 1066.
(17) Compound 15a was prepared by alkylation of the enolate of 6
with benzyl chloride in a manner analogous to the preparation of 9.
(18) The threo:erythro ratio of 15b was ca. 12:1 and is very similar
to that reported10 for the dibenzylation of 6.
(19) Vaughn, H. L.; Robbins, M. D. J . Org. Chem. 1975, 40, 1187.

1546 J . Org. Chem., Vol. 64, No. 5, 1999
Dandekar et al.
diacid 18 (eq 5). By comparison, complete hydrolytic
conversion of 10a to diacid 18 (88% isolated yield) was
accomplished by heating an aqueous solution of 10a in
the presence of 3 equiv of Na2O2 at 70-75 °C for 24 h.
compound 23 (12%) were obtained, along with R,â-
unsaturated diamide 22 (31%) and ring amination prod-
uct 24 (3%).23 The trans stereochemical assignment for
21a was based on the results of an NOE experiment.
Irradiation of the tertiary benzylic proton at C-1 produced
enhancements in the intensities of the signals of the
N-methyl protons of the carboxamido group at C-1 (4.4%
and 2.3%), the C-2 methylene protons (6.7%), and the C-8
aryl proton (8.2%); however, the C-3 methine proton was
completely unaffected.
When the cylization of 20 was carried out in the dark
using 4 equiv of KNH2 in liquid NH3, complete consump-
tion of 20 occurred within 5 min to afford 21a (43%), 21b
(14%), 22 (12%), 23 (14%), and 24 (6%). Complete, in situ
conversion of 21a to the key synthetic intermediate,
mixed amide 21b, was accomplished by extending the cy-
clization reaction time from 5 to 45 min, in the dark, after
which 21b was isolated in 53% yield. It is interesting to
note here that similar attempts to produce the penulti-
mate intermediate, 10c, for the synthesis of target succin-
imide 4 by treating indane derivative 10a or its precur-
sor, 9, with excess KNH2 in liquid NH3 for several hours
failed to produce synthetically useful amounts of 10c.
Conversion of 21b to glutarimide 5 proceeded in high
yield (88%) under the same conditions employed for the
preparation of 4 from 10c (eq 9). Thus, the synthesis of
5 was accomplished in just three steps from starting
diamide 19.
The target succinimide 4 was then prepared from 17
in 91% yield, as shown in eq 6. Conversion of 17 to the
mixed primary/tertiary amide 10c21 was achieved by
reaction with ethyl chloroformate at 0 °C and subsequent
treatment of the intermediate mixed anhydride with
gaseous NH3 in situ. Refluxing a solution of 10c with 2.5
equiv of NaH in THF for 1 h then afforded a nearly
quantitative yield of 4. More directly, but less satisfac-
torily, 4 was prepared by the reaction of diacid 18 with
urea in refluxing ethylene glycol.22
P r epar ation of 1,2,3,4,5,6-Hexah ydr o-1,5-m eth an o-
3-ben za zocin e-2,4-d ion e (5). The successful prepara-
tion of succinimide 4 via the synthetic route just de-
scribed prompted us to apply similar methodology to the
synthesis of glutarimide 5. Thus, alkylation of the lithium
monoenolate of N,N,N′,N′-tetramethylpentanediamide
(19), prepared by means of 1.1 equiv of LiNH2 in liquid
NH3 with 2-iodobenzyl chloride, proceeded smoothly to
afford monobenzylation product 20 in 87% yield (eq 7).
Mech a n istic Asp ects of th e Cycliza tion Rea ction s
of 9 a n d 20. We have found evidence for the existence
of competing and occasionally divergent mechanisms in
the cyclization reactions of diamides 9 and 20. These
efficient processes proceed rapidly (2-5 min) in the dark
at -33 °C with 3-4 equiv of KNH2 and are not affected
by up to 40 mol % of the radical scavenger, di-tert-
butylnitroxide (DTBN),24 thereby seeming to implicate
mainly an aryne pathway.25 To test this hypothesis, the
cyclization of 9 was carried out in liquid ND3 using 3
equiv of KND2 (eq 10). Following isolation of deuterated
Treatment of 20 with 3 equiv of KNH2 in liquid NH3 and
irradiation for 30 min led to formation of the product
mixture shown in eq 8. As in the analogous cyclization
of diamide 9 (eq 4), the corresponding trans C-cyclized
(21) This compound was identical in all respects with that obtained
previously in the cyclization reaction of 9.
(22) Kondrat′eva, G. Y.; Huang, C. H. Zh. Priklad. Khim. 1962, 35,
199.
(23) Although the corresponding ring amination product was never
isolated from cyclization reactions of 9, evidence for its presence in
trace amounts was obtained by 1H NMR.
products 21a (39%) and 21b20 (2%) and N-cyclized
(24) (a) Hoffmann, A. K.; Feldman, A. M.; Gelblum, E.; Hodgson,
W. G. J . Am. Chem. Soc. 1964, 86, 639. (b) Nelsen, S. F.; Bartlett, P.
D. J . Am. Chem. Soc. 1966, 88, 143.
(20) The regiochemical and stereochemical assignments were un-
ambiguously confirmed by X-ray crystallographic analysis.

Synthesis of Succinimido[3,4-b]indane
J . Org. Chem., Vol. 64, No. 5, 1999 1547
Sch em e 3
of a radical-chain component in the cyclization milieu.
In an analogous reaction, Semmelhack and Bargar30
reported formation of R,â-unsaturated ketones in photo-
induced SRN1 cyclization reactions of certain haloaryl
ketone enolates. Based on their study, it seems likely that
22 arises through a divergent, chain propagating path-
way within the traditional SRN1 mechanism. Thus,
intermediate radical anion 29, which is analogous to
radical anion 26 formed in step 2 of Scheme 3, undergoes
an intramolecular hydrogen atom transfer from the
â-position of the enolate to the sp2 radical site on the
phenyl ring rather than an intramolecular cyclization
reaction. Oxidation of the resulting radical anion, 30,
possibly by electron transfer to the aryl system of the
enolate derived from 20, would yield 22 and at the same
time effect propagation of the chain (eq 12).
Additional evidence for operation of SET mechanisms
in the cyclization processes was obtained from the
successful cyclization of aryne-blocked diamide substrate,
31, which occurred without the need for photostimulation
to give the products shown in eq 13. Furthermore, this
reaction, which would not be expected to proceed by the
addition-elimination route of the SNAr mechanism, was
strongly inhibited by the addition of 40 mol % of DTBN.
These findings make a compelling argument for a ther-
10a by MPLC, its 1H NMR spectrum indicated the
absence of the H-1 resonance at 5.01δ and integrated
intensities of the H-2 and H-7 resonances at δ 4.18 and
δ 7.01 corresponding to 0.5 and 0.4 deuteruim atom,
respectively. These results strongly support the inter-
mediacy of aryne in the cyclization reaction, but also
allow for the operation of nonaryne processes.9,26 Indeed,
evidence for single electron transfer (SET) pathways may
be found in the cyclization reactions of both 9 and 20.
For example, the presence of reduction product 15a in
the reaction of diamide 9 is indicative of the participation
of a radical-chain SRN1 process27 (Scheme 3). Compound
15a may result when intermediate aryl radical anion 26
reacts by hydrogen atom acquisition or when 26 under-
goes further reduction to the corresponding phenyl anion
followed by protonation.27
An alternative, nonchain SET mechanism initiated by
intramolecular electron transfer may also play a part in
the cyclization process (eq 11). Transfer of an electron
from the carboxamide enolate to the aromatic ring in 14
would be facilitated by their close proximity. Subsequent
fragmentation of the C-I bond would then yield diradical
28, which would undergo ring closure via a radical
coupling reaction. Evidence for similar competing non-
chain radical coupling mechanisms in SRN1 reactions has
been previously observed.28,29
mally initiated electron transfer cyclization and may
imply28 a preponderance of the typical radical-chain SRN
1
mechanism over radical coupling. The different responses
to inhibition by DTBN in the reactions of unblocked 9
and blocked 31 may be accounted for by the fact that in
the presence of inhibitor, cyclization of 9, but not 31, may
divert entirely to a facile aryne pathway. The presence
of R,â-unsaturated diamide 33 and the absence of its
desmethyl analogue in the corresponding reaction of 9
may also be attributable to the difference in mechanistic
The production of R,â-unsaturated diamide 22 from
diamide 20 provides indirect evidence for the presence
(25) Other indications of aryne participation in the cyclization
reactions of 9 and 20 include the formation of ring amination product
24 and N-cyclized compounds 16 and 23.
(26) Scamehorn, R. G.; Bunnett, J . F. J . Org. Chem. 1977, 42, 1449.
(27) Reductive dehalogenation of the substrate is a common side
(28) Galli, C. Tetrahedron 1988, 44, 5205 and references therein.
(29) Ahbala, M.; Hapiot, P.; Houmam, A.; J ouini, M.; Pinson, J .;
Save´ant, J .-M. J . Am. Chem. Soc. 1995, 117, 11488.
(30) (a) Semmelhack, M. F.; Bargar, T. M. J . Org. Chem. 1977, 42,
1481. (b) Semmelhack, M. F.; Bargar, T. M. J . Am. Chem. Soc. 1980,
102, 7765.
reaction which competes with substitution in
SRN1 reactions see:
Santiago, A. N.; Stahl, A. E.; Rodriguez, G. L.; Rossi, R. A. J . Org.
Chem. 1997, 62, 4406.

1548 J . Org. Chem., Vol. 64, No. 5, 1999
Dandekar et al.
options available in these two reactions. The greater in-
volvement of SET pathways in the case of 31 would favor
the formation of 33, since it is likely formed by a SET
process. Furthermore, since 33 and hydrogenolysis prod-
uct 34 were obtained in comparable yields (11% and 16%,
repectively), it seems reasonable to assume that these
compounds may arise via a redox reaction involving eno-
late 36 and intermediate radical-anion 37, as illustrated
in eq 14. Finally, in the absence of aryne possibilities,
the genesis of N-cyclized product 35 may be rationalized
in terms of a SET mechanism for ring amination of 37
with amide ion,31 followed by cyclization involving the
nonenolized N,N-dimethyl carboxamide function.
of Bacon and Lindsay.36 All other reagents were ob-
tained commercially from Aldrich Chemical. 1H NMR and
13C NMR spectra were determined on either a Varian
EM-390 or a Bruker WP 270 spectrophotometer using
CDCl3 as the solvent, unless otherwise indicated. El-
emental analyses were performed by Atlantic Microlab,
Inc., Norcross, GA. Medium-pressure liquid chromatog-
raphy (MPLC) was carried out using Kiesel gel 60 (230-
400 mesh) silica gel. Melting points are uncorrected.
2-(2-Iod oben zyl)su ccin im id e (3a ). This compound
was prepared by a modification of the procedure de-
scribed by Wolfe and Rogers.37 Succinimide (0.50 g, 5
mmol) was added to a slurry of LiNH2 prepared from
lithium wire (0.43 g, 11 mmol) in 250 mL of liquid NH3.
The mixture was stirred while cooling to -60 °C in a dry
ice-CHCl3 bath over a period of 40 min. A solution of
2-iodobenzyl chloride (1.26 g, 5.0 mmol) in 30 mL of ether
was then added dropwise over a period of 15 min. After
stirring for an additional 30 min at -55 °C, standard
workup followed by evaporation of the solvent gave a
viscous oil from which trans-2,2′-diiodostilbene (12) (0.19
g, 18%), mp 127-128.5 °C, lit.38 mp 128-128.5 °C, and
3a (0.79 g, 50%), mp 132-133 °C, were obtained following
1
MPLC with 2% MeOH in CH2Cl2; H NMR: δ 2.55 (dd,
1H, J ) 5.4, 18 Hz), 2.73 (dd, 1H, J ) 8.8, 18 Hz), 2.94
(dd, 1H, J ) 9.5, 14 Hz), 3.33 (m, 1H), 3.44 (dd, 1H, J )
5.0, 14 Hz), 6.96 (t, 1H, J ) 7.6 Hz), 7.21 (d, 1H, J ) 7.6
Hz), 7.32 (t, 1H, J ) 7.5 Hz), 7.86 (d, 1H, J ) 7.9 Hz),
8.63 (bs, 1H); 13C NMR: δ 34.9, 41.0, 41.9, 100.9, 128.8,
129.0, 130.0, 140.0, 140.1, 176.5, 179.1. Anal. Calcd for
C11H10INO2: C, 41.90; H, 3.17; N, 4.44. Found: C, 42.01;
H, 3.26; N, 4.52.
Con clu sion s
In the present study, we have developed efficient routes
to target compounds 4 and 5 based on several new dis-
coveries concerning the chemistry of carboxamide eno-
lates. For example, we have found a high-yield, general
method for clean R-monoalkylation of tertiary amides
derived from dicarboxylic acids which compares very
favorably with similar alkylations of other dicarboxylic
acid derivatives.11,15,32 In addition, such amides have the
potential of being superior to these other derivatives as
synthetic intermediates because they are less susceptible
to side reactions with strongly nucleophilic bases. The
high reactivity of the enolates derived from carboxamides
9, 20, and 31 in intramolecular aromatic nucleophilic
substitutions observed in this study, even in the absence
of photostimulation, bring to such intermediates a previ-
ously unrecognized synthetic utility. In fact, the present
cyclization of 20 to produce 1,2,3,4-tetrahydronaphtha-
lene-1,3-dicarboxylic acid derivatives 21a ,b represents a
rare synthesis of such 1,3-disubstituted tetralins.33
2-(2-Iod oben zyl)glu ta r im id e (3b). Compound 3b
was prepared in 42% yield by a reported procedure,37 mp
1
109-110 °C; H NMR (DMSO-d6): δ 1.69 (m, 2H), 2.08
(m, 1H), 2.19 (m, 1H), 2.61 (m, 1H), 2.73 (m, 1H), 2.92
(m, 1H), 6.97 (t, 1H, J ) 7.0 Hz), 7.27 (m, 2H), 7.81 (d,
1H, J ) 7.8 Hz), 8.42 (br s, 1H); MS: m/z (relative
intensity) (M + 1)+, 330 (100), 204 (70), 176 (18), 130 (45),
112 (25), 85 (15). Anal. Calcd for C12H12INO2: C, 43.77;
H, 3.65; N, 4.25. Found: C, 43.66; H, 3.68; N, 4.32.
At t em p t ed P h ot ocycliza t ion of 3a a n d 3b w it h
KNH2/NH3(l). To a solution of KNH2 prepared from
potassium metal (0.47 g, 12 mmol) in 300 mL of liquid
NH3 was added succinimide 3a (0.95 g, 3 mmol) as a
solid, and the resulting slurry was stirred under irradia-
tion for 1 h. The reaction mixture was poured onto excess
solid NH4Cl in a beaker, combined with a 50 mL ether
rinse of the reaction of flask, and allowed to evaporate
overnight. The yellow solid residue was dissolved in 50
mL of water, made acidic (pH ) 1) by the addition of 2
M HCl, and extracted twice with 100 mL portions of
CH2Cl2. The organic extracts were combined, extracted
once with 50 mL of a saturated NaCl solution, dried, and
concentrated to a light orange oil, 0.47 g. 1H NMR
analysis indicated that the oil mainly consisted of a 4:3
Exp er im en ta l Section
Gen er a l. Photostimulated reactions were carried out
in a 36 mm × 420 mm double-jacketed cylindrical
reaction vessel under N2 using either a Rayonet RPR-
100 or Rayonet RPR-240 photochemical reactor equipped
with lamps emitting maximally at 350 nm. Dark reac-
tions were performed in a 500 mL three-neck round-
bottomed flask wrapped in a black cloth. Commercial
anhydrous NH3(l) (Matheson) and ND3(l) (Cambridge
Isotope Laboratories) were used directly from the tanks.
N,N,N′,N′-Tetramethylbutanediamide (6) and N,N,N′,N′-
tetramethylpentanediamide (19) were obtained via the
reactions of the corresponding diacids with HMPA.34
2-Iodo-3-methylbenzyl bromide was prepared from
2,6-dimethyliodobenzene35 according to the procedure
(31) Kim, J . K.; Bunnett, J . F. J . Am. Chem. Soc. 1970, 92, 7463.
(32) Kofron, W. G.; Wideman, L. G. J . Org. Chem. 1972, 37, 555.
(33) Araneo, S.; Fontana, F.; Minisci, F.; Recupero, F.; Serri, A.
Tetrahedron Lett. 1995, 36, 4307.
(34) Kopecky, J .; Smejkal, J . Chem. Ind. 1966, 36, 1529.
(35) J acobs, T. L.; Reed, R.; Pacovska, E. J . Am. Chem. Soc. 1951,
73, 4505.
(36) Bacon, R. G. R.; Lindsay, W. S. J . Chem. Soc. 1958, 1375.
(37) Wolfe, J . F.; Rogers, T. G. J . Org. Chem. 1970, 35, 3600.
(38) Kelly, T. R.; Li, Q.; Bhushan, V. Tetrahedron Lett. 1990, 31,
161.

Synthesis of Succinimido[3,4-b]indane
J . Org. Chem., Vol. 64, No. 5, 1999 1549
mixture of succinimido[3,4-b]indane (4) and 2-benzylsuc-
cinimide (1a , R ) H), respectively. Attempted separation
of this mixture by TLC using a variety of solvents and
solvent mixtures was unsuccessful. MPLC using 2%
MeOH-CH2Cl2 resulted in the isolation of the pure 4:3
mixture of 4 and (1a , R ) H) respectively, as a pale yellow
semisolid, 0.39 g, which leads to calculated yields of 0.22
g (40%) for 4 and 0.17 g (30%) for 1a (R ) H). The
analogous cyclization reaction of glutarimide 3b (0.99 g,
3 mmol) returned only unreacted 3b (0.79 g, 80%) isolated
as a light brown solid which was insoluble in the aqueous
or CH2Cl2 layers during the usual workup and 2-benzylglu-
tarimide (1b, R ) H) (0.05 g, 8%) from concentration of
the CH2Cl2 layer, mp 136-140 °C, lit.37 mp 142-144 °C.
2-(2-Iod oben zyl)-N,N,N′,N′-tetr a m eth ylbu ta n ed i-
a m id e (9). A. Via Alk yla tion of N,N,N′,N′-Tetr a m eth -
ylbu ta n ed ia m id e (6) Usin g LDA in THF a t -78 °C.
LDA was prepared by the slow addition of n-BuLi (9.8
mL of a 2.25 M solution in hexane, 22 mmol) to a solution
of diisopropylamine (2.22 g, 22 mmol) in 60 mL of dry
THF under N2 at 0 °C. After stirring for 15 min, the pale
yellow solution was cooled to -78 °C in a dry ice-acetone
bath. A solution of 6 (1.72 g, 10 mmol) in 40 mL of THF
was then added, and the resulting yellow solution of the
dianion was stirred for 30 min. 2-Iodobenzyl chloride
(2.53 g, 10 mmol) dissolved in 40 mL of THF and cooled
to -78 °C in a jacketed pressure equalizing funnel with
dry ice-acetone was added dropwise over a period of 30
min. The resulting solution was stirred for an additional
20 min at -78 °C and then slowly warmed to room
temperature. The reaction mixture, now containing
precipitated LiCl, was quenched by the addition of 10 mL
of a saturated solution of NH4Cl. The organic layer was
separated and the aqueous layer extracted with 2 × 50
mL portions of ether. The combined organic layers were
dried (MgSO4) and concentrated to yield a viscous brown
oil, which was chromatographed initially with CH2Cl2 as
the eluent to remove stilbene derivative 12 (0.12 g, 10%)
and then with 2% MeOH in CH2Cl2 to yield first threo-
2,3-bis(2-iodobenzyl-N,N,N′,N′-tetramethylbutanedia-
mide) (11) (1.49 g, 47%), as a colorless solid, mp 150-
152 °C, which was recrystallized from ether/hexane, mp
159-160 °C. Further elution gave 9 (1.32 g, 34%) as a
viscous, pale yellow oil which crystallized when triturated
with ether. Recrystallization from ether in the cold
°C. To a slurry of LiNH2 prepared from lithium wire (0.15
g, 22 mmol) in 300 mL of liquid NH3 at -65 °C was added
rapidly a solution of 6 (3.44 g, 20 mmol) in 30 mL of THF
under N2. The reaction temperature rose to ca. -60 °C
and was maintained at that temperature with a dry ice-
acetone bath as the mixture was stirred for 30 min. A
solution of 2-iodobenzyl chloride (5.05 g, 20 mmol) in 30
mL of THF was then added dropwise over a period of 15
min, and the reaction mixture became clear. The solution
was allowed to warm to -33 °C and then poured slowly
onto solid excess NH4Cl in a beaker. The NH3 was
evaporated, and the remaining THF solution was de-
canted from the solid residue, which was dissolved in 50
mL of water. The aqueous solution was extracted with 2
× 100 mL portions of ether, and the combined organic
solutions were dried (MgSO4) and concentrated on a
rotary evaporator to give 7.25 g of a pale yellow viscous
oil. MPLC using CH2Cl2 as the eluent resulted in the
recovery of 0.35 g (7%) of unreacted halide. The eluent
was then changed to 5% MeOH in CH2Cl2, and 9 (6.82 g,
88%) was eluted as a nearly colorless oil which crystal-
lized on standing, mp 80-82 °C.
When the above reaction was carried out at -33 °C,
an oily brown residue was obtained following concentra-
tion of 2 × 100 mL CH2Cl2 extracts of the reaction mix-
ture. Upon trituration of this oil with ether, a white solid
separated which after recrystallization from CH2Cl2/
hexane gave 1.58 g (22%) of 3-(N,N-dimethylcarboxa-
mido)-4-(2-iodophenyl)butanamide (13) as white crystals,
1
mp 163-164 °C; H NMR: δ 2.35 (dd, 1H, J ) 4.0, 15
Hz), 2.71 (s, 3H), 2.78 (m, 1H), 2.82 (s, 3H), 2.92 (m, 2H),
3.67 (m, 1H), 5.55 (br s, 1H), 6.10 (br s, 1H), 6.92 (t, 1H,
J ) 7.5 Hz), 7.14 (d, 1H, J ) 7.6 Hz), 7.24 (t, 1H, J ) 7.5
Hz), 7.81 (d, 1H, J ) 7.8 Hz); 13C NMR: δ 35.5, 37.1,
37.5, 38.6, 43.6, 100.5, 128.1, 128.4, 130.4, 139.7, 141.3,
174.0, 174.3; MS: m/z (relative intensity) M+ 360 (0.9),
302 (55), 233 (100), 217 (30), 188 (40), 174 (25), 144 (20),
115 (35), 84 (45), 72 (70). Anal. Calcd for C13H17IN2O2:
C, 43.33; H, 4.72; I, 35.28; N, 7.78. Found: C, 43.40; H,
4.78; I, 35.20; N, 7.70. Evaporation of the ethereal
1
solution gave an oil whose H NMR spectrum indicated
it to be a mixture of mostly 9 along with unreacted 6.
Separation by MPLC using 5% MeOH in CH2Cl2 afforded
initially 9 (3.57 g, 46%) followed by 6 as a colorless liquid
which solidified after drying in vacuo, 0.49 g (14%).
2-Be n zyl-N ,N ,N ′,N ′-t e t r a m e t h ylb u t a n e d ia m id e
(15a ). This compound was prepared by a procedure
strictly analogous to that described previously for the
preparation of 9 from 6 using 1.1 equiv of LiNH2 in NH3(l)
at -60 °C. The reaction of LiNH2, prepared from lithium
wire (0.15 g, 22 mmol) in 300 mL of liquid NH3, 6 (3.44
g, 20 mmol), and benzyl chloride (2.53 g, 20 mmol) at
-60 °C gave 5.22 g of a viscous yellow oil which after
MPLC with EtOAc afforded 0.31 g (12%) of unreacted
benzyl chloride followed by 4.36 g (83%) of essentially
pure 15a as a nearly colorless oil. An analytical sample
was prepared by distillation at 130-132 °C/0.04 mm. 1H
NMR: δ 2.29 (dd, 1H, J ) 3.7, 14 Hz), 2.68 (dd, 1H, J )
1
afforded pure 9, mp 82-83 °C. H NMR for 11: δ 2.38
(s, 6H), 2.64 (s, 6H), 3.10 (m, 4H), 3.56 (m, 2H), 6.92 (t,
2H, J ) 7.5 Hz), 7.15 (d, 2H, J ) 7.6 Hz), 7.23 (t, 2H, J
) 7.5 Hz), 7.82 (d, 2H, J ) 7.8 Hz);13 C NMR: δ 35.1,
37.0, 42.2, 44.0, 100.7, 127.9, 128.2, 130.7, 139.1, 141.8,
173.9; MS: m/z (relative intensity) M+, 604 (1.2), 559 (6),
547 (10), 314 (25), 259 (85), 214 (20), 128 (20), 115 (25),
91 (20), 72 (100). Anal. Calcd for C22H26I2N2O2: C, 41.51;
1
H, 4.09; N, 4.40. Found: C, 41.55; H, 4.17; N, 4.46. H
NMR for 9: δ 2.32 (dd,1H, J ) 3.2, 16 Hz), 2.76 (s, 3H),
2.88 (s, 3H), 2.92 (s, 3H), 2.93 (m, 2H), 3.06 (s, 3H), 3.10
(dd, 1H, J ) 11, 16 Hz), 3.65 (m, 1H), 6.90 (t, 1H, J )
7.5 Hz), 7.15 (d, 1H, J ) 7.6 Hz), 7.22 (t, 1H, J ) 7.5
Hz), 7.80 (d, 1H, 7.6 Hz); 13C NMR: δ 35.1, 35.5, 36.9,
37.0, 37.1, 37.2, 43.5, 100.5, 128.0, 128.5, 130.5, 139.5,
141.5, 171.0, 174.3; MS: m/z (relative intensity) M+, 388
(3), 344 (20), 316 (35), 302 (40), 272 (15), 261 (100), 217
(30), 188 (40), 174 (20), 144 (18), 115 (33), 84 (48), 72
(70). Anal. Calcd for C15H21IN2O2: C, 46.39; H, 5.41: I,
32.73; N, 7.22. Found: C, 46.49; H, 5.47; I, 32.65; N, 7.19.
B. Via Alk yla tion of 6 Usin g LiNH2 in NH3(l) a t -60
7.1, 14 Hz), 2.78 (s, 3H), 2.85 (s, 3H), 2.87 (s, 3H), 2.98
13
(s, 3H), 2.98 (m, 2H), 3.51 (m, 1H), 7.22 (m, 5H);
C
NMR: δ 35.6, 35.7, 36.2, 36.6, 36.9, 38.7, 40.1, 124.3,
127.1, 127.9, 128.8, 129.6, 141.3, 172.8, 173.8; MS: m/z
(relative intensity) M+, 262 (25), 218 (22), 190 (15), 176
(83), 145 (28), 131 (19), 117 (14), 91 (22), 72 (100). Anal.
Calcd for C15H22N2O2: C, 68.70; H, 8.40; N, 10.69.
Found: C, 68.73; H, 8.45; N, 10.76.

1550 J . Org. Chem., Vol. 64, No. 5, 1999
Dandekar et al.
2-Ben zyl-3-m eth yl-N,N,N′,N′-tetr a m eth ylbu ta n e-
d ia m id e (15b). A solution of 15a (1.31 g, 5.0 mmol) in
15 mL of THF was added rapidly via syringe to a KNH2
solution prepared from potassium (0.22 g, 5.5 mmol) in
150 mL of liquid NH3. After stirring for 15 min, a solution
of CH3I (0.78 g, 5.5 mmol) in 15 mL of THF was added,
and the resulting solution was stirred for 15 min. The
reaction mixture was then poured onto excess NH4Cl in
a beaker, and the NH3 and THF were evaporated on a
steam bath. The solid residue was partitioned between
water (20 mL) and ether (100 mL), and the ethereal layer
was separated, dried over MgSO4, and concentrated to a
yellow oil. TLC analysis using ether as the eluent
indicated the oil to be a mixture of mainly one product
along with some unreacted 15a . Column chromatography
with ether gave 0.97 g (70%) of the threo isomer of 15b
as a pale yellow oil which solidified on standing, mp 70-
72 °C. Recrystallization from ether-hexane gave pure
15b as colorless crystals, mp 73-74 °C. Further elution
with EtOAc afforded 0.38 g of a yellow oil which was a
4:1 mixture of 15a :erythro isomer of 15b by 1H NMR
analysis. The calculated yield of 15a was 0.30 g (23%)
and for the erythro isomer of 15b, 0.08 g (6%). Upon
rechromatography with ether, a pure sample of the
(N,N-dimethylcarboxamido)indane (10b), mp 145-148
°C. Analytically pure samples of 10c and 10b were
prepared by recrystallization from EtOAc and ether-
EtOAc, respectively; 10c was obtained as fine colorless
needles, mp 166-167 °C, and 10b as pale yellow plates,
1
mp 149-150 °C. H NMR for 10a : δ 2.98 (s, 3H), 3.05
(dd, 1H, J ) 8.2, 14 Hz), 3.07 (s, 3H), 3.16 (s, 3H), 3.28
(dd, 1H, J ) 10,14 Hz), 3.31 (s, 3H), 4.18 (ddd, 1H, J )
8.2, 9.2, 10 Hz), 5.01 (d, 1H, J ) 9.2 Hz), 7.01 (m, 1H),
7.18 (m, 3H); 13C NMR: δ 35.6, 35.7, 35.8, 37.2, 37.6, 46.6,
50.4, 122.8, 124.3, 126.8, 127.3, 141.2, 141.4, 172.7, 173.4;
MS: m/z (relative intensity) M+, 260 (5), 215 (85), 188
(20), 143 (13), 115 (33), 72 (100). Anal. Calcd for
C15H20N2O2: C, 69.20; H, 7.74; N, 10.76. Found: C, 69.26;
1
H, 7.74; N, 10.71. H NMR for 10b: δ 2.92 (s, 3H), 2.96
(s, 3H), 3.08 (s, 3H), 3.10 (dd, 1H, J ) 8, 15 Hz), 3.13 (s,
3H), 3.73 (m, 1H), 3.88 (dd, 1H, J ) 10, 15 Hz), 4.63 (d,
1H, J ) 8.4 Hz), 7.22 (m, 4H); 13C NMR: δ 35.9, 36.2,
36.9, 37.6, 37.9, 47.5, 50.7, 123.7, 124.8, 126.6, 127.5,
141.3, 143.5, 171.8, 172.6; MS: m/z (relative intensity)
M+, 260 (3), 215 (28), 188 (6), 143 (4), 115 (31), 72 (100).
Anal. Calcd for C15H20N2O2: C, 69.20; H, 7.74; N, 10.76.
1
Found: C, 69.07; H, 7.70; N, 10.66. H NMR for 10c: δ
3.10 (s, 3H), 3.13 (dd, 1H, J ) 8.5, 14 Hz), 3.27 (s, 3H),
3.31 (dd, 1H, J ) 10, 14 Hz), 3.85 (ddd, 1H, J ) 8.5, 10,
10 Hz), 4.59 (d, 1H, J ) 10 Hz), 5.48 (br s, 1H), 6.20 (br
s, 1H), 7.00 (m, 1H), 7.19 (m, 3H); 13C NMR: δ 35.2, 36.1,
37.7, 49.4, 51.0, 122.9, 124.7, 126.7, 127.5, 140.4, 142.1,
172.4, 175.7; MS: m/z (relative intensity) M+, 232 (23),
215 (20), 188 (49), 160 (29), 115 (92), 91 (21), 72 (100).
Anal. Calcd for C13H16N2O2: C, 67.22; H, 6.94; N, 12.06.
1
erythro isomer as a colorless oil was obtained for H NMR
1
characterization. H NMR for threo-15b: δ 1.03 (d, 3H,
J ) 6.7 Hz), 2.45 (s, 3H), 2.73 (d, 2H, J ) 7.3 Hz), 2.79
(s, 3H), 3.02 (s, 3H), 3.13 (s, 3H), 3.21 (m, 1H), 3.39 (m,
1H), 7.18 (m, 5H). Anal. Calcd for C16H24N2O2: C, 69.53;
H, 8.75; N, 10.14. Found: C, 69.43; H, 8.78; N, 10.10. 1H
NMR for erythro-15b: δ 1.26 (d, 3H, J ) 6.5 Hz), 2.40
(s, 3H), 2.68 (s, 3H), 2.83 (d, 2H, J ) 7.2 Hz), 2.99 (s,
3H), 3.10 (s, 3H), 3.20 (m, 2H), 7.17 (m, 5H).
1
Found: C, 66.98; H, 6.92; N, 11.93. H NMR for 16: δ
2.40 (dd, 1H, J ) 8,16 Hz), 2.86 (m, 1H), 2.98 (s, 3H),
3.05 (s, 3H), 3.15 (m, 3H), 6.73 (d, 1H, J ) 7.8 Hz), 6.95
(t, 1H, J ) 7.5 Hz), 7.17 (m, 2H), 7.95 (br s, 1H); 13C
NMR: δ 31.4, 33.1, 35.6, 36.8, 37.2, 115.1, 122.9, 123.7,
127.3, 128.1, 137.1, 170.9, 173.4; MS: m/z (relative
intensity) M+, 232 (7), 188 (5), 158 (8) 146 (100), 130 (18),
87 (53), 72 (22). Anal. Calcd for C13H16N2O2: C, 67.22;
H, 6.94; N, 12.06. Found: C, 67.13; H, 6.97; N, 12.10.
Hyd r olysis of 10a w ith Aqu eou s Na 2O2. A. tr a n s-
1-(N,N-Dim et h ylca r b oxa m id o)in d a n e-2-ca r b oxyl-
ic a cid (17). Solid sodium peroxide (0.88 g of 93%, 10.5
mmol) was added portionwise to a solution of 10a (2.48
g, 9.52 mmol) in 35 mL of water with stirring. After the
peroxide had dissolved, the solution was heated in a
water bath at 50 °C for 12 h and then cooled and
extracted twice with 20 mL portions of ether by vigorous
stirring to remove unreacted 10a , 0.20 g (8%). The
aqueous solution was then cooled in an ice bath and
acidified to pH ) 1 with 2 M HCl causing a yellow gummy
solid to precipitate. Addition of 40 mL of CH2Cl2 resulted
in the dissolution of the gum, leaving a solid which was
insoluble in either layer. The solid was collected by
filtration and determined to be trans-indane-1,2-dicar-
boxylic acid (18),39 0.10 g (5%), mp 222-226 °C. The
organic and aqueous layers were separated, and the
organic layer was combined with 2 × 50 mL CH2Cl2
extractions of the aqueous layer. The combined organic
extracts were dried (MgSO4), and the CH2Cl2 was re-
moved at the rotary evaporator to give 1.71 g (77%) of
17 as a white solid, mp 198-202 °C. Recrystallization
from CH2Cl2-ether afforded tiny, colorless crystals of 17,
P h otoin d u ced Cycliza tion of 9. A solution of KNH2
was prepared from potassium metal (2.05 g, 52.5 mmol)
in 250 mL of liquid NH3. This solution was irradiated as
a solution of 9 (6.80 g, 17.5 mmol) in 50 mL of THF was
added via syringe, and irradiation was continued for a
period of 30 min. The dark red reaction mixture was then
quenched by pouring onto excess solid NH4Cl in a beaker,
and the NH3 and THF were evaporated on a steam bath.
The resulting solid-gummy mixture was partitioned
between CH2Cl2 (100 mL) and water (50 mL) and
transferred to a separatory funnel. The organic layer was
separated and the aqueous layer extracted with 2 × 100
mL portions of CH2Cl2. The combined organic layers were
dried (MgSO4) and concentrated to give 4.49 g of a dark
orange viscous oil which was subjected to flash chro-
matographic separation. A mixture of trans-1,2-bis(N,N-
dimethylcarboxamido)indane (10a ) and 3-(N,N-dimeth-
ylacetamido)-3,4-dihydro-2(1H)-quinolone (16) was eluted
first with 1:1 CH2Cl2-EtOAc as a pale yellow oil. Tritu-
ration with ether caused 16 to crystallize as a nearly
colorless solid, 0.37 g (9%), mp 172-73 °C, which after
recrystallization from EtOAc afforded colorless crystals,
mp 173-174 °C. Evaporation of the ether gave 2.73 g
1
(60%) of essentially pure 10a , by H NMR, which solidi-
fied on cooling. Recrystallization from ether-hexane gave
colorless crystals of 10a , mp 96-97 °C. The eluent was
changed to EtOAc, and 15a , contaminated with a small
amount of trans-1-(N,N-dimethylcarboxamido)indane-2-
carboxamide (10c), was eluted next. Kugelrohr distilla-
tion of this pale yellow oil at 140 °C/0.1 mm afforded 0.40
g (9%) of pure 15a as a colorless oil. Further gradient
elution with 5-10% MeOH-EtOAc gave 0.08 g (2%) of
10c as a tan solid followed by 0.32 g (7%) of cis-1,2-bis-
1
mp 201-202 °C; H NMR: δ 3.11 (s, 3H), 3.20 (dd, 1H,
(39) Cook, J . W.; Preston, R. W. G. J . Chem. Soc. 1944, 553.

Synthesis of Succinimido[3,4-b]indane
J . Org. Chem., Vol. 64, No. 5, 1999 1551
J ) 9.2, 16 Hz), 3.31 (s, 3H), 3.41 (dd, 1H, J ) 9.0, 16
Hz), 4.01 (ddd, 1H, J ) 8.8, 9.0, 9.2 Hz), 4.70 (d, 1H, J )
8.8 Hz), 7.04 (d, 1H, J ) 6.7 Hz), 7.20 (m, 3H); 13C NMR:
δ 35.6, 35.8, 36.2, 46.8, 50.7, 124.9, 125.1, 126.7, 127.4,
140.6, 141.5, 173.6, 174.1; MS: m/z (relative intensity)
M+, 233 (12), 188 (9), 161 (2), 115 (30), 72 (100). Anal.
Calcd for C13H15NO3: C, 66.95; H, 6.44; N, 6.01. Found:
C, 66.87; H, 6.39; N, 5.92.
1H), 4.36 (d, 1H, J ) 7.9 Hz), 7.28 (m, 3H), 7.55 (d, 1H,
J ) 6.2 Hz), 7.99 (br s, 1H); 13C NMR: δ 34.4, 45.0, 53.0,
125.1, 127.6, 128.8, 130.2, 136.9, 141.1, 177.5, 180.2;
MS: m/z (relative intensity) M+, 187 (45), 116 (100), 115
(35), 84 (25), 63 (10), 58 (12). Anal. Calcd for C11H9NO2:
C, 70.58; H, 4.81; N, 7.49. Found: C, 70.63; H, 4.89; N,
7.53. B. F r om 18. Urea (0.18 g, 3.0 mmol) and diacid 18
(0.20 g, 0.97 mmol) were weighed in a 25 mL round-
bottomed flask followed by the addition of 5 mL of
ethylene glycol. The mixture was stirred and heated at
190-195 °C in an oil bath for 30 min and cooled, and
the ethylene glycol was Kugelrohr distilled at 90 °C/0.10
mm. The brown residue was chromatographed with
ether, and the first fraction off the column was collected
and concentrated to a pale yellow oil which solidified on
standing to give 0.09 g (50%) of 4, mp 138-140 °C.
2-(2-Iod oben zyl)-N,N,N′,N′-tetr a m eth ylp en ta n ed i-
a m id e (20). This compound was prepared in the same
manner as that described previously for the alkylation
of 6 using 1.1 equiv of LiNH2 in liquid NH3 at -60 °C.
Thus, reaction of 19 (7.45 g, 40.0 mmol) with 2-iodobenzyl
chloride (10.10 g, 40.0 mmol) gave 15.7 g of a viscous,
orange oil, which after removal of unreacted halide (0.84
g, 8%) by MPLC with 1:1 hexanes-EtOAc afforded, upon
subsequent elution with 10% MeOH-EtOAc, 14.05 g
(87%) of 20 as a nearly colorless, viscous oil; 1H NMR: δ
1.85 (m, 1H), 2.04 (m, 1H), 2.21 (m, 1H), 2.45 (m, 1H),
2.62 (s, 3H), 2.80 (s, 3H), 2.91 (s, 3H), 2.93 (m, 2H), 2.98
(s, 3H), 3.28 (m, 1H), 6.87 (m, 1H), 7.19 (m, 2H), 7.78
(dd, 1H, J ) 1.0, 7.8 Hz); 13C NMR: δ 27.7, 30.6, 35.5,
37.0, 37.2, 40.0, 43.5, 100.9, 128.0. 128.1, 130.5, 139.5,
142.0, 172.5, 174.6; MS: m/z (relative intensity) M+, 402
(7), 358 (8), 329 (20), 316 (18), 302 (32), 275 (40), 230
(15), 217 (15), 188 (22), 176 (20), 149 (15), 140 (22), 131
(10), 116 (15), 100 (12), 84 (100), 72 (90), 55 (20). Anal.
Calcd for C16H23IN2O2: C, 47.76; H, 5.72; N, 6.96.
Found: C, 47.83; H, 5.77; N, 6.90.
P h otoin d u ced Cycliza tion of 20. To an irradiated
solution of KNH2 prepared from potassium (1.17 g, 30
mmol) in 250 mL of liquid NH3 was added a solution of
20 (4.02 g, 10 mmol) in 40 mL of THF via syringe.
Irradiation was continued for 30 min, and the resulting
orange solution was poured onto excess solid NH4Cl in a
beaker. A 100 mL ether rinse of the reaction vessel was
added to the reaction solution, and the NH3 was evapo-
rated on a steam bath. The resulting ethereal solution
was decanted from the solid residue which was then
dissolved in 50 mL of water and extracted with 2 × 100
mL portions of CH2Cl2. The combined organic solutions
were extracted with 25 mL of 2 M NaHSO3 to remove I2
and 50 mL of water, dried (MgSO4), and concentrated to
a pale yellow oil, 2.78 g, which was subjected to flash
chromatography. The first and major fraction, eluted with
1:1 ether-EtOAc, was obtained as a pale yellow oil (1.70
g) and was identified by 1H NMR as a 1:1 molar mixture
of trans-1,3-bis(N,N-dimethylcarboxamido)-1,2,3,4-tet-
rahydronaphthalene (21a ) and 1,3-bis(N,N-dimethylcar-
boxamido)-4-phenyl-2-butene (22), respectively. A second
fraction was eluted next with EtOAc as a nearly colorless
oil (0.52 g), which when triturated with ether gave 0.29
g (12%) of 3-(N,N-dimethyl-â-propanamido)-3,4-dihydro-
2(1H)-quinolone (23) as a white solid, mp 143-144 °C
after recrystallization from EtOAc. Concentration of the
ether solution gave 0.22 g of nearly pure 21a . Further
elution with 5% MeOH-EtOAc afforded trans-1-(N,N-
dimethylcarboxamido)-1,2,3,4-tetrahydronaphthalene-3-
B. tr a n s-In d a n e-1,2-d ica r boxylic Acid (18). A solu-
tion containing 10a (0.32 g, 1.23 mmol) and sodium
peroxide (0.31 g of 93%, 3.69 mmol) in 10 mL of water
was heated at 70-75 °C for 24 h, cooled to room
temperature, and poured onto 10 mL of ice-cold 2 M HCL
with stirring. The precipitated white solid was filtered,
washed twice with 20 mL portions of ice-water, and air-
dried to yield 0.22 g (88%) of pure trans diacid 18, mp
1
227-228 °C, lit.39 mp 228 °C; H NMR (acetone-d6): δ
3.20 (dd, 1H, J ) 8.2, 16 Hz), 3.39 (dd, 1H, J ) 9.3, 16
Hz), 3.78 (ddd, 1H, J ) 8.2, 9.3, 16 Hz), 4.23 (d, 1H, J )
7.8 Hz), 7.25 (m, 3H), 7.47 (m, 1H); 13C NMR: δ 35.9,
46.9, 53.7, 125.0, 125.1, 127.7, 128.4, 140.2, 142.5, 173.6,
175.1; MS: m/z (relative intensity) M+, 206 (1), 188 (16),
160 (50), 133 (10), 116 (100), 91 (14), 77 (12), 63 (15).
P r ep a r a tion of 10c fr om 17. To a solution of ethyl
chloroformate (0.69 g, 6.39 mmol) in 20 mL of CH2Cl2
cooled to 0 °C in an ice bath was added dropwise a solu-
tion of 17 (1.49 g, 6.39 mmol) and triethylamine (0.71 g,
7.03 mmol) in 100 mL of CH2Cl2. Triethylamine hydro-
chloride precipitated immediately, and the mixture was
stirred at 0 °C for 1 h. Anhydrous NH3 was then bubbled
through the reaction mixture for 15 min. The cooling bath
was removed, and 2 M HCl was added with vigorous
stirring until pH ) 1 was reached. The CH2Cl2 layer was
separated and combined with a 50 mL of CH2Cl2 extract
of the aqueous layer. The combined CH2Cl2 solutions
were dried (MgSO4), and the CH2Cl2 was removed at the
rotary evaporator to yield a light tan oil which solidified
when triturated with ether. The solid was filtered and
washed twice with 10 mL portions of cold ether to give
1
1.45 g of a pale tan solid, the H NMR of which indicated
it to be 10c containing a small amount of urethane, which
was removed by heating at 70 °C/0.05 mm in a sublima-
tor. The urethane which condensed on the coldfinger as
a white solid amounted to 0.05 g leaving 1.40 g (95%) of
pure 10c. The 1H NMR of this material was identical with
that obtained in the cyclization reaction of 9.
Su ccin im id o[3,4-b]in d a n e (4). A. F r om 10c. Sodium
hydride (0.60 g of a 60% dispersion in mineral oil, 15.1
mmol) was weighed into a 200 mL round-bottomed flask,
and the mineral oil was removed by washing twice with
20 mL of hexane followed by decantation. The hy-
dride was covered with 20 mL of dry THF, a THF solution
of 10c (1.40 g, 6.03 mmol) was added in a slow stream,
and the mixture was heated slowly to reflux under N2.
Hydrogen gas evolution became vigorous on heating, and
refluxing was continued for 1 h. The flask was then cooled
in an ice bath, the excess hydride was quenched with a
few drops of isopropyl alcohol, and the reaction mixture
was brought to pH ) 1 by the dropwise addition of 2 M
HCl. The THF solution was separated, and the aqueous
layer was extracted twice with 50 mL portions of
CH2Cl2. The combined organic layers were dried (MgSO4)
and concentrated on a rotary evaporator to a yellow,
viscous oil, which when triturated with 5 mL of ether,
gave 1.08 g (96%) of 4 as a white solid, mp 140-141 °C,
1
lit.6 mp 170-172 °C; H NMR: δ 3.42 (m, 2H), 3.67 (m,

1552 J . Org. Chem., Vol. 64, No. 5, 1999
Dandekar et al.
carboxamide (21b), 0.06 g (2%), mp 181-183 °C. After
recrystallization from EtOAc, pale yellow crystals of 21b
were obtained, mp 184-185 °C. A final fraction was
collected as an orange oil, 0.12 g, when the eluent was
changed to 15% MeOH-EtOAc. After Kugelrohr distil-
lation at 185 °C/0.10 mm, 0.10 g (3%) of 2-(3-aminoben-
zyl)-N,N,N′,N′-tetramethylpentanediamide (24) was ob-
tained as a yellow oil. Partial separation of the mixture
of 21a and 22 was achieved by rechromatography with
ether. Pure 21a , 0.30 g, obtained in the first chromato-
graphic fractions, crystallized from ether-hexane in fan
shaped crystals, mp 83-84 °C. Intermediate fractions
contained a mixture of 21a and 22, 1.08 g. Compound
22, 0.24 g, was isolated from latter fractions as a pale
yellow oil, which was Kugelrohr distilled at 150 °C/0.10
mm. 1H NMR for 21a : δ 2.10 (m, 2H), 2.96 (m, 2H), 2.97
(s, 3H), 3.01 (s, 3H), 3.08 (s, 3H), 3.22 (s, 3H), 3.48 (m,
1H), 4.24 (dd, 1H, J ) 3.7, 6.2 Hz), 6.96 (d, 1H, J ) 6.9
Hz), 7.13 (m, 3H); 13C NMR: δ 29.2, 32.0, 33.5, 35.7, 35.9,
37.2, 38.0, 39.5, 126.1, 126.7, 128.1, 129.4, 135.0, 137.1,
175.8, 176.5; MS: m/z (relative intensity) M+, 274 (12),
229 (4), 201 (14), 157 (3), 129 (26), 102 (3), 72 (100). Anal.
Calcd for C16H22N2O2: C, 70.04; H, 8.08; N, 10.21.
mL of EtOAc. On standing, 0.92 g of 21b crystallized as
a nearly colorless solid, mp 183-184 °C. The mother
liquor was concentrated and chromatographed with
EtOAc. The first fraction was obtained as a yellow oil
which on trituration with ether gave 0.68 g of 23 as a
nearly colorless solid. The mother liquor, which contained
mostly 22 was concentrated and combined with a second
fraction eluted with 5% MeOH-EtOAc to give 0.25 g of
1
an ether soluble yellow oil, H NMR analysis of which
indicated a 4:1 mixture of 22:23. Thus, the yield of 22
calculated from its molar fraction was 0.20 g (7%), and
the total yield of 23 was 0.73 g (30%). Further elution
with 15% MeOH-EtOAc gave 0.38 g of additional 21b;
total yield 1.30 g (53%).
1,2,3,4,5,6-Hexa h yd r o-1,5-m eth a n o-3-ben za zocin e-
2,4-d ion e (5). Compound 5 was prepared by the same
procedure used in the synthesis of indane 4 from 10c.
Thus, a solution of 21b (2.71 g, 11 mmol) in 150 mL of
THF was refluxed in the presence of sodium hydride (1.10
g of a 60% dispersion in mineral oil, 27.5 mmol) for 1 h
to afford a tan-colored solid which after chromatography
with EtOAc gave 5, 1.94 g (88%), as a white solid, mp
201-202 °C; 1H NMR: δ 2.15 (m, 1H), 2.49 (m, 1H), 3.12
(d, 1H, J ) 17 Hz), 3.20 (m, 1H), 3.31 (dd, 1H, J ) 6.5,
17 Hz), 3.82 (s, 1H), 7.13 (d, 1H, J ) 5.2 Hz), 7.22 (m,
2H), 7.33 (d, 1H, J ) 5.4 Hz), 7.92 (br s, 1H); 13C NMR:
δ 25.6, 31.8, 36.1, 42.5, 127.0, 128.4, 129.4, 129.6, 132.0,
133.1, 173.8, 175.3; MS: m/z (relative intensity) M+, 201
(63), 158 (14), 130 (100), 115 (57), 102 (13), 77 (16), 64
(39). Anal. Calcd for C12H11NO2: C, 71.63; H, 5.51; N,
6.96. Found: C, 71.43; H, 5.56; N, 6.90.
1
Found: C, 69.95; H, 8.06; N, 10.28. H NMR for 21b: δ
2.15 (m, 2H), 3.00 (s, 3H), 3.02 (m, 3H), 3.22 (s, 3H), 4.24
(t, 1H, J ) 5.0 Hz), 5.42 (br s, 1H), 5.86 (br s, 1H), 6.94
(d,1H, J ) 7.7 Hz), 7.14 (m, 3H); 13C NMR: δ 29.2, 32.4,
35.9, 37.1, 37.8, 39.7, 126.2, 126.8, 128.3, 129.2, 134.4,
136.2, 174.7, 177.6; MS: m/z (relative intensity) M+, 246
(36), 201 (58), 174 (11), 129 (75), 115 (22), 91 (19), 72
(100). Anal. Calcd for C14H18N2O2: C, 68.27; H, 7.37; N,
1
11.37. Found: C, 68.02; H, 7.41; N, 11.35. H NMR for
Cycliza tion of 9 w ith KND2 in ND3. To a solution
of KND2 prepared from potassium (0.12 g, 3 mmol) in 20
mL of ND3 contained in a three-neck round-bottomed
flask draped with a black cloth was added a solution of
9 (0.39 g, 1.0 mmol) in 3 mL of THF under N2. After
stirring for 15 min, the reaction was quenched by the
addition of solid, anhydrous ND4Cl (0.25 g, 4.3 mmol).
The ammonia and THF were evaporated under a stream
of N2 to give a tan solid, which was extracted twice with
25 mL portions of CH2Cl2. The combined extracts were
concentrated to a tan-colored viscous oil, 0.25 g, which
was chromatographed with EtOAc to obtain 0.13 g of
deuterated 10a as a yellow, viscous oil and 0.03 g of
deuterated 16 as a pale yellow solid. The 1H NMR
spectrum of indane 10a showed the absence of the H-1
benzylic proton resonance at δ 5.01 and integration of
the H-2 (δ 4.18) and H-7 (δ 7.01) resonances indicated
0.5 D atom at C-2 and 0.4 D atom at C-7. The integrated
1H NMR spectrum of quinolone 16 was consistent with
0.35 D atom incorporation at C-8.
22: δ 2.83 (s, 6H), 2.96 (s, 3H), 3.00 (s, 3H), 3.26 (d, 2H,
J ) 7.0 Hz), 3.66 (s, 2H), 5.80 (t, 1H, J ) 7.0 Hz), 7.22
(m, 5H); 13C NMR: δ 32.4, 35.2, 35.5, 37.0, 37.2, 42.5,
124.2, 126.4, 128.3, 128.4, 128.8, 128.9, 136.8, 138.0,
170.3, 172.1; MS: m/z (relative intensity) M+, 274 (3),
229 (12), 202 (8), 188 (4), 157 (8), 128 (10), 91 (13), 72
(100). HRMS: Calcd 274.1681. Found 274.1685. 1H NMR
for 23: δ 1.95 (m, 1H), 2.03 (m, 1H), 2.56 (m, 2H), 2.64
(m, 1H), 2.80 (dd, 1H, J ) 9.6, 15 Hz), 2.93 (s, 3H), 3.01
(s, 3H), 3.07 (dd, 1H, J ) 5.8, 15 Hz), 6.71 (d, 1H, J )
8.2), 6.97 (t, 1H, J ) 7.5), 7.17 (m, 2H), 7.79 (br s, 1H);
13C NMR: δ 25.7, 31.0, 31.6, 35.4, 37.2, 39.5, 115.0, 123.0,
123.4, 127.4, 128.2, 136.9, 172.5, 173.7; MS: m/z (relative
intensity) M+, 246 (3), 202 (3), 172 (4), 146 (100), 128 (14),
101 (17), 72 (15). Anal. Calcd for C14H18N2O2: C, 68.27;
H, 7.37; N, 11.37. Found: C, 68.42; H, 7.40; N, 11.27. 1H
NMR for 24: δ 1.86 (m, 1H), 2.00 (m, 1H), 2.16 (m, 1H),
2.35 (m, 1H), 2.58 (dd, 1H, J ) 5.9, 13 Hz), 2.69 (s, 3H),
2.80 (dd, 1H, J ) 8.9, 13 Hz), 2.86 (s, 3H), 2.90 (s, 3H),
2.95 (s, 3H), 3.14 (m, 1H), 3.54 (br s, 2H), 6.49 (s, 1H),
6.52 (m, 2H), 7.01 (t, 1H, J ) 7.6 Hz); MS: m/z (relative
intensity) M+, 291 (24), 219 (8), 191 (76), 174 (27), 146
(54), 132 (28), 106 (37), 72 (100); HRMS: Calcd 291.1947.
Found 291.1957.
Cycliza tion of 20 in th e Da r k . To a solution of KNH2
prepared from potassium (1.57 g, 40 mmol) in 250 mL of
liquid NH3 contained in a 500 mL three-neck round-
bottomed flask covered with a black cloth was introduced
a solution of 20 (4.02 g, 10 mmol) in 40 mL of THF. The
resulting solution was stirred under N2 for 45 min and
then quenched on excess solid NH4Cl in a beaker.
Following the workup procedure previously described for
the photostimulated cyclization of 20, 2.12 g of a viscous
orange oil was obtained, which was then dissolved in 25
2-(2-Iod o-3-m et h ylb en zyl)-N,N,N′,N′-t et r a m et h -
ylbu ta n ed ia m id e (31). The procedure for the prepara-
tion of 31 was the same as that described previously for
the analogous synthesis of 9 from 6 with 1.1 equiv of
LiNH2 in liquid NH3 at -60 °C. Reaction of 2-iodo-3-
methylbenzyl bromide (9.33 g, 30 mmol) and the lithium
enolate of 6 (5.16 g, 30 mmol) at -60 °C for 45 min gave
9.85 g of a yellow solid. After two recrystallizations from
CH2Cl2-hexane, 7.65 g (63%) of pure 31 was obtained
1
as colorless crystals, mp 128-129 °C; H NMR: δ 2.33
(dd, 1H, J ) 3.0, 16 Hz), 2.47 (s, 3H), 2.72 (s, 3H), 2.82
(s, 3H), 2.88 (s, 3H), 2.94 (m, 2H), 3.00 (s, 3H), 3.09 (dd,
1H, J ) 11, 16 Hz), 3.68 (m, 1H), 6.95 (dd, 1H, J ) 5.4,
5.6 Hz), 7.23 (two overlapping d, 2H, J ) 5.4, 5.6 Hz);
13C NMR: δ 30.0, 35.2, 35.3, 35.7, 35.8, 36.7, 37.2, 45.2,

Synthesis of Succinimido[3,4-b]indane
J . Org. Chem., Vol. 64, No. 5, 1999 1553
108.0, 127.3, 127.7, 128.0, 142.2, 142.3, 171.1, 174.7;
MS: m/z (relative intensity) M+, 402 (4), 358 (18), 316
(44), 275 (65), 202 (34), 126 (48), 87 (67), 72 (100). Anal.
Calcd for C16H23IN2O2: C, 47.76; H, 5.72; N, 6.97.
Found: C, 47.87; H, 5.77; N, 6.91.
37.3, 37.7, 47.3, 49.4, 122.0, 127.7, 127.8, 133.4, 140.6,
143.4, 171.7, 172.5; MS: m/z (relative intensity) M+, 274
(1), 229 (33), 201 (8), 157 (7), 128 (93), 115 (72), 72 (100).
Anal. Calcd for C16H22N2O2: C, 70.04; H, 8.08; N, 10.21.
1
Found: C, 70.10; H, 8.15; N, 10.29. H NMR for 32c: δ
Cycliza tion of 31 in th e Da r k . A solution of KNH2
was prepared from potassium (0.59 g, 15 mmol) in 150
mL of liquid NH3. The reaction flask was covered with a
black cloth, and 31 (2.02 g, 5 mmol) was added as a solid.
After stirring for 5 min, the deep red solution was poured
onto excess NH4Cl in a beaker. A 50 mL ether rinse of
the flask was added cautiously to the NH3 solution, and
the NH3 and ether were evaporated. The orange solid
residue was dissolved in water (20 mL) and CH2Cl2 (100
mL). The aqueous layer was separated and extracted
with additional 100 mL of CH2Cl2, and the combined
CH2Cl2 solutions were dried (MgSO4) and concentrated.
The resulting orange-brown viscous oil was chromato-
graphed using EtOAc as the eluent, and 3-(N,N-dimethyl-
acetamido)-3,4-dihydro-8-methyl-2(1H)-quinolone (35) was
eluted as a pale yellow oil which upon trituration with
ether crystallized, mp 142-143.5 °C, 0.06 g (5%). Re-
crystallization from ether afforded an analytical sample
as colorless crystals, mp 143-143.5 °C. A 0.54 g mixture
of trans-1,2-bis-(N,N-dimethylcarboxamido)-7-methylin-
dane (32a ) and 1,2-bis-(N,N-dimethylcarboxamido)-7-
methyl-1-indene (33) was eluted next. This mixture was
rechromatographed by gradient elution with 0-4% MeOH
in CH2Cl2, and indane 32a was eluted first as a pale
yellow oil which crystallized when triturated with ether,
0.27 g (20%). Recrystallization from ether-hexane gave
pure 32a as colorless crystals, mp 87-88 °C. Indene 33
was then eluted as a yellow oil which crystallized on
standing, mp 120-122 °C, 0.15 g (11%). After recrystal-
lization from ether-hexane, pale yellow plates of pure
33, mp 122.5-123 °C, were obtained. The eluent from
the initial chromatography was changed from EtOAc to
10% MeOH-EtOAc, and a third fraction was eluted as
a light yellow oil, 0.27 g. Trituration with ether resulted
in the crystallization of 0.05 g (4%) of trans-1-(N,N-
dimethylcarboxamido)-7-methylindane-2-carboxamide
(32c) as a light tan solid, mp 210-212 °C. Recrystalli-
zation from EtOAc-ether afforded nearly colorless, pure
32c, mp 213-214 °C. Evaporation of the ether gave a
2.11 (s, 3H), 3.03 (s, 3H), 3.11 (dd, 1H, J ) 9.1, 15 Hz),
3.25 (s, 3H), 3.27 (dd, 1H, J ) 8.8, 15 Hz), 3.44 (ddd, 1H,
J ) 8.2, 8.8, 9.1 Hz), 4.81 (d, 1H, J ) 8.2 Hz), 5.39 (br s,
1H), 6.45 (br s, 1H), 6.96 (d, 1H, J ) 7.3 Hz), 7.02 (d,
1H, J ) 7.5 Hz), 7.11 (t, 1H, J ) 7.4 Hz); 13C NMR: δ
18.7, 36.2, 36.9, 38.1, 49.6, 50.3, 121.9, 127.8, 128.6,
133.7, 140.3, 141.9, 174.3, 175.9; MS: m/z (relative
intensity) M+, 246 (2), 202 (4), 129 (24), 115 (25), 91 (53),
72 (100). Anal. Calcd for C14H18N2O2: C, 68.27; H, 7.37;
1
N, 11.37. Found: C, 68.14; H, 7.44; N, 11.43. H NMR
for 33: δ 2.32 (s, 3H), 2.96 (s, 3H), 3.04 (s, 6H), 3.08 (s,
3H), 3.59 (d, 1H, J ) 23 Hz), 3.81 (d, 1H, J ) 23 Hz),
7.09 (d, 1H, J ) 7.4), 7.18 (t, 1H, J ) 7.4 Hz), 7.32 (d,
1H, J ) 7.4 Hz); 13C NMR: δ 18.0, 34.4, 36.6, 38.1, 38.7,
39.8, 121.6, 126.4, 129.1, 131.8, 137.0, 137.7, 139.5, 142.5,
168.2; MS: m/z (relative intensity) M+, 272 (1), 229 (4),
200 (3), 184 (6), 156 (8), 127 (38), 72 (100). Anal. Calcd
for C16H20N2O2: C, 70.56; H, 7.40; N, 10.29. Found: C,
70.48; H, 7.37; N, 10.27. 1H NMR for 34: δ 2.28 (dd, 1H,
J ) 3.6, 13 Hz), 2.32 (s, 3H), 2.64 (dd, 1H, J ) 7.2, 13
Hz), 2.82 (s, 3H), 2.85 (m, 1H), 2.87 (s, 3H), 2.88 (s, 3H),
2.99 (s, 3H), 3.01 (m, 1H), 3.52 (m, 1H), 7.02 (m, 3H),
7.14 (m, 1H); 13C NMR; δ 21.2, 35.3, 35.6, 36.0, 36.2, 37.0,
39.0, 39.6, 126.0, 127.1, 128.1, 129.6, 137.8, 139.0, 171.4,
175.0; MS: m/z (relative intensity) M+, 276 (27), 232
(12), 190 (100), 159 (31), 145 (18), 126 (21), 105 (17), 72
(95). HRMS: Calcd for C16H24N2O2: 276.1838. Found:
276.1846. 1H NMR for 35: δ 2.24 (s, 3H), 2.40 (dd, 1H, J
) 8.2, 16 Hz), 2.84 (m, 1H), 2.99 (s, 3H), 3.06 (s, 3H),
3.14 (m, 3H), 6.89 (t, 1H, J ) 7.5 Hz), 7.03 (d, 2H, J )
7.5 Hz), 7.72 (br s, 1H); 13C NMR: δ 16.6, 31.8, 33.0, 35.4,
36.8, 37.1, 122.4, 122.6, 123.9, 125.9, 128.9, 135.3, 170.8,
172.9; MS: m/z (relative intensity) M+, 246 (4), 202 (2),
172 (8), 160 (87), 130 (32), 87 (31), 72 (100). Anal. Calcd
for C14H18N2O2: C, 68.27; H, 7.37; N, 11.37. Found: C,
68.21; H, 7.41; N, 11.43.
When a similar dark reaction was carried out in the
1
presence of 40 mol % of DTBN, H NMR analysis of the
reaction mixture indicated a 6:1 ratio of unreacted 31 to
32a ,b.
1
pale yellow oil whose H NMR spectrum indicated it to
be essentially pure 2-(3-methylbenzyl)-N,N,N′,N′-tetra-
methylbutanediamide (34), 0.22 g (16%). A final fraction
was then eluted which crystallized to a tan solid, 0.38 g,
which was rechromatographed with 2% MeOH-CH2Cl2
to give 0.31 g (23%) of pure cis-1,2-bis-(N,N-dimethyl-
carboxamido)-7-methylindane (32b) as colorless crystals,
Xr a y Cr ysta llogr a p h ic An a lysis of 4, 13, 17, a n d
21b.40 X-ray data were collected at 25 °C on a Siemens
R3m/v diffractometer with Mo KR radiation using a
graphite monochromator. Other relevant experimental
details are included in Supporting Information. The
structures were solved by direct methods and refined
using the SHELXTL-PLUS suite of programs.
1
mp 185-186 °C. H NMR for 32a : δ 2.13 (s, 3H), 2.99
(s, 3H), 3.00 (dd, 1H, J ) 8.2, 15 Hz), 3.03 (s, 3H), 3.10
(s, 3H), 3.32 (s, 3H), 3.39 (dd, 1H, J ) 9.2, 15 Hz), 3.83
(ddd, 1H, J ) 8.0, 8.2, 9.2 Hz), 5.07 (d, 1H, J ) 8.0 Hz),
6.95 (d, 1H, J ) 7.4 Hz), 7.01 (d, 1H, J ) 7.4 Hz), 7.09 (t,
1H, J ) 7.4 Hz); 13C NMR: δ 18.6, 35.9, 36.1, 36.7, 37.4,
38.2, 48.1, 49.1, 121.6, 127.5, 128.6, 133.6, 140.8, 141.3,
173.3, 174.5; MS: m/z (relative intensity) M+, 274 (3),
229 (18), 202 (26), 157 (20), 128 (76), 115 (46), 72 (100).
Anal. Calcd for C16H22N2O2: C, 70.04; H, 8.08; N, 10.21.
Ack n ow led gm en t. We are pleased to acknowledge
generous financial support from the Harvey W. Peters
Research Center for Parkinson’s Disease and Disorders
of the Central Nervous System Foundation and from
the National Science Foundation through Grant
CHE-8513216.
J O982000B
1
Found: C, 69.93; H, 8.12; N, 10.17. H NMR for 32b: δ
(40) The author has deposited atomic coordinates for structures 4,
13, 17, and 21b with the Cambridge Crystallographic Data Centre.
The coordinates can be obtained, on request, from the Director,
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge,
CB2 1EZ, U.K.
2.22 (s, 3H), 2.93 (s, 3H), 2.98 (s, 3H), 3.01 (s, 3H), 3.12
(m, 1H), 3.15 (s, 3H), 3.78 (m, 2H), 4.53 (m, 1H), 6.96
(m, 1H), 7.11 (m, 2H); 13C NMR: δ 18.9, 36.0, 36.1, 36.3,