A Cycloaddition Approach toward the Synthesis of Substituted Indolines and Tetrahydroquinolines

Article abstract of DOI:10.1021/jo982453g

The intramolecular Diels-Alder reaction of 2-substituted aminofurans (IMDAF) results in the formation of various indolines and tetrahydroquinolines. The isolation of these ring systems from the IMDAF reaction can be rationalized in terms of an initial [4 + 2]-cycloaddition that first produces an oxa-bridged cycloadduct, which was not detected since it readily underwent nitrogen-assisted ring opening. Proton exchange followed by an eventual dehydration provides the aromatic product. In certain cases, the intermediate cyclohexadienol can be isolated and independently converted to the final product in high yield. The starting 2-aminofurans were readily prepared from furanyl acyl azide by a Curtius rearrangement in the presence of an alcohol. Alkylation of the resulting N-alkyl carbamate with an alkenyl bromide allows for the synthesis of a wide variety of cycloaddition precursors. The scope of the IMDAF reaction was evaluated by using mono- and disubstituted alkenes, electron rich and electron deficient olefins, and acetylenic tethers. Cyclic 2-amidofurans were also synthesized using a related intramolecular Diels-Alder reaction of 2-amido-substituted oxazoles which contain a tethered alkyne. This transformation represents a new route to this rare heterocyclic ring system. The sequential cycloaddition method was used for a formal synthesis of the pyrrolophenanthridone alkaloid hippadine.

Full text of DOI:10.1021/jo982453g

J . Org. Chem. 1999, 64, 3595-3607
3595
A Cycloa d d ition Ap p r oa ch tow a r d th e Syn th esis of Su bstitu ted
In d olin es a n d Tetr a h yd r oqu in olin es
Albert Padwa,* Michael A. Brodney,† Bing Liu, Kyosuke Satake, and Tianhua Wu
Department of Chemistry, Emory University, Atlanta, Georgia, 30322
Received December 16, 1998
The intramolecular Diels-Alder reaction of 2-substituted aminofurans (IMDAF) results in the
formation of various indolines and tetrahydroquinolines. The isolation of these ring systems from
the IMDAF reaction can be rationalized in terms of an initial [4 + 2]-cycloaddition that first produces
an oxa-bridged cycloadduct, which was not detected since it readily underwent nitrogen-assisted
ring opening. Proton exchange followed by an eventual dehydration provides the aromatic product.
In certain cases, the intermediate cyclohexadienol can be isolated and independently converted to
the final product in high yield. The starting 2-aminofurans were readily prepared from furanyl
acyl azide by a Curtius rearrangement in the presence of an alcohol. Alkylation of the resulting
N-alkyl carbamate with an alkenyl bromide allows for the synthesis of a wide variety of cycloaddition
precursors. The scope of the IMDAF reaction was evaluated by using mono- and disubstituted
alkenes, electron rich and electron deficient olefins, and acetylenic tethers. Cyclic 2-amidofurans
were also synthesized using a related intramolecular Diels-Alder reaction of 2-amido-substituted
oxazoles which contain a tethered alkyne. This transformation represents a new route to this rare
heterocyclic ring system. The sequential cycloaddition method was used for a formal synthesis of
the pyrrolophenanthridone alkaloid hippadine.
In tr od u ction
has long been a topic of fundamental interest to organic
and medicinal chemists.6
Functionalized indoles1 and quinolines,2 along with
their dihydro and tetrahydro derivatives, have been of
interest to organic chemists for many years due to the
large number of natural products that contain these
heterocycles.3 Indoles display a wide range of biological
activities,4 and an unusually large number of drugs
contain this heterocyclic nucleus.5 This is exemplified by
the amino acid tryptophan, the hormones serotonin and
melatonin, the antiarthritic indomethacin, and the psy-
chotropic indole LSD.6 The potent antitumor agent Dyne-
micin A7 and the antiviral agent Virantmycin8 represent
important natural products that contain the quinoline
core. Accordingly, the synthesis of indoles and quinolines
The closely related indolines9 and tetrahydroquino-
lines10 have also attracted considerable attention due to
their pronounced activity in many physiological pro-
cesses.11 These heterocycles are found in numerous
commercial products, including pharmaceuticals, fra-
grances, and dyes.12 Many strategies have been developed
for the preparation of these compounds.13 One of the
major routes involves the partial reduction of the het-
eroaromatic ring system.14 Other methods utilize a nu-
cleophilic aromatic cyclization reaction of an N-substi-
tuted aniline derivative containing a suitable π-acceptor,15
a 1,5-electrocyclization reaction,16 and a nucleophilic
attack of styrene derivatives onto a transient nitrene
species.17 Recently, Larock has reported that the pal-
† Recipient of a Graduate Fellowship from the Organic Chemistry
Division of the American Chemical Society (1997-1998) sponsored by
Dupont Merck Pharmaceutical Co.
(1) Saxton, J . E. Nat. Prod. Rep. 1997, 14, 559. Ihara, M.; Fukumoto,
K. Nat. Prod. Rep. 1997, 14, 413. J oshi, K. C.; Chand, P. Pharm. 1982,
37, 1-12. Gilchrist, T. L. Heterocyclic Chemistry; Pitman: London,
1981. Pindur, U.; Adam, R. J . Heterocycl. Chem. 1988, 25, 1.
(2) Michael, J . P. Nat. Prod. Rep. 1997, 14, 605. Balasubramanian,
M.; Keay, J . G. In Comprehensive Heterocyclic Chemistry II; McKillop,
A., Ed.; Pergamon Press: Oxford, 1996; Vol. 5, Chapter 5.06, pp 246-
300. Yates, F. S. In Comprehensive Heterocyclic Chemistry; Boulton,
A. J ., McKillop, A., Eds.; Pergamon Press: Oxford, 1984; Vol. 2, part
2A, Chapter 2.09, pp 511-524.
(9) J oshi, K. C.; Chand, P. Pharm. 1982, 37, 1. Somei, M.; Saida,
Y.; Funamoto, T.; Ohta, T. Chem. Pharm. Bull. 1987, 35, 3146.
Takahashi, K.; Kametani, T. Heterocycles 1979, 13, 411. Kamentani,
T.; Takahashi, K. Heterocycles 1978, 9, 293.
(10) De Kimpe, N.; Keppens, M. Tetrahedron 1996, 52, 3705.
(11) Carling, R. W.; Leeson, P. D.; Moseley, A. M.; Smith, J . D.;
Saywell, K.; Tricklebank, M. D.; Kemp, J . A.; Marshall, G. R.; Foster,
A. C.; Grimwood, S. Bioorg. Med. Chem. Lett. 1993, 3, 65.
(12) Wright, G. C.; Portlock, D. E. Ger. Offen. 3004370, 1980; Chem.
Abstr. 1980, 93, 239262u. Kurahashi, Y.; Shiokawa, K.; Goto, T.;
Kagabu, S.; Kamochi, A.; Moriya, K.; Hayakawa, H. Eur. Patent
173208, 1986; Chem. Abstr. 1986, 105, 78937s. Rose, D.; Busch, P.;
Lieske, E. Ger. Offen. 2714955, 1978; Chem. Abstr. 1979, 90, 43672w.
(13) Beckwith, A. L. J .; Meijs, G. F. J . Org. Chem. 1987, 52, 1922.
Beckwith, A. L. J .; Gara, W. B. J . Chem. Soc., Perkin Trans. 2 1975,
795. Dittami, J . P.; Ramanathan, H. Tetrahedron Lett. 1988, 29, 45.
J ones, K.; Storey, J . M. D. J . Chem. Soc., Chem. Commun. 1992, 1766.
Murphy, J . A.; Kizil, M.; Lampard, C. Tetrahedron Lett. 1996, 37, 2511.
Ozlu, Y.; Cladingboel, D. E.; Parsons, P. J . Synlett 1993, 357.
(14) Gribble, G. W.; Heald, P. W. Synthesis 1975, 650. Draper, P.
M.; MacLean, D. B. Can. J . Chem. 1968, 46, 1499. Kikugawa, Y.; Saito,
K.; Yamada, S. Synthesis 1978, 447. Ferles, M.; Kocia´n, O. Collect.
Czech. Chem. Commun. 1979, 44, 3141. Scopes, D. I. C.; J oule, J . A.
J . Chem. Soc., Perkin Trans. 1 1972, 2810. Stutz, R. L.; Reynolds, C.
A.; McEwen, W. E. J . Org. Chem. 1961, 26, 1684. Metzger, J .; Larive´,
H.; Vincent, E. J .; Dennilauler, R. Bull. Soc. Chim. Fr. 1967, 46.
(3) Hesse, M. Alkaloid Chemistry; Wiley: New York, 1978. Cordell,
G. A. Introduction to Alkaloids: A Biogenetic Approach; Wiley: New
York, 1981.
(4) Hugel, H. M.; Kennaway, D. J . Org. Prep. Proc. Int. 1995, 27, 1.
Glennon, R. A. J . Med. Chem. 1987, 30, 1.
(5) Sundberg, R. J . Indoles; Academic Press: San Diego, 1996; and
references therein.
(6) For reviews, see: Gribble, G. W. Contemporary. Org. Synth. 1994,
145-172. Gribble, G. W. In Comprehensive Heterocyclic Chemistry II;
Bird, C. W., Ed.; Pergamon Press: Oxford, 1996; Vol. 2, Chapter 2.04,
pp 207-257.
(7) Isobe, M.; Nishikawa, T.; Yamamoto, N.; Tsukiyama, T.; Ino, A.;
Okita, T. J . Heterocycl. Chem. 1992, 29, 619. Magnus, P.; Parry, D.;
IIiadis, T.; Eisenbeis, S. A.; Fairhuist, R. A. J . Chem. Soc., Chem.
Commun. 1994, 1543.
(8) Morimoto, Y.; Matsuda, F.; Shirahama, H. Synlett 1991, 202.
10.1021/jo982453g CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/14/1999

3596 J . Org. Chem., Vol. 64, No. 10, 1999
Padwa et al.
Sch em e 1
Sch em e 2
ladium-catalyzed cross-coupling of o-vinylic and allylic
anilides with vinylic halides and triflates produces di-
hydroindoles and tetrahydroquinolines.18 In all of these
examples, the degree of substitution on the benzenoid
portion of the molecule is set prior to the cyclization step.
A method that would generate the aromatic portion of
an indoline or tetrahydroquinoline ring system by a
cycloaddition reaction would be extremely useful and
complementary to the existing methods. To date, cyclo-
addition approaches to these ring systems are limited to
the [4 + 2]-cycloaddition of azadienes19 and o-xylylenes20
which, in turn, are derived from substituted anilines. Our
ongoing interest in the synthesis of heterocyclic com-
pounds by the [4 + 2]-cycloaddition of aminofurans21
coupled with our recent success in the development of
an efficient procedure for the synthesis of octahydro-
indole-based alkaloids22 by an intramolecular furan Di-
els-Alder reaction (IMDAF)23-25 encouraged us to inves-
tigate the possible application of this methodology to the
synthesis of a variety of substituted indolines (2) and
tetrahydroquinolines (3). Our planned approach is out-
lined in Scheme 1 and involves an IMDAF reaction of
2-amino-substituted furans. During the course of our
studies, we also had the occasion to extend this cyclo-
addition strategy to include 2-amido-substituted oxazoles
that possess tethered alkynes since we were interested
in using this reaction as an approach toward the syn-
thesis of the pyrrolophenanthridone alkaloids.26 The
present paper documents the results of this investigation.
Resu lts a n d Discu ssion
Synthesis of the 2-aminofuranyl system was accom-
plished using a number of different procedures depending
upon the scale and the specific furan desired (Scheme
2). The most frequently employed method involved
converting a 2-furoic acid such as 4 into the correspond-
ing acid chloride with thionyl chloride followed by reac-
tion with sodium azide which provided the acyl azide 5
in good overall yield. A Curtius rearrangement was
carried out by heating azide 5 in the appropriate alcohol.
This method was used for the large scale preparation (i.e.
>50 g) of several of the furanyl carbamate derivatives
(vide infra). An alternative synthesis that was employed,
when smaller quantities of the carbamate (i.e. <1 g) were
needed, consisted of heating the 2-furoic acid with
diphenyl phosphorylazidate27 in an alcoholic solvent. A
third method that was used to prepare amido-substituted
furans such as 9 involved the in situ generation of furyl
isocyanate 8 from the appropriate acyl azide. Subsequent
quenching with either a higher order cyanocuprate or a
Grignard reagent afforded the desired 2-amido-substi-
tuted furanyl system 9.28
(15) Hegedus, L. S.; Allen, G. F.; Bozell, J . T.; Wateman, E. L. J .
Am. Chem. Soc. 1978, 100, 5800. Venkataramu, S. D.; Macdonell, G.
D.; Purdum, W. R.; Dilbeck, G. A.; Berlin, K. D. J . Org. Chem. 1977,
42, 2195. Bringi, N. V.; Deshmukh, P. V. J . Org. Chem. 1962, 27, 4117.
Mortelmans, C.; Van Binst, G. Tetrahedron 1978, 34, 363. Katritzky,
A. R.; Rachwal, B.; Rachwal, R. J . Org. Chem. 1995, 60, 7631.
(16) Thummel, R. P.; Kohli, D. K. J . Org. Chem. 1977, 42, 2742.
(17) Sundberg, R. J . In The Chemistry of Indoles; Academic Press:
New York and London, 1970; pp 142-213. Speckamp, N. W. Hetero-
cycles 1984, 21, 211.
In tr a m olecu la r Diels-Ald er Rea ction of 2-Am id -
ofu r a n s. We began our investigation of the intramolecu-
lar [4 + 2]-aminofuran cycloaddition reaction by first
preparing the Boc-protected furans 10 and 12 which
contain unactivated π-bonds (Scheme 3). Attachment of
the alkenyl tether was accomplished by treating furan-
2-ylcarbamic acid tert-butyl ester (7) with potassium
carbonate/sodium hydroxide/tetrabutylammonium hy-
drogen sulfate in benzene followed by the addition of
1-bromo-3-butene or 1-bromo-4-pentene. Furanyl car-
bamates 10 and 12 were obtained in 77% and 81% yields,
respectively. The IMDAF reaction was carried out by
heating a benzene solution of the carbamate in a sealed
tube at 155-165 °C for 17 h. Disappointingly, under
these conditions, indoline 11 was obtained in only 16%
yield. The reaction mixture contained a significant
amount of a dark tar which was present in even greater
quantities when carbamate 10 was heated for longer
periods of time. We assume that the thermal instability
of the tert-butyl carbamate portion of the molecule at the
elevated temperatures is responsible for the low yield of
product. Another possibility is that the transient cyclo-
(18) Larock, R. C.; Yang, H.; Pace, P.; Cacchi, S.; Fabrizi, G.
Tetrahedron Lett. 1998, 39, 1885.
(19) Beifuss, U.; Ledderhose, S. J . Chem. Soc., Chem. Commun.
1995, 2137. Beifuss, U.; Kunz, O.; Ledderhose, S.; Toraschewski, M.;
Tonko, C. Synlett 1996, 34. Boger, D. L.; Weinreb, S. N. Hetero Diels-
Alder Methodology in Organic Synthesis; Academic Press: San Diego,
1987. Noland, W. E.; Kim, J . K.; Lee, C. K.; Bae, S. K.; Hahn, C. S. J .
Org. Chem. 1980, 45, 4582. Lucchini, V.; Prato, M.; Scorrano, G.;
Stivanello, M.; Valle, G. J . Chem. Soc., Perkin Trans. 2 1992, 259.
Crousse, B.; Begue, J . P.; Bonnet-Delphon, D. Tetrahedron Lett. 1998,
39, 5765.
(20) Wojciechowski, K. Synlett 1991, 571. Letulle, M.; Guenot, P.;
Ripoll, J . L. Tetrahedron Lett. 1991, 32, 2013.
(21) Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J . Org. Chem.
1997, 62, 4088; 1998, 63, 3986.
(22) Padwa, A.; Brodney, M. A.; Dimitroff, M. J . Org. Chem. 1998,
63, 5304.
(23) Kappe, C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997,
53, 14179.
(24) Sternbach, D. D.; Rossana, D. M.; Onan, K. D. J . Org. Chem.
1984, 49, 3427.
(25) J ung, M. E.; Gervey, J . J . Am. Chem. Soc. 1989, 111, 5469.
Klein, L. L. J . Org. Chem. 1985, 50, 1770.
(26) For a preliminary report, see: Liu, B.; Padwa, A. Tetrahedron
Lett. 1999, 40, 1645.
(27) Shioiri, T.; Ninomiya, K.; Yamada, S. J . Am. Chem. Soc. 1972,
94, 6203.
(28) Singleton, H. M.; Edwards, W. R. J r. J . Org. Chem. 1938, 60,
540.

Substituted Indoline and Tetrahydroquinoline Synthesis
J . Org. Chem., Vol. 64, No. 10, 1999 3597
Sch em e 3
Sch em e 4
At this point in our studies we became interested in
determining what effect a leaving group on the 2-position
of the olefinic tether would have on the cycloaddition
reaction. To this end, we treated furan-2-ylcarbamic acid
tert-butyl ester (7) with 2,4-dibromo-1-butene which
afforded furan 24 in 90% yield. Unfortunately, the
thermolysis of this carbamate provided less than 5% of
the desired cycloadduct 25. Instead, significant quantities
of several unindentified decomposition products were
obtained. We assume that the low yield of 25 is related
to the loss of hydrogen bromide under the thermal
conditions which facilitate decomposition of the starting
tert-butyl carbamate. To overcome this problem, we
examined the thermal behavior of furan 26 which con-
tained a thiophenyl-substituted alkenyl group. Heating
this carbamate now provided the phenolic indoline 25 in
87% yield by elimination of thiophenol rather than HBr
from the initially formed cycloadduct. We also examined
the cycloaddition behavior of the thermally more robust
N-ethyl carbamate derivative 27 which furnished phenol
28 in 80% yield upon heating at 160 °C for 7 h. Isolation
of 28, in such high yield relative to the tert-butyl
carbamate system, is clearly a reflection of the greater
thermal and acid stability of the N-ethyl derivative,
thereby allowing the [4 + 2]-cycloaddition reaction to
occur prior to carbamate decomposition. The phenolic
functionality present in the aromatic ring of indolines 25
and 28 has the potential to be transformed into an aryl
triflate and used for palladium-catalyzed cross-coupling
chemistry to afford more highly functionalized products.29
We next investigated the Diels-Alder cycloaddition
reaction of 2-amido-substituted furans that contained
tethered acetylenic π-bonds. The thermal IMDAF reac-
tion of furan 29 occurred at 170 °C over a 24 h period to
give indoline 30 in only 25% yield. Once again, we
attribute the low yield of the product to the thermal
lability of the tert-butyl carbamate portion of the mol-
ecule. Simply changing the tert-butyl to the N-ethyl
carbamate (i.e. 31) had a major effect on the cycloaddition
yield. The thermal reaction of 31 gave the 4,5-disubsti-
tuted-2,3-indoline 32 in 82% yield. The tetrahydroquino-
line ring system could also be easily generated by
adjusting the tether length. Thus, furans 33 and 35 were
hexadienol that is initially formed (i.e. 23) may not
undergo an easy dehydration in this case and, conse-
quently, alternate pathways may compete with indoline
formation. When the homologous carbamate 12 was
subjected to the same thermal conditions, cyclohexadienol
13 (28%) and tetrahydroquinoline 14 (33%) were ob-
tained. Alcohol 13 was quantitatively converted to 14
upon further heating in toluene. The overall yield of
tetrahydroquinoline 14 corresponded to a respectable
60% by carrying out the thermolysis of 12 at 165 °C for
24 h.
Having established that 2-amino-substituted furans
can undergo the IMDAF cycloaddition to produce the
indoline and tetrahydroquinoline ring systems, we next
examined the effect of placing an aryl or alkyl substituent
at the 5-position of the furan ring. These carbamates
were synthesized from the corresponding 2-furoic acid
derivatives using the one-step protocol of heating the
carboxylic acid with diphenyl phosphorylazidate and
triethylamine in tert-butyl alcohol at 80 °C which resulted
in the formation of furans 15 and 18 in 87% and 86%
yields, respectively. The carbamates were subjected to
the standard alkylation conditions (see Experimental
Section) using 1-bromo-3-butene to produce furans 16 and
19 in 68% and 95% yields, respectively. Thermolysis of
16 and 19 at 165 °C for 24 h furnished indolines 17 and
20 in 77% and 57% yields.
The formation of the indoline and tetrahydroquinoline
rings from this reaction can be rationalized in terms of
an initial Diels-Alder cycloaddition that first produces
an oxa-bridged cycloadduct, which was not detected since
it readily underwent nitrogen-assisted ring opening
(Scheme 4). Proton exchange followed by an eventual
dehydration provides the aromatic product. In certain
cases, the intermediate cyclohexadienol (i.e. 23) can be
isolated and independently converted to the final product
in high yield.
(29) Arcadi, A.; Cacchi, S.; Marinelli, F.; Morera, E.; Ortar, G.
Tetrahedron 1990, 46, 7151. Barf, T. A.; Boer, P.; Wikstro¨m, H.;
Peroutka, S. J .; Svensson, K.; Ennis, M. D.; Ghazab, N. B.; McGuire,
J . C.; Smith, M. W. J . Med. Chem. 1996, 39, 4717.

3598 J . Org. Chem., Vol. 64, No. 10, 1999
Padwa et al.
Sch em e 5
readily obtained by alkylation of furan-2-ylcarbamic acid
ethyl ester (6) with the appropriate acetylenic mesylate.
The Diels-Alder reaction of each compound provided
1,2,3,4-tetrahydroquinolines 34 and 36 in 88% and 80%
yields, respectively. When the terminal position of the
alkyne contained a methyl group, it was necessary to
carry out the thermolysis at 240 °C (24 h) in order for
the cycloaddition reaction to occur (i.e. 35 f 36). The
Sch em e 6
reaction rate and yield were greatly diminished relative
to the case where the terminal alkynyl carbon contains
the electron-withdrawing carbomethoxy group. This dif-
ference in reactivity is consistent with FMO theory.30
Placement of an electron-withdrawing group on the
π-bond lowers the LUMO energy of the dienophile and
significantly enhances the rate of the [4 + 2]-cycloaddi-
tion reaction.
For comparison purposes, we have also studied the
IMDAF chemistry of several 2-substituted furanamides.
These compounds were prepared by generating 2-furyl
isocyanate 8 as a transient intermediate and allowing it
to react with either a Grignard reagent or a higher order
cuprate. In the case of (E)-5-iodo-2-pentene, the cuprate
reagent was utilized, whereas the Grignard reagent was
employed with 2-bromostyrene. Using this protocol, we
were able to synthesize furans 37 and 41 in 42% and 32%
yields, respectively. Furan 37 was also converted to the
corresponding p-methoxybenzyl amide 38 in 66% yield.
When furans 37, 38, and 41 were subjected to the IMDAF
reaction, the substituted quinolones 39, 40, and 42 were
obtained in 89%, 80%, and 97% yields (Scheme 5).
An Ap p r oa ch tow a r d th e Am a r yllid a cea e Cla ss
of Alk a loid s. The tetrahydroquinoline ring system is a
structural feature found in a large number of azapoly-
cycles belonging to the Amaryllidaceae class of alka-
loids.31 One of the goals of our work in this area was to
utilize the IMDAF reaction of amidofurans as a method
to synthesize this core skeleton. The requisite styryl
carbamate (i.e. 45) necessary for the IMDAF cycloaddi-
tion that we were interested in studying was prepared
in high yield by treating carbamate 6 with the iodo-
substituted benzyl bromide 43 in the presence of base.
Stille coupling of the resulting aryl iodide 44 with
vinyltributyltin32 provided the cycloaddition precursor 45
in 72% yield. The intramolecular Diels-Alder reaction
of 45 furnished tetrahydroquinoline 46 in 79% yield,
thereby demonstrating the efficacy of the method (Scheme
6).
P yr r olop h en a n th r id on e Alk a loid Syn th esis. The
pyrrolophenanthridone alkaloids33 are a group of com-
(31) Lewis, J . R. Nat. Prod. Rep. 1993, 10, 291.
(32) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. Stille,
J . K. Pure Appl. Chem. 1985, 57, 1771.
(30) Fleming, I. Frontier Orbitals and Organic Reactions; Wiley
Science: New York, 1976.

Substituted Indoline and Tetrahydroquinoline Synthesis
J . Org. Chem., Vol. 64, No. 10, 1999 3599
pounds isolated from Amaryllidaceae plants.34 These
alkaloids have attracted the attention of chemists and
pharmacologists due to the interesting properties of some
of the members.35 One of the more prevalent members
of this family is hippadine (47), which is known to inhibit
fertility in male rats.36 While several procedures for the
synthesis of individual pyrrolophenanthridones have
been developed,37-40 a short and efficient general method
is not yet available. In connection with our work on the
IMDAF reaction of 2-aminofurans, we became interested
in using the Diels-Alder cycloaddition of a cyclic 2-
amidofuran such as 48 as an approach toward hippadine
and related structures.26
Before investigating the intramolecular cycloaddition
behavior of acetylenic aminooxazoles, we decided to first
conduct an experiment on a simpler model system. In
1957, Kondrat’eva described the first example of a Diels-
Alder cycloaddition of an oxazole with an alkene to
produce a pyridine.46 In a later report, Weinreb and Levin
showed that annulated pyridines were formed in good
yield by an intramolecular Kondrat’eva cycloaddition of
an oxazole with a tethered alkene.47 This approach was
used as a strategy for the synthesis of several aza-
phenanthrene alkaloids.48 As a target to test the feasibil-
ity of the proposed intramolecular Diels-Alder cyclo-
addition of a 2-amino-substituted oxazole, we chose to
study the thermal behavior of oxazole 51. Refluxing a
solution of 51 in a sealed tube at 180 °C furnished 53 in
modest yield. The initially formed bicyclic adduct 52 was
not detected as it readily underwent loss of water to give
53.
A synthetic sequence in which cyclic amidofurans
would be elaborated from amidooxazoles seemed attrac-
tive. Oxazoles have been extensively used as azadienes
in cycloadditions,41 particularly for the synthesis of furans
by the J acobi bis-heteroannulation procedure.42 The
feasibility of this approach clearly hinged upon 2-ami-
dooxazoles undergoing [4 + 2]-cycloaddition chemistry
with acetylenic dipolarophiles.43 Since this tactic was the
focal point of our plan, we opted to first verify the viability
of this reaction. Unlike the 2-aminofuran system,44
2-amino-substituted oxazoles are quite stable and do not
undergo ready hydrolysis. Preparation of 2-aminooxazole
49 was easily accomplished by acylation of the readily
available amine.45 We were gratified to find that the
reaction of 49 with dimethyl acetylenedicarboxylate
proceeded smoothly to give 2-acetamidofuran 50 in 92%
yield.
To further illustrate the scope and utility of the
amidooxazole cycloaddition sequence, we examined the
thermal behavior of oxazole 54 where an acetylenic
π-bond has been tethered to the amido nitrogen atom.
We were pleased to find that heating a sample of 54 at
160 °C provided the expected amidofuran 55 in 85% yield.
(33) Martin, S. F. In The Alkaloids; Brossi, A., Ed.; Academic
Press: 1987; Vol. 30, pp 252-376.
(34) Llabres, J . M.; Viladomat, F.; Bastida, J .; Codina, C.; Rubiralta,
M. Phytochemistry 1986, 25, 2637.
(35) Ghosal, S.; Rao, P. H.; J aiswal, D. K.; Kumar, Y.; Frahm, A.
W. Phytochemistry 1981, 20, 2003.
(36) Chattopadhyay, S.; Chattopadhyay, U.; Marthur, P. P.; Saini,
K. S.; Ghosal, S. Planta Med. 1982, 49, 252.
(37) Black, D. St. C.; Keller, P. A.; Kumar, N. Tetrahedron 1993,
49, 151. Castedo, L.; Guitia´n, E.; Pe´rez, D. Tetrahedron Lett. 1992,
33, 2407. Castedo, L.; Guitia´n, E.; Meira´s, D. P. Tetrahedron Lett. 1990,
31, 2331.
(38) Grigg, R.; Teasdale, A.; Sridharan, V. Tetrahedron Lett. 1991,
32, 3859. Snieckus, V.; Siddiqui, M. A. Tetrahedron Lett. 1990, 31,
1523. Kanematsu, K.; Yasukouchi, T.; Hayakawa, K. Tetrahedron Lett.
1987, 28, 5895.
(39) Meyers, A. I.; Hutchings, R. H. Tetrahedron Lett. 1993, 34, 6185.
Hutchings, R. H.; Meyers, A. I. J . Org. Chem. 1996, 61, 1004 and
references cited therein.
(40) Banwell, M. G.; Bissett, B. D.; Busato, S.; Cowden, C. J .;
Hockless, D. C. R.; Holman, J . W.; Read, R. W.; Wu, A. W. J . Chem.
Soc., Chem. Commun. 1995, 2551.
We next focused our attention on the structurally
related acetylenic amidooxazole 57 which presented the
opportunity to further test the intramolecular cyclo-
addition/cycloreversion/bis-heteroannulation approach.42
The preparation of 57 involved a palladium-catalyzed
cross-coupling reaction of acetamidooxazole 56 with
trimethylsilylacetylene using the Sonogashira catalyst
system.49 Thermolysis of 57 proceeded smoothly at 200
°C to give the desired 2-amidofuran 58 in 93% yield.
Our planned approach toward hippadine involves the
preparation of an amidooxazole (i.e. 66) where the
carbonyl group of the amide has been switched from
(41) Turchi, I. J .; Dewar, M. J . S. Chem. Rev. 1975, 75, 389. Hassner,
A.; Fischer, B. Heterocycles 1993, 35, 1441.
(42) For leading references, see: J acobi, P. A. Advances in Hetero-
cyclic Natural Product Synthesis; Pearson, W. H., Ed.; J AI Press: 1992;
Vol. 2, pp 251-299.
(43) For an example of an earlier Diels-Alder reaction of a 2-amino-
substituted oxazole, see: Crank, G.; Khan, H. R. J . Heterocycl. Chem.
1985, 22, 1281.
(44) Lythgoe, D. J .; McClenaghan, I.; Ramsden, C. A. J . Heterocycl.
Chem. 1993, 30, 113. Bite, P.; Ramonczai, J .; Vargha, L. J . Am. Chem.
Soc. 1948, 70, 371. Edwards, W. R., J r.; Singleton, H. M. J . Am. Chem.
Soc. 1938, 60, 540. Marquis, R. Ann. Chim. Phys. 1905, 4, 196.
(45) Cockerill, A. F.; Deacon, A.; Harrison, R. G.; Osborne, D. J .;
Prime, D. M.; Ross, W. J .; Todd, A.; Verge, J . P. Synthesis 1976, 591.
(46) Kondrat’eva, G. Y. Khim. Nauka Prom. 1957, 2, 666. Kondrat’eva,
G. Y. Izv. Akad. Nauk SSSR, Ser. Khim. 1959, 484.
(47) Levin, J . I.; Weinreb, S. M. J . Am. Chem. Soc. 1983, 105, 1397.
Levin, J . I.; Weinreb, S. M. J . Org. Chem. 1984, 49, 4325.
(48) Subramanyam, C.; Noguchi, M.; Weinreb, S. M. J . Org. Chem.
1989, 54, 5580.
(49) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467.

3600 J . Org. Chem., Vol. 64, No. 10, 1999
Padwa et al.
Sch em e 7
“outside” the tether to the “inside” position. In an attempt
to work out the experimental conditions necessary for the
preparation of 66, we opted to first examine a simpler
model system. Bromoaryl amide 59 was cross-coupled
with TMS-acetylene. The initially formed alkyne 60 was
not isolated as it underwent ready intramolecular [4 +
2]-cycloaddition under the cross-coupling conditions (80
°C) to form the cyclic amidofuran 61 in 88% yield (Scheme
7). Similar results were obtained with the corresponding
methylenedioxy-substituted aromatic amides 62 and 65
which afforded furano[2,3-c]isoquinolones 64 and 67
under the cross-coupling conditions. The accelerating
effect encountered by having the carbonyl group internal
to the tether is probably related to a shortening of the
path between the ground state and the corresponding
transition state, thereby reducing the activation barrier.
Alternatively, the amido carbonyl could act as an electron
withdrawing group so as to activate the acetylenic π-bond
toward Diels-Alder cycloaddition. This rate enhance-
ment is clearly of synthetic advantage as it offers the
opportunity to facilitate the intramolecular [4 + 2]-cy-
cloaddition reaction of these systems.
Sch em e 8
Having established the suitability of the intramolecular
[4 + 2]-cycloaddition of 2-amidooxazoles as a method for
preparing cyclic 2-amidofurans, we turned our attention
to the application of the reaction toward the synthesis of
hippadine (47). A short route to this alkaloid was
achieved by the thermolysis of 67 as depicted in Scheme
8. The IMDAF reaction of furan 67 had to be carried out
at 320 °C in order for the [4 + 2]-cycloaddition to take
place across the unactivated alkenyl π-bond. The high
temperature (320 °C) required for the conversion of 67
to 68 may reflect the fact that, unlike all of the other
examples of this reaction, the flat tricyclic system of 67
imposes steric constraints on the orientation of the
olefinic side chain which makes it difficult to attain the
transition state required for the initial cycloaddition
reaction. As a consequence of the elevated temperatures
employed, desilylation of the trimethylsilyl group oc-
curred, and indolinone 68 was isolated in only 30% yield.
The above sequence constitutes a formal synthesis of
hippadine (47) based on the successful DDQ oxidation
of 68 to 47.39,40 Even though the critical IMDAF cyclo-
addition step proceeded in modest yield, the short
number of steps from easily available starting materials
suggests that this approach could be useful for the
synthesis of other members of the pyrrolophenanthridone
class of alkaloids.
procedure described here involves an intramolecular
Diels-Alder reaction of 2-amidofurans containing a
tethered alkenyl group on the nitrogen atom. When the
tethered olefin posseses a suitable leaving group or when
substituted alkynes are used, phenolic indolines and
tetrahydroquinolines are formed. Cyclic 2-amidofurans
were synthesized by using a related intramolecular
Diels-Alder reaction of 2-amido-substituted oxazoles
which contain a tethered alkyne. This transformation
represents a new route to this rare heterocyclic ring
system, and this protocol was used for a formal synthesis
of the pyrrolophenanthridone alkaloid hippadine. Further
applications of this cycloaddition approach toward other
alkaloids are in progress and will be reported in due
course.
Exp er im en ta l Section
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise noted,
all reactions were performed in flame-dried glassware under
an atmosphere of dry argon. Solutions were evaporated under
reduced pressure with a rotary evaporator, and the residue
was chromatographed on a silica gel column using an ethyl
acetate/hexane mixture as the eluent unless specified other-
wise. Solid samples were recrystallized from an ethyl acetate/
hexane solvent combination unless specified otherwise.
ter t-Bu tyl N-(3-Bu ten yl)-N-(2-fu r yl)ca r ba m a te (10). A
solution containing 2.0 g (11 mmol) of furan-2-yl carbamic acid
In conclusion, this paper describes a versatile new
approach toward indolines and tetrahydroquinolines that
contain various substitution patterns. The synthetic

Substituted Indoline and Tetrahydroquinoline Synthesis
J . Org. Chem., Vol. 64, No. 10, 1999 3601
tert-butyl ester (7),21 2.8 g (11 mmol) of tetrabutylammonium
bromide, and 2.5 mL (24 mmol) of 4-bromo-1-butene in 100
mL of CH2Cl2 at 0 °C was treated dropwise with a 50% aqueous
NaOH solution. The mixture was heated at reflux for 15 h,
cooled to room temperature, diluted with water, and extracted
with CH2Cl2. The combined organic phase was washed with 3
N HCl, water, and brine and dried over sodium sulfate. The
solvent was removed under reduced pressure, and the residue
was purified by silica gel chromatography to give 2.0 g (77%)
of 10 as a colorless oil: IR (neat) 3081, 2981, 1710, and 1614
cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.45 (s, 9H), 2.32 (dd, 2H,
J ) 14.4 and 7.2 Hz), 3.59 (m, 2H), 5.06 (m, 2H), 5.79 (m, 1H),
6.00 (brs, 1H), 6.33 (dd, 1H, J ) 3.0 and 2.1 Hz), and 7.18 (t,
1H, J ) 0.9 Hz); 13C NMR (CDCl3, 75 MHz) δ 28.1, 33.1, 47.9,
81.0, 101.2, 110.8, 116.6, 135.0, 138.0, 148.4, and 153.8. Anal.
Calcd for C13H19NO3: C, 65.80; H, 8.07; N, 5.90. Found: C,
65.89; H, 8.12; N, 5.81.
ter t-Bu tyl 2,3-Dih yd r oin d ole-1-ca r boxyla te (11). A 2.9
g (12 mmol) sample of carbamate 10 in 15 mL of benzene was
heated in a sealed tube at 165 °C for 16 h. After cooling to
room temperature, the solution was concentrated under
reduced pressure and the residue was purified by flash silica
gel chromatography to give 0.5 g (16%) of indoline 11 as a
white solid: mp 48-49 °C; IR (KBr) 3068, 2932, 1701, and
1481 cm-1; 1H NMR (DMSO-d6, 400 MHz) δ 1.49 (s, 9H), 3.01
(t, 2H, J ) 8.8 Hz), 3.86 (t, 2H, J ) 8.8 Hz), 6.87 (m, 1H), 7.11
(m, 2H), and 7.58 (brs, 1H); 13C NMR (DMSO-d6, 100 MHz) δ
27.2, 28.4, 47.4, 79.7, 114.6, 122.0, 124.6, 127.2, 130.9, 141.9,
and 151.4. Anal. Calcd for C13H17NO2: C, 71.21; H, 7.82; N,
6.38. Found: C, 71.08; H, 7.79; N, 6.37.
Indoline 11 was independently synthesized by treating a
2.0 g (17 mmol) sample of indoline with 0.2 g (1.7 mmol) of
dimethylaminopyridine in 75 mL of CH2Cl2 at 0 °C. To this
mixture was added 4.0 g (18 mmol) of di-tert-butyl dicarbonate.
After the addition was complete, the mixture was stirred at 0
°C for 1 h and then for an additional 30 min at room
temperature. The solution was quenched with 10 mL of a
saturated NaHCO3 solution, and the organic phase was
washed with water and brine and dried over MgSO4. Concen-
tration under reduced pressure followed by silica gel chroma-
tography gave 2.8 g (72%) of 11 as a white solid whose spectral
properties were indentical to those obtained from the Diels-
Alder reaction of carbamate 10.
The minor fraction isolated from the column contained 0.33
g (28%) of tert-butyl 6-hydroxy-3,4,5,6-tetrahydro-2H-quino-
line-1-carboxylate (13) which showed the following spectral
properties: IR (neat) 3415, 2943, 1708, and 1431 cm-1 1H
;
NMR (CDCl3, 400 MHz) δ 1.42 (s, 9H), 1.76 (p, 2H, J ) 6.0
Hz), 2.11 (m, 2H), 2.34 (m, 3H), 3.35 (m, 1H), 3.59 (m, 1H),
4.20 (m, 1H), 5.77 (dd, 1H, J ) 9.8 and 4.5 Hz), and 6.13 (d,
1H, J ) 9.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 23.2, 28.0, 28.3,
37.3, 44.0, 63.3, 80.6, 118.9, 124.1, 127.4, 129.5, and 153.9.
Anal. Calcd for C14H21NO3: C, 66.91; H, 8.42; N, 5.57. Found:
C, 66.88; H, 8.36; N, 5.52. Heating a sample of the above
alcohol in toluene at 165 °C for 24 h afforded 14 in 96% yield.
ter t-Bu tyl N-[2-(5-Meth ylfu r yl)]ca r ba m a te (15). A solu-
tion of 2.3 g (18 mmol) of 5-methylfuran-2-carboxylic acid, 5.8
g (21 mmol) of diphenylphosphoryl azide,27 and 2.2 g (22 mmol)
of triethylamine in 25 mL of tert-butyl alcohol was heated at
reflux for 15 h. The reaction mixture was cooled to room
temperature and poured into 250 mL of a saturated sodium
bicarbonate solution at 0 °C. The resulting precipitate was
collected by filtration, washed with 50 mL of H2O, and dried
under reduced pressure to give 3.1 g (87%) of 15 as a white
solid: mp 76-77 °C; IR (KBr) 3331, 1710, and 1550 cm-1; 1H
NMR (CDCl3, 400 MHz) δ 1.49 (s, 9H), 2.21 (s, 3H), 5.90 (brs,
2H), and 6.42 (brs, 1H); 13C NMR (CDCl3, 100 MHz) δ 13.3,
28.2, 81.0, 97.4, 106.7, 143.1, 146.2, and 152.4; HRMS calcd
for C10H15NO3 197.1052, found 197.1056.
ter t-Bu tyl N-(3-Bu ten yl)-N-[2-(5-m eth ylfu r yl)]ca r ba m -
a te (16). A solution containing 2.7 g (14 mmol) of furan 15,
1.9 g (48 mmol) of powdered sodium hydroxide, 3.9 g (28 mmol)
of potassium carbonate, and 0.5 g (1.38 mmol) of tetrabuty-
lammonium hydrogen sulfate in 50 mL of benzene was heated
at reflux for 30 min, and then 2.8 g (21 mmol) of 4-bro-
mobutene in 25 mL of benzene was added dropwise to the
solution. The mixture was heated at reflux for an additional
4 h, quenched with 50 mL of H2O, and extracted with CH2Cl2.
The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. The residue was sub-
jected to flash silica gel chromatography to give 2.4 g (68%) of
16 as a colorless oil: IR (neat) 2975, 1709, 1623, and 1573
1
cm-1; H NMR (CDCl3, 400 MHz) δ 1.44 (s, 9H), 2.24 (s, 3H),
2.32 (m, 2H), 3.57 (t, 2H, J ) 7.6 Hz), 5.01 (d, 1H, J ) 10.4
Hz), 5.07 (dd, 1H, J ) 16.8 and 1.6 Hz), 5.77 (m, 1H), 5.86
(brs, 1H), and 5.90 (brs, 1H); 13C NMR (CDCl3, 100 MHz) δ
13.5, 28.1, 33.0, 48.1, 80.6, 102.6, 106.4, 116.5, 135.0, 146.3,
147.7, and 154.0; HRMS calcd for C14H21NO3 251.1521, found
251.1520.
ter t-Bu tyl N-(4-P en ten yl)-N-(2-fu r yl)ca r ba m a te (12). A
solution containing 2.5 g (14 mmol) of carbamate 7, 4.4 g (14
mmol) of tetrabutylammonium bromide, and 3.6 mL (30 mmol)
of 5-bromo-1-pentene in 100 mL of CH2Cl2 at 0 °C was treated
dropwise with a 50% aqueous NaOH solution. The mixture
was heated at reflux for 18 h, cooled to room temperature, and
diluted with water, and the aqueous phase was extracted with
CH2Cl2. The combined organic phase was washed with 3 N
HCl, water, and brine and dried over Na2SO4. The solvent was
removed under reduced pressure, and the residue was purified
by silica gel chromatography to give 2.8 g (81%) of 12 as a
ter t-Bu t yl 2,3-Dih yd r o-5-m et h ylin d ole-1-ca r b oxyla t e
(17). A solution containing 0.18 g (0.7 mmol) of furan 16 in 12
mL of benzene was heated in a sealed tube at 160 °C for 15 h
under an argon atmosphere. The solvent was removed under
reduced pressure, and the residue was subjected to flash silica
gel chromatography to give 0.13 g (77%) of 17 as a white
solid: mp 101-102 °C; IR (KBr) 2925, 1701, 1623, and 1573
1
cm-1; H NMR (CDCl3, 400 MHz) δ 1.56 (s, 9H), 2.28 (s, 3H),
1
colorless oil: IR (neat) 3409, 2975, 2925, and 1716 cm-1; H
3.04 (t, 2H, J ) 8.4 Hz), 3.96 (brs, 2H), 6.96 (brs, 2H), and
7.72 (brs, 1H); 13C NMR (CDCl3, 100 MHz) δ 20.8, 27.3, 28.4,
47.6, 80.6, 114.3, 125.3, 127.7, 130.9, 131.5, 140.6, and 152.5.
Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found:
C, 72.02; H, 8.31; N, 5.99.
NMR (CDCl3, 300 MHz) δ 1.43 (s, 9H), 1.66 (p, 2H, J ) 7.5
Hz), 2.06 (dd, 2H, J ) 14.4 and 6.9 Hz), 3.55 (m, 2H), 5.01 (m,
2H), 5.77 (m, 1H), 5.90 (brs, 1H), 6.32 (dd, 1H, J ) 3.0 and
2.1 Hz), and 7.16 (t, 1H, J ) 0.9 Hz); 13C NMR (CDCl3, 75
MHz) δ 27.8, 28.1, 30.7, 48.1, 80.9, 101.0, 110.8, 114.9, 137.8,
137.9, 148.6, and 153.8. Anal. Calcd for C14H21NO3: C, 66.91;
H, 8.42; N, 5.57. Found: C, 66.85; H, 8.39; N, 5.54.
ter t-Bu tyl 1,2,3,4-Tetr a h yd r oqu in olin e-1-ca r boxyla te
(14). A 1.2 g (4.8 mmol) sample of carbamate 12 in 10 mL of
benzene was heated in a sealed tube at 165 °C for 18 h. After
cooling to room temperature, the solution was concentrated
under reduced pressure, and the residue was purified by flash
silica gel chromatography to give 0.37 g (33%) of 14 as a pale
yellow oil: IR (neat) 3066, 2930, 1704, and 1478 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 1.52 (s, 9H), 1.92 (m, 2H), 2.77 (t, 2H, J
) 6.6 Hz), 3.71 (m, 2H), 6.95-7.12 (m, 3H), and 7.64 (d, 1H,
J ) 8.1 Hz); 13C NMR (CDCl3, 100 MHz) δ 22.6, 27.5, 28.4,
44.6, 80.7, 123.2, 124.1, 125.7, 128.5, 129.9, 138.6, and 151.5.
Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found:
C, 72.11; H, 8.18; N, 5.93.
ter t-Bu tyl N-[2-(5-p-Nitr op h en ylfu r yl)]ca r ba m a te (18).
A solution of 3.0 g (13 mmol) of 5-(p-nitrophenyl)furan-2-
carboxylic, 3.9 g (14 mmol) of diphenylphosphoryl azide, and
1.5 g (15 mmol) of triethylamine in 50 mL of tert-butyl alcohol
was heated at reflux for 16 h. The reaction mixture was
quenched with H2O, washed with 300 mL of a saturated
sodium bicarbonate solution, and extracted with ether. The
combined organic layers were dried over MgSO4 and concen-
trated under reduced pressure. The residue was subjected to
flash silica gel chromatography to give 3.4 g (86%) of 18 as a
yellow solid: mp 147-148 °C; IR (KBr) 3407, 1706, 1557, 1331,
and 1160 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.53 (s, 9H), 6.22
(brs, 1H), 6.84 (d, 1H, J ) 3.6 Hz), 7.10 (brs, 1H), 7.59 (d, 2H,
J ) 9.2 Hz), and 8.17 (d, 2H, J ) 9.2 Hz); 13C NMR (CDCl3,
100 MHz) δ 28.1, 82.0, 96.1, 111.6, 122.6, 124.3, 136.1, 144.3,

3602 J . Org. Chem., Vol. 64, No. 10, 1999
Padwa et al.
145.5, 147.7, and 150.9. Anal. Calcd for C15H16N2O5: C, 59.21;
H, 5.30; N, 9.21. Found: C, 59.01; H, 5.31; N, 9.00.
H2O, and extracted with ether. The combined organic layers
were dried over MgSO4 and concentrated under reduced
pressure. The residue was subjected to flash silica gel chro-
matography to give 0.7 g (44%) of 26 as a light yellow oil: IR
(neat) 1713, 1610, 1391, and 1149 cm-1; 1H NMR (CDCl3, 400
MHz) δ 1.46 (s, 9H), 2.51 (t, 2H, J ) 7.2 Hz), 3.79 (t, 2H, J )
7.2 Hz), 4.96 (s, 1H), 5.22 (s, 1H), 5.98 (s, 1H), 6.33 (dd, 1H, J
) 7.2 and 2.0 Hz), 7.16 (dd, 1H, J ) 2.0 and 0.8 Hz), 7.29-
7.35 (m, 3H), and 7.40-7.43 (m, 2H); 13C NMR (CDCl3, 100
MHz) δ 28.4, 35.8, 48.0, 81.4, 101.2, 111.1, 115.0, 128.0, 129.3,
133.0, 133.3, 138.1, 142.6, 148.6, and 153.8; HRMS calcd for
ter t-Bu tyl N-(3-Bu ten yl)-N-[2-(5-p-n itr op h en ylfu r yl)]-
ca r ba m a te (19). A solution containing 1.0 g (3.2 mmol) of
furan 18, 0.5 g (13 mmol) of powdered sodium hydroxide, 2.3
g (17 mmol) of potassium carbonate, and 0.1 g (0.3 mmol) of
tetrabutylammonium hydrogen sulfate in 25 mL of benzene
was heated at reflux for 30 min, and then 0.6 g (4.4 mmol) of
4-bromobutene in 5 mL of benzene was added dropwise to the
solution. The mixture was heated at reflux for an additional
2 h, quenched with 25 mL of H2O, and extracted with CH2Cl2.
The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. The residue was sub-
jected to flash silica gel chromatography to give 1.0 g (95%) of
19 as a yellow solid: mp 44-45 °C; IR (KBr) 1715, 1514, and
1335 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.49 (s, 9H), 2.40 (m,
2H), 3.78 (m, 2H), 5.07 (m, 2H), 5.80 (m, 1H), 6.21 (brs, 1H),
6.85 (d, 1H, J ) 3.6 Hz), 7.64 (d, 2H, J ) 8.8 Hz), and 8.18 (d,
2H, J ) 8.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 28.0, 33.2, 47.2,
81.8, 102.2, 111.0, 117.0, 122.8, 124.2, 134.7, 136.2, 145.7,
145.8, 150.1, and 152.7. Anal. Calcd for C19H22N2O5: C, 63.68;
H, 6.19; N, 7.82. Found: C, 63.63; H, 6.13; N, 7.76.
C
19H23NO3S 345.1399, found 345.1399.
ter t-Bu tyl 5-Hyd r oxy-2,3-d ih yd r oin d ole-1-ca r boxyla te
(25). A solution containing 0.15 g (0.4 mmol) of furan 26 in 10
mL of benzene was heated in a sealed tube at 160 °C for 6 h
under an argon atmosphere. The solvent was removed under
reduced pressure, and the residue was subjected to flash silica
gel chromatography to give 0.09 g (87%) of 25 as a white solid
after recrystallization: mp 162-163 °C; IR (KBr) 3370, 1655,
1
1487, 1365, and 1132 cm-1; H NMR (DMSO-d6, 400 MHz) δ
1.49 (s, 9H), 2.96 (t, 2H, J ) 6.4 Hz), 3.84 (t, 2H, J ) 6.4 Hz),
6.53 (d, 1H, J ) 6.4 Hz), 6.62 (s, 1H), and 7.22-7.42 (m, 2H);
13C NMR (DMSO-d6, 100 MHz) δ 26.7, 27.9, 47.2, 79.4, 112.0,
112.9, 114.4, 128.8, 131.5, 151.5, and 152.6. Anal. Calcd for
ter t-Bu tyl 2,3-Dih yd r o-5-(p-n itr op h en yl)in d ole-1-ca r -
boxyla te (20). A solution of 0.1 g (0.3 mmol) of furan 19 in
12 mL of benzene was heated in a sealed tube at 165 °C for
15 h under an argon atmosphere. The solvent was removed
under reduced pressure, and the residue was subjected to flash
silica gel chromatography to give 0.06 g (57%) of 20 as yellow
C
13H17NO3: C, 66.36; H, 7.28; N, 5.95. Found: C, 66.38; H,
7.33; N, 5.92.
A small amount (<5%) of phenol 25 was also obtained from
the thermolysis of carbamate 24.
needles: mp 121-122 °C; IR (KBr) 1700, 1520, and 1349 cm-1
;
Eth yl N-(3-Br om o-3-bu ten yl)-N-(2-fu r yl)car bam ate (27).
A solution containing 0.5 g (3.2 mmol) of carbamate 6, 0.45 g
(11 mmol) of powdered sodium hydroxide, 0.9 g (6.4 mmol) of
potassium carbonate, and 0.2 g (0.6 mmol) of tetrabutyl-
ammonium hydrogen sulfate in 50 mL of benzene was heated
at reflux for 30 min, and then 0.8 g (3.9 mmol) of 2,4-dibromo-
1-butene50 in 5 mL of benzene was added dropwise to the
solution. The mixture was heated for an additional 4 h at
reflux, quenched with 40 mL of H2O, and extracted with CH2-
Cl2. The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. The residue was sub-
jected to flash silica gel chromatography to give 0.02 g (40%)
of 27 as a pale yellow oil: IR (neat) 2982, 1716, 1609, 1410,
1H NMR (CDCl3, 400 MHz) δ 1.58 (s, 9H), 3.16 (t, 2H, J ) 8.8
Hz), 4.03 (t, 2H, J ) 8.8 Hz), 7.41 (s, 1H), 7.43 (d, 1H, J ) 8.4
Hz), 7.67 (d, 2H, J ) 8.8 Hz), 7.94 (brs, 1H), and 8.23 (d, 2H,
J ) 8.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 27.1, 28.4, 47.8,
80.9, 114.9, 123.5, 124.0, 126.9, 127.0, 132.3, 132.4, 144.0.
146.4, 147.3, and 152.4. Anal. Calcd for C19H20N2O4: C, 67.03;
H, 5.93; N, 8.23. Found: C, 67.06; H, 5.91; N, 8.18.
ter t-Bu tyl N-(3-Br om o-3-bu ten yl)-N-(2-fu r yl)ca r ba m -
a te (24). To a solution containing 0.2 g (1.0 mmol) of carbam-
ate 7 and 15 mL of CH2Cl2 at room temperature was added
0.1 g (3 mmol) of sodium hydroxide, 0.2 g (2 mmol) of
potassium carbonate, 0.4 g (1.3 mmol) of tetrabutylammonium
bromide, and 0.8 g (3.8 mmol) of 2,4-dibromo-1-butene.50 The
mixture was heated at reflux for 12 h, quenched with 25 mL
of H2O, and extracted with CH2Cl2. The combined organic
layers were dried over MgSO4 and concentrated under reduced
pressure. The residue was subjected to flash silica gel chro-
matography to give 0.07 g (90%) of 24 as a pale yellow oil: IR
(neat) 2979, 2117, 1717, 1631, and 1614 cm-1; 1H NMR (CDCl3,
400 MHz) δ 1.46 (s, 9H), 2.70 (t, 2H, J ) 6.8 Hz), 3.78 (t, 2H,
J ) 7.2 Hz), 5.45-5.45 (m, 1H), 5.62-5.63 (m, 1H), 6.02 (brs,
1H), 6.34-6.35 (m, 1H), and 7.18-7.19 (m, 1H); 13C NMR
(CDCl3, 100 MHz) δ 28.2, 28.4, 47.4, 81.7, 101.7, 111.2, 118.9,
130.6, 138.4, 148.4, and 153.9; HRMS calcd for C13H18NO3Br
315.0471, found 315.0470.
ter t-Bu tyl N-(3-P h en ylth io-3-bu ten yl)-N-(2-fu r yl)ca r -
ba m a te (26). To a solution containing 1.0 g (5.6 mmol) of
3-phenylthio-3-butenol51 and 0.9 mL (6.7 mmol) of triethyl-
amine in 20 mL of CH2Cl2 was added dropwise 0.5 mL (6.1
mmol) of methanesulfonyl chloride at 0 °C. After the addition,
the mixture was stirred overnight at room temperature and
quenched with brine, and the aqueous phase was extracted
with CH2Cl2. The combined organic phase was washed with
brine, dried over MgSO4, and concentrated under reduced
pressure to give 1.4 g (100%) of the crude mesylate as an oil
which was used in the next step without further purification.
To a solution containing 0.9 g (4.6 mmol) of carbamate 7 in
8 mL of DMF was added 4.5 g (14 mmol) of CsCO3. The
mixture was stirred for 30 min at 60 °C, and 1.4 g (5.6 mmol)
of the above mesylate in 2 mL of THF was added. The resulting
mixture was heated at 60 °C for 7 h, quenched with 20 mL of
1
and 1203 cm-1; H NMR (CDCl3, 400 MHz) δ 1.24 (brs, 3H),
2.71 (dt, 2H, J ) 7.2 and 0.8 Hz), 3.82 (t, 2H, J ) 7.2 Hz),
4.18 (q, 2H, J ) 6.4 Hz), 5.45 (d, 1H, J ) 1.6 Hz), 5.62-5.63
(m, 1H), 6.05 (brs, 1H), 6.36 (dd, 1H, J ) 3.4 and 1.8 Hz), and
7.20-7.21 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.6, 40.7,
47.8, 62.6, 102.8, 111.2, 118.9, 130.5, 138.9, 147.8, 155.0;
HRMS calcd for C11H14NO3Br 287.0158, found 287.0156.
Eth yl 5-Hyd r oxy-2,3-d ih yd r oin d ole-1-ca r boxyla te (28).
A solution of 0.08 g (0.3 mmol) of furan 27 in 10 mL of benzene
was heated in a sealed tube at 160 °C for 7 h under an argon
atmosphere. The solvent was removed under reduced pressure,
and the residue was subjected to flash silica gel chromatog-
raphy to give 0.07 g (80%) of 28 as a white solid: mp 126-
1
127 °C; IR (KBr) 3514, 1743, 1708, 1600, and 1507 cm-1; H
NMR (DMSO-d6, 400 MHz) δ 1.24 (brs, 3H), 2.99 (t, 2H, J )
8.4 Hz), 3.88 (t, 2H, J ) 8.4 Hz), 4.14 (brs, 2H), 6.34 (d, 1H, J
) 8.8 Hz), 6.62 (s, 1H), 7.49 (s, 1H), and 9.07 (s, 1H); 13C NMR
(DMSO-d6, 100 MHz) δ 14.6, 27.1, 47.1, 60.6, 112.1, 113.0,
114.4, 132.5, 134.5, 152.9, and 153.0. Anal. Calcd for C11H13
-
O3N: C, 63.76; H, 6.32; N, 6.76. Found: C, 63.73; H, 6.38; N,
6.73.
ter t-Bu t yl N-(3-P en t yn yl)-N-(2-fu r yl)ca r b a m a t e (29).
To a solution containing 2.5 g (14 mmol) of carbamate 7 and
100 mL of a 4:1 DMF/THF mixture at room temperature was
added 6.2 g (19 mmol) of CsCO3. The mixture was stirred at
room temperature for 45 min and then charged with 5.0 g (34
mmol) of 5-bromo-2-pentyne.52 The solution was heated at 70
°C for 6 h, quenched with 50 mL of H2O, and extracted with
ether. The combined organic layers were dried over MgSO4
and concentrated under reduced pressure. The residue was
subjected to flash silica gel chromatography to give 0.9 g (78%)
(50) Barton, T. J .; Lin, J .; Ijadi-Maghsoodi, S.; Power, M. D.; Zhang,
X.; Ma, Z.; Shimizu, H.; Gordon, M. S. J . Am. Chem. Soc. 1995, 117,
11695.
(51) Perron, F.; Albizati, K. F. J . Org. Chem. 1987, 52, 4128.
(52) Flahaut, J .; Miginiac, P. Helv. Chim. Acta 1978, 61, 2275.

Substituted Indoline and Tetrahydroquinoline Synthesis
J . Org. Chem., Vol. 64, No. 10, 1999 3603
of 29 as a colorless oil: IR (neat) 2975, 1709, 1609, and 1367
cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.44 (s, 9H), 1.74 (t, 3H, J
) 2.6 Hz), 2.37-2.42 (m, 2H), 3.66 (t, 2H, J ) 7.6 Hz), 6.02
mesylate in 5 mL of benzene was added dropwise to the
solution. The mixture was heated at reflux for 5 h, quenched
with 25 mL of H2O, and extracted with CH2Cl2. The combined
organic layers were dried over MgSO4 and concentrated under
reduced pressure. The residue was subjected to flash silica gel
chromatography to give 0.04 g (9%) of 33 as a colorless oil: IR
(neat) 3127, 2953, 2234, 1732, and 1613 cm-1; 1H NMR (CDCl3,
400 MHz) δ 1.24-1.25 (m, 3H), 1.87 (pent, 2H, J ) 7.2 Hz),
2.39 (t, 2H, J ) 7.2 Hz), 3.69 (t, 2H, J ) 7.2 Hz), 3.75 (s, 3H),
4.18 (q, 2H, J ) 6.4 Hz), 6.06 (brs, 1H), 6.36 (dd, 1H, J ) 3.2
and 2.0 Hz), and 7.20 (d, 1H, J ) 1.2 Hz); 13C NMR (CDCl3,
100 MHz) δ 14.6, 16.3, 26.9, 52.8, 62.6, 73.4, 77.5, 88.7, 102.2,
(brs, 1H), 6.32 (t, 1H, J ) 2.4 Hz), and 7.16-7.17 (m, 1H); 13
C
NMR (CDCl3, 100 MHz) δ 3.7, 19.1, 28.4, 48.0, 75.9, 77.2, 81.4,
101.5, 111.1, 138.3, 148.5, and 153.8. Anal. Calcd for C14H19
-
NO3: C, 67.45; H, 7.68; N, 5.62. Found: C, 67.54; H, 7.74; N,
5.55.
ter t-Bu t yl 5-H yd r oxy-4-m et h yl-2,3-d ih yd r oin d ole-1-
ca r boxyla te (30). A solution of 0.7 g (2.6 mmol) of furan 29
in 15 mL of benzene was heated in a sealed tube at 170 °C for
24 h under an argon atmosphere. The solvent was removed
under reduced pressure, and the residue was subjected to flash
silica gel chromatography to give 0.17 g (25%) of 30 as a white
solid: mp 213-214 °C; IR (KBr) 3267, 2975, 1645, 1602, and
1481 cm-1; 1H NMR (DMSO-d6, 400 MHz) δ 1.49 (s, 9H), 2.00
(s, 3H), 2.91 (t, 2H, J ) 8.4 Hz), 3.85 (t, 2H, J ) 8.4 Hz), 6.55
(d, 1H, J ) 8.8 Hz), 7.21 (s, 1H), and 8.67 (s, 1H); 13C NMR
(DMSO-d6, 100 MHz) δ 12.1, 26.2, 28.4, 47.6, 79.7, 111.8, 112.9,
111.3, 138.9, 147.8, 154.3, and 155.5; HRMS calcd for C14H17
NO5 279.1107, found 279.1103.
-
6-Hyd r oxy-1,2,3,4-tetr a h yd r oqu in olin e-1,5-d ica r boxy-
lic Acid 1-Eth yl 5-Meth yl Diester (34). A solution contain-
ing 0.1 g (0.4 mmol) of furan 33 in 12 mL of benzene was
heated in a sealed tube at 175 °C for 8 h under an argon
atmosphere. The solvent was removed under reduced pressure,
and the residue was subjected to flash silica gel chromatog-
raphy to give 0.08 g (88%) of 34 as a white solid: mp 106-
113.0, 120.8, 131.7, 150.9, and 151.9. Anal. Calcd for C14H19
-
O3N: C, 67.45; H, 7.68; N, 5.62. Found: C, 67.33; H, 7.74; N,
5.64.
1
107 °C; IR (KBr) 1697, 1655, 1592, and 1446 cm-1; H NMR
(CDCl3, 400 MHz) δ 1.29 (t, 3H, J ) 6.8 Hz), 1.89 (p, 2H, J )
6.4 Hz), 3.04 (t, 2H, J ) 6.8 Hz), 3.68 (t, 2H, J ) 6.0 Hz), 3.96
(s, 3H), 4.21 (q, 2H, J ) 7.2 Hz), 6.84 (d, 1H, J ) 8.8 Hz), 7.60
(d, 1H, J ) 8.8 Hz), and 10.35 (s, 1H); 13C NMR (CDCl3,100
MHz) δ 14.8, 24.1, 26.9, 44.0, 52.5, 62.1, 111.5, 115.5, 131.3,
Eth yl N-(3-P en tyn yl)-N-(2-fu r yl)ca r ba m a te (31). A so-
lution containing 0.5 g (3.2 mmol) of carbamate 6, 0.45 g (11
mmol) of sodium hydroxide, 0.9 g (6.4 mmol) of potassium
carbonate, and 0.2 g (0.6 mmol) of tetrabutylammonium
hydrogen sulfate in 50 mL of benzene was heated at reflux
for 30 min, and then 1.1 g (7.8 mmol) of 5-bromo-2-pentyne52
in 5 mL of benzene was added dropwise to the solution. The
mixture was heated at reflux for 5 h, quenched with 50 mL of
H2O, and extracted with CH2Cl2. The combined organic layers
were dried over MgSO4 and concentrated under reduced
pressure. The residue was subjected to flash silica gel chro-
matography to give 0.44 g (72%) of 31 as a colorless oil: IR
(neat) 2918, 1716, 1609, 1410, and 1296 cm-1; 1H NMR (CDCl3,
400 MHz) δ 1.24 (t, 3H, J ) 6.0 Hz), 1.75 (t, 3H, J ) 2.4 Hz),
2.39-2.45 (m, 2H), 3.71 (t, 2H, J ) 8.0 Hz), 4.18 (q, 2H, J )
6.0 Hz), 6.07 (brs, 1H), 6.35 (dd, 1H, J ) 3.2 and 2.4 Hz), and
7.19 (d, 1H, J ) 0.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 3.5,
14.5, 18.9, 48.3, 62.3, 75.7, 77.4, 102.6, 111.0, 138.7, 147.8, and
154.8; HRMS calcd for C12H15NO3 231.1052, found 231.1057.
132.5, 133.6, 155.4, 159.4, and 171.9. Anal. Calcd for C14H17
-
O5N: C, 60.21; H, 6.14; N, 5.02. Found: C, 60.11; H, 6.08; N,
4.91.
Eth yl N-(4-Hexyn l)-N-(2-fu r yl)ca r ba m te (35). To a solu-
tion containing 5.0 g (51 mmol) of 4-hexyn-1-ol54 in 200 mL of
CH2Cl2 at 0 °C were added 7.7 g (76 mmol) of triethylamine
and 6.4 g (56 mmol) of methanesulfonyl chloride. The solution
was stirred at 0 °C for 1 h, quenched with 50 mL of H2O, and
extracted with ether. The combined organic layers were dried
over MgSO4 and concentrated under reduced pressure to give
8.9 g (100%) of methanesulfonic acid hex-4-ynyl ester as a
colorless oil which was used in the next step without further
purification.
A solution containing 4.0 g (26 mmol) of carbamate 6, 21 g
(52 mmol) of sodium hydroxide, 7.1 g (52 mmol) of potassium
carbonate, and 1.8 g (5.2 mmol) of tetrabutylammonium
hydrogen sulfate in 300 mL of benzene was heated at reflux
for 30 min, and then 6.8 g (40 mmol) of the above mesylate in
25 mL of benzene was added dropwise to the solution. The
mixture was heated for 3 h at reflux, quenched with 120 mL
of H2O, and extracted with CH2Cl2. The combined organic
layers were dried over MgSO4 and concentrated under reduced
pressure. The residue was subjected to flash silica gel chro-
matography to give 3.7 g (61%) of 35 as a colorless oil: IR
(neat) 3120, 2939, 1711, 1613, and 1397 cm-1; 1H NMR (CDCl3,
400 MHz) δ 1.20 (t, 3H, J ) 6.8 Hz), 1.68-1.76 (m, 5H), 2.11-
2.16 (m, 2H), 3.64 (t, 2H, J ) 7.6 Hz), 4.14 (q, 2H, J ) 6.8
Hz), 6.02 (brs, 1H), 6.32 (dd, 1H, J ) 3.2 and 2.4 Hz), and
7.16-7.17 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 3.6, 14.6,
16.3, 28.1, 48.5, 62.3, 76.0, 78.1, 102.2, 111.1, 138.7, 148.1, and
155.1. Anal. Calcd for C13H17NO3: C, 66.36; H, 7.28; N, 5.95.
Found: C, 66.60; H, 7.21; N, 5.88.
6-Hyd r oxy-5-m eth yl-1,2,3,4-tetr a h yd r oqu in olin e-1-ca r -
boxylic Acid Eth yl Ester (36). A solution of 1.2 g (5 mmol)
of furan 35 in 12 mL of benzene was heated in a sealed tube
at 210 °C for 8 h under an argon atmosphere. The solvent was
removed under reduced pressure, and the residue was sub-
jected to flash silica gel chromatography to give 0.4 g (80%) of
36 as a white solid: mp 115-116 °C; IR (KBr) 3336, 2939,
1662, 1585, and 1488 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.30
(t, 3H, J ) 7.2 Hz), 1.95 (pent, 2H, J ) 6.0 Hz), 2.11 (s, 3H),
2.66 (t, 2H, J ) 6.8 Hz), 3.69-3.73 (m, 2H), 4.23 (q, 2H, J )
7.2 Hz), 6.56 (brs, 1H), 6.63 (d, 1H, J ) 8.4 Hz), and 7.24 (d,
1H, J ) 8.4 Hz); 13C NMR (CDCl3,100 MHz) δ 11.4, 14.7, 23.6,
Eth yl 5-Hydr oxy-4-m eth yl-2,3-d ih yd r oin d ole-1-ca r box-
yla te (32). A solution of 0.4 g (1.7 mmol) of furan 31 in 12 mL
of benzene was heated in a sealed tube at 210 °C for 8 h under
an argon atmosphere. The solvent was removed under reduced
pressure, and the residue was subjected to flash silica gel
chromatography to give 0.3 g (82%) of 32 as a white solid: mp
184-185 °C; IR (KBr) 3288, 2975, 1680, 1602, and 1488 cm-1
;
1H NMR (DMSO-d6, 400 MHz) δ 1.26 (t, 3H, J ) 7.2 Hz), 2.01
(s, 3H), 2.94 (t, 2H, J ) 8.8 Hz), 3.91 (t, 2H, J ) 8.8 Hz), 4.16
(q, 2H, J ) 7.2 Hz), 6.58 (d, 1H, J ) 8.4 Hz), 7.27 (s, 1H), and
8.74 (s, 1H); 13C NMR (DMSO-d6, 60 °C, 100 MHz) δ 11.7, 14.3,
25.9, 46.9, 60.3, 111.3, 112.6, 120.4, 131.2, 133.7, 150.7, and
152.2. Anal. Calcd for C12H15O3N: C, 65.14; H, 6.83; N, 6.33.
Found: C, 64.90; H, 6.85; N, 6.23.
Eth yl N-(2-F u r yl)-N-(5-ca r bom eth oxy-4-p en tyn yl)ca r -
ba m a te (33). To a solution containing 2.0 g (14.1 mmol) of
methyl 6-hydroxy-2-hexynoate53 in 100 mL of CH2Cl2 at 0 °C
were added 2.1 g (21 mmol) of triethylamine and 1.8 g (16
mmol) of methanesulfonyl chloride. The solution was stirred
at 0 °C for 1 h, quenched with 25 mL of H2O, and extracted
with ether. The combined organic layers were dried over
MgSO4 and concentrated under reduced pressure to give 3.2
g (100%) of 6-methanesulfonylhex-2-ynoic acid methyl ester
as a pale yellow oil which was used in the next step without
further purification.
A solution containing 0.3 g (1.7 mmol) of carbamate 6, 0.01
g (2.5 mmol) of sodium hydroxide, 0.5 g (3.4 mmol) of
potassium carbonate, and 0.1 g (0.4 mmol) of tetrabutyl-
ammonium hydrogen sulfate in 35 mL of benzene was heated
at reflux for 30 min, and then 0.8 g (3.5 mmol) of the above
(53) Kita, Y.; Okunaka, R.; Honda, T.; Shindo, M.; Taniguchi, M.;
Kondo, M.; Sasho, M. J . Org. Chem. 1991, 56, 119.
(54) Semmelhack, M. F.; Bozell, J . J .; Keller, L.; Sato, T.; Spiess, E.
J .; Wulff, W.; Zask, A. Tetrahedron 1985, 41, 5803.

3604 J . Org. Chem., Vol. 64, No. 10, 1999
Padwa et al.
25.0, 44.1, 62.1, 112.7, 122.2, 122.7, 130.1, 131.1, 150.8, and
155.6. Anal. Calcd for C13H17O3N: C, 66.35; H, 7.29; N, 5.96.
Found: C, 66.67; H, 7.30; N, 5.97.
and 170.4. Anal. Calcd for C18H19NO2: C, 76.84; H, 6.81; N,
4.98. Found: C, 76.57; H, 6.86; N, 4.91.
N-(F u r a n -2-yl)-2-vin ylben za m id e (41). To a mixture
containing 0.2 g (6 mmol) of magnesium metal in 10 mL of
ether at room temperature were added 0.5 mL (4.0 mmol) of
2-bromostyrene and 10 mg (0.04 mmol) of 1,2-diiodoethane.
The suspension was heated at reflux for 30 min and then
stirred at room temperature for 8 h. The phenyl Grignard
reagent was transferred via cannula through a pad of glass
wool into a flask at 0 °C. To this Grignard solution was added
via cannula a sample of 2-furyl isocyanate (8) at 0 °C which
was prepared by heating 0.5 g (4.0 mmol) of 2-furoyl azide (5)
in 40 mL of a 2:1-benzene-toluene mixture for 2 h. The
solution was allowed to warm to room temperature and was
stirred for an additional 1 h. The resulting mixture was diluted
with ether, quenched with aqueous NH4Cl, and extracted with
ether. The combined organic layers were dried over Na2SO4,
and the solvent was removed under reduced pressure. The
residue was subjected to flash silica gel chromatography to
give 0.27 g (32%) of 41 as an orange solid: mp 92-93 °C; IR
(KBr) 3241, 1656, and 1551 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 5.40 (d, 1H, J ) 11.2 Hz), 5.73 (dd, 1H, J ) 9.4 and 1.0 Hz),
6.41 (t, 1H, J ) 2.4 Hz), 6.46 (d, 1H, J ) 3.2 Hz), 7.05-7.12
(m, 2H), 7.30 (t, 1H, J ) 7.6 Hz), 7.43 (t, 1H, J ) 7.4 Hz),
7.52-7.58 (m, 2H), and 8.16 (brs, 1H); 13C NMR (CDCl3, 100
MHz) δ 95.3, 111.5, 117.6, 126.7, 127.6, 127.8, 130.9, 133.5,
Hex-4-en oic Acid F u r a n -2-yl Am id e (37). To a solution
containing 1.2 g (6.0 mmol) of (E)-5-iodo-2-pentene55 in 10 mL
of ether at - 78 °C was added 8.1 mL (13.0 mmol) of 1.6 M
t-BuLi. The mixture was stirred at -78 °C for 30 min and then
allowed to warm to room temperature. The resulting mixture
was transferred via cannula through a pad of glass wool to a
suspension of 0.25 g (2.8 mmol) of CuCN in 6 mL of THF at
-78 °C. The organocopper reagent was stirred at -78 °C for
1 h, and then 2-furoyl isocyanate (8) was transferred via
cannula to the solution at -78 °C. The 2-furyl isocyanate (8)
was prepared by heating 0.6 g (2.8 mmol) of 2-furoyl azide (5)
in 30 mL of a 2:1-benzene-toluene mixture at reflux for 2 h.
After cannulation, the mixture was warmed to room temper-
ature and stirred for 1 h. The mixture was diluted with ether,
quenched with 10 mL of NH4Cl, and extracted with ether. The
combined organic layers were dried over Na2SO4, and the
solvent was evaporated under reduced pressure. The residue
was subjected to flash silica gel chromatography to give 0.2 g
(42%) of 37 as a white solid: mp 65-66 °C; IR (KBr) 3203,
3063, 1667, and 1560 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.66
(d, 3H, J ) 6.0 Hz), 2.41 (m, 4H), 5.44-5.55 (m, 2H), 6.31 (d,
1H, J ) 3.2 Hz), 6.34 (m, 1H), 7.04 (d, 1H, J ) 0.8 Hz), and
7.61 (brs, 1H); 13C NMR (CDCl3, 100 MHz) δ 17.9, 28.2, 36.5,
95.2, 111.5, 127.0, 129.0, 135.2, 145.0, and 168.8. Anal. Calcd
for C10H13NO2: C, 67.02; H, 7.31; N, 7.82. Found: C, 67.30;
H, 7.32; N, 7.68.
134.3, 135.4, 136.4, 145.2, and 164.9. Anal. Calcd for C13H11
-
NO2: C, 73.23; H, 5.20; N, 6.57. Found: C, 73.53; H, 5.25; N,
6.52.
5-Meth yl-1,2,3,4-tetr a h yd r oqu in olin -2-on e (39). A solu-
tion of 0.2 g (0.8 mmol) of furan 37 in 10 mL of toluene was
heated in a sealed tube at 200 °C for 36 h under an argon
atmosphere. The solvent was removed under reduced pressure,
and the residue was subjected to flash silica gel chromatog-
raphy to give 0.12 g (89%) of 39 as a white solid: mp 163-
5H-P h en a n th r id in -6-on e (42). A solution containing 0.18
g (0.8 mmol) of benzamide 41 in 10 mL of toluene in a sealed
tube was heated at 160 °C for 4 days. Removal of the solvent
under reduced pressure followed by silica gel chromatography
1
gave 0.16 g (97%) of 42 as a white solid: mp 290-292 °C; H
NMR (DMSO-d6, 400 MHz) δ 3.50 (brs, 1H), 7.27 (m, 1H), 7.37
(dd, 1H, J ) 8.0 and 1.2 Hz), 7.49 (m, 1H), 7.65 (m, 1H), 7.86
(dt, 1H, J ) 7.4 and 1.2 Hz), 8.32 (dd, 1H, J ) 8.0 and 1.2
Hz), 8.40 (m, 1H) and 8.51 (d, 1H, J ) 8.0 Hz). Structure 42
was unequivocally established by comparison with an authen-
tic sample acquired from Aldrich Chemical Co.
1
164 °C; IR (KBr) 3438, 3196, 1676, and 1393 cm-1; H NMR
(CDCl3, 400 MHz) δ 2.29 (s, 3H), 2.64 (t, 2H, J ) 7.6 Hz), 2.92
(t, 2H, J ) 7.6 Hz), 6.69 (d, 1H, J ) 8.0 Hz), 6.86 (d, 1H, J )
7.6 Hz), 7.07 (t, 1H, J ) 7.6 Hz), and 9.03 (brs, 1H); 13C NMR
(CDCl3, 100 MHz) δ 19.3, 21.9, 30.3, 113.5, 121.9, 124.9, 127.0,
136.0, 137.2, and 171.9. Anal. Calcd for C10H11NO: C, 74.51;
H, 6.88; N, 8.69. Found: C, 74.25; H, 6.90; N, 8.62.
E t h yl N-(6-Iod ob en zo[1,3]d ioxolo-5-ylm et h yl)-N-(2-
fu r yl)ca r ba m a te (44). A solution containing 1.1 g (7.3 mmol)
of carbamate 6, 1.0 g (26 mmol) of sodium hydroxide, 2.0 g
(14.7 mmol) of potassium carbonate, and 0.5 g (1.5 mmol) of
tetrabutylammonium hydrogen sulfate in 125 mL of benzene
was heated at reflux for 30 min, and then 3.0 g (9 mmol) of
5-bromomethyl-6-iodobenzo[1,3]dioxole56 in 20 mL of benzene
was added dropwise to the solution. The mixture was heated
at reflux for an additional 3 h, quenched with 50 mL of H2O,
and extracted with CH2Cl2. The combined organic layers were
dried over MgSO4 and concentrated under reduced pressure.
The residue was subjected to flash silica gel chromatography
to give 2.0 g (67%) of 44 as a white solid: mp 67-68 °C; IR
(KBr) 2987, 1725, 1585, 1523, and 1264 cm-1; 1H NMR (CDCl3,
400 MHz) δ 1.24 (t, 3H, J ) 6.8 Hz), 4.21 (q, 2H, J ) 6.8 Hz),
4.75 (s, 2H), 5.95 (s, 2H), 5.96 (brs, 1H), 6.30-6.31 (m, 1H),
6.89 (s, 1H), 7.17 (d, 1H, J ) 0.8 Hz), and 7.20 (s, 1H); 13C
NMR (CDCl3, 100 MHz) δ 14.7, 57.5, 62.8, 86.3, 101.9, 103.1,
108.6, 111.2, 118.7, 133.0, 138.9, 147.4, 147.9, 148.8, and 155.3.
Anal. Calcd for C15H14NO5: C, 43.39; H, 3.40; N, 3.37. Found:
C, 43.13; H, 3.38; N, 3.38.
Hex-4-en oic Acid F u r a n -2-yl(4-m eth oxyben zyl)a m id e
(38). A suspension containing 0.2 g (1.1 mmol) of 37, 0.2 g
(4.0 mmol) of powdered potassium hydroxide, 0.15 g (1.1 mmol)
of potasium carbonate, and 0.2 g (0.5 mmol) of tetrabutylam-
monium hydrogen sulfate in 5 mL of benzene was stirred at
room temperature for 1 h. To the above mixture was added
0.3 mL (2.2 mmol) of 4-methoxybenzyl chloride. After stirring
at room temperature for 4 h, the mixture was filtered through
a pad of Celite. The solvent was removed under reduced
pressure, and the residue was subjected to flash silica gel
chromatography to give 0.2 g (66%) of 38 as a colorless oil: IR
(neat) 2931, 1680, 1611, and 1513 cm-1; 1H NMR (CDCl3, 400
MHz) δ 1.60 (d, 3H, J ) 5.5 Hz), 2.18-2.20 (m, 2H), 2.24-
2.29 (m, 2H), 3.78 (s, 3H), 4.71 (s, 2H), 5.30-5.40 (m, 2H), 5.84
(d, 1H, J ) 3.2 Hz), 6.31 (m, 1H), 6.80-6.82 (m, 2H), 7.13-
7.16 (m, 2H), and 7.24 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ
17.9, 28.1, 33.9, 51.0, 55.2, 105.0, 111.0, 113.6, 125.8, 129.4,
129.6, 129.9, 140.0, 148.3, 158.9, and 173.5; HRMS calcd for
C
18H21NO3 299.1521, found 299.1520.
1-(4-Meth oxyben zyl)-5-m eth yl-1,2,3,4-tetr a h yd r oqu in -
E t h yl N-(6-Vin ylb en zo[1,3]d ioxolo-5-ylm et h yl)-N-(2-
fu r yl)ca r ba m a te (45). To a solution containing 0.1 g (0.2
mmol) of iodide 44 in 10 mL of dry THF were added 0.06 g
(0.05 mmol) of tetrakis(triphenylphosphine)palladium and 0.12
g (0.4 mmol) of tributyl(vinyl)tin. The solution was heated at
reflux for 8 h and quenched with 10 mL of a saturated KF
solution. The mixture was allowed to stir for 8 h at room
temperature, 25 mL of water was added, and the mixture was
extracted with ether. The combined organic layers were dried
over MgSO4 and concentrated under reduced pressure. The
residue was subjected to flash silica gel chromatography to
olin -2-on e (40). A solution of 0.2 g (0.7 mmol) of 39 in 10 mL
of toluene was heated in a sealed tube at 160 °C for 24 h. The
solvent was removed under reduced pressure, and the residue
was subjected to flash silica gel chromatography to give 0.2 g
(80%) of 40 as a white solid: mp 136-137 °C; IR (KBr) 1666,
1513, and 1250 cm-1 1H NMR (CDCl3, 400 MHz) δ 2.30 (s,
;
3H), 2.75 (m, 2H), 2.91 (m, 2H), 3.77 (s, 3H), 5.11 (s, 2H), 6.77-
6.86 (m, 4H), 7.01 (t, 1H, J ) 7.6 Hz), and 7.15 (m, 2H); 13C
NMR (CDCl3, 100 MHz) δ 19.7, 21.7, 31.5, 45.8, 55.2, 113.7,
114.1, 124.9, 126.8, 127.6, 129.2, 135.5, 139.5, 140.0, 158.6,
(55) Fisher, M. J .; Overman, L. E. J . Org. Chem. 1990, 55, 1447.
(56) Fuchs, P. L.; J in, Z. Tetrahedron Lett. 1993, 34, 5205.

Substituted Indoline and Tetrahydroquinoline Synthesis
J . Org. Chem., Vol. 64, No. 10, 1999 3605
give 0.06 g (72%) of 45 as a colorless oil: IR (neat) 2981, 1718,
1606, 1481, and 1034 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.23
(t, 3H, J ) 7.2 Hz), 4.20 (q, 2H, J ) 7.2 Hz), 4.79 (s, 2H), 5.16
(dd, 1H, J ) 11.0 and 1.2 Hz), 5.46 (dd, 1H, J ) 17.2 and 1.2
Hz), 5.87 (brs, 1H), 5.93 (s, 2H), 6.27 (dd, 1H, J ) 3.4 and 2.0
Hz), 6.72 (s, 1H), 6.78 (dd, 1H, J ) 17.2 and 11.0 Hz), 6.94 (s,
1H), and 7.16 (dd, 1H, J ) 2.0 and 0.8 Hz); 13C NMR (CDCl3,
100 MHz) δ 14.7, 49.8, 62.7, 101.3, 105.8, 109.2, 111.2, 114.9,
120.2, 128.4, 131.2, 133.5, 138.9, 139.0, 147.6, 149.8, and 155.4;
HRMS calcd for C17H17NO5 315.1107, found 315.1105.
in 40 mL of THF was added dropwise 4.5 mL (30 mmol) of
benzyl chloroformate at 0 °C. The resulting mixture was
heated at reflux for 24 h. The solvent was removed under
reduced pressure, and the residue was purified by silica gel
chromatography to give 2.9 g (43%) of the above carbamate
as a white solid: mp 138-139 °C; IR (neat) 3140, 1750, 1641,
1236, and 1082 cm-1 1H NMR (CDCl3, 300 MHz) δ 1.92 (s,
;
3H), 5.22 (s, 2H), 7.12 (s, 1H), 7.35-7.41 (m, 6H); 13C NMR
(CDCl3, 75 MHz) δ 11.2, 67.9, 128.7, 128.8, 129.0, 130.6, 135.1,
135.6, and 154.3; HRMS calcd for C12H12N2O3 232.0848, found
232.0855.
6a ,11a -Dih yd r o-6H-[1,3]d ioxolo[4,5-j]p h en a n th r id in e-
5-ca r boxylic Acid Eth yl Ester (46). A solution of 0.1 g (0.3
mmol) of furan 45 in 15 mL of toluene was heated at reflux
for 24 h under an argon atmosphere. The solvent was removed
under reduced pressure, and the residue was subjected to flash
silica gel chromatography to give 0.08 g (79%) of 46 as a
Oxa zol-2-ylp en t-4-yn ylca r ba m ic Acid Ben zyl Ester . A
mixture containing 1.7 g (7 mmol) of the above carbamate, 7.0
g (22 mmol) of CsCO3, 0.9 mL (9 mmol) of 5-chloropentyne,
and 0.05 g of potassium iodide in 16 mL of DMF and 4 mL of
THF was stirred at 60 °C for 36 h. The mixture was diluted
with water and extracted with ether, and the combined ether
layers were washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was purified
by silica gel chromatography to give 1.5 g (71%) of the above
carbamate as a yellow oil: IR (neat) 3298, 1728, 1578, 1402,
and 1098 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.88 (p, 2H, J )
7.2 Hz), 1.92 (t, 1H, J ) 2.8 Hz), 2.15 (d, 3H, J ) 1.2 Hz), 2.24
(dt, 2H, J ) 7.2 and 2.8 Hz), 3.90 (t, 2H, J ) 7.2 Hz), 5.24 (s,
2H), 7.22 (p, 1H, J ) 1.2 Hz), and 7.33-7.37 (m, 5H); 13C NMR
(CDCl3, 100 MHz) δ 12.0, 16.0, 27.5, 48.1, 68.4, 69.1, 83.2,
128.2, 128.4, 128.7, 132.5, 135.8, 136.7, 153.8, and 154.7;
HRMS calcd for C17H18N2O3 298.1317, found 298.1312.
6-(Ben zyloxyca r b on yloxa zol-2-yla m in o)h ex-2-yn oic
Acid Meth yl Ester (54). To a solution containing 1.0 g (3
mmol) of the above carbamate in 20 mL of THF at -78 °C
was added dropwise 4.0 mL (4.0 mmol) of a 2.0 M lithium bis-
(trimethylsilyl)amide/THF solution. The solution was stirred
at -78 °C for 1 h, and then 0.4 mL (5.0 mmol) of methyl
chloroformate was added. The resulting mixture was stirred
at -78 °C for 1 h and then at room temperature for 20 h and
was then partitioned between brine and ether. The ether layer
was dried over MgSO4 and concentrated under reduced pres-
sure. The residue was purified by silica gel chromatography
to give 0.8 g (72%) of 54 as a light yellow oil: IR (neat) 2234,
1717, 1577, 1400, and 1262 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.94 (p, 2H, J ) 7.2 Hz), 2.15 (s, 3H), 2.39 (t, 2H, J ) 7.2
Hz), 3.75 (s, 3H), 3.89 (t, 2H, J ) 7.2 Hz), 5.24 (s, 2H), 7.22 (s,
1H), and 7.33-7.37 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 12.1,
16.4, 26.8, 48.1, 52.8, 68.6, 73.4, 88.3, 128.0, 128.4, 128.7, 132.5,
135.6, 136.6, and 153.6; HRMS calcd for C19H20N2O5 356.1372,
found 356.1372.
colorless oil: IR (neat) 2904, 1697, 1620, 1481, and 1223 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 1.27 (t, 3H, J ) 7.2 Hz), 4.20 (q,
2H, J ) 7.2 Hz), 4.69 (s, 2H), 5.95 (s, 2H), 6.73 (s, 1H), 7.16-
7.19 (m, 2H), 7.22-7.26 (m, 1H), and 7.56 (m, 2H); 13C NMR
(CDCl3, 100 MHz) δ 15.6, 47.9, 63.2, 102.3, 105.1, 107.4, 124.4,
125.8, 126.2, 127.1, 128.1, 129.4, 129.8, 137.6, 148.3, 148.8,
and 154.9; HRMS calcd for C17H15NO4 297.1001, found 297.1005.
2-(Acetylben zyla m in o)fu r a n -3,4-d ica r boxylic Acid Di-
m eth yl Ester (50). A solution containing 0.07 g (0.3 mmol)
of the known amidooxazole 4945 and 0.04 g (0.3 mmol) of
dimethyl acetylenedicarboxylate in 3 mL of toluene was stirred
in a sealed tube at 150 °C for 18 h. The solvent was removed
under reduced pressure, and the residue was subjected to flash
silica gel chromatography to give 0.09 g (92%) of 50 as a yellow
oil: IR (neat) 1736, 1694, 1551, 1289, and 1065 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 1.96 (s, 3H), 3.57 (s, 3H), 3.77 (s, 3H),
4.75 (s, 2H), 7.10-7.21 (m, 5H), and 7.73 (s, 1H); 13C NMR
(CDCl3, 100 MHz) δ 22.1, 51.4, 52.2, 52.4, 112.6, 119.1, 128.0,
128.6, 129.1, 135.9, 144.9, 151.3, 161.4, 161.6, and 170.8. Anal.
Calcd for C17H17NO6: C, 61.63; H, 5.17; N, 4.23. Found: C,
61.60; H, 5.19; N, 4.23.
N-(4-Meth yloxa zol-2-yl)-N-(p en t-4-en yl)a ceta m id e (51).
A mixture containing 0.4 g (3.0 mmol) of 2-acetamidooxazole,45
2.6 g (7.8 mmol) of CsCO3 in 8 mL of DMF, and 4 mL of THF
was stirred at 60 °C for 30 min. To this mixture was added
0.5 mL (3.9 mmol) of 5-bromo-1-pentene,57 and the solution
was stirred at 60 °C for 4 h. The reaction mixture was
quenched with 25 mL of water and extracted with ether. The
combined organic layers were washed with brine and dried
over Na2SO4. The solvent was removed under reduced pres-
sure, and the residue was purified by silica gel chromatography
to give 0.4 g (70%) of 51 as a light yellow oil: IR (neat) 1693,
1577, 1399, 1275, and 1092 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.64-1.72 (m, 2H), 2.07 (q, 2H, J ) 6.8 Hz), 2.17 (s, 3H),
2.22 (s, 3H), 3.80 (t, 2H, J ) 7.6 Hz), 4.94-5.03 (m, 2H), 5.73-
5.83 (m, 1H), and 7.25 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ
11.9, 23.6, 27.4, 30.8, 46.4, 115.2, 132.4, 137.0, 137.6, 155.8,
and 170.2. Anal. Calcd for C11H16N2O2: C, 63.44; H, 7.74; N,
13.45. Found: C, 63.25; H, 7.78; N, 13.25.
1-Acet yl-7-m et h yl-1,2,3,4-t et r a h yd r o-1,8-n a p h t h yr i-
d in e (53). A solution containing 0.1 g (0.5 mmol) of 51 and
0.06 g (0.4 mmol) of DBU in 2 mL of toluene was heated in a
sealed tube at 180 °C for 20 h under an argon atmosphere.
The solvent was removed under reduced pressure, and the
residue was purified by flash silica gel chromatography to give
0.3 g (39%) of 53 as a pale yellow oil: IR (neat) 1662, 1571,
1460, 1369, and 1009 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.92
(m, 2H), 2.46 (s, 3H), 2.49 (s, 3H), 2.73 (t, 2H, J ) 6.4 Hz),
3.88 (t, 2H, J ) 6.4 Hz), 6.86 (d, 1H, J ) 7.4 Hz), and 7.32 (d,
1H, J ) 7.4 Hz); 13C NMR (CDCl3, 100 MHz) δ 23.2, 24.1, 25.8,
26.7, 43.1, 119.3, 121.9, 137.6, 154.6, and 171.8; HRMS calcd
for C11H14N2O 190.1106, found 190.1102.
4,5,6,7-Tetr a h yd r ofu r o[2,3-b]p yr id in e-3,7-d ica r boxyl-
ic Acid 7-Ben zyl Meth yl Diester (55). A solution containing
0.2 g (0.6 mmol) of 54 in 8 mL of toluene was heated in a sealed
tube at 160 °C for 30 h. The solvent was removed under
reduced pressure, and the residue was purified by silica gel
chromatography to give 0.15 g (85%) of 55 as a colorless oil:
IR (neat) 1720, 1634, 1551, 1394, 1256, and 1124 cm-1 1H
;
NMR (CDCl3, 400 MHz) δ 1.92 (p, 2H, J ) 6.4 Hz), 2.68 (t,
2H, J ) 6.4 Hz), 3.76-3.78 (m, 2H), 3.80 (s, 3H), 5.26 (s, 2H),
7.31-7.42 (m, 5H), and 7.72 (s, 1H); 13C NMR (CDCl3, 100
MHz) δ 20.2, 22.9, 45.4, 51.4, 67.9, 103.4, 118.4, 127.9, 128.2,
128.6, 136.0, 142.0, 145.5, 152.7, and 163.9; HRMS calcd for
C
17H17NO5 315.1107, found 315.1107.
N -(6-Br om o-3,4-m e t h yle n e d ioxyb e n zyl)-N -(4-m e t h -
yloxa zol-2-yl)a ceta m id e (56). A mixture containing 0.6 g
(4.3 mmol) of 2-acetamidooxazole45 and 4.2 g (13.0 mmol) of
CsCO3 in 4 mL of DMF and 2 mL of THF was stirred at 60 °C
for 30 min. To this mixture was added 1.4 g (4.7 mmol) of
6-bromopiperonyl bromide,58 and the solution was heated at
60 °C for 2 h. The reaction mixture was quenched with 25 mL
of water and extracted with ether. The combined organic layers
were washed with brine and dried over Na2SO4. The solvent
was removed under reduced pressure, and the residue was
purified by flash silica gel chromatography to give 1.3 g (89%)
of 56 as a white solid: mp 106-107 °C; IR (neat) 1694, 1578,
Oxa zol-2-ylca r ba m ic Ben zyl Ester . To a solution con-
taining 2.8 g (30 mmol) of 2-aminooxazole, 0.7 g (6 mmol) of
(dimethylamino)pyridine, and 8 mL (60 mmol) of triethylamine
(57) Nico, J . L. M.; Broekholf, N.; Wittevenn, J . G.; Weerdt, A. J .
Recl. Trav. Chim. Pays-Bas 1986, 105, 436.
(58) Barthel, W. F.; Alexander, B. H. J . Org. Chem. 1958, 23, 1012.

3606 J . Org. Chem., Vol. 64, No. 10, 1999
Padwa et al.
1
1480, 1396, and 932 cm-1; H NMR (CDCl3, 400 MHz) δ 2.14
7.2 Hz), 7.26 (t, 1H, J ) 7.2 Hz), 7.41 (d, 1H, J ) 8.0 Hz), and
8.14 (d, 1H, J ) 8.0 Hz); 13C NMR (CDCl3, 100 MHz) δ -0.4,
46.9, 102.9, 117.1, 123.0, 123.6, 124.8, 127.8, 128.5, 128.6,
130.0, 132.7, 133.5, 136.5, 143.1, 150.0, and 161.0; HRMS calcd
for C21H21NO2Si 347.1342, found 347.1342.
N-Ben zyl-6-br om o-N-(4-m eth yloxa zol-2-yl)-3,4-m eth yl-
en ed ioxyben za m id e (62). To a stirred suspension containing
1.0 g (4.3 mmol) of 6-bromopiperonylic acid in 25 mL of CH2-
Cl2 was added 3 drops of DMF followed by 3.2 mL (6.4 mmol)
of a 2.0 M oxalyl chloride/CH2Cl2 solution. The mixture was
stirred at room temperature for 2 h and concentrated under
reduced pressure to give the expected acid chloride as a yellow
oil. This material was used in the next step without further
purification.
(d, 3H, J ) 1.2 Hz), 2.27 (s, 3H), 4.98 (s, 2H), 5.94 (s, 2H),
6.83 (s, 1H), 6.95 (s, 1H), and 7.23 (d, 1H, J ) 1.2 Hz); 13C
NMR (CDCl3, 100 MHz) δ 12.0, 23.3, 50.3, 101.9, 109.0, 112.8,
113.7, 129.0, 133.0, 137.3, 147.7, 147.9, 155.2, and 170.4. Anal.
Calcd for C14H13BrN2O4: C, 47.61; H, 3.71; N, 7.93. Found:
C, 47.81; H, 3.73; N, 7.84.
N-(4-Meth yloxa zol-2-yl)-N-(6-tr im eth ylsilyleth yn yl-3,4-
m eth ylen ed ioxyben zyl)a ceta m id e (57). To a solution con-
taining 0.4 g (1.1 mmol) of 56 in 10 mL of triethylamine were
added 0.02 g (0.03 mmol) of bis(triphenylphosphine)palladium-
(II) chloride, 0.04 g (0.02 mmol) of triphenylphosphine, 0.02 g
(0.01 mmol) of copper(I) iodide, and 0.6 mL (4 mmol) of
trimethylsilylacetylene. The mixture was heated at reflux for
24 h, cooled to room temperature, diluted with ether, and
filtered through a pad of Celite. The solvent was removed
under reduced pressure, and the residue was purified by silica
gel chromatography to give 0.28 g (60%) of 57 as a light yellow
To a stirred suspension containing 0.3 g (6.4 mmol) of 60%
NaH in 20 mL of THF was added dropwise a solution
containing 0.8 g (4 mmol) of 2-benzylaminooxazole45 in 10 mL
of THF at 0 °C. After 15 min of stirring, a solution containing
the above acid chloride in 20 mL of THF was added dropwise.
The resulting mixture was stirred at room temperature for
12 h and then heated at reflux for 1.5 h. The mixture was
cooled to room temperature, quenched with 5 mL of brine, and
extracted with ether. The combined organic layers were dried
over Na2SO4 and concentrated under reduced pressure. The
residue was subjected to flash silica gel chromatography to
give 1.0 g (56%) of 62 as a white solid: mp 186-187 °C; IR
(KBr) 1790, 1711, 1507, 1491, and 1023 cm-1; 1H NMR (CDCl3,
400 MHz) δ 2.02 (s, 3H), 5.18 (s, 2H), 5.96 (s, 2H), 6.76 (s,
1H), 6.91 (s, 1H), 6.95 (s, 1H, J ) 1.6 Hz), 7.25-7.32 (m, 3H),
and 7.40 (d, 2H, J ) 7.2 Hz); 13C NMR (CDCl3, 100 MHz) δ
11.9, 51.2, 102.3, 108.7, 111.3, 113.0, 127.9, 128.4, 128.7, 130.7,
132.7, 136.3, 136.9, 147.2, 149.5, 154.6, and 167.7; HRMS calcd
for C19H15BrN2O4 [M+ - Br] 335.1032, found 335.1030.
4-Ben zyl-7,8-m et h ylen ed ioxy-1-t r im et h ylsilylfu r a n o-
[2,3-c]isoqu in ol-5-on e (64). To a solution containing 0.8 g
(1.9 mmol) of amide 62 in 10 mL of triethylamine were added
0.04 g (0.05 mmol) of bis(triphenylphosphine)palladium(II)
chloride, 0.08 g (0.03 mmol) of triphenylphosphine, 0.08 g (0.4
mmol) of copper(I) iodide, and 0.5 mL (4 mmol) of trimethyl-
silylacetylene. The resulting mixture was heated at reflux for
18 h, cooled to room temperature, diluted with ether, and
filtered through a pad of Celite. The solvent was removed
under reduced pressure, and the residue was purified by silica
gel chromatography to give 0.36 g (48%) of 64 as a yellow
solid: mp 178-179 °C; IR (KBr) 1650, 1575, 1497, 1469, and
1041 cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.41 (s, 9H), 5.60 (s,
2H), 6.08 (s, 2H), 7.16 (s, 1H), 7.18 (s, 1H), 7.26-7.30 (m, 3H),
7.49 (d, 2H, J ) 7.2 Hz), and 7.89 (s, 1H); 13C NMR (CDCl3,
100 MHz) δ -0.3, 46.0, 101.7, 101.9, 103.2, 107.9, 116.9, 118.6,
127.9, 128.6, 128.7, 130.8, 136.6, 143.0, 146.2, 149.5, 152.4,
and 160.2; HRMS calcd for C22H21NO4Si 391.1240, found
391.1235.
oil: IR (neat) 2148, 1694, 1578, and 1481 cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 0.22 (s, 9H), 2.12 (d, 3H, J ) 1.2 Hz),
2.25 (s, 3H), 5.08 (s, 2H), 5.92 (s, 2H), 6.80 (s, 1H), 6.83 (s,
1H), and 7.21 (d, 1H, J ) 1.2 Hz); 13C NMR (CDCl3, 100 MHz)
δ 0.2, 12.0, 23.2, 48.4, 97.8, 101.6, 102.5, 107.8, 111.9, 115.3,
133.0, 134.1, 137.2, 146.6, 148.6, 155.3, and 170.5; HRMS calcd
for C19H22N2O4Si 370.1349, found 370.1350.
4-Acetyl-4,5-d ih yd r o-7,8-m eth ylen ed ioxy-1-tr im eth yl-
silylfu r a n o[2,3-c]isoqu in olin e (58). A solution containing
0.05 g (0.13 mmol) of 57 in 5 mL of toluene was heated in a
sealed tube at 200 °C for 17 h under an argon atmosphere.
The solvent was removed under reduced pressure, and the
residue was purified by silica gel chromatography to give 0.04
g (93%) of 58 as a yellow oil: IR (neat) 1683, 1586, 1507, 1238,
and 839 cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.37 (s, 9H), 2.31
(s, 3H), 4.93 (s, 2H), 5.96 (s, 2H), 6.74 (s, 1H), 6.92 (s, 1H),
and 7.07 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ -0.1, 23.3,
47.6, 101.3, 104.3, 107.7, 111.1, 117.1, 124.3, 124.6, 143.6,
145.8, 146.6, 147.4, and 168.8; HRMS calcd for C17H19NO4Si
329.1083, found 329.1081.
N -B e n zy l-2-b r o m o -N -(4-m e t h y lo x a zo l-2-y l)b e n za -
m id e (59). To a stirred suspension containing 1.0 g (5.0 mmol)
of 2-bromobenzoic acid in 25 mL of CH2Cl2 was added 3 drops
of DMF followed by 4.0 mL (8.0 mmol) of a 2.0 M oxalyl
chloride-CH2Cl2 solution. The mixture was stirred at room
temperature for 2 h and concentrated under reduced pressure
to give the expected acid chloride as a yellow oil. This material
was used in the next step without further purification.
To a solution containing the above benzoyl chloride and 0.9
g (5.0 mmol) of 2-benzylaminooxazole45 in 20 mL of benzene
was added 1.4 mL (10.0 mmol) of triethylamine. The mixture
was heated at reflux for 4 days, cooled to room temperature,
diluted with ether, quenched with brine, and extracted with
ether. The combined organic layers were washed with brine,
dried over Na2SO4, and concentrated under reduced pressure.
The residue was subjected to flash silica gel chromatography
to give 0.8 g (40%) of 59 as a yellow oil: IR (neat) 1685, 1574,
2-(Bu t-3-en yla m in o)oxa zole. To a suspension containing
7.2 g (68 mmol) of cyanogen bromide and 19 g (140 mmol) of
potassium carbonate in 100 mL of dry ether was added
dropwise a solution containing 4.8 g (70 mmol) of 4-amino-1-
butene59 in 20 mL of ether at -10 °C. The mixture was stirred
at -10 °C for 2 h and then allowed to warm to 0 °C. The
mixture was filtered through a pad of Celite and concentrated
under reduced pressure. The residue was taken up in 50 mL
of THF and 50 mL of water and then treated with 5 mL (70
mmol) of 90% acetol, followed by the dropwise addition of 8
mL of a 2 M NaOH solution. The resulting mixture was stirred
at 50 °C for 2 h, diluted with water, and extracted with ether.
The combined organic layers were dried over Na2SO4 and
concentrated under reduced pressure. The residue was sub-
jected to flash silica gel chromatography to give 3.9 g (38%) of
the above oxazole as a light yellow oil: IR (neat) 3218, 1637,
1
1397, 1284, and 700 cm-1; H NMR (CDCl3, 400 MHz) δ 1.98
(s, 3H), 5.22 (s, 2H), 6.88 (s, 1H), 7.17-7.33 (m, 6H), 7.42 (d,
2H, J ) 7.6 Hz), and 7.50 (d, 1H, J ) 7.6 Hz); 13C NMR (CDCl3,
100 MHz) δ 11.9, 51.0, 119.7, 127.2, 127.9, 128.4, 128.6, 128.7,
131.0, 132.7, 132.9, 136.3, 136.9, 137.7, 154.6, and 168.1;
HRMS calcd for C18H15BrN2O2 370.0317, found 370.0319.
4-Be n zyl-1-t r im e t h ylsilylfu r a n o[2,3-c]isoq u in ol-5-
on e (61). To a solution containing 0.7 g (1.8 mmol) of 59 in 10
mL of triethylamine were added 0.01 g (0.01 mmol) of bis-
(triphenylphosphine)palladium(II) chloride, 0.03 g (0.01 mmol)
of triphenylphosphine, 0.03 g (0.01 mmol) of copper(I) iodide,
and 0.6 mL (4.5 mmol) of trimethylsilylacetylene. The resulting
mixture was heated at reflux for 24 h, cooled to room
temperature, diluted with ether, and filtered through a pad
of Celite. The solvent was removed under reduced pressure,
and the residue was subjected to flash silica gel chromatog-
raphy to give 0.62 g (88%) of 61 as a yellow oil: IR (neat) 1657,
1551, 1518, 1446, and 839 cm-1; 1H NMR (CDCl3, 400 MHz) δ
0.01 (s, 9H), 5.05 (s, 2H), 6.76 (s, 1H), 6.79-6.82 (m, 1H), 6.86
(t, 2H, J ) 7.2 Hz), 6.98 (t, 1H, J ) 7.2 Hz), 7.08 (d, 2H, J )
1
1603, 1328, and 916 cm-1; H NMR (CDCl3, 400 MHz) δ 2.04
(s, 3H), 2.35 (q, 2H, J ) 6.4 Hz), 3.39 (q, 2H, J ) 6.4 Hz), 4.64
(brs, 1H), 5.08-5.15 (m, 2H), 5.73-5.84 (m, 1H), and 6.87 (s,
(59) Koziara, A.; Osowska, P.; Zawadzki, S.; Zwierzak, A. Synthesis
1985, 202.

Substituted Indoline and Tetrahydroquinoline Synthesis
J . Org. Chem., Vol. 64, No. 10, 1999 3607
1H); 13C NMR (CDCl3, 100 MHz) δ 12.1, 34.2, 42.3, 117.7,
127.5, 135.2, 136.0, and 161.0; HRMS calcd for C8H12N2O
152.0950, found 152.0955.
for 20 h, cooled to room temperature, diluted with ether, and
filtered through a pad of Celite. The solvent was removed
under reduced pressure, and the residue was subjected to flash
silica gel chromatography to give 0.2 g (77%) of 67 as a yellow
oil: IR (neat) 1655, 1576, 1467, 1239, and 1037 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 0.44 (s, 9H), 2.59 (q, 2H, J ) 7.6 Hz), 4.35
(t, 2H, J ) 7.6 Hz), 5.03-5.13 (m, 2H), 5.83-5.92 (m, 1H),
6.10 (s, 2H), 7.18 (s, 1H), 7.19 (s, 1H), and 7.87 (s, 1H); 13C
NMR (CDCl3, 100 MHz) δ -0.2, 32.9, 42.3, 101.6, 101.8, 102.9,
107.7, 116.8, 117.4, 118.5, 130.5, 134.5, 142.7, 146.0, 149.5,
152.1, and 159.9; HRMS calcd for C19H21NO4Si 355.1240, found
355.1238.
N-(Bu t-3-en yl)-6-iod o-N-(4-m eth yloxa zol-2-yl)-3,4-m e-
th ylen ed ioxyben za m id e (65). To a stirred suspension con-
taining 1.0 g (3.4 mmol) of 6-iodopiperonylic acid in 25 mL of
CH2Cl2 was added 3 drops of DMF followed by 2.6 mL (5.2
mmol) of a 2.0 M oxalyl chloride/CH2Cl2 solution. The mixture
was stirred at room temperature for 2 h and concentrated
under reduced pressure, to give the expected acid chloride as
a yellow solid. This material was used in the next step without
further purification.
To a suspension containing 0.20 g of 60% of sodium hydride/
mineral oil in 20 mL of THF was added dropwise a solution
containing 0.52 g (3.4 mmol) of 2-(but-3-enylamino)oxazole in
5 mL of THF at 0 °C. The resulting mixture was stirred at 0
°C for 30 min and was added to a solution containing the above
acid chloride in 20 mL of THF at 0 °C. The resulting mixture
was stirred at room temperature for 36 h, quenched by the
slow addition of 10 mL of brine, and extracted with ether. The
combined organic layers were dried over Na2SO4 and concen-
trated under reduced pressure. The residue was subjected to
flash silica gel chromatography to give 0.72 g (49%) of 65 as a
An h yd r olycor in -7-on e (68). A solution containing 0.08 g
(0.2 mmol) of 67 in 5 mL of 1,2,4-trichlorobenzene was heated
in a sealed tube at 320 °C for 24 h. The solvent was removed
under reduced pressure, and the residue was subjected to flash
silica gel chromatography to give 0.02 g (30%) of 68 as a yellow
solid: mp 230-231 °C; IR (neat) 1655, 1576, 1467, 1239, and
1
1037 cm-1; H NMR (CDCl3, 400 MHz) δ 3.42 (t, 2H, J ) 8.0
Hz), 4.46 (t, 2H, J ) 8.0 Hz), 6.13 (s, 2H), 7.19 (t, 1H, J ) 8.0
Hz), 7.28 (dd, 1H, J ) 7.2 and 0.8 Hz), 7.52 (s, 1H), 7.73 (d,
1H, J ) 7.2 Hz) and 7.90 (s, 1H); 13C NMR (CDCl3, 100 MHz)
δ 27.6, 46.7, 101.0, 102.2, 106.9, 116.9, 119.6, 123.1, 123.4,
123.9, 130.8, 131.0, 139.5, 148.5, 152.0, and 159.6; HRMS calcd
for C16H11NO3 265.0739, found 265.0734.
colorless oil: IR (neat) 1678, 1574, 1477, 1237, and 1034 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 2.03 (d, 3H, J ) 1.2 Hz), 2.46 (q,
2H, J ) 7.2 Hz), 4.00 (t, 2H, J ) 7.2 Hz), 5.00-5.09 (m, 2H),
5.71-5.81 (m, 1H), 5.94 (s, 2H), 6.68 (s, 1H), 6.97 (d, 1H, J )
1.2 Hz), and 7.11 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 11.9,
32.6, 47.4, 81.7, 102.1, 108.4, 117.4, 118.8, 132.6, 134.4, 135.1,
Ack n ow led gm en t. We gratefully acknowledge the
National Science Foundation (Grant CHE-9806331) for
generous support of this work. High-field NMR spec-
trometers used in these studies were made possible
through equipment grants from the NIH and NSF.
136.9, 147.9, 149.1, 154.6, and 168.9; HRMS calcd for C16H15
IN2O4 426.0078, found 426.0075.
-
4-(Bu t-3-en yl)-7,8-m eth ylen edioxy-1-tr im eth ylsilylfu r a-
n o[2,3-c]isoqu in ol-5-on e (67). To a solution containing 0.3
g (0.7 mmol) of 65 in 5 mL of diisopropylamine were added
0.01 g (0.01 mmol) of bis(triphenylphosphine)palladium(II)
chloride, 0.02 g (0.01 mmol) of triphenylphosphine, 0.02 g (0.01
mmol) of copper(I) iodide, and 0.14 mL (1.0 mmol) of trimeth-
ylsilylacetylene. The resulting mixture was heated at reflux
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for new compounds lacking elemental analyses.
This material is available free of charge via the Internet at
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