Cyclizations of substituted benzylidene-3-alkenylamines: Synthesis of the tricyclic core of the martinellines

Article abstract of DOI:10.1021/jo990843c

The martinellines (1 and 2) are natural products that possess both interesting biological activity and chemical structure. During the investigation of a hetero Diels-Alder route to these molecules, alternate Lewis acid-dependent cyclizations of (2'-amino-N'-tert-butoxycarbonyl-5'- chlorobenzylidene)-3-butenylamine (10) were observed. The reaction of a variety of imines with TMSOTf or TiCl₄ led to the formation of different heterocycles including iminodibenzo[b,f][1,5]diazocines, hexahydropyrido[1,2- c]quinazolin-6-ones, tetrahydropyrrolo[1,2-c]quinazolin-5-ones, 2- arylpiperidines, and 2-arylpyrrolidines. Tetrahydropyrrolo[1,2-c]quinazolin- 5-one 54, obtained via this new methodology, was used as an intermediate in the synthesis of the tricyclic ring system (65) of the martinellines.

Full text of DOI:10.1021/jo990843c

J . Org. Chem. 2000, 65, 655-666
655
Cycliza tion s of Su bstitu ted Ben zylid en e-3-a lk en yla m in es:
Syn th esis of th e Tr icyclic Cor e of th e Ma r tin ellin es
Kristine E. Frank† and J effrey Aube´*
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045-2506
Received May 24, 1999
The martinellines (1 and 2) are natural products that possess both interesting biological activity
and chemical structure. During the investigation of a hetero Diels-Alder route to these molecules,
alternate Lewis acid-dependent cyclizations of (2′-amino-N′-tert-butoxycarbonyl-5′-chloroben-
zylidene)-3-butenylamine (10) were observed. The reaction of a variety of imines with TMSOTf or
TiCl4 led to the formation of different heterocycles including iminodibenzo[b,f][1,5]diazocines,
hexahydropyrido[1,2-c]quinazolin-6-ones, tetrahydropyrrolo[1,2-c]quinazolin-5-ones, 2-arylpipe-
ridines, and 2-arylpyrrolidines. Tetrahydropyrrolo[1,2-c]quinazolin-5-one 54, obtained via this new
methodology, was used as an intermediate in the synthesis of the tricyclic ring system (65) of the
martinellines.
Preparations from the root bark of Martinella species
have been used by Amazon Indian tribes for the treat-
ment of a variety of eye ailments including conjunctivi-
tis.1 Fractionation of an ethanolic extract of Martinella
iquitosensis root bark by workers at Merck led to the
isolation of martinelline (1) and martinellic acid (2)
(Figure 1). These compounds showed modest activity as
bradykinin receptor antagonists, which could contribute
to the antiinflammatory effect of the root bark prepara-
tions. Additionally, martinelline demonstrated antagonist
activity at histaminergic, R-adrenergic, and muscarinic
receptors as well as weak antibacterial activity, which
could further contribute to the efficacy of the folkloric
preparations.
The martinellines are interesting from a chemical
standpoint due to the pyrroloquinoline ring system,
which had not been previously detected in a natural
product.1 Several groups have recently published syn-
thetic approaches to the tricyclic core of these natural
products, but the total synthesis of 1 or 2 has not yet
been achieved.2 Our initial retrosynthetic analysis re-
volved around an intramolecular Diels-Alder reaction
of an o-quinone methide imide (o-azaxylene) formed in
situ from an imine (Scheme 1). This material could
conceivably arise from the deprotonation of the aniline
or via Lewis acid activation of same. The appeal of this
disconnection was that it would set all three stereocenters
of the martinellines in one step. The relative stereochem-
istry at C-2 and C-2a would be controlled by the double
bond geometry of the dienophile and it was proposed that
the 5,6-fused ring system would prefer to be cis, which
would set the desired relative stereochemistry at C-2a
F igu r e 1. Martinellines and their numbering system.
Sch em e 1
* To whom correspondence should be addressed. Tel: 1.785.864.4496.
Fax: 1.785.864.5326. E-mail: jaube@ukans.edu.
† Current Address: Pharmacia & Upjohn, 7254-209-619, 301 Hen-
reitta Street, Kalamazoo, MI 49007.
and C-5a. Although numerous examples of Diels-Alder
reactions of o-quinone imides3 or o-quinone methides4
with terminal amido substitution exist, only a single
example of a species containing nitrogen atoms at both
positions has been reported.5,6
(1) Witherup, K. M.; Ransom, R. W.; Graham, A. C.; Bernard, A.
M.; Salvatore, M. J .; Lumma, W. C.; Anderson, P. S.; Pitzenberger, S.
M.; Varga, S. L. J . Am. Chem. Soc. 1995, 117, 6682-6685.
(2) (a) Gurjar, M. K.; Pal, S.; Rao, A. V. R. Heterocycles 1997, 45,
231-234. (b) Ho, T. C. T.; J ones, K. Tetrahedron 1997, 53, 8287-8294.
(c) Hadden, M.; Stevenson, P. J . Tetrahedron Lett. 1999, 40, 1215-
1218. (d) Lovely, C. J .; Mahmud, H. Tetrahedron Lett. 1999, 40, 2079-
2082. (e) Batey, R. A.; Simoncic, P. D.; Lin, D.; Smyj, R. P.; Lough, A.
J . Chem. Commun. 1999, 651-652. (f) Snider, B. B.; Ahn, Y.; Foxman,
B. M. Tetrahedron Lett. 1999, 40, 3339-3342.
Resu lts a n d Discu ssion
Mod el Rea ction s. A model imine was prepared to
study the proposed Diels-Alder reaction. A para-
10.1021/jo990843c CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/14/2000

656 J . Org. Chem., Vol. 65, No. 3, 2000
Frank and Aube´
Sch em e 2
ortho position (8), and shifts even further downfield after
imine formation (10). If this hydrogen bond is indeed
responsible for the lack of electrophile activation at the
imine nitrogen lone pair (and therefore lack of diene
formation), then use of an alternate aniline protecting
group might ultimately permit [4 + 2] cyclization. In light
of other developments, however, this tactic was not
pursued.
Although 11 was not formed in any of the reactions of
imine 10, two alternate products were observed. The
reaction of 10 with TMSOTf in the presence of triethyl-
amine gave iminodibenzo[b,f][1,5]diazocine 12 in 85%
yield (eq 2). The reaction of 10 with TiCl4/Ti(OiPr)4 gave
hexahydropyrido[1,2-c]quinazolin-6-ones 13 and 14, in a
total of 47% yield (eq 3). The Lewis acid-dependent
formation of both heterocycles from imine 10 warranted
further investigation.6
substituted aniline (3 or 4) was protected as the tert-butyl
carbamate (5 or 6) in order to direct ortho-lithiation with
sec-butyllithium (Scheme 2). When ethyl p-aminoben-
zoate (3) was used as the starting material the o-
lithiation was unsuccessful. Thus, p-chloroaniline (4) was
used to rapidly enter into an appropriately substituted
aldehyde (8) for the model system. The reduction of
3-butenenitrile with lithium aluminum hydride gave
amine 9, which was condensed with aldehyde 8 to give
imine 10.
F igu r e 2. 1H NMR evidence for intramolecular hydrogen
bonding.
The Diels-Alder adduct (11) was not observed under
a variety of reaction conditions including heat, acid, and
base (eq 1). Also unsuccessful were attempts to activate
the imine using a variety of electrophiles including acetic
anhydride, methylchloroformate, 2,2,2-trichloroethylchlo-
roformate, chlorotrimethylsilane, methyl iodide, boron
trifluoride diethyl etherate, and ytterbium triflate.
The iminodibenzo[b,f][1,5]diazocine ring system has
been observed in a variety of reactions involving o-
aminobenzaldehydes.7 Recent reports have described the
preparation of this ring system from the reaction of
primary amines with the iminophosphorane derived from
2-azidobenzaldehyde.8 In the present case, 12 probably
arises from the pseudodimerization of the deprotected9
aniline derived from imine 10 (Scheme 3).
The formation of the hexahydropyrido[1,2-c]quinazolin-
6-one ring system was interesting primarily because it
appeared to occur via an imine-olefin cyclization with
an unusual acyl iminium intermediate (Scheme 4). This
intermediate may close directly as shown but may also
involve an isocyanate intermediate. Chloride addition
could occur along with C-C bond formation to give the
isomer shown. Alternatively, nonstereospecific trapping
of an initially formed cation could account for the
formation of both stereoisomers.
Many methods for the addition of alkenes to iminium
species have been developed for the formation of a variety
of heterocycles.10 A key feature in a number of applica-
tions of such olefin cyclizations is the use of a silyl group
to direct the ring closure via stabilization of the develop-
The inability to externally activate the imine may be
due to intramolecular hydrogen bonding as shown in
Figure 2. This hypothesis is supported by the observa-
tions that the 1H NMR signal of the aniline hydrogen
shifts significantly downfield when 6 is formylated at the
(3) (a) Mao, Y.; Boekelheide, V. J . Org. Chem. 1980, 45, 1547-1548.
(b) Ito, Y.; Nakajo, E.; Nakatsuka, M.; Saegusa, T. Tetrahedron Lett.
1983, 24, 2881-2884. (c) Hodgetts, I.; Noyce, S. J .; Storr, R. C.
Tetrahedron Lett. 1984, 25, 5435-5438. (d) Ito, Y.; Nakajo, E.; Saegusa,
T. Synth. Commun. 1986, 16, 1073-1080. (e) Migneault, D.; Bernstein,
M. A.; Lau, C. K. Can. J . Chem. 1995, 73, 1506-1513. (f) Steinhagen,
H.; Corey, E. J . Org. Lett. 1999, 1, 823-824. (g) Steinhagen, H.; Corey,
E. J . Angew. Chem., Int. Ed. Engl. 1999, 38, 1928-1931.
(4) (a) Oppolzer, W. Synthesis 1978, 793-802. (b) Gallagher, T.;
Magnus, P. Tetrahedron 1981, 37, 3889-3897.
(5) Gomper, R.; Lehmann, H.-D. Angew. Chem., Int. Ed. Engl. 1968,
7, 74-75.
(6) Some of the work contained herein has been communicated:
Frank, K.; Aube´, J . Tetrahedron Lett. 1998, 39, 7239-7242.
(7) Albert, A.; Yamamoto, H. J . Chem. Soc. B 1966, 956-963.
(8) (a) Molina, P.; Arques, A.; Cartagena, I.; Obo´n, M. d. R.
Tetrahedron Lett. 1991, 32, 2521-2524. (b) Molina, P.; Arques, A.;
Ta´rraga, A.; Obo´n, M. d. R. Tetrahedron 1998, 54, 997-1004.
(9) Sakaitani, M.; Ohfune, Y. Tetrahedron Lett. 1985, 26, 5543-
5546.
(10) Recent reviews: (a) Speckamp, W. N.; Hiemstra, H. Tetrahedron
1985, 41, 4367-4416. (b) Schinzer, D. Synthesis 1988, 263-273. (c)
Overman, L. E. Acc. Chem. Res. 1992, 25, 352-359.

Cyclizations of Substituted Benzylidene-3-alkenylamines
Sch em e 3
J . Org. Chem., Vol. 65, No. 3, 2000 657
Ta ble 1. F or m a tion of Im in es 25-36
Sch em e 4
entry
R1
R2
R3
alkene
imine
1
2
3
4
5
6
7
8
9
NHBoc
NHBoc
H
H
H
H
H
H
OMe
NO2
Cl
H
H
H
H
15
9
9
9
9
25
26
27
28
29
30
31
32
33
34
35
36
H
CO2Me
H
9
9
NO2
NHBoc
NHBoc
NH2
NO2
NHPiv
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
21
24
21
21
21
10
11
12
Sch em e 5a
ing â-carbocation. The use of a silyl directing group in
quinazolinone formation merited exploration for its po-
tential application toward the formation of the pyrrolo-
quinolone ring system.
A number of additional imines were prepared to
explore the formation of iminodibenzo[b,f][1,5]diazocines,
hexahydropyrido[1,2-c]quinazolin-6-ones, and related het-
erocycles (Table 1). Imine 25 was formed via condensa-
tion of aldehyde 8 with amine 15. Imines 26-31 were
formed from reaction of the corresponding aldehyde with
amine 9. The preparation of imines 32-36 required allyl
silanes 21 and 24, which were themselves prepared from
known precursors (Scheme 5). Thus, alcohols 1911 and
2212 were converted to the corresponding azides (21 and
24, respectively) via mesylation followed by azide dis-
placement. In a one-pot Staudinger/aza-Wittig reaction,
each azide was reacted with triphenylphosphine to form
the corresponding iminophosphorane prior to the addition
of an aldehyde to give imines 32-36. These reactions
afforded imines in high yields, which were used without
further purification.
a
Reaction conditions: (a) DHP, p-TsOH, 88%; (b) n-BuLi, then
TMSCH2OTf or TMSCH2I, 50-81%; (c) MeOH, p-TsOH, 84%; (d)
H2, Lindlar’s catalyst, quinoline, 90%; (e) MsCl, Et3N, 97%; (f)
NaN3, 91%; (g) LAH, 61%; (h) MsCl, Et3N, 95%; (f) NaN3, 91%.
The first set of imines (10, 25, and 26) were investi-
gated for their differential reactivity with a variety of
Lewis acids (Table 2). The reaction of TMSOTf with
either imine 10 or 25 gave iminodibenzo[b,f][1,5]diazocine
12 or 37, respectively (entries 1 and 4). The absence of
triethylamine lowered the yield of this transformation
(11) Schinzer, D.; Allagiannis, C.; Wichmann, S. Tetrahedron 1988,
44, 3851-3868.
(12) Hiemstra, H.; Sno, M. H. A. M.; Vijn, R. J .; Speckamp, W. N.
J . Org. Chem. 1985, 50, 4014-4020.

658 J . Org. Chem., Vol. 65, No. 3, 2000
Frank and Aube´
Ta ble 2. Lew is Acid -P r om oted Cycliza tion of Im in es 10,
25, a n d 26
product(s)
F igu r e 3. Comparison of possible transition structures for
cyclization reactions: synchronous cyclization/trapping cases
resulting from (a) carbamate activation or (b) Lewis acid
activation, or (c) stepwise cyclization followed by trapping via
conformationally mobile intermediates (trapping step not
shown; however, see Scheme 4 for an analogous example).
Lewis
acid
a
b
entry imine
R
X
(yield, %)a
(yield, %)
1
2
3
4
5
6
10
10
10
25
25
26
H
Cl TMSOTf
TiCl4
b
12 (61)
13 (35-42) 12 (ca. 13)
Ti(OiPr)4
b
b
b
CH3 Cl TMSOTf
TiCl4
H
37 (64)
37 (30)
b
38 (40)
Ta ble 3. TiCl4-P r om oted Cycliza tion Rea ction s of
H
TiCl4
39 (65)c
Im in es 27-31
a
Formed as a >9:1 ratio of R/â chloride epimers (based on 1H
NMR). Not isolated. c Reaction run in refluxing CH2Cl2.
b
(cf. entry 1 vs eq 2). The reaction of these imines with
TiCl4 led to varying mixtures of iminodibenzo[b,f][1,5]-
diazocines and hexahydropyrido[1,2-c]quinazolin-6-ones
(entries 2, 5, and 6). However, in contrast to the results
with TiCl4/Ti(OiPr)4 (eq 3), the hexahydropyrido[1,2-c]-
quinazolin-6-one diastereomeric ratio was >9:1. This
suggests that the lower Cl- concentration in the mixed
Lewis acid system may favor stepwise addition (Scheme
4). Additionally, treatment of imine 10 with Ti(OiPr)4
alone did not promote either reaction pathway (entry 3).
Imines 27-31 allowed for exploration of the imine-
olefin reaction in the absence of urea formation (Table
3). This series of reactions was carried out at CH2Cl2
reflux for 72 h. This increased reaction time and tem-
perature was needed for product formation. Although
some product (40-44) was obtained from each of these
examples, none approached efficiencies consistent with
synthetic utility. Neither starting material nor other
products could be cleanly isolated from these low-yielding
cases. On the other hand, those examples containing an
o-NHBoc substituent gave consistently higher yields and
cleaner products, observations that are consistent with
the mechanism for the examples involving acyl iminium
ion formation prior to attack by the olefin as shown in
Scheme 4. Interestingly, the stereochemistry of the
piperidine products depended upon the electronic nature
of the aromatic ring, with trans products preferred from
Ar ) Ph and for electron-rich aromatics. As the electronic-
withdrawing character of the aromatic ring was in-
creased, the amount of cis isomer went up. The trans
isomer favored in the former cases might arise from a
transition structure in which the aryl group occupies a
pseudoaxial orientation to avoid steric interactions with
the titanium presumably bound to the nitrogen atom
(Figure 3). The cis isomers could result from an increas-
ing incursion of a stepwise process, possibly involving a
ring flip of the initially formed carbocation adduct. These
points were not further examined due to the relatively
poor yields of these processes.
entry imine R1
R2
R3 product yield (%) trans/cisa
1
2
3
4
5
27
28
29
30
31
H
H
H
H
H
H
H
H
H
Cl
40
41
42
43
44
25
18
31
19:1
9:1
1:3
7:3
1:19
OCH3
NO2
CO2CH3
H
52
NO2
e21b
a
b
Based on 1H NMR integration. Product impure.
unprotected aniline, an imine-olefin reaction was not
seen, instead iminodibenzo[b,f][1,5]diazocine 46 was
formed (entry 3). Once again, imine-olefin cyclizations
in the absence of urea formation gave lower yields
(entries 4 and 5). Also, both pyrrolidine products (47 and
48) appeared to be unstable on silica gel and were
therefore not obtained cleanly.
Although imine 34 underwent pseudodimerization in
the presence of TiCl4, it was worthy of further study
because the aniline hydrogens showed no evidence of
hydrogen bonding to the imine nitrogen (2H at δ 6.39 in
the 1H NMR). When trichloroacetic anhydride (TCAA)
was used in an attempt to activate the imine to initiate
diene formation, two different heterocycles were observed
depending on the amount of TCAA present. When 1.1
equiv of TCAA was used, the product was not readily
identified by spectroscopic methods. Instead, it was
necessary to prepare imine 49 which underwent cycliza-
tion with TCAA to give a product (50) that was unam-
biguously identified by X-ray crystallography (Scheme 6).
Spectral comparisons with 50 allowed for the identifica-
tion of urea 52 as the product of the reaction shown in
Scheme 7. When this reaction was run at lower temper-
atures (83 °C), it was possible to isolate imine 51 which
could then be carried on to urea 52 upon heating at 130
°C. These results further support the intermediacy of an
acyl iminium ion in the previously described imine-olefin
cyclizations. However, in this case, the acyl iminium ion
intermediate is trapped by the trichloromethyl group
liberated from the amide intermediate (51) upon urea
formation.
The final set of imines investigated contained the allyl
silane substituent (Table 4). The cis-allyl silane gave a
higher yield and higher diastereomeric ratio than the
trans-allyl silane (entries 1 and 2). In the case of the

Cyclizations of Substituted Benzylidene-3-alkenylamines
J . Org. Chem., Vol. 65, No. 3, 2000 659
Ta ble 4. TiCl4-P r om oted Cycliza tion Rea ction s of Im in es 32-36
entry
imine
R1
alkene geometry
product
yield (%)
diastereomeric ratioa
1
2
3
4
5
32
33
34
35
36
NHBoc
NHBoc
NH2
NO2
NHPiv
Z
E
Z
Z
Z
45
45
46
47
48
62-75
55
19:1
3:1
b
d
17:3
39
e23c
e31c
a
b
d
Based on 1H NMR integration. Not applicable. c Product impure. Not determined.
Sch em e 6
Sch em e 8
Sch em e 9a
Sch em e 7
a
Reaction conditions: (a) NaH, TsCl, 90%; (b) 50% aq NaOH,
65%; (c) AcCl, DMAP, Pyr, 85%; (d) I2, 84%.
Ap p lica tion to th e Syn th esis of th e Ma r tin ellin e
Rin g System . Imine-olefin product 45, obtained in up
to 75% yield from imine 32, was seen as a useful
intermediate in martinelline synthesis due to the cis
relationship of the pyrrolidine substituents. The urea
moiety in 45 was hydrolyzed by activation with p-tol-
uenesulfonyl chloride followed by NaOH treatment to
give pyrrolidine 56 (Scheme 9). After acylation of the
pyrrolidine nitrogen, iodoamidation gave pyrroloquino-
line 58. The tricyclic core of martinelline was thus ob-
tained with complete control over relative stereochem-
istry, as established by an X-ray crystallographic analysis
of pyrroloquinoline 58.
Having seen that the first equivalent of TCAA reacted
with the aniline nitrogen and that higher temperatures
(>83 °C) were needed for amide 51 to react further, an
excess of TCAA (5 equiv) was used at room temperature
in an attempt to activate the imine prior to urea forma-
tion. Apparently the excess TCAA successfully activated
the imine, since imine-olefin product 53 was formed
(Scheme 8). This product was identified as the trans
diastereomer when basic hydrolysis led to the formation
of urea 54, previously seen as the minor product of the
cyclization of imines 32 and 33 (Table 4).
A similar sequence was also carried out in a series
including the carbomethoxy group present in the natural
product (Scheme 10). Aldehyde 61 was formed from
carbamate 5 in three steps and 66% overall yield. In these
experiments, a ca. 2:1 mixture of cis- and trans-alkene

660 J . Org. Chem., Vol. 65, No. 3, 2000
Frank and Aube´
butoxycarbonylaniline,15 2-amino-N-tert-butoxycarbonylben-
zaldehyde,17 2-aminobenzaldehyde.18 Known compounds pre-
pared by modified procedures have been included in the
supplemental information: 4-[(tetrahydropyran-2-yl)oxy]-1-
butyne (16), 5-[(tetrahydropyran-2-yl)oxy]-1-(trimethylsilyl)-
2-pentyne (17), 5-(trimethylsilyl)-3-pentyn-1-ol (18), (Z)-5-
(trimethylsilyl)-3-penten-1-ol (19), (Z)-1-methanesulfonyloxy-
5-(trimethylsilyl)-3-pentene (20), (E)-5-(trimethylsilyl)-3-penten-
1-ol (22), (E)-1-methanesulfonyloxy-5-(trimethylsilyl)-3-pentene
(23), N-(4-chlorophenyl)-2,2-dimethylpropionamide, and N-(4-
chloro-2-formylphenyl)-2,2-dimethylpropionamide.
Sch em e 10a
2-Am in o-N -t er t -b u t oxyca r b on yl-5-ch lor ob e n za ld e -
h yd e (8). To a solution of 615 (3.00 g, 13.2 mmol) in THF (20.0
mL) at -78 °C under argon was added s-BuLi (1.3 M in
cyclohexane, 25.0 mL, 32.5 mmol) dropwise over 5 min. The
reaction was stirred for 15 min at -78 °C and then at -20 °C
for 3.5 h. DMF was added, and the reaction was stirred at
-20 °C for 1 h. The reaction mixture was partitioned between
H2O and Et2O (50 mL each). The layers were separated, and
the aqueous layer was extracted with Et2O (2 × 50 mL). The
combined organic layers were dried (Na2SO4), decanted, and
concentrated under reduced pressure. The crude product was
purified by silica gel chromatography with hexanes/EtOAc (19:
1) to give 1.82 g of 8 (54%) as white plates: mp 115 °C; 1H
NMR (500 MHz, CDCl3) δ 1.51 (s, 9H), 7.46 (dd, J ) 9.1, 2.5
Hz, 1H), 7.54 (d, J ) 2.5 Hz, 1H), 8.41 (d, J ) 9.1 Hz, 1H),
9.80 (s, 1H), 10.26 (br s, 1H); 13C NMR (125.7 MHz, CDCl3) δ
28.1, 81.2, 119.9, 122.0, 126.4, 134.8, 135.6, 140.2, 152.5, 193.6;
IR (KBr) 3370, 2980, 1715 cm-1; MS (CI) m/z 256 (M+ + H),
217, 156, 127, 57; HRMS calcd for C12H15NO3Cl 256.0740,
found 256.0754.
a
Reaction conditions: (a) Br2, HOAc, 100%; (b) n-Bu3Sn-
(CHdCH2), (Ph3P)4Pd, 85%; (c) O3, then DMS, 78%; (d) 21/24,
PPh3, 100-123% (crude); (e) TiCl4, 80%; (f) NaH, TsCl, 91%; (g)
50% aq NaOH, (h) H2SO4, MeOH, 57% over two steps, (i) I2, 44%.
(2′-Am in o-N′-ter t-bu toxycar bon yl-5′-ch lor oben zyliden e)-
3-bu ten yla m in e (10). A mixture of 8 (0.50 g, 2.0 mmol) and
916 (0.28 g, 3.9 mmol) was heated to 90 °C for 1 h. The reaction
was then cooled to room temperature, and the excess amine
was removed under reduced pressure to give 0.60 g (99%) of
crude imine as a pale yellow solid: 1H NMR (300 MHz, CDCl3)
δ 1.52 (s, 9H), 2.46 (m, 2H), 3.70 (td, J ) 6.6, 1.1 Hz, 2H),
5.04-5.18 (m, 2H), 5.95 (m, 1H), 7.25 (d, J ) 2.5 Hz, 1H), 7.29
(dd, J ) 8.9, 2.5 Hz, 1H), 8.24 (s, 1H), 8.36 (d, J ) 8.9 Hz,
1H), 11.92 (br s, 1H); 13C NMR (100.6 MHz, CDCl3) δ 28.3,
35.6, 60.6, 80.1, 116.5, 119.5, 121.4, 125.8, 130.9, 132.2, 135.9,
139.3, 153.4, 162.6; IR (KBr) 2980, 1710 cm-1; MS (CI) m/z
309 (M+ + H), 253, 235, 208, 167, 57; HRMS calcd for
isomers (21/24) was used in the synthesis of 62. The
cyclization of imine 62 gave urea 63 as an inseparable
mixture of diastereomers (17:3, cis/trans). Tosylation of
urea 63 gave 64, which was subjected to basic hydrolysis
conditions. Hydrolysis of the ester accompanied urea
hydrolysis; thus, re-esterification was required prior to
the iodoamination reaction which gave pyrroloquinoline
66 (isolated as a single diastereomer).
C
16H22N2O2Cl 309.1370, found 309.1372.
(6R *,12S *)-2,8-Dich lor o-13-(b u t -3-e n yl)-6,12-im in o-
Su m m a r y
d iben zo[b,f][1,5]-5,6,11,12-tetr a h yd r od ia zocin e (12). To a
solution of 10 (0.10 g, 0.32 mmol) in chlorobenzene (3.0 mL)
at 0 °C was added TMSOTf (0.10 mL, 0.52 mmol) dropwise.
The reaction was allowed to warm to room temperature over
1 h, and then triethylamine (0.09 mL, 0.65 mmol) was added.
After 4 h, the reaction was quenched with saturated aqueous
NH4Cl (0.5 mL). The reaction was diluted with CH2Cl2 and
then washed with saturated aqueous NaCl (5 mL), dried (Na2-
SO4), decanted, and concentrated under reduced pressure. The
crude product was purified by silica gel chromatography with
hexanes/EtOAc (4:1) to give 47.9 mg (81%) of a white foam:
1H NMR (400 MHz, CDCl3) δ 2.37 (m, 2H), 2.54 (m, 1H), 2.75
(m, 1H), 4.57 (br s, 1H), 4.90 (s, 2H), 5.01-5.11 (m, 2H), 5.81
(m, 1H), 6.52 (d, J ) 8.5 Hz, 2H), 7.00 (dd, J ) 8.5, 2.4 Hz,
2H), 7.04 (d, J ) 2.3 Hz, 2H); 13C NMR (100.6 MHz, CDCl3) δ
32.2, 49.3, 65.5, 116.2, 117.4, 123.3, 125.1, 127.7, 128.6, 135.9,
139.2; IR (film) 3390, 2930, 2840 cm-1; MS (CI) m/z 346 (M+
+ H), 304, 290, 209, 72; HRMS calcd for C18H18Cl2N3 346.0878,
found 346.0882.
A variety of interesting heterocycles can be formed
from the Lewis acid-mediated cyclizations of imines. In
respect to the martinellines, the in situ formation of an
acyl iminium ion aided in imine-olefin cyclization yield
and diastereoselectivity, while the use of an allyl silane
directed ring closure for pyrrolidine formation. In another
key step, haloamidation gave the tricyclic core ring
system. This advanced intermediate is suitably function-
alized for the elongation of the C-2 side chain and further
elaboration to form the martinellines.
Exp er im en ta l Section
Gen er a l m eth od s have been published.13
Ma ter ia ls. Except where noted, all starting materials were
purchased from Aldrich, Fluka, Fisher, Lancaster, or TCI
chemical companies and used as received. The following known
compounds were prepared by literature procedures: ethyl
4-(N-tert-butoxycarbonyl)aminobenzoate (5),14 N-tert-butoxy-
carbonyl-4-chloroaniline (6),15 3-buten-1-amine (9),16 N-tert-
TiCl4/Ti(OiP r )4-P r om oted Im in e-Olefin Cycliza tion of
10. To a solution of Ti(OiPr)4 (1.2 mL, 4.0 mmol) in CH2Cl2
(45 mL) at room temperature was added TiCl4 (0.44 mL, 4.0
mmol). After 10 min, the solution was cooled to -78 °C. Then,
(13) Gracias, V.; Frank, K. E.; Milligan, G. L.; Aube´, J . Tetrahedron
1997, 53, 16241-16252.
(16) Sato, T.; Nakamura, N.; Ikeda, K.; Okada, M.; Ishibashi, H.;
Ikeda, M. J . Chem. Soc., Perkin Trans. 1 1992, 2399-2407.
(17) Muchowski, J . M.; Venuti, M. C. J . Org. Chem. 1980, 45, 4798-
4801.
(14) Grehn, L.; Gunnarsson, K.; Ragnarsson, U. Acta Chem. Scand.,
Ser. B 1987, 41, 18-23.
(15) Croce, P. D.; LaRosa, C.; Ritieni, A. J . Chem. Res., Synop. 1988,
346-347.
(18) Horner, J . K.; Henry, D. W. J . Med. Chem. 1968, 11, 946-949.

Cyclizations of Substituted Benzylidene-3-alkenylamines
J . Org. Chem., Vol. 65, No. 3, 2000 661
a solution of 10 (0.25 g, 0.81 mmol) in CH2Cl2 (5 mL) was
added, and the reaction was warmed to room temperature.
After 6 h, the reaction was quenched with 10% aqueous NaOH
(50 mL). The layers were separated, and the aqueous layer
was extracted with CH2Cl2 (3 × 50 mL). The combined organic
extracts were then dried (Na2SO4), decanted, and concentrated
under reduced pressure. Repeated silica gel chromatography
with EtOAc/hexanes/2% Et2NH (30/19/1) gave 76 mg (34%) of
13 and 29 mg (13%) of 14.
3400 (br), 2920 cm-1; MS (CI) m/z 86 (M+ + H), 69; HRMS
calcd for C5H12N 86.0970, found 86.0963.
(2′-Am in o-N′-ter t-bu toxycar bon yl-5′-ch lor oben zyliden e)-
tr a n s-3-p en ten yla m in e (25). A mixture of 8 (0.50 g, 2.0
mmol) and 15 (0.33 g, 3.9 mmol) was heated to 90 °C for 1.5
h. The reaction was then cooled to room temperature, and the
excess amine was removed under reduced pressure to give 0.63
g of crude imine as a pale yellow solid: 1H NMR (500 MHz,
CDCl3) δ 1.53 (s, 9H), 1.66 (d, J ) 4.9 Hz, 3H), 2.38 (q, J ) 6.5
Hz, 2H), 3.61 (m, 2H), 5.52 (m, 2H), 7.23 (d, J ) 2.5 Hz, 1H),
7.28 (dd, J ) 9.0, 2.5 Hz, 1H), 8.21 (s, 1H), 8.36 (d, J ) 9.0
Hz, 1H), 11.91 (br s, 1H); 13C NMR (125.7 MHz, CDCl3) δ 18.0,
28.3, 34.2, 61.2, 80.1, 119.5, 121.5, 125.7, 127.1, 128.2, 130.8,
(10R*,11a S*)-2,10-Dich lor o-5,8,9,10,11,11a -h exa h yd r o-
p yr id o[1,2-c]qu in a zolin -6-on e (13): yellow solid; mp 240-
241.5 °C; 1H NMR (400 MHz, CDCl3) δ 1.86 (qd, J ) 12.3, 4.5
Hz, 1H), 1.97 (dd, J ) 4.5, 12.0 Hz, 1H), 2.23 (m, 1H), 2.41
(m, 1H), 2.69 (td, J ) 13.6, 2.5 Hz, 1H), 4.11 (tt, J ) 11.8, 4.4
Hz, 1H), 4.47 (dd, J ) 11.8, 2.3 Hz, 1H), 4.68 (dq, J ) 13.9,
2.3 Hz, 1H), 6.66 (d, J ) 8.5 Hz, 1H), 7.02 (d, J ) 2.1 Hz, 1H),
7.14 (dd, J ) 8.5, 2.2 Hz, 1H), 8.23 (br s, 1H); 13C NMR (100.6
MHz, CDCl3) δ 35.4, 43.2, 44.2, 55.7, 57.5, 115.3, 120.9, 125.4,
132.2, 139.3, 152.4, 162.5; IR (KBr) 2970, 1705, 1635 cm-1
;
MS (CI) m/z 323 (M+ + H), 267, 249, 167, 57; HRMS calcd for
C
17H24N2O2Cl 323.1526, found 323.1509.
Gen er a l P r oced u r e for th e Syn th esis of Im in es w ith
Am in e 9. A mixture of the aldehyde (0.10-0.50 g) and 9 (1.5
equiv) was heated to 90 °C for 2 h. The reaction was then
cooled to room temperature, and the excess amine was
removed under reduced pressure to give the crude imine,
which was used without further purification.
127.1, 128.7, 134.3, 152.3; IR (KBr) 3180, 2280, 1655 cm-1
;
MS (EI) m/z 270 (M+ + H), 235, 181, 55; HRMS calcd for
C
C
12H13Cl2N2O 271.0405, found 271.0395. Anal. Calcd for
12H12Cl2N2O: C, 53.16; H, 4.46; N, 10.33. Found: C, 52.99;
H, 4.20; N, 10.00.
3-Bu ten yl-(2′-a m in o-N′-ter t-bu toxyca r bon ylben zylid e-
n e)a m in e (26). Prepared by the general procedure: yellow
oil, 0.12 g; 1H NMR (500 MHz, CDCl3) δ 1.54 (s, 9H), 2.47 (m,
2H), 3.68 (m, 2H), 5.05-5.18 (m, 2H), 5.96 (m, 1H), 7.00 (m,
1H), 7.27 (dd, J ) 7.6, 1.5 Hz, 1H), 7.34 (m, 1H), 8.31 (s, 1H),
8.39 (d, J ) 8.4 Hz, 1H), 12.01 (br s, 1H); 13C NMR (125.7
MHz, CDCl3) δ 28.4, 35.4, 60.6, 79.7, 116.3, 118.0, 120.2, 120.9,
131.2, 133.0, 136.2, 140.8, 153.6, 163.9; IR (film) 3400 (br)
3060, 1710, 1625 cm-1; MS (CI) m/z 275 (M+ + H), 219, 201,
174, 133, 57; HRMS calcd for C16H23N2O2 275.1760, found
275.1765.
(N′-ter t-Bu toxycar bon yl-2′-am in o-5′-ch lor oben zyliden e)-
[(Z)-5-(tr im eth ylsilyl)-3-p en ten yl]a m in e (32). A solution
of 21 (0.51 g, 2.8 mmol) and triphenylphosphine (0.76 g, 2.9
mmol) in THF (5.0 mL) was stirred at room temperature for 2
h. Next, 8 (0.71 g, 2.8 mmol) was added, and the reaction was
heated at reflux for 16 h. The reaction was then cooled to room
temperature, concentrated under reduced pressure, triturated
with ether, filtered through Florisil, and concentrated under
reduced pressure to give 1.12 g of a crude yellow oil: 1H NMR
(300 MHz, CDCl3) δ 0.02 (s, 9H), 1.52 (s, 1H), 2.39 (q, J ) 6.8
Hz, 2H), 3.63 (t, J ) 6.4 Hz, 2H), 5.42 (m, 1H), 5.49 (m, 1H),
7.24 (d, J ) 2.4 Hz, 1H), 7.29 (dd, J ) 8.9, 2.4 Hz, 1H), 8.23
(s, 1H), 8.37 (d, J ) 8.9 Hz, 1H), 12.00 (br s, 1H); 13C NMR
(100.6 MHz, CDCl3) δ -1.86, 18.6, 28.2, 28.6, 61.0, 79.8, 119.3,
121.3, 123.8, 125.6, 127.4, 130.7, 132.1, 139.3, 153.3, 162.3;
IR (film) 2990, 1710, 1625 cm-1; MS (CI) m/z 395 (M+ + H),
339, 321, 167, 73, 57; HRMS calcd for C20H32ClN2O2Si 395.1922,
found 395.1939.
(N′-ter t-Bu toxycar bon yl-2′-am in o-5′-ch lor oben zyliden e)-
[(E)-5-(tr im eth ylsilyl)-3-p en ten yl]a m in e (33). A solution
of 24 (0.25 g, 1.4 mmol) and triphenylphosphine (0.36 g, 1.4
mmol) in THF (3.0 mL) was stirred at room temperature for
2.5 h. Next, 8 was added, and the reaction was heated at re-
flux for 18 h. The reaction was then cooled to room tempera-
ture, concentrated under reduced pressure, triturated with
ether, filtered through Florisil, and concentrated under re-
duced pressure to give 0.57 g of a crude yellow oil: 1H
NMR (400 MHz, CDCl3) δ -0.03 (s, 9H), 1.44 (d, J ) 8.1 Hz,
2H), 1.56 (s, 9H), 2.43 (q, J ) 6.7 Hz, 2H), 3.64 (t, J ) 6.7
Hz, 2H), 5.31 (m, 1H), 5.52 (m, 1H), 7.32 (m, 1H), 8.23 (s,
1H), 8.39 (d, J ) 9.0 Hz, 1H), 11.98 (s, 1H); 13C NMR (100.6
MHz, CDCl3) δ -2.1, 22.8, 28.2, 34.4, 61.8, 80.0, 119.5, 121.5,
125.4, 125.7, 128.7, 130.8, 132.1, 139.3, 153.4, 162.4; IR
(film) 2960, 1710, 1630 cm-1; MS (CI) m/z 395 (M+ + H),
339, 263; HRMS calcd for C20H32ClN2O2Si 395.1921, found
395.1949.
(10R*,11a R*)-2,10-Dich lor o-5,8,9,10,11,11a -h exa h yd r o-
p yr id o[1,2-c]qu in a zolin -6-on e (14): white solid; mp 242.5-
1
243 °C; H NMR (400 MHz, d-DMSO) δ 1.79 (d, J ) 14.5 Hz,
1H), 1.96 (m, 1H), 2.08 (m, 2H), 3.02 (td, J ) 12.7, 2.2 Hz,
1H), 4.21 (dd, J ) 13.6, 2.8 Hz, 1H), 4.79 (br s, 1H), 4.86 (dd,
J ) 10.0, 4.1 Hz, 1H), 6.74 (d, J ) 8.5 Hz, 1H), 7.17 (m, 2H),
9.49 (s, 1H); 13C NMR (100.6 MHz, d-acetone) δ 31.6, 37.6,
40.1, 51.9, 58.5, 115.0, 121.7, 124.8, 125.3, 128.1, 135.7, 151.6;
IR (KBr) 3180, 1660 cm-1; MS (CI) m/z 271 (M+ + H), 235,
181, 74; HRMS calcd for
271.0379.
C12H13Cl2N2O 271.0405, found
(Z)-5-Azid o-1-(tr im eth ylsilyl)-2-p en ten e (21). To a solu-
tion of 2011 (3.20 g, 13.5 mmol) in DMF (50.0 mL) at room
temperature was added sodium azide (3.52 g, 54.1 mmol). The
reaction was heated to 110 °C over 45 min. The reaction was
cooled to room temperature and partitioned between H2O and
Et2O (50 mL each). The layers were separated, and the
aqueous layer was extracted with Et2O (3 × 100 mL). The
combined organic layers were washed with saturated aqueous
NaCl (100 mL), dried (Na2SO4), decanted, and concentrated
under reduced pressure at room temperature. The crude
product was purified by silica gel chromatography with pen-
tane/Et2O (9:1) to give 2.25 g (91%) of a colorless oil: 1H NMR
(500 MHz, CDCl3) δ 0.01 (s, 9H), 1.50 (d, J ) 8.9 Hz, 2H),
2.31 (m, 2H), 3.26 (d, J ) 7.2 Hz, 2H), 5.25 (m, 1H), 5.55 (m,
1H); 13C NMR (125.7 MHz, CDCl3) δ -1.8, 18.8, 26.8, 51.2,
122.2, 128.9; IR (film) 3005, 2080 cm-1; MS (CI) m/z 184 (M+
+ H), 156, 90, 73; HRMS calcd for C8H18N3Si 184.1270, found
184.1283.
(E)-5-Azid o-1-(tr im eth ylsilyl)-2-p en ten e (24). To a solu-
tion of 2312 (0.65 g, 2.7 mmol) in DMF (10 mL) at room
temperature was added sodium azide (0.71 g, 11 mmol). The
reaction was heated to 110 °C over 1 h. The reaction was cooled
to room temperature and partitioned between H2O and Et2O
(10 mL each). The layers were separated and the aqueous layer
was extracted with Et2O (3 × 20 mL). The combined organic
layers were washed with saturated aqueous NaCl (20 mL),
dried (Na2SO4), decanted, and concentrated under reduced
pressure at room temperature. The crude product was purified
by silica gel chromatography with pentane/Et2O (19:1) to give
0.45 g (91%) of a colorless oil: 1H NMR (400 MHz, CDCl3) δ
0.00 (s, 9H), 1.44 (d, J ) 8.2 Hz, 2H), 2.28 (m, 2H), 3.24 (t, J
) 7.0 Hz, 2H), 5.22 (m, 1H), 5.54 (m, 1H); 13C NMR (100.6
MHz, CDCl3) δ -2.1, 22.9, 32.3, 51.5, 123.8, 130.0; IR (film)
2940, 2080 cm-1; MS (CI) m/z 184 (M+ + H), 156, 90, 73; HRMS
calcd for C8H18N3Si 184.1270, found 184.1252.
(E)-3-P en ten -1-a m in e (15). Prepared based on literature
procedure.16 The crude product was purified by distillation:
bp 93-95 °C; colorless liquid, 3.25 g (62%); 1H NMR (500 MHz,
CDCl3) δ 1.54 (m, 3H), 1.99 (q, J ) 6.7 Hz, 2H), 2.57 (t, J )
6.6 Hz, 2H), 4.61 (s, 2H), 5.23 (m, 2H), 5.39 (m, 2H); 13C NMR
(125.7 MHz, CDCl3) δ 17.7, 36.5, 41.4, 127.0, 128.3; IR (film)
(2′-Am in o-5′-ch lor oben zylid en e)-[(Z)-5-(tr im eth ylsilyl)-
3-p en ten yl]a m in e (34). A solution of 21 (1.41 g, 7.71 mmol)
and triphenylphosphine (2.02 g, 7.71 mmol) in THF (50 mL)
was stirred at room temperature for 4 h. Next, 2-amino-5-
chlorobenzaldehyde18 was added and the reaction was heated
at reflux for 16 h. The reaction was then cooled to room

662 J . Org. Chem., Vol. 65, No. 3, 2000
Frank and Aube´
temperature, concentrated under reduced pressure, triturated
with ether, filtered through Florisil, and concentrated under
reduced pressure to give 3.09 g of a crude dark yellow oil: H
(10R*,11a S*)- a n d (10R*,11a R*)-2-Ch lor o-5,8,9,10,11,-
11a -h exa h yd r op yr id o[1,2-c]qu in a zolin -6-on e (39). Pre-
pared by the general procedure except the reaction was run
for 24 h. The crude product was purified by silica gel chroma-
tography with EtOAc/hexanes (1:1) to give 0.056 g (65%) of a
white solid as a 19:1 mixture of diastereomers, based on 1H
NMR integration, mp 214-214.5 °C dec. Major isomer,
(10R*,11aS*)-39: 1H NMR (400 MHz, CDCl3) δ 1.87 (qd, J )
12.4, 4.5 Hz, 1H), 1.98 (q, J ) 12.4 Hz, 1H), 2.22 (m, 1H), 2.42
(m, 1H), 2.70 (td, J ) 13.5, 2.3 Hz, 1H), 4.13 (tt, J ) 11.8, 4.3
Hz, 1H), 4.51 (dd, J ) 11.7, 2.1 Hz, 1H), 4.69 (dq, J ) 13.7,
2.1 Hz, 1H), 6.69 (d, J ) 8.0 Hz, 1H), 6.96 (t, J ) 7.5 Hz, 1H),
7.03 (d, J ) 7.5 Hz, 1H), 7.18 (t, J ) 7.7 Hz, 1H), 7.68 (br s,
1H); 13C NMR (125.7 MHz, CDCl3) δ 35.5, 43.2, 44.4, 56.1, 57.9,
114.0, 119.4, 122.2, 125.3, 128.7, 135.6, 152.6; IR (film) 3165,
3015, 1640 cm-1; MS (CI) m/z 237 (M+ + H), 201, 147; HRMS
calcd for C12H14ClN2O 237.0794, found 237.0812. Minor isomer,
(10R*,11aR*)-39 (diagnostic peaks only): 1H NMR (400 MHz,
CDCl3) δ 2.16 (m, 1H), 3.27 (m, 1H), 5.04 (m, 1H).
(2R*,4S*)- a n d (2R*,4R*)-4-Ch lor o-2-p h en ylp ip er id in e
(40). Prepared by the general procedure. The crude product
was purified by silica gel chromatography with EtOAc/hexanes
(2:1) to give 0.030 g (25%) of a pale yellow solid as a 94:6
mixture of diastereomers, based on 1H NMR integration, mp
58-59 °C. Major isomer, (2R*,4S*)-40: 1H NMR (400 MHz,
CDCl3) δ 1.88 (br s, 1H), 1.97 (m, 2H), 2.07 (m, 2H), 3.02 (dq,
J ) 11.9, 2.6 Hz, 1H), 3.32 (td, J ) 11.9, 2.7 Hz, 1H), 4.16 (dd,
J ) 10.9, 2.5 Hz, 1H), 4.62 (t, J ) 3.0 Hz, 1H), 7.25 (m, 1H),
7.32 (m, 2H), 7.37 (m, 2H); 13C NMR (125.7 MHz, CDCl3) δ
33.5, 41.3, 42.1, 55.3, 58.2, 126.7, 127.3, 128.5, 144.0; IR (film)
3440 (br), 3240, 2930 cm-1; MS (CI) m/z 196 (M+ + H), 160,
131, 118, 91; HRMS calcd for C11H15ClN 195.0893, found
196.0909. Minor isomer, (2R*,4R*)-40 (diagnostic peaks
only): 1H NMR (400 MHz, CDCl3) δ 2.22 (m, 1H), 2.34 (m,
1H), 2.82 (m, 1H), 3.22 (m, 1H), 3.61 (m, 1H), 4.03 (m, 1H).
(2R*,4S*)- a n d (2R*,4R*)-4-Ch lor o-2-(4′-m eth oxyp h en -
yl)p ip er id in e (41). Prepared by the general procedure. The
crude product was purified by silica gel chromatography with
EtOAc/hexanes (2:1) to give 0.022 g (18%) of a pale yellow solid
as a 9:1 mixture of diastereomers, based on 1H NMR integra-
tion, mp 71-74 °C. Major isomer, (2R*,4S*)-41: 1H NMR (300
MHz, CDCl3) δ 1.75-2.34 (m, 5H), 3.30 (dt, J ) 11.7, 2.7 Hz,
1H), 3.32 (td, J ) 11.7, 2.7 Hz, 1H), 3.79 (s, 3H), 4.11 (dd, J )
10.2, 2.7 Hz, 1H), 4.61 (t, J ) 2.7 Hz, 1H), 6.85 (m, 2H), 7.28
(m, 2H); 13C NMR (125.7 MHz, CDCl3) δ 33.3, 41.3, 41.9, 54.7,
55.3, 58.1, 113.8, 127.7, 127.9, 158.9; IR (KBr) 3420 (br), 3305,
2935 cm-1; MS (CI) m/z 226 (M+ + H), 190, 161; HRMS calcd
for C12H17ClNO 226.0998, found 226.0985. Minor isomer,
(2R*,4R*)-41 (diagnostic peaks only): 1H NMR (300 MHz,
CDCl3) δ 3.21 (m, 1H), 3.58 (m, 1H), 4.00 (m, 1H).
1
NMR (400 MHz, CDCl3) δ 0.01 (s, 9H), 1.49 (d, J ) 8.4 Hz,
2H), 2.37 (q, J ) 7.1 Hz, 2H), 3.58 (td, J ) 7.1, 1.0 Hz, 2H),
5.32 (m, 1H), 5.49 (m, 1H), 6.39 (br s, 2H), 6.59 (d, J ) 8.6 Hz,
1H), 7.07 (dd, J ) 8.6, 2.4 Hz, 1H), 7.16 (d, J ) 2.4 Hz, 1H),
8.25 (s, 1H); 13C NMR (100.6 MHz, CDCl3) δ -1.8, 18.6, 29.1,
61.5, 116.7, 124.2, 127.2, 128.4, 128.5, 130.3, 132.1, 146.9,
162.5; IR (film) 3460, 3250, 3005, 1630 cm-1; MS (CI) m/z 295
(M+ + H), 279, 263, 167, 73; HRMS calcd for C15H24ClN2Si
295.1397, found 295.1410.
TiCl4-P r om oted Im in e-Olefin Cycliza tion of 10. To a
solution of 10 (0.10 g, 0.32 mmol) in CH2Cl2 (5 mL) at 0 °C
was added TiCl4 (0.14 mL, 1.3 mmol). The reaction was allowed
to warm slowly to room temperature. After 24 h, the reaction
was quenched with 10% aqueous NaOH (5 mL) and extracted
with CH2Cl2 (3 × 10 mL). The combined organic extracts were
then dried (Na2SO4), decanted, and concentrated under re-
duced pressure. The crude product was purified by silica gel
chromatography with hexanes/EtOAc (2:1 to 1:3) to give 31.1
mg (35%) of 13 and 7.4 mg (13%) of 12.
(6R *,12S *)-2,8-D ic h lo r o -13-((E )-p e n t -3-e n y l)-6,12-
im in odiben zo[b,f][1,5]-5,6,11,12-tetr ah ydr odiazocin e (37).
To a solution of 25 (0.10 g, 0.31 mmol) in CH2Cl2 (5.0 mL) at
0 °C was added TMSOTf (0.09 mL, 0.47 mmol). The reaction
was allowed to warm slowly to room temperature. After 3 h,
the reaction was quenched with 10% aqueous NaOH (5 mL)
and extracted with CH2Cl2 (3 × 10 mL). The combined organic
extracts were then dried (Na2SO4), decanted, and concentrated
under reduced pressure. The crude product was purified by
silica gel chromatography with hexanes/EtOAc (3:1) to give
36 mg (64%) of a tan foam: 1H NMR (400 MHz, CDCl3) δ 1.62
(d, J ) 5.9 Hz, 3H), 2.29 (m, 2H), 2.47 (m, 1H), 2.69 (m, 1H),
4.57 (br s, 2H), 4.89 (s, 2H), 5.40 (m, 1H), 5.48 (m, 1H), 6.51
(d, J ) 8.5 Hz, 2H), 6.99 (dd, J ) 8.5, 2.3 Hz, 2H), 7.03 (d, J
) 2.3 Hz, 2H); 13C NMR (100.6 MHz, CDCl3) δ 17.9, 31.0, 49.9,
65.5, 117.3, 123.2, 125.1, 126.7, 127.6, 128.2, 128.5, 139.2; IR
(KBr) 3390, 2920, 1600 cm-1; MS (CI) m/z 360 (M+ + H), 49;
HRMS calcd for C19H20Cl2N3 360.1034, found 360.1023. Anal.
Calcd for C19H19Cl2N3: C, 63.34; H, 5.32; N, 11.66. Found: C,
62.88; H, 5.59; N, 11.15.
(10R*,11R*,11aS*)-2,10-Dich lor o-5,8,9,10,11,11a-h exah y-
d r o-11-m eth ylp yr id o[1,2-c]qu in a zolin -6-on e (38). To a
solution of 25 (0.10 g, 0.31 mmol) in CH2Cl2 (5.0 mL) at 0 °C
was added TiCl4 (0.14 mL, 1.3 mmol). The reaction was allowed
to warm slowly to room temperature. After 24 h, the reaction
was quenched with 10% aqueous NaOH (5 mL) and extracted
with CH2Cl2 (3 × 10 mL). The combined organic extracts were
then dried (Na2SO4), decanted, and concentrated under re-
duced pressure. The crude product was purified by silica gel
chromatography with hexanes/EtOAc (2:1) to give 23 mg (40%)
of 38 as a tan foam and 26 mg (30%) of 37 a tan solid. An
analytical sample of 38 was crystallized from EtOH/CH3CN:
colorless prisms; mp 245-246 °C; 1H NMR (400 MHz, CDCl3)
δ 1.08 (d, J ) 6.5 Hz, 3H), 1.91 (m, 1H), 2.13 (qd, J ) 12.6, 4.7
Hz, 1H), 2.25 (m, 1H), 2.77 (td, J ) 13.1, 2.6 Hz, 1H), 3.80 (td,
J ) 10.6, 4.8 Hz, 1H), 3.94 (d, J ) 10.5 Hz, 1H), 4.51 (m, 1H),
6.69 (d, J ) 8.5 Hz, 1H), 7.02 (d, 2.0 Hz, 1H), 7.19 (dd, J )
8.5, 2.0 Hz, 1H), 7.95 (br s, 1H); 13C NMR (100.6 MHz, CDCl3)
δ 15.4, 35.3, 44.1, 44.3, 63.6, 64.1, 115.4, 119.7, 126.4, 127.6,
128.8, 135.1, 154.0; IR (KBr) 3180, 3070, 1645 cm-1; MS (CI)
(2R*,4S*)- a n d (2R*,4R*)-4-Ch lor o-2-(4′-n itr op h en yl)-
p ip er id in e (42). Prepared by the general procedure. The
crude product was purified by silica gel chromatography with
EtOAc/hexanes (2:1) to give 0.037 g (31%) of a light orange
solid as a 3:1 mixture of diastereomers, based on 1H NMR
integration: mp 77-80 °C. Major isomer, (2R*,4S*)-42: 1H
NMR (400 MHz, CDCl3) δ 1.77 (q, J ) 11.8 Hz, 1H), 1.85 (m,
2H), 2.23 (m, 1H), 2.31 (m, 1H), 2.83 (td, J ) 12.3, 2.4 Hz,
1H), 3.28 (dq, J ) 12.2, 2.7 Hz, 1H), 3.79 (dd, J ) 11.3, 2.1
Hz, 1H), 4.02 (m, 1H), 7.56 (m, 2H), 8.18 (m, 2H); 13C NMR
(125.7 MHz, CDCl3) δ 37.0, 45.6, 46.6, 57.4, 61.3, 124.3, 127.9,
151.1; IR (film) 3300 cm-1; MS (CI) m/z 241 (M+ + H), 205;
HRMS calcd for C11H14ClN2O2 241.0744, found 241.0753.
Minor isomer, (2R*,4R*)-42 (diagnostic peaks only): 1H NMR
(400 MHz, CDCl3) δ 1.99 (m, 1H), 2.07 (m, 2H), 3.06 (m, 1H),
3.36 (dd, J ) 11.9, 2.8 Hz, 1H), 4.30 (dd, J ) 11.1, 2.1 Hz,
1H), 4.62 (t, J ) 2.8 Hz, 1H); 13C NMR (125.7 MHz, CDCl3) δ
33.6, 41.4, 42.7, 55.3, 57.9, 124.2, 128.0, 147.7, 152.1.
m/z 285 (M+ + H), 249, 181, 85; Anal. Calcd for C13H14
-
Cl2N2O: C, 54.75; H, 4.95; N, 9.82. Found: C, 55.02; H, 5.04;
N, 9.56. X-ray data for this compound are available in the
Supporting Information.
Gen er a l P r oced u r e for Im in e-Olefin Cycliza tion s of
Im in es. To a solution of the imine (0.10 g) in CH2Cl2 (10 mL)
at room temperature was added TiCl4 (5.0 equiv). The reaction
was heated at reflux for 72 h and then cooled to room
temperature. The reaction was quenched by slow addition of
10% aqueous NaOH (10 mL) and was extracted with CH2Cl2
(3 × 100 mL). The combined organic layers were then dried
(Na2SO4), decanted, and concentrated under reduced pressure
to give cyclized product after silica gel chromatography.
(2R*,4S*)- a n d (2R*,4R*)-4-Ch lor o-2-(4′-ca r bom eth -
oxyp h en yl)p ip er id in e (43). Prepared by the general proce-
dure. The crude product was purified by silica gel chromatog-
raphy with EtOAc/hexanes (2:1) to give 0.062 g (52%) of a light
orange solid as a 7:3 mixture of diastereomers, based on 1H
NMR integration, mp 58.5-61 °C. Major isomer, (2R*,4S*)-
43: 1H NMR (400 MHz, CDCl3) δ 1.84 (m, 2H), 1.95 (m, 2H),

Cyclizations of Substituted Benzylidene-3-alkenylamines
J . Org. Chem., Vol. 65, No. 3, 2000 663
2.06 (m, 2H), 3.03 (m, 1H), 3.32 (td, J ) 11.9, 2.7 Hz, 1H),
3.90 (s, 3H), 4.22 (dd, J ) 11.0, 2.2 Hz, 1H), 4.61 (t, J ) 2.9
Hz, 1H), 7.44 (m, 2H), 7.99 (m, 2H); 13C NMR (125.7 MHz,
CDCl3) δ 33.3, 41.0, 42.1, 51.9, 55.0, 57.8, 126.6, 129.1, 129.7,
149.3, 166.8; IR (film) 3400 (br), 3300, 2930, 1695 cm-1; MS
(CI) m/z 254 (M+ + H), 218; HRMS calcd for C13H17ClNO2
254.0948, found 254.0948. Minor isomer, (2R*,4R*)-43 (diag-
nostic peaks only): 1H NMR (400 MHz, CDCl3) δ 2.20 (m, 1H),
2.30 (m, 1H), 2.81 (td, J ) 12.3, 2.4 Hz, 1H), 3.26 (m, 1H),
3.70 (dd, J ) 11.2, 2.1 Hz, 1H), 4.01 (m, 1H); 13C NMR (125.7
MHz, CDCl3) δ 36.7, 45.1, 46.2, 52.0, 57.3, 61.2, 126.5, 129.3,
129.8, 148.4, 166.7.
(2R*,4S*)- a n d (2R*,4R*)-4-Ch lor o-2-(5′-ch lor o-2′-n itr o-
p h en yl)p ip er id in e (44). Prepared by the general procedure.
The crude product was purified by silica gel chromatography
with EtOAc/hexanes (2:1) to give 0.025 g (21%) of a yellow oil
as an approximately 9:1 mixture of product to impurity which
may include the minor diastereomer, based on 1H NMR
integration: 1H NMR (500 MHz, CDCl3, minor impurities
present) δ 1.77 (q, J ) 11.7 Hz, 1H), 1.89 (qd, J ) 12.4, 4.4
Hz, 1H), 2.24 (m, 2H), 2.50 (m, 1H), 2.82 (td, J ) 12.3, 2.3 Hz,
1H), 3.25 (m, 1H), 4.01 (m, 1H), 4.17 (dd, J ) 11.0, 2.2 Hz,
1H), 7.37 (dd, J ) 8.7, 2.2 Hz, 1H), 7.79 (d, J ) 8.7 Hz, 1H),
7.92 (d, J ) 2.2 Hz, 1H); 13C NMR (125.7 MHz, CDCl3) δ 36.4,
44.0, 46.1, 55.7, 56.4, 125.8, 128.5, 129.1, 139.6, 140.0, 147.0;
IR (film) 3300, 3080 cm-1; MS (CI) m/z 275 (M+ + H); HRMS
calcd for C11H13Cl2N2O2 275.0354, found 275.0333.
(1R*,10b R*)-9-Ch lor o-1-et h en yl-2,3,6,10b -t et r a h yd r o-
1H-p yr r olo[1,2-c]qu in a zolin -5-on e (45). To a solution of 32
(0.50 g, ca. 1.3 mmol) in CH2Cl2 (50 mL) at room temperature
was added TiCl4 (0.70 mL, 6.4 mmol). The reaction was
quenched after 18.5 h with 10% aqueous NaOH (50 mL) and
extracted with CH2Cl2 (3 × 150 mL). The combined organic
layers were dried (Na2SO4), decanted, and concentrated under
reduced pressure. The crude product was purified by silica gel
chromatography with EtOAc/hexanes (2:1) to give 0.23 g (75%)
of a pale yellow solid as a 19:1 mixture of diastereomers, based
on 1H NMR. This solid was crystallized from acetone/H2O or
CH2Cl2/CH3CN to get an analytical sample of 45. Colorless or
light yellow prisms, respectively: mp 213.5-215 °C (after
crystallization from CH2Cl2/CH3CN); 1H NMR (400 MHz,
CDCl3) δ 2.01 (ddd, J ) 12.6, 8.0, 1.3 Hz, 1H), 2.23 (m, 1H),
3.24 (m, 1H), 3.57 (m, 1H), 3.75 (m, 1H), 4.81 (d, J ) 4.6 Hz,
1H), 5.07-5.19 (m, 2H), 5.59 (m, 1H), 6.61 (d, J ) 8.5 Hz, 1H),
6.94 (s, 1H), 7.13 (br s, 1H); 13C NMR (100.6 MHz, CDCl3) δ
29.4, 43.0, 45.6, 61.4, 115.3, 117.5, 119.8, 126.4, 126.7, 128.1,
135.6, 136.3, 153.1; IR (KBr) 3270, 3065 cm-1; MS (CI) m/z
249 (M+ + H), 194, 165. Anal. Calcd for C13H13ClN2O: C, 62.78;
H, 5.27; N, 11.26. Found: C, 62.82; H, 5.40; N, 11.24. X-ray
data for this compound are available in the Supporting
Information.
(6R*,12S*)-2,8-Dich lor o-13-(p en t -4-en yl)-6,12-im in o-
d iben zo[b,f][1,5]-5,6,11,12-tetr a h yd r od ia zocin e (46). To a
solution of 34 (0.25 g, ca. 0.62 mmol) in CH2Cl2 at room
temperature was added TiCl4 (0.34 mL, 3.1 mmol). The
reaction was quenched with 10% aqueous NaOH (10 mL) after
16 h and extracted with CH2Cl2 (3 × 50 mL). The combined
organic layers were dried (Na2SO4), decanted, and concen-
trated under reduced pressure. The crude product was purified
by silica gel chromatography with hexanes/EtOAc (4:1) to give
43.4 mg (39%) of a white foam: 1H NMR (400 MHz, CDCl3) δ
1.70 (m, 2H), 2.09 (dd, J ) 14.2, 7.2 Hz, 2H), 2.46 (m, 1H),
2.67 (m, 1H), 4.56 (br s, 2H), 4.87 (s, 2H), 4.94-5.03 (m, 2H),
5.79 (m, 1H), 6.51 (d, J ) 8.5 Hz, 2H), 6.99 (dd, J ) 8.5, 2.4
Hz, 2H), 7.03 (d, J ) 2.3 Hz, 2H); 13C NMR (100.6 MHz, CDCl3)
δ 26.8, 31.3, 49.3, 65.5, 114.9, 117.3, 123.2, 125.2, 127.6, 128.5,
138.1, 139.3; IR (film) 3400, 2930, 2850 cm-1; MS (CI) m/z 360
(M+ + H), 304, 290, 206, 84; HRMS calcd for C19H20Cl2N3
360.1034, found 360.1014. Anal. Calcd for C19H19Cl2N3: C,
63.34; H, 5.32; N, 11.66. Found: C, 63.32; H, 4.87; N, 11.28.
(2R*,3R*)- a n d (2R*,3S*)-2-(5′-Ch lor o-2′-n itr op h en yl)-
3-eth en ylp yr r olid in e (47). To a solution of 35 (0.20 g, ca.
0.54 mmol) in CH2Cl2 (20 mL) was added TiCl4 (0.27 mL, 2.5
mmol). The reaction was quenched after 24 h with 10%
aqueous NaOH (20 mL) and extracted with CH2Cl2 (3 × 100
mL). The combined organic layers were dried (Na2SO4),
decanted, and concentrated under reduced pressure. The crude
product was purified by silica gel chromatography with EtOAc/
hexanes (2:1) to give 33 mg (23%) of a brown oil as a 19:1
mixture of product to impurity which may include the minor
diastereomer, based on 1H NMR integration: 1H NMR (300
MHz, CDCl3, minor impurities present) δ 1.80 (m, 1H), 2.05
(m, 1H), 2.16 (br s, 1H), 2.57 (m, 1H), 3.21 (m, 2H), 4.68 (d, J
) 7.0 Hz, 1H), 4.94 (m, 1H), 4.99 (m, 1H), 5.81 (m, 1H), 7.31
(dd, J ) 8.7, 2.4 Hz, 1H), 7.76 (d, J ) 8.6 Hz, 1H), 7.87 (d, J
) 2.5 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ 32.2, 46.0, 52.7,
62.0, 115.6, 125.7, 127.6, 129.1, 138.6 (2 carbons), 139.3, 141.7;
IR (film) 3060 cm-1; MS (CI) m/z 253 (M+ + H), 239; HRMS
calcd for
C12H14ClN2O2 253.0744, found 253.0766. Minor
isomer (diagnostic peaks only): 1H NMR (300 MHz, CDCl3) δ
4.20 (m, 2H), 5.20 (m, 1H), 7.12 (m, 1H), 7.47 (m, 1H).
(2′R*,3′R*)- a n d (2′R*,3′S*)-N-[4′-Ch lor o-2′-(3′′-et h e-
n ylp yr r olid in -2′′-yl)p h en yl]-2,2-d im et h ylp r op ion a m id e
(48). To a solution of 36 (0.10 g, ca. 0.23 mmol) in CH2Cl2 (10
mL) was added TiCl4 (0.15 mL, 1.4 mmol). The reaction was
heated at reflux for 24 h, then quenched with 10% aqueous
NaOH (10 mL) and extracted with CH2Cl2 (3 × 50 mL). The
combined organic layers were dried (Na2SO4), decanted, and
concentrated under reduced pressure. The crude product was
purified by silica gel chromatography with EtOAc/hexanes (2:
1) to give 22 mg (31%) of a brown oil as a 17:3 mixture of
diastereomers, based on 1H NMR integration. Major isomer,
(2′R*,3′R*)-48: 1H NMR (400 MHz, CDCl3) δ 1.34 (s, 9H), 1.90
(m, 1H), 2.18 (m, 1H), 3.15 (dd, J ) 13.3, 6.4 Hz, 1H), 3.68
(td, J ) 9.3, 2.8 Hz, 1H), 3.84 (m, 1H), 4.89 (d, J ) 4.8 Hz,
1H), 5.06 (d, J ) 10.4 Hz, 1H), 5.13 (d, J ) 16.6 Hz, 1H), 5.73
(m, 1H), 6.79 (m, 1H), 6.97 (d, J ) 8.4 Hz, 1H), 7.05 (dd, J )
8.4, 2.5 Hz, 1H). Minor isomer, (2′R*,3′S*)-48 (diagnostic peaks
only): 1H NMR (400 MHz, CDCl3) δ 1.33 (s, 9H), 2.68 (m, 1H),
3.04 (m, 1H), 3.63 (m, 1H), 4.12 (m, 1H), 4.40 (d, J ) 8.6 Hz,
1H), 5.22 (d, J ) 10.2 Hz, 1H), 5.36 (d, J ) 17.2 Hz, 1H), 5.96
(m, 1H), 7.01 (s, 1H), 7.12 (m, 1H), 7.18 (m, 1H). This
compound was not characterized further.
(2R *,3S *)-2-(5′-Ch lor o-2′-(2,2,2-t r ich lor oa ce t yl)a m i-
n op h e n yl)-1-(2,2,2-t r ich lor oa ce t yl)-3-e t h e n ylp yr r oli-
d in e (53). To a solution of 34 (0.10 g, ca. 0.30 mmol) in CH3CN
(5.0 mL) was added trichloroacetic anhydride (0.27 mL, 1.5
mmol). After 16.5 h, the reaction mixture was diluted with
Et2O (15 mL) and washed with saturated aqueous NaHCO3
(3 × 5 mL). The organic layer was dried (Na2SO4), decanted,
and concentrated under reduced pressure. Silica gel chroma-
tography with hexanes/EtOAc (15:1) gave impure product (67
mg) which was crystallized from acetone/hexane to give 50 mg
1
(33%) of waxy colorless prisms: mp 200.5-202 °C; H NMR
(300 MHz, CDCl3) δ 1.98 (m, 1H), 2.36 (m, 1H0, 3.04 (m, 1H),
3.95 (td, J ) 11.4, 5.4 Hz, 1H), 4.52 (ddd, J ) 11.4, 7.2, 1.8
Hz, 1H), 4.84 (d, J ) 8.1 Hz, 1H), 5.00-5.09 (m, 2H), 5.72 (m,
1H), 7.27 (d, J ) 2.4 Hz, 1H), 7.35 (dd, J ) 8.4, 2.4 Hz, 1H),
7.56 (d, J ) 8.4 Hz, 1H), 9.48 (br s, 1H); 13C NMR (125.7 MHz,
CDCl3) δ 32.3, 50.2, 51.1, 63.3, 92.6, 92.7, 117.6, 126.6, 127.4,
129.0, 133.2, 133.3, 135.3, 135.9, 160.1, 160.6; IR (KBr) 3310
(br), 2970, 1700, 1650 cm-1; MS (CI) m/z 518 (M+ + NH4), 511
(M+ + H), 479, 367, 117, 96; HRMS calcd for C16H13Cl7N2O2
510.8875, found 510.8862.
(1R*,10b S*)-9-Ch lor o-1-et h en yl-2,3,6,10b -t et r a h yd r o-
1H-p yr r olo[1,2-c]qu in a zolin -5-on e (54). To a solution of 53
(0.050 g, 0.097 mmol) in MeOH (3 mL) was added a solution
of K2CO3 (0.5 g, 3.6 mmol) in H2O (2 mL). The reaction was
heated at reflux for 20 h, then cooled to room temperature and
extracted with CH2Cl2 (3 × 50 mL). The combined organic
layers were dried (Na2SO4), decanted, and concentrated under
reduced pressure. The crude product was purified by silica gel
chromatography with EtOAc/hexanes (2:1) to give 14 mg (59%)
1
of light yellow flakes: mp 213-214 °C; H NMR (400 MHz,
CDCl3) δ 1.90 (m, 1H), 2.21 (m, 1H), 2.97 (m, 1H), 3.63 (dd, J
) 9.7, 5.2 Hz, 1H), 4.43 (d, J ) 9.6 Hz, 1H), 5.31 (d, J ) 10.3
Hz, 1H), 5.38 (d, J ) 17.1 Hz, 1H), 5.95 (m, 1H), 6.69 (d, J )
8.5 Hz, 1H), 7.12 (dd, J ) 8.5, 1.7 Hz, 1H), 7.35 (d, J ) 1.2 Hz,
1H), 7.90 (br s, 1H); 13C NMR (100.6 MHz, CDCl3) δ 30.9, 43.5,
49.8, 60.3, 114.8, 117.9, 123.2, 124.6, 127.0, 128.3, 135.9, 138.1,

664 J . Org. Chem., Vol. 65, No. 3, 2000
Frank and Aube´
152.8; IR (film) 3430, 3190, 3080, 1670 cm-1; MS (CI) m/z 249
(M+ + H), 194, 165. Anal. Calcd for C13H13ClN2O: C, 62.78;
H, 5.27; N, 11.26. Found: C, 62.42; H, 5.42; N, 10.95.
7.71 (d, J ) 8.2 Hz, 2H), 9.79 (s, 1H); 13C NMR (125.7 MHz,
d-DMSO) δ 20.9, 22.4, 28.6, 45.0, 46.6, 57.2, 116.1, 123.9, 126.6,
126.9, 127.1, 127.2, 128.9, 129.7, 134.1, 135.2, 137.1, 143.3,
168.9.
(1R*,10b R*)-9-Ch lor o-6-p -t olu en esu lfon yl-1-et h en yl-
2,3,6,10b -t et r a h yd r o-1H -p yr r olo[1,2-c]q u in a zolin -5-on e
(55). To a solution of 45 (4.00 g, 16.1 mmol) in THF (400 mL)
at 0 °C was added NaH (60% dispersion in mineral oil, 2.00 g,
50.0 mmol). After 1 h, p-toluenesulfonyl chloride (3.40 g, 17.8
mmol) was added, and the reaction was allowed to warm to
room temperature while stirring for an additional 15 h. The
reaction was then quenched with saturated aqueous NH4Cl
(100 mL) and extracted with EtOAc (3 × 200 mL). The
combined organic layers were dried (Na2SO4), decanted, and
concentrated under reduced pressure. The crude product was
purified by silica gel chromatography with EtOAc/hexanes (1:
1) to give 5.80 g (90%) of a dark yellow solid. An analytical
sample was prepared by crystallization from CH3CN/CH2Cl2.
Dark tan cubes: mp 184-184.5 °C; 1H NMR (400 MHz, CDCl3)
δ 1.96 (m, 1H), 2.24 (m, 1H), 2.45 (s, 3H), 3.33 (m, 1H), 3.52
(td, J ) 11.5, 7.1 Hz, 1H), 3.74 (m, 1H), 4.71 (d, J ) 4.8 Hz,
1H), 5.11 (dd, J ) 11.1, 1.2 Hz, 1H), 5.22 (dd, J ) 17.1, 1.2
Hz, 1H), 5.37 (m, 1H), 7.02 (d, J ) 1.3 Hz, 1H), 7.23 (dd, J )
8.8, 2.0 Hz, 1H), 7.37 (m, 3H), 8.10 (d, J ) 8.4 Hz, 1H); 13C
NMR (100.6 MHz, CDCl3) δ 21.6, 30.6, 44.3, 45.2, 59.5, 118.4,
122.4, 127.2, 127.7, 128.1, 128.3, 129.7, 130.5, 134.1, 134.9,
137.5, 144.7, 149.4; IR (KBr) 2960 cm-1; MS (CI) m/z 403 (M+
+ H); HRMS calcd for C20H20ClN2O3S 403.0883, found 403.0861.
(2R *,3R *)-2-(5′-Ch lor o-2′-p -t olu e n e su lfon yla m in o-
p h en yl)-3-eth en ylp yr r olid in e (56). A solution of 55 (5.80
g, 14.4 mmol) in THF/MeOH/50% aqueous NaOH (3:2:1, 150
mL) was heated at reflux for 96 h. The reaction was cooled to
0 °C, acidified to pH ∼1 with 10% HCl, and extracted with
CH2Cl2 (5 × 200 mL). The combined organic layers were dried
(Na2SO4), decanted, and concentrated under reduced pressure.
The crude product was purified by silica gel chromatography
with CH2Cl2/MeOH/EtNH2 (97:2:1) to give 3.52 g (65%) of a
tan solid: mp 61-62.5 °C, mp (HCl salt) 222-225 °C (dec);
1H NMR (400 MHz, CDCl3) δ 1.87 (m, 1H), 2.09 (m, 1H), 2.39
(s, 3H), 2.95 (m, 1H), 3.05 (dt, J ) 9.9, 7.6 Hz, 1H), 3.34 (m,
1H), 4.37 (m, 1H), 4.61 (dd, J ) 10.1, 1.6 Hz, 1H), 4.76 (d, J )
16.9 Hz, 1H), 5.27 (dt, J ) 16.9, 9.7 Hz, 1H), 6.87 (d, J ) 2.4
Hz, 1H), 7.04 (dd, J ) 8.8, 2.4 Hz, 1H), 7.25 (d, J ) 8.2 Hz,
2H), 7.35 (d, J ) 8.8 Hz, 1H), 7.77 (d, J ) 8.2 Hz, 2H); 13C
NMR (100.6 MHz, CDCl3) δ 21.5, 32.0, 45.4, 48.5, 66.2, 116.3,
119.0, 127.0, 127.4, 127.6, 127.8, 129.4, 129.6, 137.0, 137.5,
137.7, 143.4; IR (film) 3320, 3070, 1475 cm-1; MS (CI) m/z 377
(M+ + H), 221, 167; HRMS calcd for C19H22ClN2O2S 377.1090,
found 377.1112.
(2R*,3R*)-1-Acetyl-2-(5′-ch lor o-2′-p-tolu en esu lfon ylam i-
n op h en yl)-3-eth en ylp yr r olid in e (57). To a solution of 56
(0.50 g, 1.3 mmol) in CH2Cl2 (5.0 mL) at room temperature
was added DMAP (16 mg, 0.13 mmol), pyridine (0.16 mL, 2.0
mmol), and acetyl chloride (0.14 mL, 2.0 mmol). After 3 h,
saturated aqueous NaHCO3 (5 mL) was added, and the
reaction mixture was extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were dried (Na2SO4), decanted, and
concentrated under reduced pressure. The crude product was
purified by silica gel chromatography with EtOAc/hexanes (2:
1) to give 0.48 g (85%) of a pale yellow solid as a 3:2 mixture
of rotamers, based on 1H NMR integration: mp 67.5-69 °C;
Major rotamer: 1H NMR (400 MHz, d-DMSO) δ 1.54 (s, 3H),
1.70 (m, 1H), 1.86 (m, 1H), 2.36 (s, 3H), 3.27 (m, 1H), 3.41 (m,
1H), 3.72 (m, 1H), 4.82 (d, J ) 10.5 Hz, 1H), 4.95 (m, 1H),
5.34 (m, 1H), 5.61 (d, J ) 8.0 Hz, 1H), 6.74 (d, J ) 8.7 Hz,
1H), 6.91 (d, J ) 2.4 Hz, 1H), 7.18 (dd, J ) 8.6, 2.4 Hz, 1H),
7.38 (m, 2H), 7.63 (d, J ) 8.2 Hz, 2H), 9.48 (s, 1H); 13C NMR
(125.7 MHz, d-DMSO) δ 21.0, 22.0, 26.4, 45.5, 47.1, 59.2, 116.6,
126.5, 127.0, 127.8, 129.8, 130.9, 133.3, 135.5, 135.8, 136.8,
138.4, 143.6, 168.8; IR (KBr) 3060, 2950 cm-1; MS (CI) m/z
419 (M+ + H), 263; HRMS calcd for C21H24ClN2O3S 419.1196,
found 419.1203. Minor rotamer: 1H NMR (400 MHz, d-DMSO)
δ 1.98 (s, 3H), 2.01 (m, 2H), 2.34 (s, 3H), 3.05 (m, 1H), 3.58
(m, 1H), 3.84 (m, 1H), 4.76 (d, J ) 10.4, 1H), 4.89 (m, 1H),
5.10 (m, 1H), 5.29 (m, 1H), 6.94 (d, J ) 2.4 Hz, 1H), 7.07 (d, J
) 8.7 Hz, 1H), 7.14 (dd, J ) 8.7, 2.4 Hz, 1H), 7.35 (m, 2H),
(3a R*,4R*,9bS*)-1-Acetyl-8-ch lor o-4-(iod om eth yl)-5-p-
tolu en esu lfon yl-2,3,3a ,4,5,9b-h exa h yd r o-1H-p yr r olo[3,2-
c]qu in olin e (58). To a solution of 57 (0.10 g, 0.24 mmol) in
CH3CN (5.0 mL) at room temperature was added I2 (0.61 g,
2.4 mmol). The reaction was heated at reflux for 24 h and then
cooled to room temperature and diluted with Et2O (20 mL).
The resulting solution was washed with saturated NaHCO3
(5 mL), 10% aqueous Na2S2O3 (3 × 10 mL), and saturated
aqueous NaCl (10 mL). The organic layer was dried (Na2SO4),
decanted, and concentrated under reduced pressure. The crude
product was purified by silica gel chromatography with EtOAc/
hexanes (2:1) to give 0.11 g (84%) of a yellow solid. An
analytical sample was crystallized from CH2Cl2/CH3CN: thick
colorless prisms; mp 189.5-190 °C; 1H NMR (400 MHz, CDCl3)
δ 1.91 (m, 1H), 2.09 (s, 3H), 2.15 (m, 1H), 2.44 (s, 3H), 3.01
(m, 1H), 3.11 (t, J ) 10.4 Hz, 1H), 3.26 (dd, J ) 10.3, 5.2 Hz,
1H), 3.50 (m, 2H), 4.84 (m, 1H), 5.43 (d, J ) 7.8 Hz, 1H), 7.11
(dd, J ) 9.0, 2.5 Hz, 1H), 7.35 (d, J ) 8.2 Hz, 2H), 7.45 (d, J
) 9.0 Hz, 1H), 7.83 (m, 3H); 13C NMR (100.6 MHz, CDCl3) δ
5.1, 21.5, 22.5, 28.1, 38.0, 46.7, 52.0, 57.7, 121.7, 127.1, 128.4,
128.8, 129.9, 130.0, 131.5, 132.0, 137.5, 144.5, 171.1; IR (KBr)
3440 (br), 3130, 3015, 1625 cm-1; MS (CI) m/z 545 (M+ + H),
375, 263, 249, 219, 112, 91, 65, 43; Anal. Calcd for C21H22
-
ClIN2O3S: C, 46.29; H, 4.07; N, 5.14. Found: C, 46.08; H, 4.23;
N, 5.44. X-ray data for this compound are available in the
Supporting Information.
E t h yl 3-Br om o-4-(N-ter t-b u t oxyca r b on yl)a m in ob en -
zoa te (59). Bromine (12.0 mL, 233 mmol) was added dropwise
to a solution of 514 (35.0 g, 132 mmol), sodium acetate (43.0 g,
524 mmol), and acetic acid (700 mL). After 41 h, the reaction
was cooled to 0 °C, 50% aqueous NaOH (600 mL) was added
slowly, and the mixture was extracted with EtOAc (3 × 500
mL). The combined organic layers were washed with 10%
aqueous NaOH (2 × 150 mL) and saturated aqueous NaCl (150
mL), then dried (Na2SO4), filtered, and concentrated under
reduced pressure. The crude product was purified by silica gel
chromatography with hexanes/EtOAc (4:1) to give 45.9 g
(100%) of a pale pink solid: mp 82.5-84 °C; 1H NMR (400
MHz, CDCl3) δ 1.39 (t, J ) 7.1 Hz, 3H), 1.56 (s, 9H), 4.36 (q,
J ) 7.1 Hz, 2H), 7.22 (br s, 1H), 7.95 (dd, J ) 8.7, 1.9 Hz, 1H),
8.19 (d, J ) 1.9 Hz, 1H), 8.27 (d, J ) 8.7 Hz, 1H); 13C NMR
(100.6 MHz, CDCl3) δ 14.3, 28.2, 61.1, 81.8, 111.3, 118.4, 125.5,
129.8, 133.6, 140.2, 151.8, 165.1; IR (KBr) 3380, 2960, 1720,
1690 cm-1; MS (CI) m/z 344 (M+ + H), 305, 288, 243, 224, 198,
57. Anal. Calcd for C14H18BrNO4: C, 48.55; H, 5.27; N, 4.07.
Found: C, 48.63; H, 5.18; N, 3.82.
Eth yl 4-(N-ter t-Bu toxyca r bon yl)a m in o-3-eth en ylben -
zoa te (60). A solution of 59 (7.50 g, 21.8 mmol) and 2,6-di-
tert-butyl-4-methylphenol (50 mg) in toluene (50 mL) was
deoxygenated with argon. The flask and reflux condenser were
covered with aluminum foil. Next, (Ph3P)4Pd (1.25 g, 1.08
mmol) and tributyl(vinyl)tin (9.00 mL, 30.8 mmol) were added,
and the mixture was heated at reflux for 24 h. The reaction
was then cooled to room temperature, filtered through a short
pad of silica gel and concentrated under reduced pressure. The
crude product was purified by silica gel chromatography with
hexanes/EtOAc (9:1) to give 5.40 g (85%) of a thick pale yellow
oil: 1H NMR (400 MHz, CDCl3) δ 1.39 (t, J ) 7.1 Hz, 3H),
1.53 (s, 9H), 4.36 (q, J ) 7.1 Hz, 2H), 5.52 (dd, J ) 11.0, 1.0
Hz, 1H), 5.73 (dd, J ) 17.3, 1.0 Hz, 1H), 6.66 (br s, 1H), 6.77
(dd, J ) 17.3, 11.0 Hz, 1H), 7.93 (dd, J ) 8.6, 1.9 Hz, 1H),
8.02 (d, J ) 1.9 Hz, 1H), 8.06 (d, J ) 8.6 Hz, 1H); 13C NMR
(100.6 MHz, CDCl3) δ 14.4, 28.3, 60.8, 81.3, 119.1, 119.8, 125.0,
127.5, 128.9, 130.0, 131.4, 139.3, 152.3, 166.3; IR (film) 3320
(br), 2960, 1720 (sh), 1695 cm-1; MS (CI) m/z 292 (M+ + H),
236,191, 57. Anal. Calcd for C16H21NO4: C, 65.96; H, 7.27; N,
4.81. Found: C, 65.81; H, 7.33; N, 4.53.
E t h yl 4-(N-ter t-Bu t oxyca r bon yl)a m in o-3-for m ylb en -
zoa te (61). Alkene 60 (4.00 g, 13.7 mmol) was dissolved in
CH2Cl2, cooled to -78 °C, and then ozone was bubbled through
the solution until it turned blue (ca. 30 min). The reaction was

Cyclizations of Substituted Benzylidene-3-alkenylamines
J . Org. Chem., Vol. 65, No. 3, 2000 665
quenched with DMS (2.0 mL), allowed to warm to room
temperature, and then was concentrated under reduced pres-
sure. The crude product was purified by silica gel chromatog-
raphy with hexanes/EtOAc (5:1) to give 3.13 g (78%) as a white
solid: mp 100.5-101 °C; 1H NMR (400 MHz, CDCl3) δ 1.42 (t,
J ) 7.1 Hz, 3H), 1.55 (s, 9H), 4.40 (q, J ) 7.1 Hz, 2H), 8.20
(dd, J ) 8.9, 1.7 Hz, 1H), 8.34 (d, J ) 1.8 Hz, 1H), 8.55 (d, J
) 8.9 Hz, 1H), 9.96 (s, 1H), 10.60 (br s, 1H); 13C NMR (100.6
MHz, CDCl3) δ 14.3, 28.2, 61.2, 81.3, 117.9, 120.5, 123.6, 136.7,
137.9, 145.3, 152.4, 165.1, 194.6; IR (KBr) 3250, 2985, 1715,
1695 cm-1; MS (CI) m/z 294 (M+ + H), 255, 238, 194, 57. Anal.
Calcd for C15H19NO5: C, 61.42; H, 6.53; N, 4.78. Found: C,
61.45; H, 6.83; N, 4.80.
(N′-ter t-Bu t oxyca r b on yl-2′-a m in o-5′-ca r b et h oxyb en -
zylid en e)-[(Z)-5-(tr im eth ylsilyl)-3-p en ten yl]a m in e (62). A
solution of 21 (0.12 g, 0.65 mmol) and triphenylphosphine (0.17
g, 0.65 mmol) in THF (5.0 mL) was stirred at room tempera-
ture for 3 h. Next, 61 (0.19 g, 0.65 mmol) was added, and the
reaction was heated at reflux for 20 h. The reaction was then
cooled to room temperature, concentrated under reduced
pressure, triturated with ether, filtered through Florisil, and
concentrated under reduced pressure to give 0.35 g of a crude
colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.01 (s, 9H), 1.39
(t, J ) 7.0 Hz, 3H), 1.54 (s, 9H), 2.40 (q, J ) 6.8 Hz, 2H), 3.64
(t, J ) 6.7 Hz, 2H), 4.36 (q, J ) 7.2 Hz, 1H), 5.42 (m, 1H),
5.50 (m, 1H), 8.00 (m, 2H), 8.37 (s, 1H), 8.46 (d, J ) 9.3 Hz,
1H), 12.38 (br s, 1H); 13C NMR (100.6 MHz, CDCl3) δ -1.8,
14.4, 18.7, 28.3, 28.7, 60.8, 61.0, 80.3, 117.4, 119.6, 122.8, 123.9,
127.5, 132.4, 134.7, 144.7, 153.2, 163.1, 165.9; IR (film) 2960,
2940, 1715, 1700 cm-1; MS (CI) m/z 433 (M+ + H), 377, 279,
263, 208, 194, 183; HRMS calcd for C23H37N2O4Si 433.2522,
found 433.2526. This compound was used immediately in the
next step without further purification.
product was purified by silica gel chromatography with hex-
anes/EtOAc (2:1) to give 2.8 g (91%) of a yellow solid as a 17:3
mixture of diastereomers, based on 1H NMR integration, mp
148.5-151.5 °C. Major isomer, (1R*,10bR*)-64: 1H NMR (400
MHz, CDCl3) δ 1.37 (t, J ) 7.1 Hz, 3H), 1.98 (dd, J ) 12.6, 6.9
Hz, 1H), 2.25 (m, 1H), 2.46 (s, 3H), 3.44 (m, 1H), 3.54 (m, 1H),
3.79 (m, 1H), 4.36 (m, 1H), 4.81 (d, J ) 4.7 Hz, 1H), 5.07 (d, J
) 9.9 Hz, 1H), 5.25 (dd, J ) 17.0, 1.3 Hz, 1H), 5.34 (m, 1H),
7.38 (d, J ) 8.1 Hz, 2H), 7.51 (d, J ) 8.7 Hz, 1H), 7.75 (s, 1H),
7.94 (dd, J ) 8.7, 1.1 Hz, 1H), 7.98 (m, 1H), 8.15 (d, J ) 8.3
Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ 14.1, 21.2, 30.2, 44.2,
45.1, 59.4, 60.9, 118.2, 120.4, 126.2, 126.6, 128.0, 128.7, 128.8,
129.3, 129.5, 134.8, 137.1, 139.0, 144.6, 148.9; IR (KBr) 2960,
2880, 1705 (sh), 1690 cm-1; MS (CI) m/z 441 (M+ + H). Anal.
Calcd for C23H24N2O5S: C, 62.71; H, 5.49; N, 6.36. Found: C,
62.35; H, 5.72; N, 6.37. Minor isomer, (1R*,10bS*)-64 (diag-
nostic peaks only): 1H NMR (400 MHz, CDCl3) δ 2.43 (s, 3H),
3.05 (m, 1H), 3.38 (m, 1H), 3.82 (m, 1H), 4.50 (d, J ) 9.6 Hz,
1H), 5.42 (m, 1H), 6.01 (m, 1H), 7.30 (d, J ) 8.0 Hz, 2H), 7.46
(d, J ) 8.6 Hz, 1H), 7.81 (d, J ) 8.2 Hz, 1H), 8.19 (d, J ) 8.3
Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ 14.0, 21.4, 30.9, 44.6,
48.2, 59.0, 117.8, 120.2, 125.2, 126.1, 127.3, 128.1, 129.1, 130.2,
137.2, 139.2.
(2R*,3R*)- a n d (2R*,3S*)-2-(5′-Ca r bom eth oxy-2′-p-tolu -
en esu lfon yla m in op h en yl)-3-eth en ylp yr r olid in e (65). A
solution of 64 (2.50 g, 5.68 mmol) in THF/MeOH/50% aqueous
NaOH (3:2:1, 120 mL) was heated at reflux for 67 h. The
reaction was acidified to pH ∼1 with 10% HCl and extracted
with CH2Cl2 (3 × 200 mL). The combined organic layers were
dried (Na2SO4), decanted, and concentrated under reduced
pressure to give 2.41 g of crude 2-(5′-carboxy-2′-p-toluenesulfo-
nylaminophenyl)-3-ethenylpyrrolidine as a brown oil: IR (KBr)
3650-2300 (br), 3400, 3050, 1645 cm-1; MS (CI) m/z 387 (M+
+ H), 259, 189; HRMS calcd for C20H23N2O4S 387.1378, found
387.1375. To a solution of the crude acid (2.41 g) in MeOH
(100 mL) was added concentrated H2SO4 (0.5 mL). The reaction
was heated at reflux for 20 h, then cooled to room temperature
and concentrated. To the resulting residue was added satu-
rated aqueous NaHCO3 (50 mL). This aqueous solution was
extracted with CH2Cl2 (3 × 75 mL). The combined organic
layers were dried (Na2SO4), decanted, and concentrated under
reduced pressure. The crude product was purified by silica gel
chromatography with CH2Cl2/MeOH (19:1) to give 1.31 g (57%
over two steps) of a white foam as a 17:3 mixture of diaster-
(1R*,10bR*)- a n d (1R*,10bS*)-9-Ca r beth oxy-1-eth en yl-
2,3,6,10b -t et r a h yd r o-1H -p yr r olo[1,2-c]q u in a zolin -5-on e
(63). To a solution of 62 (9.13 g, ca. 21.1 mmol, as a ca. 2:1
1
mixture of Z and E isomers, based on H NMR integration) in
CH2Cl2 (500 mL) at room temperature was added TiCl4 (12.0
mL, 109 mmol). After 18 h, 10% aqueous NaOH (500 mL) was
added slowly, and the reaction mixture was extracted with
CH2Cl2 (3 × 400 mL). The combined organic layers were dried
(Na2SO4), decanted, and concentrated under reduced pressure.
The crude product was purified by silica gel chromatography
with EtOAc/hexanes (2:1) to give 4.83 g (80%) of a light yellow
solid as a 17:3 mixture of diastereomers, based on 1H NMR
integration, mp 161-164 °C. Major isomer, (1R*,10bR*)-63:
1H NMR (400 MHz, CDCl3) δ 1.37 (t, J ) 7.1 Hz, 3H), 2.02
(m, 1H), 2.24 (m, 1H), 3.32 (m, 1H), 3.59 (m, 1H), 3.81 (m,
1H), 4.33 (q, J ) 7.1 Hz, 2H), 4.87 (d, J ) 4.6 Hz, 1H), 5.03 (d,
J ) 10.6 Hz, 1H), 5.16 (d, J ) 17.2 Hz, 1H), 5.59 (m, 1H), 6.84
(d, J ) 8.4 Hz, 1H), 7.66 (s, 1H), 7.82 (dd, J ) 8.3, 1.7 Hz,
1H), 9.33 (s, 1H); 13C NMR (100.6 MHz, CDCl3) δ 14.3, 29.0,
43.1, 45.6, 60.7, 61.5, 113.8, 117.4, 117.8, 123.7, 128.7, 129.9,
135.6, 141.7, 153.0, 166.1; IR (KBr) 3180, 2960, 1685, 1660
cm-1; MS (CI) m/z 287 (M+ + H), 232. Anal. Calcd for
1
eomers, based on H NMR integration. Major isomer, (2R*,3R*)-
65: 1H NMR (400 MHz, CDCl3) δ 1.90 (m, 1H), 2.12 (m, 1H),
2.35 (s, 3H), 2.99 (m, 1H), 3.11 (m, 1H), 3.36 (m, 1H), 3.82 (s,
3H), 4.53 (m, 2H), 4.70 (m, 1H), 5.28 (m, 1H), 7.23 (d, J )
8.1 Hz, 1H), 7.36 (d, J ) 8.7 Hz, 1H), 7.53 (d, J ) 2.0 Hz,
1H), 7.69 (dd, J ) 8.6, 2.0 Hz, 1H), 7.77 (d, J ) 8.3 Hz, 1H);
13C NMR (100.6 MHz, CDCl3) δ 21.4, 31.8, 45.1, 48.5, 51.8,
66.7, 116.3, 116.5, 122.9, 124.3, 126.8, 129.4, 129.5, 131.2,
136.5, 137.9, 143.2, 144.4, 166.6; IR (KBr) 3440 (br), 2930,
1690, 1590 cm-1; MS (CI) m/z 401 (M+ + H), 191; HRMS calcd
for C21H25N2O4S 401.1535, found 401.1559. Minor isomer,
(2R*,3S*)-65 (diagnostic peaks only): 1H NMR (400 MHz,
CDCl3) δ 1.74 (m, 1H), 2.16 (m, 1H), 2.34 (s, 3H), 3.18 (m,
1H), 3.29 (m, 1H), 3.82 (s, 3H), 4.46 (m, 1H), 4.85 (m, 1H),
5.52 (m, 1H), 7.21 (m, 1H), 7.48 (d, J ) 2.0 Hz, 1H), 7.52 (m,
1H), 7.72 (d, J ) 8.3 Hz, 1H), 7.76 (m, 1H); 13C NMR (100.6
MHz, CDCl3) δ 21.4, 31.2, 44.2, 49.2, 51.9, 68.9, 116.9, 118.3,
123.4, 125.9, 126.7, 129.5, 129.7, 131.2, 137.1, 137.8, 143.4,
166.6.
C
16H18N2O3: C, 67.12; H, 6.34; N, 9.78. Found: C, 67.09; H,
6.32; N, 9.55. Minor isomer, (1R*,10bS*)-63 (diagnostic peaks
only): 1H NMR (400 MHz, CDCl3) δ 1.36 (t, J ) 7.1 Hz, 3H),
1.91 (m, 1H), 3.00 (m, 1H), 3.67 (m, 1H), 4.32 (m, 2H), 4.47 (d,
J ) 9.6 Hz, 1H), 5.32 (d, J ) 10.7 Hz, 1H), 5.40 (d, J ) 17.1
Hz, 1H), 5.99 (m, 1H), 6.87 (d, J ) 8.4 Hz, 1H), 7.85 (dd, J )
8.4, 1.7 Hz, 1H), 8.11 (s, 1H); 13C NMR (100.6 MHz, CDCl3) δ
14.2, 30.6, 43.5, 50.1, 60.4, 60.6, 117.7, 121.0, 123.8, 126.3,
130.1, 138.3, 141.5, 153.3, 166.5.
(1R*,10bR*)- a n d (1R*,10bS*)-9-Ca r beth oxy-6-p-tolu -
en esu lfon yl-1-eth en yl-2,3,6,10b-tetr a h yd r o-1H-p yr r olo-
[1,2-c]qu in a zolin -5-on e (64). To a solution of 63 (2.0 g, 7.0
mmol) in THF (150 mL) at 0 °C was added NaH (60%
dispersion in mineral oil, 0.80 g, 20 mmol). After 45 min,
p-toluenesulfonyl chloride (1.6 g, 8.4 mmol) was added and the
reaction was allowed to warm to room temperature. After an
additional 22 h, saturated aqueous NH4Cl (100 mL) was added
slowly and the reaction mixture was extracted with EtOAc (3
× 150 mL). The combined organic layers were dried (Na2SO4),
decanted, and concentrated under reduced pressure. The crude
(3a R*,4R*,9bS*)-8-Ca r bom eth oxy-4-(iod om eth yl)-5-p-
tolu en esu lfon yl-2,3,3a ,4,5,9b-h exa h yd r o-1H-p yr r olo[3,2-
c]qu in olin e (66). To a solution of 65 (0.50 g, 1.2 mmol) in
CH3CN (30 mL) at room temperature was added iodine (3.0
g, 12 mmol). The reaction was heated at reflux for 21 h, then
cooled to room temperature, and diluted with Et2O (200 mL).
The resulting solution was washed with saturated NaHCO3
(20 mL) and 10% aqueous Na2S2O3 (3 × 25 mL). The combined
aqueous layers were extracted with Et2O (50 mL). The
combined organic layers were dried (Na2SO4), decanted, and
concentrated under reduced pressure. The crude product was
purified by silica gel chromatography with EtOAc/hexanes (2:

666 J . Org. Chem., Vol. 65, No. 3, 2000
Frank and Aube´
1) to give 0.29 g (44%) of a beige foam: 1H NMR (400 MHz,
CDCl3) δ 1.82 (m, 1H), 2.20 (m, 1H), 2.42 (s, 3H), 2.77 (m, 2H),
2.92 (m, 1H), 3.06 (m, 2H), 3.90 (s, 3H), 4.17 (d, J ) 8.7 Hz,
1H), 4.71 (m, 1H), 7.31 (d, J ) 8.2 Hz, 2H), 7.62 (d, J ) 8.6
Hz, 1H), 7.78 (d, J ) 8.3 Hz, 2H), 7.87 (dd, J ) 8.6, 2.1 Hz,
1H), 7.99 (d, J ) 2.0 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ
7.5, 21.6, 32.8, 43.0, 46.1, 52.1, 56.4, 61.2, 122.9, 127.0, 127.5,
129.6, 129.9, 131.4, 131.7, 136.9, 138.7, 144.6, 166.2; IR (KBr)
3410, 2930, 1700 cm-1; MS (CI) m/z 527 (M+ + H), 401, 342,
91; HRMS calcd for C21H24IN2O4S: 527.0501, found 527.0511.
NMR spectroscopy, and Soo-Ho Ban for valuable as-
sistance. Additionally, K.E.F. acknowledges receipt of
a Madison A. and Lila Self-Graduate Fellowship.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for compounds 16-22, 23, 27-31, 35, 36, 40-44, 49-
52, N-(4-chlorophenyl)-2,2-dimethyl-propionamide, and N-(4-
chloro-2-formylphenyl)-2,2-dimethylpropionamide; X-ray data
1
for compounds 38, 45, 50, and 58; and H and 13C NMR data
for compounds 8, 10, 12, 14, 15, 21, 24-36, 39-44, 47-53,
55-57, 62, 64, and 65 (compounds 36 and 48 have 1H data
only). This material is available free of charge via the Internet
at http://pubs.acs.org.
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (GM 49093). We thank
Lawrence Seib for carrying out the X-ray structure
determinations, Martha Morton for assistance with
J O990843C