Synthesis of medium-ring nitrogen heterocycles via palladium-catalyzed heteroannulation of 1, 2-dienes

Article abstract of DOI:10.1021/jo980516p

Seven-, eight-, and nine-membered-ring nitrogen heterocycles are readily prepared by the palladiumcatalyzed heteroannulation of a variety of 1, 2-dienes by a range of tosylamide- and amine-containing aryl and vinylic halides. The ease of ring formation is

Full text of DOI:10.1021/jo980516p

J . Org. Chem. 1998, 63, 6859-6866
6859
Syn th esis of Med iu m -Rin g Nitr ogen Heter ocycles via
P a lla d iu m -Ca ta lyzed Heter oa n n u la tion of 1,2-Dien es
Richard C. Larock,* Chi Tu, and Paola Pace
Department of Chemistry, Iowa State University, Ames, Iowa 50011
Received March 18, 1998
Seven-, eight-, and nine-membered-ring nitrogen heterocycles are readily prepared by the palladium-
catalyzed heteroannulation of a variety of 1,2-dienes by a range of tosylamide- and amine-containing
aryl and vinylic halides. The ease of ring formation is seven > eight > nine, and better results are
obtained using aryl halides, rather than vinylic halides, and tosylamide functionality, rather than
amine functionality. The reaction is suggested to proceed by the formation and addition of an aryl
or vinylic palladium compound to the allene to generate a π-allylpalladium intermediate, which
subsequently undergoes nucleophilic displacement of palladium at the less hindered end of the
π-allyl system.
In tr od u ction
on the synthesis of nitrogen heterocycles by palladium-
catalyzed annulation of allenes, because nitrogen nucleo-
philes have proven to be among the best nucleophiles for
π-allylpalladium displacements8 and allenes appear to
be the most readily annulated of all of the unsaturated
substrates we have so far examined.
Annulation processes are among the most important
reactions in organic synthesis.1 However, few have proven
general for the formation of more than one ring size. The
palladium-catalyzed hetero- and carboannulation of un-
saturated cyclopropanes and cyclobutanes,2 1,2-dienes,3
1,3-dienes,4 1,4-dienes,5 and alkynes6 has proven to be a
very versatile method for the synthesis of a wide variety
of five- and six-membered ring heterocycles and car-
bocycles, but it has not previously been applied to the
synthesis of cyclic products of larger ring sizes. In view
of the ease with which large ring carbocyclic and hetero-
cyclic products are formed by intramolecular π-allylpal-
ladium displacement processes7 and the pronounced
biological activity of many such compounds, particularly
nitrogen heterocycles, we have chosen to examine the
utility of this annulation process for the synthesis of
medium-ring compounds. Our initial efforts have focused
Resu lts a n d Discu ssion
A variety of reaction conditions similar to those em-
ployed previously by us for palladium-catalyzed annu-
lation2-6 have been examined for the model reaction of
N-n-butyl-4-iodo-4-pentenylamine (1a ) and 4,5-nonadiene
(eq 1). This system was chosen because it was the first
example of large ring formation discovered in our group,
and it was anticipated from our earlier work that the
more difficult annulations were likely to involve more
hindered internal allenes and vinylic halides, rather than
aryl halides. The results of that study are summarized
in Table 1.
The yield has proven to be highly dependent on the
palladium catalyst, the solvent, the base, the reaction
time and temperature, and the presence or absence of
n-Bu4NCl and PPh3. As indicated in Table 1 (entry 5),
the best results were obtained by using 1 equiv of the
organic iodide (0.25 mmol), 2 equiv of allene, 5 mol % of
Pd(dba)2, 5 mol % of PPh3, 1 equiv of n-Bu4NCl, and 5
equiv of Na2CO3 in 1.0 mL of DMA at 80 °C for 1 day.
(1) (a) J ung, M. E. Tetrahedron 1976, 32, 3. (b) Trost, B. M. Chem.
Soc. Rev. 1982, 11, 141. (c) Posner, G. H. Chem. Rev. 1986, 86, 831.
(2) (a) Larock, R. C.; Yum, E. K. Synlett 1990, 529. (b) Larock, R.
C.; Yum, E. K. Tetrahedron 1996, 52, 2743.
(3) (a) Larock, R. C.; Berrios-Pen˜a, N. G.; Fried, C. A. J . Org. Chem.
1991, 56, 2615. (b) Larock, R. C.; He, Y.; Leong, W.; Han, X.; Refvik,
M. D.; Zenner, J . M. J . Org. Chem. 1998, 63, 2154. (c) Larock, R. C.;
Zenner, J . M. J . Org. Chem. 1995, 60, 482.
(4) (a) Larock, R. C.; Berrios-Pen˜a, N.; Narayanan, K. J . Org. Chem.
1990, 55, 3447. (b) Larock, R. C.; Fried, C. A. J . Am. Chem. Soc. 1990,
112, 5882. (c) O’Connor, J . M.; Stallman, B. J .; Clark, W. G.; Shu, A.
Y. L.; Spada, R. G.; Stevenson, T. M.; Dieck, H. A. J . Org. Chem. 1983,
48, 807.
(5) Larock, R. C.; Berrios-Pen˜a, N. G.; Fried, C. A.; Yum, E. K.; Tu,
C.; Leong, W. J . Org. Chem. 1993, 58, 4509.
(6) (a) Maitlis, P. M. J . Organomet. Chem. 1980, 200, 161. (b) Pfeffer,
M. Recl. Trav. Chim. Pays-Bas 1990, 109, 567. (c) Larock, R. C.; Yum,
E. K. J . Am. Chem. Soc. 1991, 113, 6689. (d) Wensbo, D.; Eriksson,
A.; J eschke, T.; Annby, U.; Gronowitz, S.; Cohen, L. A. Tetrahedron
Lett. 1993, 34, 2823. (e) Chen, C.; Lieberman, D. R.; Larsen, R. D.;
Reamer, R. A.; Verhoeven, T. R.; Reider, P. J . Tetrahedron Lett. 1994,
35, 6981. (f) Larock, R. C.; Yum, E. K.; Doty, M. J .; Sham, K. K. C. J .
Org. Chem. 1995, 60, 3270. (g) Larock, R. C.; Doty, M. J .; Cacchi, S. J .
Org. Chem. 1993, 58, 4579. (h) J eschke, T.; Wensbo, D.; Annby, U.;
Gronowitz, S.; Cohen, L. A. Tetrahedron Lett. 1993, 34, 6471. (i) Smith,
D. W.; Youcca, F. D.; Yevich, J . P.; Mattson, R. J .; Williams, A.;
Ruediger, E. H.; Combrink, K. D., Pearce, B. C. European Patent 0
548 813 A1, 1993. (j) Park, S. S.; Choi, J .-K.; Yum, E. K. Tetrahedron
Lett. 1998, 39, 627.
(8) (a) Trost, B. M. Tetrahedron 1977, 33, 2615. (b) Trost, B. M.;
Verhoeven, T. R. In Comprehensive Organometallic Chemistry; Wilkin-
son, G., Ed.; Pergamon Press: New York, 1982; Vol. 8, p 799. (c) Tsuji,
J . in The Chemistry of the Metal-Carbon Bond; Hartley, F. R., Patai,
S., Eds.; Wiley: New York, 1985; Vol. 3, p 163. (d) Godleski, S. A. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Semmel-
hack, M. F., Eds.; Pergamon Press: New York, 1991; Vol. 4, p 585. (e)
Hegedus, L. S. In The Chemistry of the Metal-Carbon Bond; Hartley,
F. R., Patai, S., Eds.; Wiley: New York, 1985; Vol. 2, p 401. (f) Pearson,
A. J . In The Chemistry of the Metal-Carbon Bond; Hartley, F. R., Patai,
S., Eds.; Wiley: New York, 1985; Vol. 4, p 889. (g) Trost, B. M. Angew.
Chem., Int. Ed. Engl. 1989, 28, 1173. (h) Frost, C. G.; Howarth, J .;
Williams, J . M. J . Tetrahedron: Asymmetry 1992, 3, 1089.
(7) (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1989, 28, 1173. (b)
Tsuda, T.; Kiyoi, T.; Saegusa, S. J . Org. Chem. 1990, 55, 3388. (c) Trost,
B. M.; Verhoeven, T. R. J . Am. Chem. Soc. 1980, 102, 4743.
S0022-3263(98)00516-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/11/1998

6860 J . Org. Chem., Vol. 63, No. 20, 1998
Larock et al.
Ta ble 1. P a lla d iu m (0)-Ca ta lyzed Rea ction of
N-n -Bu tyl-4-iod o-4-p en ten yla m in e (1A) a n d
4,5-Non a d ien e (2) (eq 1)a
at the more hindered end of the π-allylpalladium inter-
mediate, whereas analogous reactions of this allene with
N-(Z)-(3-iodo-2-methyl-2-propenyl)aniline and N-tosyl-2-
iodobenzylamine gave mixtures of six-membered-ring
regioisomers resulting from attack on both ends of the
allylic system.3a
The stereoselectivity of these annulations is generally
low and depends primarily on the structures of the allene
and the vinylic halide. With the exception of the internal
allene 4,5-nonadiene, which has usually produced exclu-
sively or almost exclusively the E-isomer (entries 3, 7,
11, and 14), we have usually observed mixtures of
stereoisomers. In all but two cases involving 1,2-undeca-
diene (entries 2 and 5), all the reactions afforded pre-
dominantly the E-isomer, as can be expected from the
thermodynamic preference for syn-π-allylpalladium in-
termediates (see the mechanistic discussion which fol-
lows).
Pd
time
base
% isolated
entry
catalyst
solvent (days)
(equiv)
yield of 3
1
2
3
4
5
6
7
8
9
PdCl2
Pd(OAc)2
Pd(PPh3)4 DMA
DMA
DMA
3
3
3
3
1
2
1
1
1
1
1
1
1
1
1
1
1
Na2CO3 (5)
Na2CO3 (5)
Na2CO3 (5)
Na2CO3 (5)
Na2CO3 (5)
Na2CO3 (5)
Na2CO3 (5)
Na2CO3 (5)
K2CO3 (5)
NaHCO3 (5)
Li2CO3 (5)
NaOAc (5)
KOAc (5)
18
41
32
42, 49
61
46
31
35
34
43
0
42
35
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
DMA
DMA
DMA
DMSO
DMF
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
10
11
12
13
14
15
16
17
Na2CO3 (2)
Na2CO3 (5)
Na2CO3 (5)
Na2CO3 (5)
37
35b
55c
48d
The stereochemistry of the products described in Table
2 has been assigned on the basis of 2-D NOESY experi-
ments and chemical shift correlations. In the E-isomer
of the product described in Table 2, entry 2, the non-
ylidene vinylic hydrogen and the methylene between the
vinylic carbon and the nitrogen generated a clear off-
diagonal contour in the NOESY spectrum; furthermore,
the allylic CH2 of the side chain interacted with one of
the two terminal methylene protons. In comparing the
1H NMR spectra of the Z- and E-isomers in Table 2, entry
2, one notices that the chemical shift of the nonylidene
vinylic hydrogen in the Z-isomer is further downfield
(5.71 ppm) than the corresponding hydrogen in the
E-isomer (5.36 ppm). In a similar manner, cross-peaks
in the NOESY spectrum were observed for the vinylic
proton of the butylidene moiety and the methine next to
the nitrogen in compound 3 and the allylic hydrogen of
the butylidene group and one of the methylene vinylic
protons. The stereochemistry of the analogous annula-
tion derivatives described in Table 2, entries 1-11, has
been assigned on the basis of these 1H NMR spectral
observations.
The NOESY spectrum of the tetrahydrobenzazepine
described in Table 2, entry 14, again exhibited strong
interactions between the vinylic hydrogen and the
methyne hydrogen in the 2-position of the nitrogen ring
and between the allylic CH2 of the butylidene side chain
and the aromatic proton at 7.00 ppm. A similar experi-
ment on the stereoisomeric mixture of the eight-mem-
bered rings described in Table 2, entry 19, showed for
the major isomer clear cross-peaks between the vinylic
proton at 5.73 ppm and the methylene protons adjacent
to nitrogen and between the allylic CH2 of the nonylidene
side chain and the aromatic proton at 6.87 ppm, sup-
porting the E configuration of the double bond. In
contrast, the vinylic proton of the minor isomer showed
a cross-peak with the aromatic signal at 6.93 ppm, and
the corresponding allylic CH2 exhibited a cross-peak with
the methylene in the 2-position of the nitrogen ring. In
both of these latter cases, the chemical shift of the vinylic
proton of the E-isomer is downfield from that of the
corresponding chemical shift of the Z-isomer. The ster-
eochemistry of the other products described in entries
12-22 are assigned on the basis of these observations.
Eight-membered-ring nitrogen heterocycles have also
been successfully formed by this annulation process, but
the process has not proven nearly as general as that
involving seven-membered ring formation (entries 15-
a
All reactions were carried out using 1 equiv of 1a (0.25 mmol),
2 equiv of 2 (0.5 mmol), 5 mol % of Pd catalyst (0.0125 mmol), 5
mol % of PPh3 (0.0125 mmol), 1 equiv of n-Bu4NCl (0.25 mmol), 2
or 5 equiv of base (0.5 or 1.25 mmol), and 1.0 mL of solvent at 80
b
d
°C. Without PPh3. c At 110 °C. With 1 equiv of LiCl and no
n-Bu4NCl.
Under these conditions, a 61% yield of a single isomer of
compound 3 was obtained. This amine was later estab-
lished to be the E-isomer by H NMR spectroscopy (see
the later discussion).
1
Employing this optimal procedure, we have studied the
heteroannulation of four representative allenes using a
variety of vinylic and aryl halides bearing either an
n-butylamino or a tosylamide group. Vinylic and aryl
halides were chosen because they have both proven
successful previously in the annulation of allenes to form
five- and six-membered ring products.3 Amine function-
ality was attractive because there is substantial litera-
ture precedent for the use of amines as nucleophiles in
π-allylpalladium chemistry and they appear to be among
the best nucleophiles for such processes.8 Although
tosylamides have been used much less frequently in
π-allylpalladium chemistry,2,3a,4a,5,9 they have proven to
be among the most successful nucleophiles in our previ-
ous work on palladium-catalyzed annulation. Our results
are summarized in Table 2.
A wide variety of seven-membered-ring nitrogen het-
erocycles have been formed by this process (Table 2,
entries 1-14). Amines and tosylamides have proven
equally successful. Good results have been obtained from
both aryl (entries 12-14) and vinylic iodides, generating
both exocyclic and endocyclic double bonds (entries 1-11),
although the aryl iodide required a higher reaction
temperature of 100 °C. All four of our representative
allenes react well, with little evidence for decreasing
yields with increasing steric hindrance.
In all the reactions examined, the annulation is
completely regioselective, the sole product being that
formed by attack of the nucleophile at the less hindered
end of the π-allylpalladium intermediate. The high
regioselectivity is a bit surprising, because previous work
on the annulation of allenes to form five- and six-
membered ring nitrogen heterocycles has not been very
regioselective.3 In fact, 1,2-undecadiene reacted with
N-tosyl-2-iodoaniline to give exclusively the five-mem-
bered ring product arising from nucleophilic displacement

Synthesis of Medium-Ring Nitrogen Heterocycles
J . Org. Chem., Vol. 63, No. 20, 1998 6861

6862 J . Org. Chem., Vol. 63, No. 20, 1998
Larock et al.
Sch em e 1
21). In fact, all attempts to generate eight-membered
rings employing vinylic iodides analogous to those used
to form the seven-membered rings in entries 1-7 failed
completely, except for trace amounts of the product
reported in entry 15. Fortunately, aryl halides proved
more useful and generally produced good yields of
heterocycles, although they again required a reaction
temperature of 100 °C. The aryl tosylamide 1g (entries
18-21) proved clearly superior to the n-butylamine
derivative 1f (entries 16 and 17), particularly with the
more highly substituted allenes vinylidene cyclohexane
and 4,5-nonadiene, which failed to produce any hetero-
cycle when allowed to react with the arylamine 1f.
Once again, these reactions forming eight-membered
rings have proven to be highly regioselective but only
modestly stereoselective. Indeed, nucleophilic attack
occurs exclusively on the less hindered end of the π-al-
lylpalladium intermediate, and the stereochemistry of the
products changes little from that observed in the forma-
tion of seven-membered rings.
Nine-membered ring formation proved very difficult.
Since aryl halides had previously proven more successful
than vinylic halides and tosyl derivatives more successful
than amines, we chose to first prepare o-IC6H4(CH2)4-
NHTs (1h ) and examine its utility as an annulating
agent. Using our four standard allenes, we were only
successful in observing the anticipated nine-membered-
ring product in the reaction of phenylallene (Table 2,
entry 22). A temperature of 100 °C and 3 days reaction
time were required for the reaction to reach completion.
All other allenes gave products which appeared to arise
by â-elimination of a palladium hydride from the antici-
pated π-allylpalladium intermediate. This appears to be
a common problem when ring closure becomes difficult
and explains the generally good results usually obtained
in the reactions of phenylallene, where this type of
elimination is impossible.
We have only briefly looked at the formation of still
larger ring nitrogen heterocycles. We have prepared
H2CdCI(CH2)9NH-n-Bu and o-IC6H4O(CH2)7NHTs and
examined their reactions with all four of our standard
allenes, but we saw no evidence of any 13-membered-
ring products in any reaction. It would appear that this
methodology is limited to the formation of only the
smaller ring nitrogen heterocycles, where the ease of ring
formation is seven > eight > nine. Various attempts to
form medium-ring lactones, ethers, and carboxamides
using this type of annulation process have so far proven
unsuccessful.
Our nitrogen heteroannulation process is believed to
proceed mechanistically as illustrated in Scheme 1 using
an aryl halide as the example. Arylpalladium formation
and addition to the allene initially produces a σ-allylpal-
ladium intermediate, which rapidly isomerizes to the
corresponding syn- and anti-π-allylpalladium intermedi-
ates. It is the relative abundance of each of these isomers
which appears to determine the stereochemistry of the
resulting products. Several factors seem to play a role
in the observed distribution of the products. Steric effects
in the π-allylpalladium intermediate exerted by substit-
uents originating in the allene and the carbon originally
bearing the halide, the number of atoms between the
nucleophile and the π-allyl system, and the nature of the
nucleophile are all important in determining the syn/
anti ratio of the π-allylpalladium intermediate and
ultimately the stereochemistry of the final product. The
π-allylpalladium intermediate eventually undergoes ex-
clusive intramolecular palladium displacement at the less
hindered end of the π-allyl moiety to produce the final
observed products.
Con clu sion s
The palladium-catalyzed heteroannulation of a variety
of allenes using both aryl and vinylic iodides bearing
tosylamide and amine functionalities provides a useful
new route to medium-ring nitrogen heterocycles. Seven-
membered-ring products are formed quite readily, while
eight-membered rings are a bit more difficult and oc-
casionally require higher temperatures and longer reac-
tion times. Nine-membered-ring products are quite
difficult to form. Best results are obtained using aryl
halides, rather than vinylic halides, and tosylamides,
rather than amines. No success has been achieved in
trying to form still larger rings, although only the
synthesis of 13-membered rings has been attempted. The
exclusive product formed in these annulations is that
formed by attack of the nitrogen nucleophile on the less
hindered end of the presumed π-allylpalladium interme-
diate. The nature of the organic halide and the allene
appears to determine the stereochemistry of the resulting
heterocycle, with the E-isomer in all but two cases being
the major product.
Exp er im en ta l Section
Allen es. The following allenes were prepared as indicated.
Vinylidene cyclohexane was prepared from (1-chlorocyclohex-
yl)acetylene using a literature procedure.10 1,2-Undecadiene,
(9) (a) Larock, R. C.; Yang, H.; Weinreb, S. M.; Herr, R. J . J . Org.
Chem. 1994, 59, 4172. (b) Harris, G. D., J r.; Herr, R. J .; Weinreb, S.
M. J . Org. Chem. 1993, 58, 5452. (c) Inoue, Y.; Taguchi, M.; Hashimoto,
H. Bull. Chem. Soc. J pn. 1985, 58, 2721. (d) Bystro¨m, S. E.; Aslanian,
R.; Ba¨ckvall, J .-E. Tetrahedron Lett. 1985, 26, 1749. (e) Stolle, A.;
Ollivier, J .; Piras, P. P.; Salaun, J .; de Meijere, A. J . Am. Chem. Soc.
1992, 114, 4051. (f) Uozumi, Y.; Tanahashi, A.; Hayashi, T. J . Org.
Chem. 1993, 58, 6826.
(10) Brandsma, L. in Synthesis of Acetylenes, Allenes, and Cumu-
lenes: a Laboratory Manual; Elsevier Scientific Publishing Co.: New
York, 1981; p 191.

Synthesis of Medium-Ring Nitrogen Heterocycles
J . Org. Chem., Vol. 63, No. 20, 1998 6863
phenylallene, and 4,5-nonadiene were prepared by treating the
corresponding 1,1-dibromocyclopropanes with methyllithium
according to a literature procedure.11
4-Iodo-4-pentenenitrile, 5-iodo-5-hexenenitrile, 2-iodophen-
ylacetonitrile, and 4-(o-iodophenyl)butanenitrile were prepared
from the mesylate of the corresponding alcohol by reaction with
NaI in acetone at reflux and displacement of the iodide by
stirring the mixture in a solution of NaCN in DMSO at 100
°C.
3-Iodo-3-butene-1-ol, 4-iodo-4penten-1-ol, 5-iodo-5-hexen-1-
ol, and 5-chloro-2-iodo-1-pentene were prepared by reacting
the corresponding alkynes with NaI and chlorotrimethylsilane
following a literature procedure.3b
Am in es a n d Tosyla m id es. N-n-Butyl-4-iodo-4-penten-
ylamine (1a ) was prepared in 76% yield from 5-chloro-2-iodo-
1-pentene following the reported procedure:3b Rf ) 0.17 (1:1
hexanes/EtOAc); 1H NMR (CDCl3) δ 0.92 (t, J ) 7.2 Hz, 3 H),
1.35 (qt, J ) 7.2, 7.2 Hz, 2 H), 1.47 (tt, J ) 7.2, 7.2 Hz, 2 H),
1.71 (tt, J ) 7.2, 7.2 Hz, 2 H), 2.44 (t, J ) 7.2 Hz, 2 H), 2.60
(t, J ) 7.2 Hz, 2 H), 2.61 (t, J ) 7.2 Hz, 2 H), 5.68 (s, 1 H),
6.10 (s, 1 H); 13C NMR (CDCl3) δ 14.0, 20.5, 29.5, 32.3, 43.2,
48.0, 49.6, 111.9, 125.4; IR (neat) 3300, 1610, 891 cm-1. The
same procedure was applied to the synthesis of compounds
1c and 1f.
(Z)-4-Iodo-3-buten-1-ol was prepared from 4-iodo-3-butyn-
1-ol following a literature procedure.14
3-(2-Iodophenyl)propanol was prepared in 90% yield by
reduction of 3-(2-iodophenyl)propanoic acid with borane fol-
lowing a literature procedure:15 1H NMR (CDCl3) δ 1.62 (br s,
1 H), 1.90 (m, 2 H), 2.85 (t, J ) 9.8 Hz, 2 H), 3.78 (t, J ) 9.8
Hz, 2 H), 6.93-7.92 (m, 4 H).
3-(2-Iodophenyl)propanoic acid was prepared in 90% yield
from diethyl 2-iodobenzyl malonate following the procedure
reported by Cooke and Widene:16 1H NMR (CDCl3) δ 2.74 (t, J
) 7.9 Hz, 2 H), 3.15 (t, J ) 7.9 Hz, 2 H), 6.93-7.92 (m, 4 H),
10.00 (br s, 1 H).
Diethyl 2-iodobenzyl malonate was prepared from 2-iodo-
benzyl chloride and diethyl malonate following a literature
procedure.17
3-(2-Iodophenyl)propanenitrile was prepared in 94% yield
by decarboxylation of ethyl 2-cyano-3-(2-iodophenyl)propanoate
following a procedure reported by Krapcho:18 1H NMR (CDCl3)
δ 2.56 (t, J ) 7.2 Hz, 2 H), 2.97 (t, J ) 7.2 Hz, 2 H), 6.93-7.92
(m, 4 H).
N-n-Butyl-(Z)-4-iodo-3-butenylamine (1c) was prepared in
80% yield from (Z)-4-iodo-3-butenyl tosylate and n-BuNH2: 1H
NMR (CDCl3) δ 0.92 (t, J ) 6.9 Hz, 3 H), 1.36 (m, 2 H), 1.50
(m, 2 H), 1.88 (br s, 1 H), 2.37 (m, 2 H), 2.65 (t, J ) 7.5 Hz, 2
H), 2.76 (t, J ) 7.2 Hz, 2 H), 6.27 (m, 2 H); 13C NMR (CDCl3)
δ 14.0, 20.4, 32.0, 35.1, 47.8, 49.4, 83.9, 139.0; IR (neat) 3305,
1610, 891 cm-1
.
N-n-Butyl-3-(o-iodophenyl)propylamine (1f) was prepared in
98% yield from 3-(o-iodophenyl)propyl chloride and n-BuNH2:
1H NMR (CDCl3) δ 0.92 (t, J ) 7.2 Hz, 3 H), 1.39 (m, 2 H),
1.50 (m, 2 H), 1.60 (s, 1 H), 1.80 (m, 2 H), 2.72 (m, 6 H), 6.80-
7.80 (m, 4 H); 13C NMR (CDCl3) δ 14.0, 20.5, 30.4, 32.2, 38.5,
49.3, 49.5, 100.5, 127.5, 128.2, 129.2, 139.2, 147.7; IR (neat)
3300, 749 cm-1
.
N-Tosyl-4-iodo-4-pentenylamine (1b) was prepared in 90%
yield from 4-iodo-4-pentenylamine following the procedure
reported by Hendrickson:12 TLC (2:1 hexanes/EtOAc) Rf ) 0.4;
1H NMR (CDCl3) δ 1.62 (m, 2 H), 2.36 (t, J ) 6.9 Hz, 2 H),
2.43 (s, 3 H), 2.94 (t, J ) 6.3 Hz, 2 H), 5.16 (br s, 1 H), 5.66 (s,
1 H), 5.99 (s, 1 H), 7.32 (d, J ) 9.3 Hz, 2 H), 7.77 (d, J ) 9.3
Hz, 2 H); 13C NMR (CDCl3) δ 21.2, 29.3, 41.1, 41.6, 110.1, 126.0,
Ethyl 2-cyano-3-(2-iodophenyl)propanoate was prepared in
90% yield from the reduction of ethyl 2-cyano-3-(2-iodophenyl)-
acrylate following the procedure reported by Nanjo:19 1H NMR
(CDCl3) δ 1.25 (t, J ) 7.2 Hz, 3 H), 3.15 (dd, J ) 9.9, 13.8 Hz,
1 H), 3.40 (m, 1 H), 3.85 (dd, J ) 9.9, 13.8 Hz, 1 H), 4.21 (q, J
) 7.2 Hz, 2 H), 6.93-7.82 (m, 4 H).
126.6, 129.3, 136.4, 142.8; IR (neat) 3300, 1160 cm-1
.
N-Tosyl-2-(o-iodophenyl)ethylamine (1d ) was prepared in
91% yield from 2-(o-iodophenyl)ethylamine: TLC (2:1 hexanes/
EtOAc) Rf ) 0.4; 1H NMR (CDCl3) δ 2.42 (s, 3 H), 2.90 (t, J )
7.2 Hz, 2 H), 3.20 (dt, J ) 7.2, 7.2 Hz, 2 H), 4.5 (br s, 1 H),
6.9-7.8 (m, 8 H); 13C NMR (CDCl3) δ 21.3, 40.4, 42.6, 100.2,
126.9, 128.2, 129.5, 129.9, 139.2, 139.5, 139.5, 140.0, 143.0;
Ethyl 2-cyano-3-(2-iodophenyl)acrylate was prepared in 96%
yield from the condensation of 2-iodobenzaldehyde and ethyl
cyanoacetate following the procedure reported by Kasturi:20
1H NMR (CDCl3) δ 1.32 (t, J ) 8.7 Hz, 3 H), 4.35 (q, J ) 8.7
Hz, 2 H), 7.10-8.00 (m, 4 H), 8.40 (s, 1 H).
Gen er a l P r oced u r e for th e P a lla d iu m -Ca ta lyzed Het-
er oa n n u la tion Rea ction s. Into a 1- or 2-dram screw-capped
vial, equipped with a Teflon-lined cap and a magnetic stirring
bar, were placed Pd(dba)2 (5 mol %), Ph3P (5 mol %), n-Bu4-
NCl (1 equiv), sodium carbonate (5 equiv), the organic halide
(0.25 mmol), the allene (2 equiv), and 1 mL of N,N-dimethy-
lacetamide (DMA). The vial was then capped and suspended
in an oil bath at the desired reaction temperature for the
appropriate period of time. The reaction was monitored by
TLC. When the reaction was considered complete as measured
by disappearance of the organic iodide, the mixture was
allowed to cool to room temperature and was directly chro-
matographed on a silica gel column (230-400 mesh silica gel)
with an appropriate eluent, unless otherwise specified. The
desired products were collected, and the solvents were re-
moved by rotary evaporation. The products were further
purified by flash column chromatography if necessary. The
following compounds have been prepared using this general
procedure.
IR (neat) 3280, 1598, 1159, 753 cm-1
.
N-Tosyl-5-iodo-5-hexenylamine (1e) was prepared in 92%
yield from 5-iodo-5-hexenylamine: TLC (1:1 hexanes/EtOAc)
1
Rf ) 0.67; H NMR (CDCl3) δ 1.46 (m, 4 H), 2.31 (t, J ) 9.7
Hz, 2 H), 2.43 (s, 3 H), 2.94 (dt, J ) 6.6, 6.6 Hz, 2 H), 4.63 (t,
J ) 6.6 Hz, 1 H), 5.66 (d, J ) 1.2 Hz, 1 H), 5.97 (d, J ) 1.2 Hz.
1 H), 7.31 (d, J ) 8.1 Hz, 2 H), 7.75 (d, J ) 8.1 Hz, 2 H); 13C
NMR (CDCl3) δ 21.3, 25.6, 27.6, 42.5, 44.2, 112.0, 125.4, 126.7,
129.4, 136.5, 143.0; IR (neat) 3520, 1616, 1159, 894 cm-1
.
N-Tosyl-3-(o-iodophenyl)propylamine (1g) was prepared in
91% yield from 3-(o-iodophenyl)propylamine: TLC (2:1 hex-
anes/EtOAc) Rf ) 0.45; 1H NMR (CDCl3) δ 1.75 (m, 2 H), 2.43
(s, 3 H), 2.69 (t, J ) 7.5 Hz, 2 H), 3.02 (m, 2 H), 4.82 (br s, 1
H), 6.86-7.78 (m, 8 H); 13C NMR (CDCl3) δ 21.7, 30.1, 37.8,
42.7, 100.6, 127.3, 128.2, 128.6, 129.7, 129.9, 137.0, 139.7,
143.6, 143.7; IR (neat) 3283, 1158, 760 cm-1
.
N-Tosyl-4-(o-iodophenyl)butylamine (1h ) was prepared in
94% yield from 4-(o-iodophenyl)butylamine: 1H NMR (CDCl3)
δ 1.54 (m, 4 H), 2.41 (s, 3 H), 2.62 (m, 2 H), 2.96 (m, 2 H), 4.79
(m, 1 H), 6.8-7.7 (m, 8 H); 13C NMR (CDCl3) δ 21.5, 27.0, 29.0,
40.0, 42.9, 100.4, 127.0, 127.3, 127.3, 129.3, 129.6, 136.4, 139.4,
N-n -Bu tyl-3-ben zylid en e-4-m eth ylen ea zep a n e (Ta ble
2, En tr y 1). Obtained as a separable mixture of the E- and
the Z-isomers (E/ Z ) 55:45). E-isomer: oil; TLC (1:2 hexanes/
143.3, 144.3; IR (neat) 3281, 1157, 751 cm-1
.
acetone) Rf ) 0.28; H NMR (CDCl3) δ 0.92 (t, J ) 7.8 Hz, 3
1
4-Iodo-4-pentenylamine, 5-iodo-5-hexenylamine, 2-(o-io-
dophenyl)ethylamine, 3-(o-iodophenyl)propylamine, and 4-(o-
iodophenylbutylamine) were prepared by reduction of the
corresponding nitrile following the procedure reported by Yoon
and Brown.13
(13) Yoon, N. M.; Brown, H. C. J . Am. Chem. Soc. 1968, 90, 2927.
(14) Dieck, H. A.; Heck, R. F. J . Org. Chem. 1975, 40, 1083.
(15) Yoon, N. M.; Pak, C. S.; Brown, H. C.; Krishnamurthy, S.;
Stocky, T. J . Org. Chem. 1973, 38, 2786.
(16) Cooke, M. P.; Widener, R. K. J . Org. Chem. 1987, 52, 1381.
(17) Ciufolini, M. A.; Browne, M. E. Tetrahedron Lett. 1987, 28, 171.
(18) Krapcho, A. P. Synthesis 1982, 893.
(11) (a) Landor, P. D. The Chemistry of Allenes; Academic Press:
New York, 1982; Vol. 3, p 867. (b) Skattebol, L. Acta Chem. Scand.
1963, 17, 1683.
(19) Nanjo, K.; Suzuki, K.; Sekiya, M. Chem. Pharm. Bull. 1977,
25, 2396.
(12) Hendrickson, J . B.; Bergeron, R.; Sternbach, D. D. Tetrahedron
1975, 31, 2517.
(20) Kasturi, T. R.; Abraham, E. M.; Prasad, R. S. Tetrahedron 1974,
30, 2887.’

6864 J . Org. Chem., Vol. 63, No. 20, 1998
Larock et al.
H), 1.20-1.40 (m, 2 H), 1.42-1.55 (m, 2 H), 1.70-1.80 (m, 2
H), 2.40-2.60 (m, 4 H), 2.77-2.85 (m, 2 H), 3.44 (s, 2 H), 4.86
(d, J ) 1.7 Hz, 1 H), 4.90 (s, 1 H), 6.27 (s, 1 H), 7.05-7.40 (m,
5 H); 13C NMR (CDCl3) δ 14.1, 20.7, 26.9, 29.7, 34.9, 54.4, 55.7,
62.8, 114.8, 126.3, 127.1, 127.5, 128.0, 128.0, 128.1, 128.8 (one
peak is not seen due to overlap); IR (neat) 1582, 1451, 751
cm-1; HRMS m/z 255.1998 (calcd 255.1987 for C18H25N).
N-Tosyl-3-cycloh exyliden e-4-m eth ylen eazepan e (Table
2, En tr y 6): oil; TLC (4:1 hexanes/EtOAc) Rf ) 0.48; 1H NMR
(CDCl3) δ 1.40-1.60 (m, 6 H), 1.60-1.75 (m, 2 H), 2.05-2.22
(m, 6 H), 2.42 (s, 3 H), 3.22-3.30 (m, 2 H), 3.91 (s, 2 H), 4.61
(s, 1 H), 4.91 (s, 1 H), 7.27 (d, J ) 8.1 Hz, 2 H), 7.36 (d, J )
8.1 Hz, 2 H); 13C NMR (CDCl3) δ 21.5, 26.7, 28.0, 28.5, 28.6,
30.1, 32.1, 36.1, 48.4, 49.5, 113.2, 127.2, 128.2, 129.5, 138.1,
142.8, 148.0 (one peak is not seen due to overlap); IR (neat)
1651, 1162, 893 cm-1; HRMS m/z 345.1756 (calcd 345.1763 for
1
Z-isomer: oil; TLC (1:2 hexanes/acetone) Rf ) 0.63; H NMR
(CDCl3) δ 0.83 (t, J ) 8.4 Hz, 3 H), 1.22-1.33 (m, 4 H), 1.71-
1.76 (m, 2 H), 2.42-2.48 (m, 4 H), 2.80 (t, J ) 5.6 Hz, 2 H),
3.53 (s, 2 H), 4.81 (s, 1 H), 5.24 (d, J ) 1.8 Hz, 1 H), 6.80 (s, 1
H), 7.22-7.34 (m, 5 H); 13C NMR (CDCl3) δ 14.1, 20.7, 28.8,
29.5, 35.6, 54.7, 55.3, 57.9, 109.8, 126.5, 128.1, 129.1, 138.1,
143.4, 153.2 (one peak is not seen due to overlap); IR (neat)
1657, 890 cm-1; HRMS m/z 255.1991 (calcd 255.1987 for
C
20H27NO2S).
N -T o s y l-3-(E )-b u t y li d e n e -4-m e t h y le n e -2-p r o p y l-
a zep a n e (Ta ble 2, En tr y 7): oil; TLC (4:1 hexanes/EtOAc)
1
Rf ) 0.51; H NMR (CDCl3) δ 0.75-0.98 (m, 6 H), 1.15-1.28
(m, 4 H), 1.45-1.65 (m, 4 H), 1.98 (q, J ) 7.9 Hz, 2 H), 2.06-
2.12 (m, 1 H), 2.22-2.38 (m, 1 H), 2.40 (s, 3 H), 3.00-3.18 (m,
1 H), 3.62-3.88 (m, 1 H), 4.41 (t, 1 H, J ) 7.8 Hz), 4.62 (s, 1
H), 4.98 (s, 1 H), 5.26 (t, J ) 7.8 Hz, 1 H), 7.24 (d, 2 H, J )
11.1 Hz), 7.69 (d, 2 H, J ) 11.1 Hz); 13C NMR (CDCl3) δ 14.0,
17.6, 23.1, 27.4, 27.6, 28.4, 29.2, 33.8, 35.2, 43.9, 50.5, 110.0,
127.1, 127.3, 128.6, 129.0, 132.7, 137.6, 143.1; IR (neat) 1627,
1456, 1157, 900 cm-1; HRMS m/z 361.2069 (calcd 361.2076 for
C
18H25N).
N-n -Bu tyl-4-m eth ylen e-3-n on ylid en ea zep a n e (Ta ble 2,
En tr y 2). Obtained as a separable mixture of the E- and the
Z-isomers (E/ Z ) 21:79). Z-isomer: oil; TLC (1:2 hexanes/
acetone) Rf ) 0.34; 1H NMR (CDCl3) δ 0.85-0.96 (m, 6 H),
1.20-1.50 (m, 16 H), 1.62-1.70 (m, 2 H), 2.06 (q, J ) 7.2 Hz,
2 H), 2.33-2.37 (m, 2 H), 2.42-2.47 (m, 2 H), 2.78 (t, J ) 5.4
Hz, 2 H), 3.36 (s, 2 H), 4.63 (t, J ) 0.9 Hz, 1 H), 5.01 (d, J )
2.4 Hz, 1 H), 5.72 (t, J ) 7.2 Hz, 1 H); 13C NMR (CDCl3) δ
14.2, 20.8, 22.7, 28.0, 28.7, 29.4, 29.5, 29.6, 29.7, 29.7, 29.9,
31.9, 35.7, 53.0, 55.0, 58.5, 108.3, 127.9, 140.2, 153.0; IR
(neat) 1463, 884 cm-1; HRMS m/z 291.2921 (calcd 291.2921
C
21H31NO2S).
N -n -B u t y l-3-b e n z y li d e n e -2,3,6,7-t e t r a h y d r o -1H -
a zep in e (Ta ble 2, En tr y 8). Obtained as a separable mixture
of the E- and Z-isomers (E/ Z ) 64:36). E-isomer: oil; 1H NMR
(CDCl3) δ 0.93 (t, J ) 7.2 Hz, 3 H), 1.28-1.35 (m, 2 H), 1.40-
1.58 (m, 2 H), 2.40-2.56 (m, 4 H), 2.93 (t, 2 H, J ) 5.4 Hz),
3.58 (s, 2 H), 5.89-5.95 (m, 1 H), 6.37 (s, 1 H), 6.43 (d, J ) 8.4
Hz, 1 H), 7.20-7.70 (m, 5 H); 13C NMR (CDCl3) δ 13.9, 20.6,
27.7, 29.9, 54.4, 54.6, 54.7, 126.7, 128.1, 128.1, 128.1, 129.2,
130.9, 132.2, 134.2; IR (neat) 1674, 1102, 760 cm-1; HRMS m/z
241.1831 (calcd 241.1831 for C17H23N). Z-isomer: oil; 1H NMR
(CDCl3) δ 0.84 (t, J ) 7.2 Hz, 3 H), 1.22-1.40 (m, 4 H), 2.38-
2.45 (m, 4 H), 3.01 (t, J ) 5.4 Hz, 2 H), 3.64 (s, 2 H), 5.73-
5.80 (m, 1 H), 6.23 (d, J ) 11.1 Hz, 1 H), 6.56 (s, 1 H), 7.20-
7.50 (m, 5 H);13C NMR (CDCl3) δ 14.1, 20.7, 27.9, 30.1, 54.0,
54.2, 61.3, 126.8, 128.0, 128.6, 129.4, 129.7, 130.1, 132.0, 133.4;
IR (neat) 1673, 1167, 760 cm-1; HRMS m/z 241.1828 (calcd
241.1831 for C17H23N).
for
C20H37N). E-isomer: oil; TLC (1:2 hexanes/acetone)
1
Rf ) 0.32; H NMR (CDCl3) δ 0.75-0.95 (m, 6 H), 1.15-1.50
(m, 16 H), 1.60-1.70 (m, 2 H), 2.17 (q, J ) 7.5 Hz, 2 H), 2.33
(t, J ) 5.9 Hz, 2 H), 2.47 (t, J ) 7.7 Hz, 2 H), 2.79 (t, J ) 5.8
Hz, 2 H), 3.33 (s, 2 H), 4.82 (d, 1 H, J ) 2.2 Hz), 5.02 (t, 1 H,
J ) 2.2 Hz), 5.74 (t, 1 H, J ) 6.7 Hz); 13C NMR (CDCl3) δ
14.1, 20.7, 22.7, 27.6, 29.3, 29.4, 29.5, 29.6, 29.6, 29.6, 30.3,
31.9, 36.0, 53.9, 61.3, 105.2, 113.6, 130.3, 148.1; IR (neat) 1688,
1604, 895 cm-1; HRMS m/z 291.2921 (calcd 291.2921 for
C
20H37N).
N -n -Bu t yl-3-(E )-b u t ylid e n e -4-m e t h yle n e -2-p r op yl-
a zep a n e (Ta ble 2, En tr y 3): oil; TLC (1:1 hexanes/EtOAc)
1
Rf ) 0.48; H NMR (CDCl3) δ 0.85-0.95 (m, 9 H), 1.20-1.50
N -n -B u t y l -3 -n o n y l i d e n e -2 ,3 ,6 ,7 -t e t r a h y d r o -1H -
a zep in e (Ta ble 2, En tr y 9). Obtained as a separable mixture
of the E- and Z-isomers (E/ Z ) 70:30). E-isomer: oil; 1H NMR
(CDCl3) δ 0.78-0.99 (m, 6 H), 1.20-1.40 (m, 14 H), 1.41-1.55
(m, 2 H), 2.10 (q, J ) 7.9 Hz, 2 H), 2.32-2.36 (m, 2 H), 2.38-
2.47 (m, 2 H), 2.87 (t, J ) 5.4 Hz, 2 H), 3.41 (s, 2 H), 5.33 (t,
J ) 7.2 Hz, 1 H), 5.72-5.80 (m, 1 H), 6.32 (d, J ) 11.7 Hz, 1
H); 13C NMR (CDCl3) δ 14.1, 20.8, 22.7, 27.8, 27.9, 29.3, 29.3,
29.3, 29.5, 29.6, 29.9, 31.9, 53.3, 54.3, 61.1, 127.8, 127.8, 130.9,
132.5; IR (neat) 1465, 721 cm-1; HRMS m/z 277.2770 (calcd
277.2770 for C19H35N). Z-isomer: oil; 1H NMR (CDCl3) δ 0.82-
0.98 (m, 6 H), 1.20-1.40 (m, 14 H), 1.41-1.52 (m, 2 H), 2.09
(q, J ) 7.9 Hz, 2 H), 2.32-2.40 (m, 2 H), 2.41-2.47 (m, 2 H),
2.89 (t, J ) 5.7 Hz, 2 H), 3.54 (s, 2 H), 5.45-5.58 (m, 2 H),
6.02 (d, J ) 12.0 Hz, 1 H); 13C NMR (CDCl3) δ 14.1, 20.7, 22.7,
28.2, 28.4, 29.3, 29.3, 29.4, 29.5, 29.8, 30.2, 31.9, 53.2, 54.2,
(m, 10 H), 1.52-1.70 (m, 2 H), 2.02-2.15 (m, 2 H), 2.29-2.37
(m, 2 H), 2.42-2.51 (m, 2 H), 2.76-2.80 (m, 2 H), 2.94 (dd, J
) 8.3, 5.7 Hz, 1 H), 4.63 (t, J ) 1.2 Hz, 1 H), 4.97-4.99 (br s,
1 H), 5.17 (t, J ) 6.9 Hz, 1 H); 13C NMR (CDCl3) δ 14.2, 14.4,
20.2, 21.0, 23.8, 24.6, 29.2, 29.9, 30.4, 34.4, 35.4, 49.9, 52.5,
68.3, 113.8, 126.4, 129.9, 146.9; IR (neat) 1622, 897, 760 cm-1
;
HRMS m/z 263.2608 (calcd 263.2613 for C18H33N).
N-Tosyl-3-ben zylid en e-4-m eth ylen ea zep a n e (Ta ble 2,
en tr y 4). Obtained as an inseparable mixture of the E- and
Z-isomers (E/ Z ) 67:33): oily mixture; 1H NMR (CDCl3) δ
1.64-1.82 (m, 2 H), 2.22-2.35 (m, 2 H), 2.39 (s, 0.99 H), 2.40
(s, 2.01 H), 3.33-3.35 (m, 1.34 H), 3.41 (t, J ) 5.7 Hz, 0.66 H),
4.05 (s, 1.34 H), 4.24 (s, 0.66 H), 4.77 (t, J ) 0.6 Hz, 0.33 H),
4.85 (d, J ) 1.5 Hz, 0.67 H), 4.99 (t, J ) 0.6 Hz, 0.67 H), 5.07
(d, J ) 1.5 Hz, 0.33 H), 6.28 (s, 0.67 H), 6.68 (s, 0.33 H), 7.18-
7.40 (m, 6 H), 7.58 (d, J ) 9.8 Hz, 1 H), 7.75 (d, J ) 8.2 Hz, 2
H); 13C NMR (CDCl3) δ 21.4, 29.8, 31.0, 34.6, 34.8, 47.8, 49.2,
51.3, 56.6, 113.0, 115.8, 126.2, 127.0, 127.1, 127.1, 127.5, 128.1,
128.6, 128.8, 129.3, 129.5, 132.3, 136.2, 136.3, 139.0, 140.7,
142.8, 145.8, 150.3; IR (neat) 1623, 1163, 734 cm-1; HRMS m/z
353.1431 (calcd 353.1450 for C20H23NO2S).
54.7, 128.0, 134.1, 134.2, 135.7; IR (neat) 1465, 722 cm-1
;
HRMS m/z 277.2771 (calcd 277.2770 for C19H35N).
N-n -Bu t yl-3-cycloh exylid en e-2,3,6,7-t et r a h yd r o-1H -
a zep in e (Ta ble 2, En tr y 10): oil; TLC (1:2 hexanes/acetone)
1
Rf ) 0.06; H NMR (CDCl3) δ 0.80-1.00 (m, 5 H), 1.20-1.40
(m, 4 H), 1.50-1.70 (m, 4 H), 2.25-2.35 (m, 4 H), 2.40-2.60
(m, 4 H), 2.70-2.95 (br s, 2 H), 3.53 (br s, 2 H), 5.69 (dt, J )
11.1, 5.1 Hz, 1 H), 6.42 (d, J ) 11.4 Hz, 1 H); 13C NMR (CDCl3)
δ 14.2, 20.9, 26.9, 28.3, 28.8, 31.3, 31.4, 52.4, 53.9, 55.3, 129.8,
130.9, 132.1, 134.3; IR (neat) 1598, 1465 cm-1; HRMS m/z
233.2140 (calcd 233.2143 for C16H27N).
N-n -Bu tyl-3-(E)-bu tyliden e-2-pr opyl-2,3,6,7-tetr ah ydr o-
1H-a zep in e (Ta ble 2, En tr y 11): oil; TLC (1:2 hexanes/
acetone) Rf ) 0.05; 1H NMR (CDCl3) δ 0.80-1.00 (m, 9 H),
1.05-1.85 (m, 8 H), 2.03 (q, J ) 7.9 Hz, 2 H), 2.08-2.18 (m, 2
H), 2.40-2.68 (m, 1 H and t, J ) 7.8 Hz, 2 H), 2.70-2.80 (m,
1 H), 2.98-3.05 (m, 2 H), 3.07-3.15 (m, 1 H), 5.30 (t, J ) 7.2
Hz, 1 H), 5.66 (dt, J ) 11.7, 6.3 Hz, 1 H), 6.09 (d, J ) 11.7 Hz,
1 H); 13C NMR (CDCl3) δ 13.7, 14.0, 14.1, 20.4, 20.8, 22.8, 28.5,
N-Tosyl-4-m eth ylen e-3-n on ylid en ea zep a n e (Ta ble 2,
En tr y 5). Obtained as an inseparable mixture of the E- and
Z-isomers (E/ Z ) 37:63): oily mixture; 1H NMR (CDCl3) δ
0.88-0.95 (m, 3 H), 1.15-1.22 (m, 12 H), 1.60-1.80 (m, 2 H),
2.00-2.28 (m, 4 H), 2.41 (s, 3 H), 3.28-3.39 (m, 2 H), 3.90 (s,
0.74 H), 4.00 (s, 1.26 H), 4.59 (s, 0.63 H), 4.68 (s, 0.37 H), 4.87
(s, 0.63 H), 4.97 (s, 0.37 H), 5.39 (t, J ) 7.5 Hz, 0.37 H), 5.69
(t, J ) 7.2 Hz, 0.63 H), 7.26 (d, J ) 7.8 Hz, 2 H), 7.65 (d, J )
7.8 Hz, 2 H); 13C NMR (CDCl3) δ 14.2, 21.4, 22.7, 27.9, 29.1,
29.2, 29.3, 29.4, 29.5, 29.8, 30.1, 30.3, 31.9, 34.7, 35.7, 47.9,
48.9, 51.1, 55.4, 110.9, 114.9, 127.0, 127.2, 127.3, 128.6, 129.4,
130.2, 136.8, 137.4, 137.7, 142.8, 145.8, 150.1; IR (neat) 1600,
1160, 734 cm-1; HRMS m/z 389.2386 (calcd 389.2389 for
C
23H35NO2S).

Synthesis of Medium-Ring Nitrogen Heterocycles
J . Org. Chem., Vol. 63, No. 20, 1998 6865
29.7, 29.9, 36.3, 47.8, 52.9, 69.6, 125.9, 129.9, 131.7, 137.1; IR
(neat) 1463 cm-1; HRMS m/z 249.2457 (calcd 249.2460 for
C17H31N).
129.5, 129.6, 140.5; IR (neat) 1457, 748 cm-1; HRMS m/z
341.3073 (calcd 341.3083 for C23H39N). The following 1H NMR
data for the Z isomer were taken from the mixture: δ 3.35 (s,
2 H), 5.33 (t, J ) 6.9 Hz, 1 H).
N-Tosyl-1-b en zylid en e-2,3,4,5-t et r a h yd r o-1H -3-b en z-
a zep in e (Ta ble 2, En tr y 12). Obtained as an inseparable
mixture of the E- and Z-isomers (E/ Z ) 78:22): oily mixture;
TLC (4:1 hexanes/EtOAc) Rf ) 0.31;1H NMR (CDCl3) δ 2.36
(s, 3 H), 2.90 (t, J ) 6.0 Hz, 0.44 H), 2.98-3.02 (m, 1.56 H),
3.42-3.45 (m, 1.56 H), 3.51 (t, J ) 12.0 Hz, 0.44 H), 3.98 (s,
1.56 H), 4.29 (s, 0.44 H), 6.72 (s, 0.22 H), 6.79 (s, 0.78 H), 6.80-
7.50 (m, 11 H), 7.68 (d, J ) 8.2 Hz, 2 H); 13C NMR (CDCl3) δ
21.4, 36.1, 47.4, 55.8, 127.2, 127.3, 127.7, 127.9, 128.5, 129.3,
129.4, 129.5, 129.6, 131.8, 132.0, 136.2, 137.3, 138.3, 140.0,
143.2; IR (neat) 1598, 1163, 920 cm-1; HRMS m/z 389.1449
(calcd 389.1450 for C24H23NO2S).
N-Tosyl-1-b en zylid en e-1,2,3,4,5,6-h exa h yd r o-3-b en z-
a zocin e (Ta ble 2, En tr y 18). Obtained as an inseparable
mixture of the E- and Z-isomers (E/ Z ) 92:8): oily mixture;
TLC (4:1 hexanes/EtOAc) Rf ) 0.31; 1H NMR (CDCl3) δ 1.60-
1.80 (m, 1 H), 1.80-1.90 (m, 1 H), 2.36 (s, 0.24 H), 2.39 (s,
2.76 H), 2.50-2.70 (m, 2 H), 3.00-3.20 (m, 1 H), 3.20-3.50
(m, 1 H), 3.80-4.00 (br s, 0.92 H), 4.00-4.18 (br s, 0.92 H),
4.20 (s, 0.16 H), 6.59 (s, 0.08 H), 6.62 (s, 0.92 H), 6.88-7.40
(m, 11 H), 7.45 (d, J ) 8.2 Hz, 2 H); 13C NMR (CDCl3) δ 21.5,
32.1, 32.2, 48.7, 60.9, 127.1, 127.1, 127.2, 127.4, 127.9, 128.2,
128.7, 129.5, 129.6, 130.2, 135.5, 135.8, 137.9, 139.1, 140.1,
142.8; IR (neat) 1598, 1162, 754 cm-1; HRMS m/z 403.1604
(calcd 403.1606 for C25H25NO2S).
N -Tosyl-1-cycloh e xylid e n e -2,3,4,5-t e t r a h yd r o-1H -3-
ben za zep in e (Ta ble 2, En tr y 13): mp 128-130 °C; TLC (4:1
1
hexanes/EtOAc) Rf ) 0.48; H NMR (CDCl3) δ 1.40-1.65 (m,
N-Tosyl-1,2,3,4,5,6-h exa h yd r o-1-n on ylid en e-3-ben za zo-
cin e (Ta ble 2, En tr y 19). Obtained as an inseparable
mixture of the E- and Z-isomers (E/ Z ) 62:38): oily mixture;
4 H), 1.68-1.70 (m, 2 H), 2.01-2.10 (m, 2 H), 2.37 (s, 3 H),
2.40-2.60 (m, 3 H), 2.61-2.81 (m, 2 H), 3.00-3.10 (m, 1 H),
3.87-3.93 (m, 1 H), 4.78 (dd, J ) 12.9, 0.9 Hz, 1 H), 6.90-
7.00 (m, 1 H), 7.02-7.18 (m, 2 H), 7.42-7.55 (m, 3 H), 7.60 (d,
J ) 8.2 Hz, 2 H); 13C NMR (CDCl3) δ 21.4, 26.6, 28.3, 28.6,
30.4, 32.4, 35.5, 48.1, 49.2, 126.2, 126.3, 126.6, 127.3, 128.8,
128.9, 129.5, 134.4, 138.2, 142.5, 142.8, 143.2; IR (neat) 1598,
1164, 714 cm-1; HRMS m/z 381.1762 (calcd 381.1763 for
1
TLC (4:1 hexanes/EtOAc) Rf ) 0.41; H NMR (CDCl3) δ 0.86
(t, J ) 6.9 Hz, 3 H), 1.18-1.30 (m, 14 H), 1.73 (q, J ) 7.2 Hz,
1.24 H), 2.35 (q, J ) 7.2 Hz, 0.76 H), 2.38 (s, 3 H), 2.50-2.70
(m, 1.24 H), 2.68-2.80 (m, 0.76 H), 2.99-3.05 (m, 0.76 H),
3.00-3.15 (m, 1.24 H), 3.80 (br s, 1.24 H), 3.90 (s, 0.76 H),
5.48 (t, J ) 6.9 Hz, 0.38 H), 5.73 (t, J ) 7.9 Hz, 0.62 H), 6.87
(dd, J ) 7.2, 0.9 Hz, 0.62 H), 6.94 (dd, J ) 7.2, 0.9 Hz, 0.38
H), 7.11-7.20 (m, 5 H), 7.48 (d, J ) 8.8 Hz, 2 H); 13C NMR
(CDCl3) δ 13.9, 21.3, 22.5, 27.8, 28.7, 28.9, 29.0, 29.1, 29.2,
31.6, 31.7, 32.2, 48.1, 48.3, 51.9, 59.0, 126.2, 126.9, 127.0, 127.4,
127.7, 128.6, 128.8, 129.3, 132.7, 133.8, 136.5, 139.0, 139.9,
142.6; IR (neat) 1588, 1162 cm-1; HRMS m/z 439.2545 (calcd
439.2545 for C27H37NO2S).
C
23H27NO2S).
N-Tosyl-1-(E)-bu tylid en e-2-p r op yl-2,3,4,5-tetr a h yd r o-
1H-3-ben za zep in e (Ta ble 2, En tr y 14). The mixture of the
E- and Z-isomers (E/ Z ) 93:7) first isolated was further
purified by flash column chromatography to afford a pure
sample of the E-isomer (85% yield): oil; TLC (4:1 hexanes/
EtOAc) Rf ) 0.47; 1H NMR (CDCl3) δ 0.70-0.80 (m, 6 H),
1.15-1.40 (m, 6 H), 1.70-1.85 (m, 1 H), 1.80-2.00 (m, 1 H),
2.40 (s, 3 H), 2.55 (dd, J ) 14.9, 5.7 Hz, 1 H), 2.80 (t, J ) 13.5
Hz, 1 H), 3.15 (dd, J ) 14.7, 10.8 Hz, 1 H), 3.93 (dd, J ) 14.7,
6.0 Hz, 1 H), 4.63-4.65 (m, 1 H), 5.69 (dd, J ) 8.1, 6.6 Hz, 1
H), 6.92-7.00 (m, 1 H), 7.00-7.10 (m, 1 H), 7.10-7.18 (m, 2
H), 7.28 (d, J ) 8.2 Hz, 2 H), 7.75 (d, J ) 8.2 Hz, 2 H); 13C
NMR (CDCl3) δ 13.9, 14.0, 19.3, 21.7, 22.9, 31.0, 33.0, 36.7,
41.5, 62.3, 126.3, 127.4, 127.6, 129.2, 129.7, 130.9, 133.4, 137.6,
N-Tosyl-1-cycloh exyliden e-1,2,3,4,5,6-h exah ydr o-3-ben -
za zocin e (Ta ble 2, En tr y 20): mp 90-92 °C; TLC (4:1
1
hexanes/EtOAc) Rf ) 0.37; H NMR (CDCl3) δ 1.38-1.49 (m,
2 H), 1.50-1.70 (m, 6 H), 1.81 (t, J ) 6.3 Hz, 2 H), 1.88-2.00
(m, 1 H), 2.38 (s, 3 H), 2.40-2.50 (m, 1 H), 2.57 (td, J ) 13.5,
3.9 Hz, 1 H), 2.80 (dt, J ) 3.6, 13.2 Hz, 1 H), 2.90-3.10 (m, 2
H), 3.35 (d, J ) 13.3 Hz, 1 H), 4.48 (d, J ) 13.5 Hz, 1 H), 6.84
(d, J ) 7.8 Hz, 1 H), 7.08-7.19 (m, 5 H), 7.48 (d, J ) 8.5 Hz,
2 H); 13C NMR (CDCl3) δ 21.4, 26.6, 27.8, 28.1, 29.9, 31.5, 32.3,
32.5, 48.5, 52.5, 126.3, 127.0, 127.0, 127.9, 128.7, 129.4, 136.4,
140.3, 141.0, 141.6, 142.6, 142.6; IR (neat) 1598, 1159, 748
cm-1; HRMS m/z 395.1917 (calcd 395.1919 for C24H29NO2S).
N-Tosyl-1-bu tylid en e-1,2,3,4,5,6-h exa h yd r o-2-p r op yl-3-
ben za zocin e (Ta ble 2, En tr y 21). Obtained as an insepa-
rable mixture of E- and Z-isomers (E/ Z ) 84:16): oily mixture;
TLC (4:1 hexanes/EtOAc) Rf ) 0.50; 1H NMR (CDCl3) δ 0.70-
0.85 (m, 6 H), 0.85-1.05 (m, 1 H), 1.10-1.70 (m, 7 H), 2.20-
2.50 (m, 4 H), 2.41 (s, 2.52 H), 2.42 (s, 0.48 H), 2.57 (dt, J )
4.5, 13.2 Hz, 0.84 H), 2.83 (dt, J ) 4.2, 13.2 Hz, 0.16 H), 3.33
(dd, J ) 14.7, 3.9 Hz, 0.16 H), 3.41 (dd, J ) 4.2, 14.7 Hz, 0.84),
4.54 (dd, J ) 8.4, 5.9 Hz, 0.84 H), 5.04 (dd, J ) 9.6, 4.4 Hz,
0.16 H), 5.34 (t, J ) 7.2 Hz, 0.16 H), 5.67 (t, J ) 7.2 Hz, 0.84
H), 6.82 (d, J ) 7.5 Hz, 0.84 H), 6.84-7.00 (m, 0.48 H), 7.00-
7.24 (m, 2.68 H), 7.27 (d, J ) 8.4 Hz, 2 H), 7.75 (d, J ) 8.4 Hz,
2 H); 13C NMR (CDCl3) δ 13.8, 19.8, 21.4, 22.2, 29.1, 30.5, 32.6,
32.7, 33.0, 39.7, 64.8, 125.6, 127.1, 127.6, 128.8, 129.3, 130.0,
133.3, 134.2, 137.4, 139.3, 139.7, 142.7; IR (neat) 1598, 1157,
138.8, 139.1, 140.3, 143.0; IR (neat) 1597, 1161, 754 cm-1
;
HRMS m/z 397.5855 (calcd 397.5852 for C24H31NO2S). The
1
following H NMR data for the Z isomer were taken from the
mixture: δ 4.93-5.05 (m, 1 H), 5.12-5.20 (m, 1 H), 5.57 (t, J
) 6.3 Hz, 1 H).
N-n -Bu tyl-1-ben zylid en e-1,2,3,4,5,6-h exa h yd r o-3-ben z-
a zocin e (Ta ble 2, En tr y 16). Obtained as a separable
mixture of the E- and Z-isomers (E/ Z ) 78:22). E-isomer: oil;
1
TLC (4:1 hexanes/EtOAc) Rf ) 0.41; H NMR (CDCl3) δ 0.80
(t, J ) 7.2 Hz, 3 H), 0.80-1.00 (m, 1 H), 1.10-1.20 (m, 2 H),
1.20-1.40 (m, 3 H), 1.60-1.80 (m, 1 H), 2.48 (t, J ) 7.5 Hz, 2
H), 2.60-2.75 (m, 3 H), 3.47 (s, 2 H), 6.52 (s, 1 H), 6.80-6.95
(m, 2 H), 7.00-7.30 (m, 7 H); 13C NMR (CDCl3) δ 13.9, 20.2,
30.0, 32.2, 33.0, 53.3, 55.8, 68.1, 126.5, 126.6, 126.7, 127.1,
127.4, 128.0, 128.6, 128.9, 136.8, 140.6, 141.5, 142.5; IR (neat)
1599, 751 cm-1; HRMS m/z 305.2139 (calcd 305.2144 for
C
22H27N). Z-isomer: oil; TLC (4:1 hexanes/EtOAc) Rf ) 0.51;
1H NMR (CDCl3) δ 0.83 (t, J ) 7.2 Hz, 3 H), 1.10-1.40 (m, 6
H), 1.60-1.75 (m, 2 H), 2.39-2.49 (m, 3 H), 2.80-2.86 (m, 1
H), 3.46 (s, 2 H), 6.46 (s, 1 H), 7.00-7.45 (m, 9 H); 13C NMR
(CDCl3) δ 14.0, 20.2, 30.2, 31.8, 32.4, 54.8, 58.0, 59.9, 125.6,
126.6, 127.0, 127.5, 127.9, 128.0, 128.0, 128.1, 128.4, 128.6,
129.2, 129.3, 129.5; IR (neat) 1599, 751 cm-1; HRMS m/z
305.2139 (calcd 305.2144 for C22H27N).
760 cm-1; HRMS m/z 411.2250 (calcd 411.2232 for C25H33
-
NO2S).
N-Tosyl-1-ben zyliden e-1,2,3,4,5,6,7-h eptah ydr o-1H-ben -
za zon in e (Ta ble 2, En tr y 22). Obtained as an inseparable
mixture of the E- and Z-isomers (E/ Z ) 86:14): oily mixture;
TLC (4:1 hexanes/EtOAc) Rf ) 0.40; 1H NMR (CDCl3) δ 1.20-
1.70 (m, 2 H), 1.80-2.00 (m, 1 H), 2.39 (s, 0.42 H), 2.43 (s,
2.58 H), 2.50-2.65 (m, 1 H), 2.80-3.00 (m, 2H + 0.86 H), 3.78
(ddd, J ) 3.9, 7.2, 12.5 Hz, 0.86 H), 3.95 (d, J ) 12.7 Hz, 0.86
H), 4.05 (d, J ) 12.7 Hz, 0.86 H), 4.18-4.28 (m, 0.28 H), 4.30-
4.33 (m, 0.28 H), 6.58 (s, 0.14 H), 6.80 (s, 0.86 H), 6.80-7.40
(m, 11 H), 7.60 (d, J ) 8.4 Hz, 2 H); 13C NMR (CDCl3) δ 21.4,
22.9, 25.6, 27.4, 27.5, 27.7, 31.0, 31.9, 48.2, 51.3, 58.3, 60.8,
126.7, 127.1, 127.4, 127.8, 127.9, 128.3, 128.8, 129.3, 129.4,
129.5, 130.8, 132.6, 136.2, 137.7, 139.4, 140.7, 143.1; IR (neat)
N-n -Bu tyl-1,2,3,4,5,6-h exa h yd r o-1-n on ylid en e-3-ben z-
a zocin e (Ta ble 2, En tr y 17). The mixture of the E- and
Z-isomers (E/ Z ) 78:22) first isolated was further purified by
flash column chromatography to obtain a pure sample of the
E-isomer (56% yield): oil; 1H NMR (CDCl3) δ 0.80-0.95 (m, 6
H), 1.05-1.40 (m, 18 H), 1.60-1.80 (m, 3 H), 2.44 (t, J ) 7.5
Hz, 2 H), 2.48-2.64 (m, 3 H), 3.28 (s, 2 H), 5.58 (t, J ) 6.9 Hz,
1 H), 6.90-6.93 (m, 1 H), 7.10-7.20 (m, 3 H); 13C NMR (CDCl3)
δ 14.0, 14.1, 20.3, 22.7, 28.8, 29.2, 29.3, 29.3, 29.4, 29.9, 31.9,
32.4, 32.7, 52.7, 52.1, 66.3, 125.7, 126.7, 127.5, 128.4, 129.5,

6866 J . Org. Chem., Vol. 63, No. 20, 1998
Larock et al.
1598, 1157, 760 cm-1; HRMS m/z 418.1802 (calcd 418.1841 for
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all products described in Table 2 (55 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
C
26H28NO2S).
Ackn owledgm en t. We gratefully acknowledge John-
son Matthey, Inc. and Kawaken Fine Chemical Co.,
Ltd., for the palladium acetate. Dr. Pace acknowledges
the NATO-CNR Advanced Fellowships Program, spon-
sored by the Consiglio Nazionale delle Ricerche, for
support.
J O980516P