Ligand effects in the synthesis of N-heterocycles by intramolecular Heck reactions

Article abstract of DOI:10.1021/jo0522660

Chemo- and regioselectivity of intramolecular Heck reactions are dependent on the type of ligand employed. Six- to eight-membered benzolactams are produced in good yields using PPh₃ as ligand. In contrast, a biaryl coupling occurred preferentially under ligandless conditions to form a dihydrophenanthridine product. Conformations of the seven- and eight-membered benzolactams in the solid state were examined by X-ray crystallography.

Full text of DOI:10.1021/jo0522660

SCHEME 1. Previous Synthesis of N-Heterocycles by
Intramolecular Heck Reaction
Ligand Effects in the Synthesis of N-Heterocycles
by Intramolecular Heck Reactions
Emma L. Cropper, Andrew J. P. White, Agnes Ford,† and
King Kuok (Mimi) Hii*
Department of Chemistry, Imperial College London, Exhibition
Road, South Kensington SW7 2AZ, United Kingdom
mimi.hii@imperial.ac.uk
ReceiVed NoVember 1, 2005
SCHEME 2. Preparation of Acyclic Precursors
Chemo- and regioselectivity of intramolecular Heck reactions
are dependent on the type of ligand employed. Six- to eight-
membered benzolactams are produced in good yields using
PPh3 as ligand. In contrast, a biaryl coupling occurred
preferentially under ligandless conditions to form a dihy-
drophenanthridine product. Conformations of the seven- and
eight-membered benzolactams in the solid state were exam-
ined by X-ray crystallography.
of such stereodirecting groups, the outcome can be unpredict-
able, often leading to mixtures of products. Ways of controlling
the regioselectivity of these cyclizations are rarely studied.7
Previously, we described the synthesis of a benzazepine
structure by an intramolecular Heck reaction, where the use of
>3 equiv of PPh3 suppressed endo cyclization, affording the
7-exo product 3 exclusively (Scheme 1).8 Thus, the amount of
ligand clearly dictates the nature of the transition state (2) and
subsequent C-C formation. This peculiar result led us to initiate
the current study to investigate the ligand effects on the
regioselectivity of intramolecular Heck reactions, particularly
in the formation of medium-sized benzolactams.
Acyclic precursors were prepared by amide coupling reactions
between N-benzyl-2-iodoaniline 5 and the requisite acid chlo-
rides, which were generated in situ from the corresponding
ω-alkenoic acids (Scheme 2).
Reactions in the Presence of Monophosphine Ligands.
Compounds 6-9 were subjected to the Heck reaction, under
the conditions established previously. Employing a metal to
ligand ratio of 1:4, cyclizations proceeded exclusively in an exo
manner, furnishing quinolinone 10, 1-benzazepinone 11, and
1-benzazocinone 12 in good yields (Scheme 3).
Among the many intramolecular processes provided by
palladium catalysis in heterocyclic chemistry, the Heck reaction
is particularly valuable for the formation of saturated rings and
the creation of quaternary and/or stereogenic carbon centers.1
Most often used for the formation of five- and six-membered
rings, it is generally perceived to be selective for exo cycliza-
tions. However, this regioselectivity can be altered in certain
cases; for example, 6-endo ring closure may be favored by
adopting “ligandless” (Jeffery’s) conditions2 or by conducting
the reaction in an aqueous medium using water-soluble phos-
phines.3,4
There is a growing number of reports in recent years that
demonstrate the synthetic utility of the intramolecular Heck
reaction for the assembly of medium-sized rings (g7). In most
cases, the substrates contain a suitably placed substituent (e.g.,
an ester group) to effect arylation at the â-position, leading to
exclusive formation of exo5 or endo6 products. In the absence
The successful formation of the seven-membered benzaze-
pinone 11 is a considerable improvement over previous cy-
clization strategies using radical9 or nickel catalysts,10 which
furnished yields of less than 40% (in the latter case, with
unspecified regiochemistry). The successful 8-exo cyclization
is also worthy of note, as our earlier work showed that the
† AstraZeneca
Leicestershire LE11 5RH, U.K.
R & D Charnwood, Bakewell Road, Loughborough,
(1) (a) Link, J. T. Org. React. (N.Y.) 2002, 60, 157. (b) Dyker, G. In
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E.-I., de Meijere, A., Eds.; Wiley: New York, 2002; Vol. 1.
(2) Jeffery, T. Tetrahedron 1996, 52, 10113.
(3) Rigby, J. H.; Hughes, R. C.; Heeg, M. J. J. Am. Chem. Soc. 1995,
117, 7834.
(4) Lemaire-Audoire, S.; Savignac, M.; Dupuis, C.; Genet, J. P.
Tetrahedron Lett. 1996, 37, 2003.
(5) (a) Di Fabio, R.; Micheli, F.; Baraldi, D.; Bertani, B.; Conti, N.; Dal
Forno, G.; Feriani, A.; Donati, D.; Marchioro, C.; Messeri, T.; Missio, A.;
Pasquarello, A.; Pentassuglia, G.; Pizzi, D. A.; Provera, S.; Quaglia, A.
M.; Sabbatini, F. M. Farmaco 2003, 58, 723. (b) Hayashi, M.; Sai, H.;
Horikawa, H. Heterocycles 1998, 48, 1331.
(6) (a) Arnold, L. A.; Luo, W.; Guy, R. K. Org. Lett. 2004, 6, 3005. (b)
Gibson, S. E.; Jones, J. O.; Kalindjinan, S. B.; Knight, J. D.; Steed, J. W.;
Tozer, M. J. J. Chem. Soc., Chem. Commun. 2002, 1938. (c) Alcaide, B.;
Polanco, C.; Sierra, M. A. Eur. J. Org. Chem. 1998, 2913. (d) Gibson, S.
E.; Middleton, R. J. J. Chem. Soc., Chem. Commun. 1995, 1743.
(7) For example, see: (a) Santos, L. S.; Pilli, R. A. Synthesis 2002, 87.
(b) Tietze, L. F.; Sommer, K. M.; Schneider, G.; Tapolzsa´nyi, P.; Wo¨lfling,
J.; Mu¨ller, P.; Noltemeyer, M.; Terlau, H. Synlett 2003, 1494.
(8) Qadir, M.; Cobb, J.; Sheldrake, P. W.; Whittall, N.; White, A. J. P.;
Hii, K. K.; Horton, P. N.; Hursthouse, M. B. J. Org. Chem. 2005, 70, 1545.
10.1021/jo0522660 CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/24/2006
1732
J. Org. Chem. 2006, 71, 1732-1735

SCHEME 3. N-Heterocycles Obtained under “Standard”
Heck Conditions
SCHEME 4. Possible Pathways for Formation of Quinoline
10
FIGURE 1. Molecular structure of the benzazepinone 11 (left) and
benzazocinone 12 (right) as determined by X-ray crystallography.
Aromatic hydrogens omitted for clarity.
carbonyl compounds, whereby a stereomutation to intermediate
17 is proposed to occur via the formation of an η1-palladium
enolate 16.12 Presently, it is difficult to determine whether one
or both of the pathways operate(s) in the present system.13
Molecular structures of 11 and 12 were established by single-
crystal X-ray diffraction studies (Figure 1). The benzazepinone
species 11 adopts a boat conformation for its seven-membered
ring in the solid state, similar to that seen for the “parent”
compound 4,5-dihydro-1,3-benzazepin-2-one.14 Interestingly, the
eight-membered ring in compound 12 displays a twist-boat-
chair conformation, very similar to those seen for closely related
heterocycles.15
N-benzoyl precursor 1 (n ) 4) failed to produce the corre-
sponding eight-membered benzazocine ring under these exact
reaction conditions. Hence, the comparative ease of formation
of the benzazocinone 12 is attributed to greater rigidity of the
acyclic chain imposed by the amide moiety, leading to a
reduction in the entropy, which favors the formation of the eight-
membered ring.11 However, the formation of the nine-membered
benzazoninone ring still proved to be difficult. In this case, only
unreacted compound 9 was recovered at the end of the reaction.
The addition of the LiCl salt was also later found to be
unnecessary, as yields of 11 and 12 were unaffected in its
absence (81% and 79% yields, respectively).
No double bond migration/isomerization occurs during the
formation of the seven- and eight-membered benzolactams, as
the exocyclic double bonds were formed exclusively in com-
pounds 11 and 12. For quinoline 10, the formation of the
endocyclic double bond may result from two possible pathways
(Scheme 4). In the first (route A), an exocylic cyclization
proceeds to generate the alkylpalladium intermediate 13, which
undergoes a series of â-hydride migrations, leading to the
formation of the thermodynamically stable conjugate π-system.
In the alternate pathway (route B), double bond isomerization
of 6 occurs first to give the acyclic enone 14. An endocyclic
Heck cyclization will generate an intermediate 15, which will
undergo a formal anti â-hydride elimination to generate the
product 10. This process is well-documented for the intra-
molecular Heck addition of aryl halides to R,â-unsaturated
Compounds 11 and 12 displayed different dynamic behavior
in solution compared to their counterparts containing saturated
heterocycles. In contrast to 3,16 benzazepinone 11 is confor-
mationally labile. At ambient temperature, the benzylic and
methylene protons of 11 give rise to time-averaged resonances
1
in the H NMR spectrum. For the eight-membered benzazoci-
none 12, each diastereotopic methylene proton gives rise to a
1
distinct resonance signal in the H NMR spectrum, changing
little even at 90 °C. This contrasts with the solution behavior
of the corresponding benzazocine ring, which undergoes ring
inversion at ambient temperature.17 Thus, the incorporation of
the amide moiety appears to decrease and increase the confor-
mational rigidity of the seven- and eight-membered rings,
respectively.
At this stage of the study, we also investigated the use of
sterically bulky monophosphine ligands such as P(t-Bu)3 and
(12) For a review on intramolecular Heck reactions involving formal
anti-elimination processes, see: Ikeda, M.; El Bialy, S. A. A.; Yakura, T.
Heterocycles 1999, 51, 1957.
(13) The reversibility of â-hydride migration and the convergence of
the intermediates rules out the determination of reaction pathways by isotopic
(deuterium) labeling.
(14) CCDC reference code YUFFOU; see: Gupta, V. K.; Goswami, K.
N.; Yadava, V. B. S.; Gupta, D. K.; Bhutani, K. K. Z. Kristallogr. 1995,
210, 154.
(15) CCDC reference codes VABGUA, VABHAH, and COPTOQ: (a)
Yoshida, K.; Nakajima, S.; Ohnuma, T.; Ban, Y.; Shibasaki, M.; Aoe, K.;
Date, T. J. Org. Chem. 1988, 53, 5355. (b) Oda, K.; Ohnuma, T.; Ban, Y.;
Aoe, K. J. Am. Chem. Soc. 1984, 106, 5378.
(16) Conformational energy barrier of compound 3 is approximately ∆Gq
(9) (a) Kaoudi, T.; Quiclet-Sire, B.; Seguin, S.; Zard, S. Z. Angew. Chem.,
Int. Ed. 2000, 39, 731. (b) Clark, A. J.; Jones, K.; McCarthy, C.; Storey, J.
M. D. Tetrahedron Lett. 1991, 32, 2829.
(10) Mori, M.; Hashimoto, Y.; Ban, Y. Tetrahedron Lett. 1980, 21, 631.
(11) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
13.7 kcal mol-1 (ref 8).
(17) Partially and fully reduced 1-benzazocine conformers have energy
barriers of approximately 17 kcal mol-1: Qadir, M.; Cobb, J.; White, A. J.
P.; Sheldrake, P. W.; Whittall, N.; Hii, K. K.; Horton, P. N.; Hursthouse,
M. B. J. Org. Chem. 2005, 70, 1552.
J. Org. Chem, Vol. 71, No. 4, 2006 1733

SCHEME 5. Formation of Double-Bond Isomers under
Ligandless Conditions
FIGURE 2. Sterically bulky monophosphine ligands employed in the
intramolecular Heck reaction.
SCHEME 6. Chemoselective π-Activation under Different
Reaction Conditions
FIGURE 3. Reduced products (18-20) of the intramolecular Heck
reaction using P(t-Bu)3 as ligand: (i) 8, Pd(dba)2, P(t-Bu)3, NEt3,
toluene, reflux, 24 h; (ii) H2, Pd/C, EtOH.
2-(di-tert-butylphosphino)biphenyl (Figure 2). These ligands are
known to stabilize coordinatively unsaturated monoligated
[L-Pd] species,18 which are highly active in many palladium-
catalyzed processes, including the Heck reaction at room
temperature.19
(67%), respectively. In the latter case, an inseparable mixture
of the benzazepinone 11 and its double bond isomer 22 was
obtained in a 1: 1 ratio (Scheme 5).
For the cyclization of substrate 8, no product formation was
observed with either ligand at room temperature. At higher
temperatures, the reactions afforded complex mixtures of
products. In the case of P(t-Bu)3, at least five products with a
combined yield of 82% was obtained, which converged upon
hydrogenation (H2, Pd/C) into three products, 18, 19, and 20,
in a ratio of 1:15:2 (Figure 3). Each of these compounds was
isolated and easily identifiable by the observation of distinctive
propyl, ethyl, and methyl signals in their 1H NMR spectra
(Supporting Information). Formation of the smaller heterocycles
clearly indicates the operation of a competitive double bond
isomerization, prior to the C-C bond-forming step (akin to route
B, Scheme 4).
Rather unexpectedly, compound 8 underwent biaryl cou-
pling21 to furnish the dihydrophenanthridine 23 in 68% yield
(Scheme 6).22 The structure was corroborated by the observation
of eight aromatic proton resonances in the 1H NMR spectrum,
accompanied by a distinctive broadening and upfield shift of
the benzylic carbon resonance from 51.5 to 45.2 ppm.23 The
formation of this tricyclic heterocycle presumably occurs via
the putative intermediate 24. Comparing this result with the
8-exo cyclization obtained earlier in the presence of triph-
enylphosphine ligands, it would suggest that for substrate 8 the
activation of the N-benzyl moiety is favored under “ligandless”
conditions.
Conducting the reaction in a more polar DMF solvent, the
isomerization process may be suppressed to a certain extent.
The benzazocinone 12 may be isolated in ca. 50% yield (using
the biphenylphosphine ligand), but the reaction mixture contains
several side products. Postulating that the competitive process
may be promoted by the formation of a hydridopalladium
intermediate, we substituted triethylamine with an inorganic base
(Cs2CO3).20 However, the reaction again proved to be capricious,
delivering a mixture of products from which the dehalogenated
product 21 was isolated in 58% yield.
Reactions in the Absence of Phosphine Ligands. Jeffery’s
[Pd/Base/QX] catalyst system was also employed in the present
study. It has been proposed that this “ligandless” protocol may
offer a smaller metal coordination sphere, allowing the formation
of sterically more demanding transition state structures for endo
cyclizations.3
As far as we are aware, this is the first example where arene
or alkene is activated chemoselectively by adopting different
Heck protocols. The result suggests that whereas olefin coor-
dination (Heck reaction) is favored by phosphine-ligation (π-
acceptor), the coordination of the aromatic π-system (biaryl
coupling) occurs preferentially in the presence of anionic Cl-
ligand (σ-donor).
In summary, the regioselective formation of medium-sized
benzolactams can be achieved using the intramolecular Heck
reaction. The reaction is found to be highly dependent on the
catalytic conditions, particularly the structure of the substrate,
as well as the nature of the ligand employed. The latter is found
to affect the chemoselectivity, regioselectivity, and competitive
double bond migration processes. Whereas six- to eight-
membered heterocycles were obtained exclusively using the
PPh3 ligand (4 equiv), biaryl coupling was preferred over 8-exo
cyclization under “ligandless” conditions.
In the present study, 6- and 7-exo ring closures were again
observed in the cyclization of 6 and 7 to give 10 (79%) and 11
(21) Suzuki, K.; Ohmori, K. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E.-I., de Meijere, A., Eds.; Wiley: New
York, 2002; Vol. 1.
(22) Similar “Heck-type” biaryl coupling was effected by employing
thallium and silver salts; see: (a) Grigg, R.; Savic, V.; Tambyrajah, V.
Tetrahedron Lett. 2000, 41, 3003. (b) Harayama, T.; Akiyama, T.; Kawano,
K. Chem. Pharm. Bull. 1996, 44, 1634. By adopting Jeffrey’s conditions,
see: (c) Garden, S. J.; Torres, J. C.; Pinto, A. C. J. Braz. Chem. Soc. 2000,
11, 441. (d) Go´mez-Lor, B.; Echavarren, A. M. Org. Lett. 2004, 6, 2993.
(23) Li, W. R.; Lin, Y. S.; Hsu, N. M. J. Comb. Chem. 2001, 3, 634.
(18) Christmann, U.; Vilar, R. Angew. Chem., Int. Ed. 2005, 44, 366
and references therein.
(19) (a) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989. (b)
Stambuli, J. P.; Stauffer, S. R.; Shaughnessy, K. H.; Hartwig, J. F. J. Am.
Chem. Soc. 2001, 123, 2677.
(20) Palladium hydride can be generated through â-hydride elimination
of a coordinated triethylamine. The choice of base has been found to affect
the generation and stability of palladium hydride species; see: Hills, I. D.;
Fu, G. C. J. Am. Chem. Soc. 2004, 126, 13176.
1734 J. Org. Chem., Vol. 71, No. 4, 2006

Hex-5-1-(6H-phenanthridin-5-yl)-hex-5-en-1-one, 23. Yield:
68% as a yellow oil. νmax(thin film)/cm-1 1657 (CO). Found: C,
82.35; H, 6.98; N, 5.01. Calcd for C19H19NO: C, 82.28; H, 6.90;
N, 5.05. δH (270 MHz, CDCl3) 1.65-1.76 (2H, m), 1.90-2.08 (2H,
m), 2.48 (2H, t, J 7.4), 4.81-4.88 (4H, m), 5.60-5.67 (1H, m),
7.20-7.42 (6H, m), 7.76-7.81 (2H, m); δC (100 MHz, CDCl3)
24.8, 33.1, 45.2, 114.9, 123.3, 124.5, 124.7, 126.2, 127.6, 128.0,
129.9, 131.9, 135.3, 137.8, 138.0, 172.2; m/z (EI) 277 (M+, 28%),
180 (100%).
Hydrogenation of Double Bonds. A mixture of 10% Pd/C (190
mg, 0.5 equiv) and the appropriate benzolactam (0.36 mmol, 1.0
equiv) in ethanol (3.6 mL, 0.1 M) was stirred under a hydrogen
atmosphere at room temperature for 18 h. Subsequently, the
suspension was filtered through a short plug of silica and the
solution was concentrated in vacuo to furnish the products.
1-Benzyl-4-propyl-3,4-dihydro-1H-quinolin-2-one, 18. δH (400
MHz, CDCl3) 0.91 (3H, t, J 7.2), 1.25-1.39 (1H, m), 1.40-1.51
(1H, m), 1.53-1.75 (2H, m), 2.69-2.74 (1H, m), 2.88-2.95 (2H,
m), 5.01 (1H, d, J 16.2), 5.35 (1H, d, J 16.2), 6.89 (1H, d, J 8.1),
6.98 (1H, t, J 7.4), 7.08-7.17 (2H, m), 7.21-7.32 (5H, m); δC
(100 MHz, CDCl3) 14.0, 20.1, 35.9, 36.0, 37.0, 46.0, 115.8, 122.8,
126.5, 127.0, 127.3, 127.8, 128.7, 130.1, 137.1, 138.9, 169.9; m/z
(EI) 279 (M+, 56%), 236 (39%), 91 (100%).
Experimental Section
General Procedure for Preparation of 10-12, under “Stan-
dard” Heck Reaction in the Presence of PPh3. A Young’s tube
was charged with Pd(dba)2 (14 mg, 0.025 mmol, 5 mol %), PPh3
(26 mg, 0.099 mmol, 20 mol %), and LiCl (23 mg, 0.54 mmol, 1.1
equiv. Note: this is optional). To this was added Et3N (0.137 mL,
0.98 mmol, 2.0 equiv), dry DMF (4 mL), and the appropriate amide
(0.49 mmol, 1.0 equiv) as a solution in dry DMF (1 mL). The vessel
was sealed by a PTFE tap and the reaction stirred at room
temperature for 15 min, followed by heating at 130 °C for 22 h.
After this time, the reaction mixture was cooled and filtered through
Celite. The solution was then concentrated and purified by column
chromatography.
1-Benzyl-4-methyl-1H-quinolin-2-one, 10. Recrystallized from
hexane after column chromatography. Yield: 87% as a yellow
crystalline solid; Rf ) 0.16 (hexane/ethyl acetate, 2/1); mp 110-
111 °C (lit.24 110.5-111.5 °C); νmax(KBr)/cm-1 1651 (CdO); δH
(270 MHz, CDCl3) 2.51 (3H, s), 5.56 (2H, s), 6.71 (1H, s), 7.20-
7.31 (7H, m), 7.42 (1H, t, J 7.9), 7.72 (1H, d, J 7.9); δC (100 MHz,
CDCl3) 19.1, 45.7, 115.3, 121.0, 121.7, 122.0, 125.3, 126.5, 127.2,
128.8, 130.4, 136.5, 139.1, 147.1, 162.3; m/z (EI) 249 (M+, 100%),
248 (72%), 143 (65%), 91 (72%).
1-Benzyl-5-methylene-1,3,4,5-tetrahydro-1-benzazepin-2-
one, 11. Yield: 85% as a pale yellow solid; Rf ) 0.28 (hexane/
ethyl acetate, 2/1); mp 89-90 °C; νmax(KBr)/cm-1 1651 (CdO).
Found: C, 81.94; H, 6.54; N, 5.22. Calcd for C18H17NO: C, 82.10;
H, 6.51; N, 5.32. δH (270 MHz, CDCl3) 2.56 (2H, t, J 6.9), 2.98-
3.01 (2H, m), 4.83 (1H, dt, J 1.6, 1.9), 5.01 (2H, s), 5.15 (1H, dt,
J 1.6, 1.9), 7.12-7.27 (9H, m, ArH); δC (100 MHz, CDCl3) 33.0,
36.3, 51.3, 115.5, 122.6, 126.4, 127.0, 127.7, 128.2, 128.5, 129.0,
137.5, 137.6, 140.8, 145.2, 173.0; m/z (EI) 263 (M+, 63%), 172
(30%), 144 (33%), 130 (27%), 91 (100%).
1-Benzyl-6-methylene-3,4,5,6-tetrahydro-1H-benzazocin-2-
one, 12. Yield: 72% as a pale yellow solid; Rf ) 0.19 (hexane/
ethyl acetate, 3/1); mp 65-66 °C; νmax(KBr)/cm-1 1658 (CO).
Found: C, 82.16; H, 6.84; N, 4.96. Calcd for C19H19NO: C, 82.28;
H, 6.90; N, 5.05. δH (270 MHz, CDCl3) 1.84-1.94 (2H, m), 2.00-
2.21 (2H, m), 2.31-2.38 (1H, m), 2.54-2.62 (1H, m), 4.00 (1H,
d, J 1.5), 4.83 (1H, d, J 14.3), 4.89 (1H, m), 4.99 (1H, d, J 14.3),
7.10-7.17 (2H, m) 7.19-7.28 (7H, m); δC (100 MHz, CDCl3) 26.1,
33.1, 36.8, 52.7, 115.5, 125.6, 127.3, 127.3, 127.8, 128.1, 129.2,
129.3, 137.0, 139.6, 142.8, 145.9, 173.6; m/z (EI) 277 (M+, 90%),
186 (61%), 91 (100%).
General Procedure for Cyclization under “Ligandless” Con-
ditions. A Young’s tube was charged with Pd(OAc)2 (6 mg, 0.025
mmol, 5 mol %), n-Bu4NCl (137 mg, 0.49 mmol, 1.0 equiv) and
KOAc (121 mg, 1.23 mmol, 2.5 equiv). To this was added the
appropriate amide (0.49 mmol, 1.0 equiv), followed by dry DMF
(5 mL). The vessel was sealed with a PTFE tap and the reaction
mixture was stirred at room temperature for 10 min, followed by
heating at 130 °C for 22 h. After this time, the reaction mixture
was cooled and filtered through Celite. The solvent was removed
under vacuum, and the product purified by column chromatography.
1-Benzyl-5-methyl-1,3-dihydro-1-benzazepin-2-one, 22. Com-
pound was not isolated but obtained as inseparable mixture with
11. δH (270 MHz, CDCl3) 2.10 (3H, s), 2.63-2.66 (1H, m), 3.06-
3.14 (1H, m), 4.86 (1H, d, J 15.6), 5.33 (1H, d, J 15.6), 5.95 (1H,
t, J 6.4), 7.04-7.40 (9H, m); δC (100 MHz, CDCl3) 21.0, 35.6,
51.7, 123.2, 123.3, 124.9, 126.7, 126.9, 127.0, 127.8, 128.3, 135.1,
135.5, 140.3, 171.4; m/z (EI) 263 (M+, 10%), 221 (100), 91 (28).
1-Benzyl-5-ethyl-1,3,4,5-tetrahydro-1-benzazepin-2-one, 19.
δH (400 MHz, CDCl3) 0.74 (3H, t, J 7.3), 1.47-1.58 (2H, m), 1.67-
1.78 (1H, m), 2.15-2.32 (2H, m), 2.34-2.42 (2H, m), 4.74. (1H,
d, J 14.6), 5.26 (1H, d, J 14.6), 7.14-7.29 (9H, m); δC (100 MHz,
CDCl3) 12.1, 24.7, 33.2, 35.8, 51.3, 123.2, 125.3,126.5, 126.9,
127.3, 128.3, 128.3, 137.7, 138.3, 142.6, 173.3; m/z (EI) 279 (M+,
100%), 91 (80%).
Benzyl-6-methyl-3,4,5,6-tetrahyro-1H-1-benzazocin-2-one, 20.
Obtained by hydrogenation of 12. Yield: 95% as a white solid;
mp 96-97 °C; νmax(KBr)/cm-1 1645 (CO). Found: C, 81.67; H,
7.55; N, 4.98. Calcd for C19H21NO: C, 81.68; H, 7.58; N, 5.01. δH
(270 MHz, CDCl3): 0.88 (3H, d, J 7.0), 1.17-1.27 (1H, m), 1.66-
1.74 (1H, m), 1.76-1.86 (2H, m), 1.87-1.96 (1H, m), 2.06-2.16
(1H, m), 2.22-2.27 (1H, m). 4.47 (1H, d, J 13.7), 5.45 (1H, d, J
13.7), 7.14-7.31 (9H, m); δC (100 MHz, CDCl3): 21.9, 25.3, 32.3,
33.1, 37.8, 52.4, 125.6, 126.0, 126.6, 127.4, 128.2, 128.3, 129.3,
136.4, 140.0, 146.0, 174.2; m/z (EI) 279 (M+, 100%), 91 (100%).
Hex-5-enoic Acid Benzyl-phenyl-amide, 21. A pure sample was
obtained via an independent route by the amidation of hex-5-enoic
acid by N-benzylaniline. Colorless oil. νmax(thin film)/cm-1 1657
(CO). Found: C, 81.80; H, 7.63; N, 5.00. Calcd for C19H21NO: C,
81.68; H, 7.58; N, 5.01. δH (270 MHz, CDCl3): 1.58-1.74 (2H,
m), 1.95-2.11 (4H, m), 4.88-4.95 (4H, m), 5.63-5.71 (1H, m),
6.95-6.97 (2H, m), 7.14-7.41 (8H, m); δC (100 MHz, CDCl3):
24.6, 33.1, 33.6, 33.6, 52.9, 114.8, 127.2, 127.8, 128.3, 128.4, 128.8,
129.4, 137.6, 138.1, 142.4, 172.7; m/z (EI) 279 (M+,34%), 183
(88), 180 (55), 91 (100).
Acknowledgment. The authors thank AstraZeneca and
EPSRC for the award of an industrial Doctoral Training Grant
(GR/P01816/01), and Johnson Matthey plc for the loan of
palladium salts.
Supporting Information Available: Description of general
experimental procedures, preparation of precursors 6-9, selected
NMR spectra and X-ray crystallographic data, and CIF files for
compounds 11 and 12. This material is available free of charge via
the Internet at http://pubs.acs.org.
(24) Kaslow, C. E.; Cook, D. J. J. Am. Chem. Soc. 1945, 67, 1969.
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