Application of the palladium-catalyzed borylation/Suzuki coupling (BSC) reaction to the synthesis of biologically active biaryl lactams

Article abstract of DOI:10.1021/jo0160726

The palladium-catalyzed, two-step, one-pot borylation/Suzuki coupling (BSC) reaction was developed to synthesize sterically hindered 2,2′-disubstituted biphenyl and phenyl-indole compounds in a short, simple, and efficient manner from two easily accessible aryl halides. High yields can be obtained by choosing properly both components according to their rough electronic properties. The illustration of the utility of this method was provided by the solution and solid-phase synthesis of seven- or eight-membered biphenyl lactams 5a-e, as well as paullone 3a. These compounds exhibit moderate albeit significant cytotoxicities and may serve as structural models for future medicinal chemistry developments.

Full text of DOI:10.1021/jo0160726

J . Org. Chem. 2002, 67, 1199-1207
1199
Ap p lica tion of th e P a lla d iu m -Ca ta lyzed Bor yla tion /Su zu k i
Cou p lin g (BSC) Rea ction to th e Syn th esis of Biologica lly Active
Bia r yl La cta m s
Olivier Baudoin,* Miche`le Cesario, Daniel Gue´nard, and Franc¸oise Gue´ritte
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
baudoin@icsn.cnrs-gif.fr
Received August 30, 2001
The palladium-catalyzed, two-step, one-pot borylation/Suzuki coupling (BSC) reaction was developed
to synthesize sterically hindered 2,2′-disubstituted biphenyl and phenyl-indole compounds in a short,
simple, and efficient manner from two easily accessible aryl halides. High yields can be obtained
by choosing properly both components according to their rough electronic properties. The illustration
of the utility of this method was provided by the solution and solid-phase synthesis of seven- or
eight-membered biphenyl lactams 5a -e, as well as paullone 3a . These compounds exhibit moderate
albeit significant cytotoxicities and may serve as structural models for future medicinal chemistry
developments.
Ch a r t 1
In tr od u ction
Biaryl axis-containing molecules bind to a great diver-
sity of proteins1 and therefore are found in almost any
therapeutic class, for instance, oncolytics, antibiotics, or
CNS and cardiovascular agents. In particular, tricyclic
biaryls constitute the framework of naturally occurring
antimitotic compounds2 such as colchicinoids (e.g., colchi-
cine and allocolchicine 1),3 steganacin, and rhazinilam 2
(Chart 1).4 These compounds interact with the mitotic
spindle: the former bind to tubulin and inhibit the
formation of microtubules;2,3 rhazinilam induces an
inhibition of both polymerization and depolymerization
of tubulin via the formation of abnormal spirallike
structures.5 Both classes of molecules are configuration-
ally stable due to the presence of the conformationally
restrictive 2,2′-bridge between the two aryl moieties and
to the possible ortho-substitution of these. Remarkable
is the fact that their biological activity is restricted to
the naturally occurring atropisomer.3,6
As part of a program of our group and collaborators
directed toward the study of structure-activity relation-
ships of 2, various phenyl-pyrrole,7 biphenyl,8 or phenyl-
pyridine9 analogues of 2 possessing different median ring
sizes have been synthesized and their biological proper-
(1) Hadjuk, P. J .; Bures, M.; Praestgaard, J .; Fesik, S. W. J . Med.
Chem. 2000, 43, 3443.
(2) For reviews, see: (a) Hamel, E. Med. Res. Rev. 1996, 16, 207. (b)
J ordan, A.; Hadfield, J . A.; Lawrence, N. J .; McGown, A. T. Med. Res.
Rev. 1998, 18, 259.
(3) Shi, Q.; Chen, K.; Morris-Natschke, S. L.; Lee, K.-H. Curr.
Pharm. Des. 1998, 4, 219 and refs therein.
(4) (a) Abraham, D. J .; Rosenstein, R. D. Tetrahedron Lett. 1972,
909. (b) De Silva, K. T.; Ratcliffe, A. H.; Smith, G. F.; Smith, G. N.
Tetrahedron Lett. 1972, 913.
(5) David, B.; Se´venet, T.; Morgat, M.; Gue´nard, D.; Moisand, A.;
Tollon, Y.; Thoison, O.; Wright, M. Cell Motil. Cytoskeleton 1994, 28,
317.
(6) David, B.; Se´venet, T.; Thoison, O.; Awang, K.; Pais, M.; Wright,
M.; Gue´nard, D. Bioorg. Med. Chem. Lett. 1997, 7, 2155.
(7) (a) Alazard, J .-P.; Millet-Paillusson, C.; Gue´nard, D.; Thal, C.
Bull. Soc. Chim. Fr. 1996, 133, 251. (b) Dupont, C.; Gue´nard, D.; Thal,
C.; Thoret, S.; Gue´ritte, F. Tetrahedron Lett. 2000, 41, 5853.
(8) (a) Pascal, C.; Dubois, J .; Gue´nard, D.; Gue´ritte, F. J . Org. Chem.
1998, 63, 6414. (b) Pascal, C.; Dubois, J .; Gue´nard, D.; Tchertanov,
L.; Thoret, S.; Gue´ritte, F. Tetrahedron 1998, 54, 14737.
ties assessed. In particular, these studies underlined the
effect of the median ring size (six- to nine-membered) on
the activity of phenyl-pyrrole analogues.7 For instance,
phenyl-pyrrole 4, which contains a seven-membered
lactam median ring, was shown to interact with tubulin
in a different manner from 2, by inhibiting only micro-
tubule assembly (IC50 ) 27 µM).7b Besides, this compound
showed an interesting cytotoxicity (IC50 ) 7 µM, KB cell
lines).
To further study the role of the size and substitution
of the median lactam ring on the nature of the interaction
(9) Pasquinet, E.; Rocca, P.; Richalot, S.; Gue´ritte, F.; Gue´nard, D.;
Godard, A.; Marsais, F.; Que´guiner, G. J . Org. Chem. 2001, 66, 2654.
10.1021/jo0160726 CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/22/2002

1200 J . Org. Chem., Vol. 67, No. 4, 2002
Baudoin et al.
Sch em e 1. Electr on ic Requ ir em en ts for th e
with tubulin, we envisioned a synthesis of biphenyl
lactams 5, possessing possibly different ring sizes and
substituents. It was indeed known from our previous data
that the pyrrole ring of rhazinilam-type compounds can
be replaced by a phenyl ring without notable changes in
the activity, which greatly simplifies the synthesis of such
compounds.8 The development of a new versatile and
straightforward synthesis of compounds 5 appeared to
be necessary in light of the very few existing methods,10
and in prospect of possible high-throughput synthesis
adaptations. Moreover, this method could possibly be
applied to the synthesis of other biologically active 2,2′-
bridged biaryls structurally close to 5,11 including allo-
colchicine 1 analogues3 and paullones 3.12,13 The latter
are seven-membered 2-phenylindole lactams which have
been recently discovered as potent inhibitors of cyclin-
dependent kinases (CDK).13 These enzymes constitute a
group of serine threonine kinases which control the
transmission between successive stages of the cell cycle
and therefore represent attractive targets for the devel-
opment of new antitumor agents.
Recently, we reported a novel one-pot palladium(0)-
catalyzed borylation-Suzuki coupling (BSC) reaction for
the synthesis of 2,2′-disubstituted biphenyl compounds.14
Based on the use of the electron-rich, sterically hindered
2-(dicyclohexylphosphino)biphenyl ligand described by
Buchwald et al.,15 as well as on the borylation reaction
developed by Masuda et al.,16 this sequence allows for
the rapid and efficient obtention of synthetically useful
biphenyls. The reaction conditions tolerate a number of
different functional groups, including primary amines,
which therefore suppresses the need for additional
protecting group chemistry steps. In addition, it is little
sensitive to steric hindrance, on the contrary to most
existing methods. These features are developed in the
present report, and applied to a practical and very short
synthesis of biphenyl lactams 5 and unsubstituted
paullone 3a , which currently serve as structural models
for the development of new cytotoxic derivatives.
Bor yla tion /Su zu k i Cou p lin g (BSC) Rea ction a
a
Reaction conditions: component I, Et3N, Pd(OAc)2, PCy2(o-
biph), (pin)BH, dioxane, 80 °C, 30 min to 1 h, then H2O, component
II, Ba(OH)2‚8H2O, 100 °C, 30 min to 1 h. X ) Br or I; EDG )
electron-donating group; EWG ) electron-withdrawing group; pin
) pinacol; PCy2(o-biph) ) 2-(dicyclohexylphosphino)biphenyl;
(pin)BH ) 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (pinacolborane).
ponent, followed by in situ Suzuki cross-coupling with
the other component (Scheme 1).14,17
The choice of the borylation and cross-coupling com-
ponent depends on the nature of the substituents present
on the aromatic ring. Thus, if R1 is electron-donating and
if R2 is electron-withdrawing, the borylation should be
performed on component I and the coupling of the
resulting boronate with component II. Indeed, we found
that the borylation reaction gives better yields with
electron-rich substrates,14 and the resulting electron-rich
boronate is more reactive for the transmetalation step
of the Suzuki coupling. Besides, it is known that Suzuki
couplings work better with electron-deficient halides
(component II) which undergo easier oxidative insertion
to the palladium. On the contrary, if R1 is rather electron-
withdrawing and R2 electron-donating, the borylation
should be performed on component II and the Suzuki
coupling with component I.
These basic rules are illustrated in the synthesis of 2,2′-
disubstituted biphenyls 8a -c, hypothetical intermediates
in the synthesis of lactams 5 (Table 1, entries 1-6). In
these reactions, 1.5 equiv of the borylation substrate
(component I, see Scheme 1) were used per Suzuki
coupling partner (component II) to account for the un-
complete character of the borylation. Indeed, isolated
yields for the borylation itself are 81% for 6a , 57% for
6b, 90% for 7a , and 87% for 7b (together with the
corresponding dehalogenated side-products).14 The BSC
reaction with unprotected 2-bromoaniline 6a as compo-
nent I and iodide 7a as component II furnished biphenyl
8a in 79% isolated yield (entry 1). In this case, component
I is electron-rich and component II rather neutral, thus
both borylation and cross-coupling steps are favored.
Reversing the sequence, i.e., starting with the borylation
of 7a and performing the cross-coupling with 6a did not
give any coupled material (entry 3). With the much more
sterically hindered 7b as component II, the corresponding
biphenyl 8b is obtained in 81% yield (entry 2). This
indicates that the Suzuki reaction, in addition to the
borylation reaction,14 is mostly unsensitive to steric
hindrance. This can be ascribed to the unique electronic
and steric properties of the phosphine ligand used in both
steps.15 It should be noted that the reverse reaction, i.e.,
with 7b as component I and 6a as component II, did not
give any cross-coupling product (entry 4) as observed with
Resu lts a n d Discu ssion
The one-pot, two-step BSC reaction allows the direct
synthesis of 2,2′-disubstituted biphenyls from two 2-ha-
logenoarene components via the borylation of one com-
(10) (a) Wiesner, K.; Valenta, Z.; Manson, A. J .; Stonner, F. W. J .
Am. Chem. Soc. 1955, 77, 675. (b) Muth, C. W.; Sung, W.-L.;
Papanastassiou, Z. B. J . Am. Chem. Soc. 1955, 77, 3393; (c) Endo, Y.;
Ohta, T.; Shudo, K.; Okamoto, T. Heterocycles 1977, 8, 367.
(11) See for instance: (a) Chen, W.-Y.; Gilman, N. W. J . Heterocycl.
Chem. 1983, 20, 663. (b) Melani, F.; Cecchi, L.; Palazzino, G.;
Filacchioni, G. J . Heterocycl. Chem. 1986, 23, 173. (c) Kunick, C. Curr.
Pharm. Des. 1999, 5, 181. (d) Norman, P.; Leeson, P. A.; Rabasseda,
X.; Castaner, J .; Castaner, R. M. Drugs Future 2000, 25, 1121.
(12) (a) Kunick, C. Arch. Pharm. (Weinheim, Ger.) 1992, 325, 297.
(b) Kozikowski, A. P.; Ma, D.; Romeo, E.; Auta, J .; Papadopoulos, V.;
Puia, G.; Costa, E.; Guidotti, A. Angew. Chem., Int. Ed. Engl. 1992,
31, 1060.
(13) (a) Schultz, C.; Link, A.; Leost, M.; Zaharevitz, D. W.; Gussio,
R.; Sausville, E. A.; Meijer, L.; Kunick, C. J . Med. Chem. 1999, 42,
2909. (b) Leost, M.; Schultz, C.; Link, A.; Wu, Y.-Z.; Biernat, J .;
Mandelkow, E.-M.; Bibb, J . A.; Snyder, G. L.; Greengard, P.; Zahare-
vitz, D. W.; Gussio, R.; Senderowicz, A. M.; Sausville, E. A.; Kunick,
C.; Meijer, L. Eur. J . Biochem. 2000, 267, 5983.
(14) Baudoin, O.; Gue´nard, D.; Gue´ritte, F. J . Org. Chem. 2000, 65,
9268.
(15) (a) Wolfe, J . P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999,
38, 8, 2413. (b) Wolfe, J . P.; Singer, R. A.; Yang, B. H.; Buchwald, S.
L. J . Am. Chem. Soc. 1999, 121, 9550.
(16) (a) Murata, M.; Watanabe, S.; Masuda, Y. J . Org. Chem. 1997,
62, 6458. (b) Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. J . Org.
Chem. 2000, 65, 164.
(17) For related BSC reactions, using bis(pinacolato)diboron as the
borylation agent, see: (a) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura,
N. Tetrahedron Lett. 1997, 38, 3447. (b) Giroux, A.; Han, Y.; Prasit, P.
Tetrahedron Lett. 1997, 38, 3841. (c) Carbonnelle, A.-C.; Zhu, J . Org.
Lett. 2000, 2, 3477.

Synthesis of Biologically Active Biaryl Lactams
J . Org. Chem., Vol. 67, No. 4, 2002 1201
Ta ble 1. Syn th esis of Bia r yl In ter m ed ia tes 8a -c a n d
10a -c Usin g th e BSC Rea ction a
rules. Indeed, using 6b or 7a as component I and 7a or
6b as component II, respectively, gave in both cases
biphenyl 8c in high yield (entries 5 and 6), despite the
steric hindrance introduced by the Boc group.
Next, the synthesis of 2-phenylindoles 10a -c, possible
intermediates in the synthesis of paullones 3, was
examined using the preceding method (Table 1, entries
7-10). The borylation of 2-bromo- or 2-iodoaniline (com-
ponent I), followed by coupling with unprotected 2-bro-
moindole 9a ,20 gave biaryl 10a in 62% yield (entry 7).21
With Boc-protected 6b, the bulkier biaryl 10b was
obtained in higher yield (entry 8), which illustrates
further the unsensitiveness of the reaction to steric
factors. Reversing the reactional sequence, i.e., using 9a
as component I and 6b as component II gave a much
lower yield (25%) of compound 10b (entry 9). As it was
shown that 6b can react efficiently as component II in
the BSC reaction (entry 5), this lower yield is imputable
to the use of 9a as component I: the borylation of 9a itself
gave an isolated yield of 52% of the corresponding
pinacolboronate. This boronate is weakly nucleophilic
because of the low electronic density of the 2-indole
position and fairly unreactive toward the transmetalation
step of the Suzuki coupling. By opposition, 2-bromoin-
doles behave as good components II in the Suzuki
reaction due to easy Pd insertion at the electron-deficient
2-indole carbon atom (entries 7, 8, 10). Finally, BSC
reaction of 6b with MOM-protected indole 9b gave the
corresponding phenylindole 10c in 76% yield (entry 10)
despite the presence of bulky substituents on both
components.
Thus, by choosing both components according to their
rough electronic properties, good to very high yields of
biaryls can be obtained through the BSC reaction.
Application of this method to the synthesis of the target
seven-membered biphenyl lactams 5a -d is shown in
Scheme 2. Thus, basic hydrolysis of the nitrile group of
8a with sodium hydroxide in refluxing methanol and
concomitant cyclization gave directly lactam 5a in 56%
yield. The bulkier diethyl derivative 8b remained intact
under the same conditions. Increasing the reaction tem-
perature by using higher-boiling alcohols such as 2-meth-
oxyethanol or switching to acidic hydrolysis with aqueous
H2SO4 gave the cyclic amidine 11b in good yield. Apply-
ing these acidic conditions to 8a gave unsubstituted
amidine 11a . These derivatives, arising from dehydration
of the putative primary amide or iminoester intermedi-
ate, proved resistant to further hydrolysis. As a result,
hydrolysis of the Boc-protected biphenyls 8c-f was
examined in order to try to avoid the apparently easy
amidine formation. Mono- or bis-alkylation of 8c with
LDA and methyl or ethyl iodide gave nitriles 8d -f in
good yields. Basic hydrolysis of 8c with sodium hydroxide
in ethanol/water gave a mixture of primary amide (major
product)22 and cyclized product 5a . 5a may form by
cyclization of the primary amide, followed by in situ
deprotection of the resulting base-labile Boc-protected
lactam. Total conversion of the mixture in favor of the
seven-membered lactam was best effected by treatment
entry
component I
component II
product (%)b
1
2
3
4
5
6
7
8
9
6a
6a
7a
7b
6b
7a
6c
6b
9a
6b
7a
7b
6a
6a
7a
6b
9a
9a
6b
9b
8a (79)
8b (81)
8a (0)
8b (0)
8c (100)
8c (93)
10a (62)
10b (89)
10b (25)
10c (76)
10
a
Reaction conditions: component I (1.0 equiv), Et3N (4.0 equiv),
Pd(OAc)2 (5 mol %), PCy2(o-biph) (0.2 equiv), (pin)BH (3.0 equiv),
dioxane, 80 °C, 30 min-1 h, then H2O, component II (0.67 equiv
for entries 1-6, 0.5 equiv for entries 7-10), Ba(OH)2‚8H2O (3.0
b
equiv), 100 °C, 1 h. Isolated yields, calculated from component
II.
7a (entry 3). As the borylation of 7a and 7b is high-
yielding as stated above, this behavior can be inferred
at least in part to the poor ability of electron-rich 6a to
undergo oxidative insertion to the palladium catalyst in
the Suzuki coupling step. Indeed, bromoaniline was
recovered unchanged after several hours and no aniline
or 2,2′-diaminobiphenyl, which could have been produced
as side-products after the oxidative insertion, were
observed in the reaction mixture. These data suggest that
the borylation and the biaryl coupling steps occur through
different mechanisms. The exact mechanism of the
borylation itself is not known.16 The fact that 6a was
converted quantitatively in the borylation reaction (ca.
80% boronate + 20% aniline) but did not react at all in
the Suzuki coupling with the same catalyst suggests that
the oxidative insertion of palladium in the carbon-
halogen bond may not be the rate-determining step of
the borylation unlike it is in the biaryl coupling.18 This
is further supported by our observations that phenyl
halides bearing electron-donating groups give higher
yields of boronates than substrates bearing electron-
withdrawing groups. Finally, the BSC reaction of Boc-
protected 2-iodoaniline 6b19 with iodide 7a was examined.
In this case both halides bear rather electronically
neutral ortho substituents; thus, the order of reactants
should be more or less indifferent according to the above
(20) Mistry, A. G.; Smith, K.; Bye, M. R. Tetrahedron Lett. 1986,
27, 1051.
(21) Using 6c instead of 6a gave higher isolated yields of 10a due
to easier purification, but conversions were nearly identical.
(22) The primary amide was isolated and characterized by 1H NMR
(amide group: two broad singlets at 5.41 and 5.88 ppm) and mass
spectrometry (ESI, m/z ) 349 for [M + Na]+).
(18) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(19) Kelly, T. A.; McNeil, D. W. Tetrahedron Lett. 1994, 35, 9003.

1202 J . Org. Chem., Vol. 67, No. 4, 2002
Baudoin et al.
Sch em e 2. Syn th esis of Seven -Mem ber ed Bip h en yl La cta m s 5a -d a n d P a u llon e 3a a
a
(a) NaOH (10 equiv), MeOH/H2O 2/1, reflux, 3.5 h; (b) aq H2SO4, MeO(CH2)2OH, reflux, 1-4 h; (c) LDA (2.0-3.0 equiv), MeI (1.0
equiv) or EtI (3.0 equiv), THF, -78 °C to 25 °C, 2 h; (d) LDA (6.0 equiv), EtI (6.0 equiv), THF, -78 °C to 25 °C, 2 h; (e) NaOH (10 equiv),
EtOH/H2O 2/1, reflux, 3-8 h; (f) concd H2SO4, 25 °C, 30 min.
Sch em e 3. Solid -P h a se Syn th esis of Bip h en yl
La cta m 5a a
of the crude material with concentrated sulfuric acid,
providing 5a in 64% yield from 8c. The same reaction
conditions were applied to monomethyl and ethyl deriva-
tives 8d -e, giving lactams 5b-c in 58% and 47% yields,
respectively. Unfortunately, the more sterically hindered
nitrile 8f, when subjected to basic hydrolysis, did not give
the expected lactam 5d . In this case, deprotection of the
Boc group occurred and the nitrile group was left unaf-
fected. Exploitation of those results in the synthesis of
unsubstituted paullone 3a is illustrated in Scheme 2.
Thus, direct basic hydrolysis of unprotected phenylindole
10a with alcoholic sodium hydroxide gave 3a cleanly in
51% yield. Submission of Boc-protected phenylindole 10b
to basic hydrolysis gave a complex mixture of products,
which may arise from competitive cyclization of the indole
nitrogen on the Boc carbonyl. Indeed, basic hydrolysis of
the MOM-protected nitrile 10c gave the corresponding
primary amide, which subsequently failed to give paullone
3a under acidic conditions. In conclusion, biphenyl 5a and
paullone 3a were obtained in a convenient and efficient
manner: two steps, 44% and 32% overall yields, respec-
tively, from commercially available materials. The BSC
method, which was used in the first step, tolerates
unprotected nitrogens well, which greatly simplifies the
whole sequence by eliminating the need for protection
and deprotection chemistry.
The application of the above findings to the solid-phase
synthesis of lactam 5a is shown in Scheme 3. It was
anticipated that replacement of the Boc group of 8c by a
resin-bound carbamate could possibly furnish 5a after
cyclization in a similar manner as precedently. Thus,
Wang resin (1.0 mmol/g, 200-400 mesh) was treated
with p-nitrophenyl chloroformate and N-methylmorpho-
line in dichloromethane to give the activated p-nitrophe-
nyl carbonate resin 12 (IR: νCdO ) 1762 cm-1).23 Depro-
tonation of 2-iodoaniline with NaHMDS in THF, followed
by addition of the resulting anion to resin 12 gave the
a
(a) 2-Iodoaniline (3.0 equiv), NaHMDS (6.0 equiv), THF, 25
°C, 30 min, then 12 (1.0 mmol/g), THF, 25 °C, 14 h; (b) 7a (1.0
equiv), Et3N (4.0 equiv), Pd(OAc)2 (5 mol %), PCy2(o-biph) (0.2
equiv), (pin)BH (3.0 equiv), dioxane, 80 °C, 30 min, then H2O, 13
(0.5 equiv), NaOH (4.0 equiv), 100 °C, 1 h; (c) 20% TFA/CH2Cl2,
25 °C, 30 min, 60% overall; (d) see Scheme 2; (e) NaOH (20 equiv),
toluene/EtOH/H2O 1/1/1, reflux, 17 h, 25% overall. pNp ) p-
nitrophenyl; NaHMDS ) sodium hexamethyldisilazane.
resin-bound carbamate 13 (IR: νN-H ) 3387, νCdO ) 1735
cm-1). BSC reaction using iodide 7a as component I and
resin 13 as component II resulted in the formation of the
resin-bound biphenyl 14 (IR: νN-H ) 3418, νC≡N ) 2248,
νCdO ) 1731 cm-1). Practically, 7a was submitted to the
borylation step (80 °C, 30 min), water was added to the
reaction medium which was then transferred via cannula
or syringe to a suspension of resin 13 in dioxane. Sodium
hydroxide was added, and the mixture was heated to 100
°C for 1 h. In this case sodium hydroxide was used
instead of barium hydroxide because the latter produces
insoluble salts which could not be washed out from the
resin. Treatment of resin 14 with TFA in dichlo-
romethane afforded 0.60 mmol of the free amine 8a per
gram of resin (i.e., 60% yield from Wang resin). 8a can
be converted to lactam 5a in 56% yield through basic
hydrolysis according to Scheme 2. Alternatively, treat-
(23) Dressman, B. A.; Spangle, L. A.; Kaldor, S. W. Tetrahedron Lett.
1996, 37, 937.

Synthesis of Biologically Active Biaryl Lactams
J . Org. Chem., Vol. 67, No. 4, 2002 1203
Sch em e 4. Syn th esis of Eigh t-Mem ber ed
Bip h en yl La cta m 5ea
a
(a) (Ph3P+CH2CN,Cl-) (1.05 equiv), aq NaOH, CH2Cl2, 25 °C,
30 min, 98% (Z/E 86/14); (b) NaBH4 (1.3 equiv), pyridine/MeOH,
reflux, 2 h, 86%; (c) 6a (1.0 equiv), Et3N (4.0 equiv), Pd(OAc)2 (5
mol %), PCy2(o-biph) (0.2 equiv), (pin)BH (3.0 equiv), dioxane, 80
°C, 1 h, then H2O, 7c (0.67 equiv), Ba(OH)2‚8H2O (3.0 equiv), 100
°C, 1 h, 98% from 7c; (d) NaOH (10.0 equiv), EtOH/H2O, reflux, 8
h; (e) Et3N (2.5 equiv), EDCI‚HCl (1.1 equiv), CH2Cl2, 25 °C, 24
h, 25% from 8g. EDCI ) 1-(3-dimethylaminopropyl)-3-ethylcar-
bodiimide.
F igu r e 1. (top) Solution conformers of 5c with exchange (+)
and NOE (-) correlations observed from NOESY spectra
(CDCl3, 20 °C); (bottom) X-ray crystal structure of 5c.
ment of resin 14 with sodium hydroxide in refluxing
toluene/ethanol/water furnished 0.25 mmol of lactam 5a
per gram of resin (25% yield from Wang resin). The direct
formation of 5a could result from two reactional se-
quences: releasing of amine 8a by cleavage of the car-
bamate and subsequent cyclization to 5a ; or hydrolysis
of the nitrile group of 14 to the primary amide, cyclization
of the carbamate nitrogen onto the primary amide and
subsequent cleavage of the base-labile amide carbamate,
releasing 5a in solution, in an analogous manner as in
Scheme 2 (‘cyclo-release’ hypothesis).24 No definite proof
could be obtained in favor of one or the other hypothesis.
We also considered the possibility of performing the
borylation on resin-bound iodide 13 as component I,
followed by coupling with 7a as component II, in a
reversed manner as above. However, similarly with Boc-
protected iodoaniline 6b, the borylation of 13 gave 30-
40% dehalogenated product, which of course remained
on the resin, decreasing the overall yield and purity of
the target lactam. In the approach shown in Scheme 3
with resin 13 as component II, negligible amounts of
aniline resulting from dehalogenation in the Suzuki
coupling step were observed, giving good yields and
purity of lactam 5a .
In conclusion, seven-membered biphenyl lactam 5a
could be obtained in a straightforward and efficient
manner through a solid-phase synthesis involving the
BSC reaction in a key step. Although the extension of
this model synthetic sequence to the synthesis of libraries
of analogues has still to be demonstrated, it may allow,
in principle, introduction of chemical diversity in a
straightforward fashion for the synthesis of analogues.
Finally, the extension of the preceding results to the
synthesis of an eight-membered biphenyl lactam 5e was
examined (Scheme 4). The requisite homologated iodide
7c was obtained as follows: Wittig olefination25 of 2-iodo-
benzaldehyde 15, obtained from the corresponding benzyl
alcohol by PCC oxidation,26 furnished unsaturated nitrile
16 which was reduced by sodium borohydride in pyridine/
methanol27 to afford 7c in 84% overall yield. BSC reaction
in the usual conditions, with 2-bromoaniline 6a as
component I and 7c as component II, furnished biphenyl
8g in 98% yield. When subjected to the previous basic
hydrolysis conditions (Scheme 2), 8g did not cyclize
spontaneously to lactam 5e, but gave carboxylic acid 17
instead. The latter was directly subjected to intramo-
lecular cyclization with EDCI, affording the eight-
membered lactam 5e in 25% yield (unoptimized).
It is interesting to note that monomethyl- and mono-
ethyl-substituted lactams 5b,c exist as a mixture of two
1
conformers in solution at 20 °C as observed from H NMR
spectra (CDCl3). The ratio between these conformers was
found to be 95/5 and 83/17 for 5b and 5c, respectively.
These conformers arise from rotation around the biphenyl
axis, as shown by NOESY experiments (Figure 1, top)
and X-ray crystallographic analysis conducted with com-
pound 5c (Figure 1, bottom). The fact that these are
indeed rotamers and not true diastereoisomers resulting
from axial chirality was demonstrated by the presence
of exchange correlation spots between the two species on
NOESY spectra recorded at 293 K. These spots disap-
peared on NOESY spectra recorded at 240 K, indicating
that rotation around the biphenyl axis is frozen at this
temperature. X-ray diffraction data (Figure 1) showed
that 5c crystallizes as the major conformer. Similarly,
1H NMR spectra (CDCl3) of the open-chain biphenyls 8d
(25) Daniel, H.; Le Corre, M. Tetrahedron Lett. 1987, 28, 1165.
(26) Grissom, J . W.; Klingberg, D.; Huang, D.; Slattery, B. J . J . Org.
Chem. 1997, 62, 603.
(27) Rhodes, R. A.; Boykin, D. W. Synth. Commun. 1988, 18, 681.
(28) (a) Eagle, H. Proc. Soc. Exp. Biol. Med. 1955, 89, 362. (b)
Tempeˆte, C.; Werner, G. H.; Favre, F.; Roja, A.; Langlois, N. Eur. J .
Chem. 1995, 30, 647.
(24) For a review on cyclo-release reactions applied to drug discov-
ery, see: Park, K.-H.; Kurth, M. J . Drugs Future 2000, 25, 1265.

1204 J . Org. Chem., Vol. 67, No. 4, 2002
Baudoin et al.
Ta ble 2. Cytotoxicity of Bia r yl La cta m s a n d Am id in es
(KB cell lin es)28
underway. Similarly, the synthesis of paullones ana-
logues, among which 10-8 M inhibitors of CDK1/cyclin
B such as alsterpaullone 3c (Figure 1) have been de-
scribed,13 can be developed in a straightforward fashion
as described for unsubstituted paullone 3a .
In conclusion, this report underlines the usefulness of
the BSC reaction for synthesizing sterically hindered 2,2′-
disubstituted biaryl compounds in a short, simple, and
efficient manner. These are important intermediates
which can be easily cyclized to seven- or eight-membered
biaryl lactams such as biphenyls 5a -e and paullone 3a .
This synthetic methodology, which tolerates the presence
of many functional groups well, may be applicable to the
solution- or solid-phase synthesis of libraries of analogues
for medicinal chemistry purposes.
compound
IC50 (µM)
2
1
4
7
5a
5b 5c 5e
11a 11b 3a
16 90
a
>100 90 32 >100 70
a
IC50 is the concentration of compound corresponding to 50%
growth inhibition after 72 h incubation.
and 8e show a 63/37 and 60/40 mixture of two nearly
identical species, respectively. Nevertheless in this case,
the absence of exchange correlation spots between these
two species on NOESY spectra recorded at 293 and 330
K indicate that the rotation around the biphenyl axis does
not occur even at 330 K, and thus that 8d ,e exist as a
mixture of configurationally stable diastereoisomers
rather than conformers. Finally, the observation of two
doublets for the methylene signal of unsubstituted lactam
5a (J ) 11.5 Hz), exchanging on NOESY spectra at 293
K but not at 240 K, indicate that the rotation around
the biphenyl bond of 5a is slow at 293 K and frozen at
240 K. On the contrary, the observation of one singlet
for the methylene signal of paullone 3a at 293 K indicates
a faster rotation around the biaryl axis,12a which may
result from the smaller steric repulsions between the two
aryl groups in 3a compared to 5a . Molecular modeling
studies conducted on seven-membered lactams 5a -c and
3a , eight-membered lactam 5e, and nine-membered
biphenyl lactam analogues of rhazinilam which were
previously synthesized,8 show that the dihedral angle
between the two aryl rings increases with the size of the
lactam ring. Thus, approximate biaryl torsion angles of
30°, 45°, 70°, and 90° were found for compounds 3a , 5a -
c, 5e and nine-membered lactams, respectively, in ac-
cordance with available X-ray diffraction data. The
modification of these angle values may strongly influence
the protein-binding properties of those compounds and
thus their biological activities, as suggested in previous
studies on rhazinilam analogues.7,8
The biaryl lactams 5a -e and amidines 11a ,b reported
above were evaluated against KB cell lines (Table 2).
Biphenyl lactams 5a -e exhibited a weak cytotoxicity
toward cancer cell lines, with 5c > 5b > 5a ≈ 5e, which
indicates that increasing the hydrophobicity by adding
larger alkyl substituents on the lactam ring improves the
cytotoxicity of these compounds. Indeed phenyl-pyrrole
4, which bears two ethyl groups on the lactam ring, is
the most active compounds of this seven-membered biaryl
lactam series. Increasing the lactam ring size from
seven- to eight-membered (compound 5e) does not in
itself improve the cytotoxicity as already stated previ-
ously with phenyl-pyrrole lactams.7a Interestingly, bi-
phenyl amidine 11b was more cytotoxic toward KB cell
lines than 11a , confirming the positive effect of additional
alkyl substituents on the median ring. Finally 3a , which
is a known inhibitor of CDK1-cyclin B (IC50 value of 7
µM), is weakly cytotoxic (9 × 10-5 M) on KB cell lines, a
value consistent with that already reported on HCT
cancer cell lines (ca. 10-5 M).13a Compounds 5a -e and
11a ,b were also evaluated on the tubulin assay, and most
of them showed no inhibition of assembly nor disassembly
of microtubules. Only compound 5c showed a very weak
inhibition of tubulin assembly, with a IC50 value of 160
µM. Further studies are under investigation to determine
the mode of action of the most cytotoxic compounds 5c
and 11b. Using the synthetic methodologies reported
therein, modifications of the substituents at the benzylic
position as well as on the aryl rings are currently
Exp er im en ta l Section
Gen er a l. Reagents were commercially available and used
without further purification unless otherwise stated. THF and
dioxane were distilled from sodium/benzophenone, methylene
chloride from diphosphorus pentoxide (P2O5), and triethy-
lamine from KOH. Methanol and pyridine were analytical
grade and stored over 3 or 4 Å molecular sieves, respectively,
prior to use. Yields refer to chromatographically and spectro-
scopically homogeneous materials. Reactions were monitored
by thin-layer chromatography carried out on 0.25 mm SDS
silica gel coated glass plates (60F254) using UV light as
visualizing agent and ethanolic sulfuric molybdate and heat
as staining agents. Merck silica gel 60 (particle size 40-63
µM) was used for flash column chromatography. NMR spectra
were recorded on Bruker AC-250, AC-300, or AMX-400 instru-
ments and calibrated using tetramethylsilane as an internal
reference. The following abbreviations were used to designate
the multiplicities: s ) singlet, d ) doublet, t ) triplet, q )
quartet, m ) multiplet, br ) broad. IR spectra were recorded
on a Nicolet FT-IR 205 spectrometer. Mass spectra (MS) and
high-resolution mass spectra (HRMS) were recorded under
liquid secondary ion (LSIMS), electronic impact (EI), chemical
ionization (CI), or electrospray ionization (ESI) conditions at
the Laboratoire de Spectrome´trie de Masse, ICSN, Gif-sur-
Yvette, France or at the Laboratoire Central d′Analyse du
CNRS, Vernaison, France. Melting points (mp) are uncorrected
and were recorded on a Bu¨chi B-540 capillary melting point
apparatus. Molecular modeling studies were conducted on a
Silicon Graphics Indigo II (R10000) workstation, using Sybyl
6.7 for the analysis of the conformational data. Conformational
searches and comparisons were performed with the Monte
Carlo procedure using MMFF94 force field parameters. The
physical data of compounds 8a ,14 8b,8b 8f,8b and 3a 12 were
previously described. The physical data of compounds 5a and
5e were partially described.10
Gen er a l P r oced u r e for th e BSC Rea ction . To a solution
of 6a (1.06 g, 6.2 mmol) in dioxane (12 mL) at 25 °C under
argon were successively added Et3N (3.4 mL, 24.6 mmol),
Pd(OAc)2 (69 mg, 0.31 mmol), PCy2(o-biph) (433 mg, 1.23
mmol), and pinacolborane (2.7 mL, 18.5 mmol) dropwise. The
solution was heated to 80 °C for 1 h. After cooling, water (4
mL) was added dropwise, 7a (1.0 g, 4.1 mmol), dissolved in
dioxane (4 mL), and Ba(OH)2‚8H2O (5.84 g, 18.5 mmol) were
added, and the solution was heated to 100 °C for 1 h. After
cooling, the mixture was filtered through Celite, brine was
added (20 mL), and the solution was extracted with methylene
chloride. After being dried over magnesium sulfate and
evaporation of the solvents under vacuum, the residue was
purified by flash chromatography (silica gel, heptane/ethyl
acetate 9/1, then 4/1), to afford 8a as an oil (681 mg, 79%).
(2′-Cya n om eth ylbip h en yl-2-yl)ca r ba m ic a cid ter t-bu -
1
tyl ester 8c: (see general BSC procedure) oil; H NMR (300
MHz, CDCl3) δ ) 1.44 (s, 9 H, tBu), 3.48 (s, 2 H, CH2), 6.02
(br s, 1 H, NH), 7.10 (m, 2 H), 7.26 (m, 1 H), 7.40 (t, J ) 7.6
Hz, 1 H), 7.48 (m, 2 H), 7.65 (dd, J ) 6.6, 1.8 Hz, 1 H), 8.11 (d,

Synthesis of Biologically Active Biaryl Lactams
J . Org. Chem., Vol. 67, No. 4, 2002 1205
J ) 8.4 Hz, 1 H) ppm; 13C NMR (75 MHz, CDCl3) δ ) 21.4
(CH2), 28.1 (CH3), 80.8 (Cq), 117.6 (Cq), 120.1 (CH), 123.3 (CH),
128.7 (CH), 129.1 (CH), 129.7 (CH), 130.6 (CH), 135.6 (Cq),
137.0 (Cq), 152.5 (Cq) ppm; IR (film) υ ) 3425, 2979, 2250,
1729 cm-1; HRMS (CI) calcd for C19H21N2O2 [(M + H)+]:
309.1603; found: 309.1600.
ppm; IR (film) υ ) 3425, 2980, 2241, 1731 cm-1; HRMS (CI)
calcd for C20H23N2O2 [(M + H)+]: 323.1760; found: 323.1729.
[2′-(1-Cya n op r op yl)bip h en yl-2-yl]ca r ba m ic Acid ter t-
Bu tyl Ester 8e. 8e was obtained in the same manner as above
for 8d from 8c (200 mg, 0.65 mmol), LDA (973 µL, 1.95 mmol),
and iodoethane (156 µL, 1.95 mmol): oil (202 mg, 93%);
mixture of two conformers (60/40); 1H NMR (250 MHz, CDCl3)
major conformer δ ) 0.84 (t, J ) 7.5 Hz, 3 H, CH3), 1.46 (s, 9
H, tBu), 1.74 (m, 2 H, CH2), 3.49 (dd, J ) 8.5, 6.8 Hz, 1 H,
CH), 6.02 (br s, 1 H, NH), 7.09 (m, 2 H), 7.22 (m, 1 H), 7.44
(m, 3 H), 7.66 (m, 1 H), 8.16 (d, J ) 8.8 Hz, 1 H) ppm; minor
conformer (distinct signals) δ ) 0.92 (t, J ) 7.5 Hz, 3 H, CH3),
1.43 (s, 9 H, tBu), 3.62 (dd, J ) 9.0, 6.0 Hz, 1 H, CH), 6.00 (br
s, 1 H, NH), 8.10 (d, J ) 9.0 Hz, 1 H) ppm; 13C NMR (75 MHz,
CDCl3) two conformers δ ) 11.4, 11.6, 27.8, 28.1, 29.2, 35.1,
80.7, 80.9, 119.7, 119.9, 120.9, 123.0, 123.2, 128.0, 128.3, 128.4,
128.5, 128.7, 129.1, 129.3, 129.9, 130.0, 130.5, 130.9, 135.1,
135.2, 135.7, 136.3, 136.6, 152.4, 152.6 ppm; IR (film) υ ) 3425,
2975, 2239, 1732 cm-1; HRMS (CI) calcd for C21H25N2O2 [(M
+ H)+]: 337.1916; found: 337.1915.
3-(2′-Am in obip h en yl-2-yl)p r op ion itr ile 8g: (see general
1
BSC procedure) oil; H NMR (300 MHz, CDCl3) δ ) 2.40 (td,
J ) 7.2, 1.8 Hz, 2 H, CH2), 2.83 (td, J ) 6.9, 1.7 Hz, 2 H, CH2),
3.46 (br s, 2 H, NH2), 6.74 (d, J ) 8.1 Hz, 1 H), 6.79 (td, J )
7.5, 1.2 Hz, 1 H), 6.98 (dd, J ) 7.5, 1.8 Hz, 1 H), 7.18 (m, 2 H),
7.35 (m, 3 H) ppm; 13C NMR (75 MHz, CDCl3) δ ) 18.1 (CH2),
29.0 (CH2), 115.2 (CH), 118.2 (CH), 119.3 (Cq), 125.8 (Cq),
127.7 (CH), 128.2 (CH), 128.8 (CH), 129.6 (CH), 129.9 (CH),
130.6 (CH), 137.0 (Cq), 138.4 (Cq), 143.5 (Cq) ppm; IR (film) υ
) 3466, 3370, 2246, 1615 cm-1; HRMS (LSIMS) calcd for
C15H15N2 [(M + H)+]: 223.1235; found: 223.1221.
[2-(2-Am in op h en yl)in d ol-3-yl]a ceton itr ile 10a : (see gen-
1
eral BSC procedure) white solid, mp ) 127 °C; H NMR (250
MHz, CDCl3) δ ) 3.75 (s, 2 H, CH2), 3.82 (br s, 2 H, NH2),
6.81 (d, J ) 7.5 Hz, 1 H), 6.87 (dd, J ) 6.8, 1.3 Hz, 1 H), 7.25
(m, 4 H), 7.39 (dd, J ) 7.5, 1.0 Hz, 1 H), 7.74 (d, J ) 6.5 Hz,
1 H), 8.25 (br s, 1 H, NH) ppm; 13C NMR (75 MHz, CDCl3) δ
) 13.9, 102.6, 111.3, 116.1, 116.3, 118.3, 118.5, 118.9, 120.7,
123.2, 127.3, 130.6, 131.0, 133.6, 136.0, 145.2 ppm; IR (film) υ
) 3379, 2248, 1618 cm-1; HRMS (LSIMS) calcd for C16H14N3
[(M + H)+]: 248.1188; found: 248.1190.
[2′-(1-Cyan o-1-eth ylpr opyl)biph en yl-2-yl]car bam ic Acid
ter t-Bu tyl Ester 8f. To a solution of 8c (150 mg, 0.49 mmol)
in THF (5 mL) under argon at -78 °C was added dropwise
LDA (730 µL, 1.46 mmol). After 30 min stirring, iodoethane
(117 µL, 1.46 mmol) was added and the solution was allowed
to warm to 25 °C for 2 h. After recooling to -78 °C, LDA (1.46
mL, 2.92 mmol) was added dropwise and the mixture was
stirred for 30 min. Iodoethane (233 µL, 2.92 mmol) was added,
and the solution was allowed to warm to 25 °C for 2 h. After
hydrolysis with a saturated aqueous NH4Cl solution, the
solution was extracted with diethyl ether. The solution was
dried over MgSO4, and the solvents were removed in vacuo.
The residue was purified by flash chromatography (silica gel,
heptane/ethyl acetate 9/1), to afford 8f as an oil (156 mg, 88%).
(2-Br om o-1-m eth oxym eth ylin d ol-3-yl)a ceton itr ile 9b.
To a solution of 2-bromo-3-indolylacetonitrile19 (1.0 g, 4.25
mmol) in THF (15 mL) at 25 °C was added dropwise NaHMDS
(2 M in THF, 2.23 mL, 4.47 mmol). After 15 min stirring, the
solution was cooled to 0 °C and chloromethyl methyl ether (355
µL, 4.68 mmol) was added dropwise. The mixture was stirred
for 5 min at 0 °C and 1 h at 25 °C. A saturated aqueous
solution of NaHCO3 was added, and the solution was extracted
with diethyl ether. After drying over MgSO4, the solvents were
evaporated under vacuum, and the residue was purified by
flash column chromatography (silica gel, heptane/ethyl acetate
75/35), to afford 9b as a yellow oil (776 mg, 65%); 1H NMR
(300 MHz, CDCl3) δ ) 3.28 (s, 3 H, CH3O), 3.79 (s, 2 H, CH2-
CN), 5.50 (s, 2 H, NCH2O), 7.21 (td, J ) 6.9, 1.5 Hz, 1 H), 7.27
(td, J ) 7.2, 1.2 Hz, 1 H), 7.45 (dd, J ) 7.5, 1.0 Hz, 1 H), 7.62
(d, J ) 7.8 Hz, 1 H) ppm; 13C NMR (62.5 MHz, CDCl3) δ )
14.3 (CH3), 56.1 (CH3), 75.3 (CH2), 104.9 (Cq), 110.2 (CH), 113.7
(Cq), 116.7 (Cq), 117.8 (CH), 121.4 (CH), 123.3 (CH), 126.3
(Cq), 136.8 (Cq) ppm; IR (film) υ ) 2942, 2248 cm-1; HRMS
[2-(3-Cyan om eth ylin dol-2-yl)ph en yl]car bam ic acid ter t-
bu tyl ester 10b: (see general BSC procedure) oil; 1H NMR
(300 MHz, CDCl3) δ ) 1.46 (s, 9 H, tBu), 3.66 (s, 2 H, CH2),
6.53 (br s, 1 H, NH Boc), 7.14 (t, J ) 7.7 Hz, 1 H), 7.27 (m, 3
H), 7.42 (m, 2 H), 7.77 (d, J ) 7.2 Hz, 1 H), 8.12 (d, J ) 9.0
Hz, 1 H), 8.59 (br s, NH indole) ppm; 13C NMR (62.5 MHz,
CDCl3) δ ) 13.5 (CH2), 28.1 (CH3), 81.2 (Cq), 102.9 (Cq), 111.5
(CH), 117.6 (Cq), 118.5 (CH), 120.3 (CH), 120.6 (CH), 123.2
(CH), 123.4 (CH), 126.9 (Cq), 130.3 (CH), 130.9 (CH), 132.1
(Cq), 136.1 (Cq), 136.7 (Cq), 153.0 (Cq) ppm;; IR (film) υ )
3400, 3325, 2979, 2250, 1709 cm-1; HRMS (LSIMS) calcd for
C
21H21N3O2 [M+]: 347.1634; found: 347.1641.
[2-(3-Cyan om eth yl-1-m eth oxym eth ylin dol-2-yl)ph en yl]-
ca r ba m ic a cid ter t-bu tyl ester 10c: (see general BSC
1
procedure) oil; H NMR (250 MHz, CDCl3) δ ) 1.43 (s, 9 H,
tBu), 3.20 (s, 3 H, CH3O), 3.58 (s, 2 H, NCH2O), 5.16 (d, J )
10.8 Hz, 1 H, CHH′), 5.24 (d, J ) 10.8 Hz, 1 H, CHH′), 6.53
(br s, 1 H, NH), 7.28 (m, 4 H), 7.50 (td, J ) 8.1, 1.8 Hz, 1 H),
7.58 (d, J ) 8.0 Hz, 1 H), 7.79 (d, J ) 7.5 Hz, 1 H), 8.23 (d, J
) 8.3 Hz, 1 H) ppm; 13C NMR (62.5 MHz, CDCl3) δ ) 13.5
(CH2), 28.1 (CH3), 56.1 (CH3O), 74.8 (NCH2O), 80.9 (Cq), 104.9
(Cq), 110.6 (CH), 117.4 (Cq), 118.2 (Cq), 118.7 (CH), 120.2
(CH), 121.3 (CH), 123.0 (CH), 123.6 (CH), 126.8 (Cq), 130.9
(CH), 131.9 (CH), 134.5 (Cq), 137.2 (Cq), 138.2 (Cq), 152.5 (Cq)
ppm; IR (film) υ ) 3410, 2979, 2248, 1728 cm-1; HRMS
(LSIMS) calcd for C23H25N3O3 [M+]: 391.1896; found: 391.1899.
[2′-(1-Cya n oeth yl)bip h en yl-2-yl]ca r ba m ic Acid ter t-
Bu tyl Ester 8d . To a solution of compound 8c (150 mg, 0.49
mmol) in THF (3 mL) under argon at -78 °C was added
dropwise LDA (2 M in THF, 486 µL, 0.97 mmol). After 30 min
stirring, iodomethane (30 µL, 0.49 mmol) was added and the
mixture was allowed to warm to 25 °C for 2 h. After hydrolysis
with a saturated aqueous NH4Cl solution, the solution was
extracted with diethyl ether. The solution was dried over
MgSO4, and the solvents were removed in vacuo. The residue
was purified by flash chromatography (silica gel, heptane/ethyl
acetate 95/5, then 9/1), to afford 8d as an oil (100 mg, 64%);
mixture of two conformers (63/37); 1H NMR (250 MHz, CDCl3)
major conformer δ ) 1.42 (s, 3H, CH3), 1.46 (s, 9 H, tBu), 3.67
(q, J ) 7.8 Hz, 1 H, CH), 6.01 (br s, 1 H, NH), 7.11 (m, 2 H),
7.22 (dt, J ) 7.8, 1.3 Hz, 1 H), 7.41 (m, 2 H), 7.52 (td, J ) 7.8,
1.3 Hz, 1 H), 7.70 (d, J ) 7.0 Hz, 1 H), 8.15 (d, J ) 8.8 Hz, 1
H) ppm; minor conformer (distinct signals) δ ) 3.77 (q, J )
7.0 Hz, 1 H, CH), 5.98 (br s, 1 H, NH), 8.10 (d, J ) 9.0 Hz, 1
H) ppm; 13C NMR (75 MHz, CDCl3) two conformers δ ) 20.4,
21.7, 27.8, 28.1, 80.8, 81.0, 120.0, 121.7, 123.1, 123.3, 127.6,
127.8, 128.4, 128.6, 128.8, 129.2, 129.4, 129.5, 129.9, 130.0,
130.5, 130.9, 135.7, 135.9, 136.2, 136.5, 136.7, 152.4, 152.6
(LSIMS) calcd for
278.0050.
C
12H11BrN2O [M+]: 278.0055; found:
5,7-Dih yd r o-d iben z[b,d ]a zep in -6-on e 5a . P r oced u r e a .
A solution of compound 8a (100 mg, 0.48 mmol) and sodium
hydroxide (192 mg, 4.8 mmol) in methanol (3 mL)/water (1.5
mL) was refluxed for 3.5 h. After cooling, a saturated aqueous
solution of NaHCO3 was added and the mixture was extracted
with ethyl acetate. The organic layers were gathered and
washed twice with a 1 N HCl aqueous solution and then once
with a saturated aqueous solution of NH4Cl. The solution was
dried over MgSO4 and evaporated under vacuum, to afford 5a
as a white powder (56 mg, 56%). P r oced u r e b. A solution of
compound 8c (334 mg, 1.08 mmol) and sodium hydroxide (433
mg, 10.8 mmol) in ethanol (8 mL)/water (4 mL) was refluxed
for 3 h. After cooling, brine was added and the mixture was
extracted with ethyl acetate. The solution was dried over
MgSO4 and evaporated under vacuum. The residue was
redissolved in 5 mL of concd H2SO4, and the solution was
stirred for 30 min at 25 °C and then poured into ice. The
solution was neutralized with a concd NaOH aqueous solution
and extracted with ethyl acetate. The gathered organic layers
were dried over MgSO4 and evaporated under vacuum until a

1206 J . Org. Chem., Vol. 67, No. 4, 2002
Baudoin et al.
precipitate formed, which was filtered, affording 5a as a white
powder (144 mg, 64%); mp 232 °C (lit.10 231-233 °C); 1H NMR
(300 MHz, CDCl3) δ ) 3.45 (d, J ) 11.4 Hz, 1 H, CHH′), 3.57
(d, J ) 11.7 Hz, 1 H, CHH′), 7.16 (d, J ) 8.1 Hz, 1 H), 7.28 (t,
J ) 7.4 Hz, 1 H), 7.39 (m, 4 H), 7.56 (m, 1 H), 7.63 (d, J ) 7.5
Hz, 1 H), 8.99 (br s, 1 H, NH) ppm; 13C NMR (75 MHz, CDCl3)
δ ) 41.8 (CH2), 122.0 (CH), 125.0 (CH), 127.7 (CH), 128.4 (CH),
128.6 (2CH), 128.8 (CH), 130.0 (CH), 132.0 (Cq), 134.2 (Cq),
135.9 (Cq), 136.6 (Cq), 173.5 (Cq) ppm; IR (film) υ ) 3175,
1682 cm-1; HRMS (CI) calcd. for C14H12NO [(M + H)+]:
210.0919; found: 210.0938.
H), 1.17 (m, 3 H), 1.40 (m, 2 H), 2.25 (m, 1 H), 2.37 (m, 1 H),
5.20 (br s, 2 H), 7.10 (td, J ) 7.5, 1.0 Hz, 1 H), 7.15 (dd, J )
8.0, 1.0 Hz, 1 H), 7.37 (m, 4 H), 7.60 (dd, J ) 7.8, 1.2 Hz, 1 H),
7.68 (m, 1 H) ppm; 13C NMR (62.5 MHz, CDCl3) δ ) 8.9, 9.4,
18.5, 23.8, 51.0, 121.8, 123.5, 125.1, 126.9, 127.5, 128.0, 128.5,
131.0, 132.7, 137.3, 140.1, 144.1, 160.8 ppm; IR (film) υ ) 3310,
1648, 1570 cm-1; HRMS (CI) calcd for C18H21N2 [(M + H)+]:
265.1705; found: 265.1682.
Solid -P h a se Syn th esis of La cta m 5a . Carbonate resin
12 was freshly prepared22 from Wang resin (loading 1.0 mmol/
g, 200-400 mesh). P r ep a r a tion of Ca r ba m a te Resin 13.
To a solution of 2-iodoaniline 6c (2.62 g, 12.0 mmol) in THF
(25 mL) under argon at 25 °C was added NaHMDS (2M in
THF, 12.0 mL, 23.9 mmol). After 30 min stirring, the mixture
was cannulated into a suspension of resin 12 (3.98 g, ca. 3.98
mmol) in THF (40 mL) and the resulting mixture was stirred
for 12 h at 25 °C. The resin was filtered, rinsed thoroughly
with DMF, dichloromethane, methanol, and diethyl ether, and
dried under vacuum, affording resin 13 (4.29 g); IR (KBr pellet)
υ ) 3387, 1735 cm-1. P r ep a r a tion of Ca r ba m a te Resin 14.
To a solution of nitrile 7a (972 mg, 4.0 mmol) in dioxane (12
mL) at 25 °C under argon were successively added Et3N (2.23
mL, 16.0 mmol), Pd(OAc)2 (45 mg, 0.20 mmol), PCy2(o-biph)
(280 mg, 0.80 mmol), and pinacolborane (1.74 mL, 12.0 mmol)
dropwise. The solution was heated to 80 °C for 30 min. After
cooling, water (3 mL) was added dropwise, and then the
mixture was added to a suspension of resin 13 (2.00 g) in
dioxane (8 mL). Sodium hydroxide (640 mg, 16.0 mmol) was
added, and the mixture was heated to 100 °C under argon for
1 h. After cooling, the resin was filtered, washed thoroughly
with DMF/H2O, methanol, dichloromethane, and diethyl ether,
and dried under vacuum, to afford resin 14 (2.03 g); IR (KBr
pellet) υ ) 3418, 2248, 1731 cm-1. Relea sin g of Bip h en yl
8a . Resin 14 (300 mg) was suspended in dichloromethane (2.4
mL), and TFA (0.6 mL) was added dropwise at 25 °C. After
30 min stirring, the mixture was filtered and the resin was
washed with dichloromethane. The filtrate was washed three
times with a saturated NaHCO3 aqueous solution, dried over
MgSO4, and evaporated under vacuum, affording analytically
pure 8a (37.4 mg, 0.60 mmol per gram of resin). Relea sin g
of La cta m 5a . A suspension of resin 14 (200 mg) and sodium
hydroxide (160 mg, 4.0 mmol) in toluene (1 mL)/ethanol (1 mL)/
water (1 mL) was refluxed for 17 h. The resin was filtered and
washed with dichloromethane and methanol. The filtrate was
evaporated and redissolved in ethyl acetate, and the solution
was washed twice with a 1 N aqueous HCl solution and once
with brine. The organic layer was dried over MgSO4 and
evaporated under vacuum, to afford analytically pure 5a (10.5
mg, 0.25 mmol per gram of resin).
3-(2-Iod op h en yl)p r op ion it r ile 7c. To a solution of 2-
iodobenzaldehyde (2.0 g, 5.62 mmol)24 in dichloromethane (100
mL) at 25 °C were added successively a 30% sodium hydroxide
aqueous solution (100 mL) and (cyanomethyl)triphenylphos-
phonium chloride (3.06 g, 9.05 mmol). After 30 min stirring,
200 mL of water was added, the organic layer was decanted,
and the aqueous layer was extracted with dichloromethane.
The gathered organic layers were dried over MgSO4 and
evaporated under reduced pressure, affording unsaturated
nitrile 16 as an oily solid (2.145 g, 98%) which was used
directly in the next step without further purification; two
diastereoisomers (Z/E ) 86/14); 1H NMR (300 MHz, CDCl3) δ
) 5.55 (d, J ) 11.4 Hz, 1 H, CHdCH Z-olefin), 5.78 (d, J )
16.2 Hz, CH ) CH E-olefin), 7.10 (td, J ) 7.5, 1.2 Hz, 1 H,
Z-olefin), 7.34 (d, J ) 11.7 Hz, 1 H, CHdCH Z-olefin), 7.45 (t,
J ) 7.5 Hz, 1 H, Z-olefin), 7.92 (m, 2 H, Z-olefin) ppm; IR (film)
υ ) 3056, 2217, 1610 cm-1; MS (EI) m/z ) 255 [M+•]. To a
solution of 16 (500 mg, 1.96 mmol) in pyridine (30 mL)/
methanol (10 mL) was added sodium borohydride (96 mg, 2.55
mmol), and the mixture was refluxed for 2 h under argon. After
cooling, the solution was poured into a mixture of 10% aqueous
HCl (100 mL) and ice, and concd aqueous HCl was added
dropwise until pH ) 1-2. The aqueous solution was extracted
with diethyl ether, and the gathered organic layers were dried
over MgSO4 and evaporated in vacuo. The residue was purified
by flash column chromatography (silica gel, heptane/ethyl
5,7-Dih yd r o-7-m eth yld iben z[b,d ]a zep in -6-on e 5b. Lac-
tam 5b was synthesized in the same manner as above for 5a
from compound 8d (100 mg, 0.31 mmol) using procedure b with
a reflux time of 6 h. The residue was purified by flash column
chromatography (silica gel, heptane/ethyl acetate 1/1), to afford
5b as a white powder (40 mg, 58%); two conformers (95/5); 1H
NMR (250 MHz, CDCl3) major conformer δ ) 1.61 (d, J ) 7.2
Hz, 3 H, CH3), 3.41 (q, J ) 6.8 Hz, 1 H, CH), 7.15 (dd, J ) 8.0,
1.2 Hz, 1 H), 7.27 (td, J ) 8.2, 1.5 Hz, 1 H), 7.38 (m, 4 H), 7.52
(d, J ) 7.3 Hz, 1 H), 7.63 (dd, J ) 8.2, 1.0 Hz, 1 H), 8.84 (br
s, 1 H, NH) ppm; minor conformer (distinct signals) δ ) 3.95
(m, 1 H, CH), 9.25 (br s, 1 H, NH) ppm; 13C NMR (62.5 MHz,
CDCl3) major conformer δ ) 11.8 (CH3), 39.4 (CH), 121.7 (CH),
123.8 (CH), 124.7 (CH), 127.1 (CH), 128.4 (CH), 128.6 (CH),
128.8 (CH), 129.8 (CH), 132.3 (Cq), 135.9 (Cq), 137.0 (Cq),
138.3 (Cq), 174.9 (Cq) ppm; IR (film) υ ) 3204, 1675 cm-1
;
HRMS (CI) calcd for C15H14NO [(M + H)+]: 224.1075; found:
224.1075.
5,7-Dih yd r o-7-eth yld iben z[b,d ]a zep in -6-on e 5c. Lactam
5c was synthesized in the same manner as above for 5a from
compound 8e (202 mg, 0.60 mmol) using procedure b with a
reflux time of 8 h. The residue was purified by flash column
chromatography (silica gel, heptane/ethyl acetate 4/1, then
3/2), to afford 5c as a white powder (67 mg, 47%); two
conformers (83/17); mp 174 °C; 1H NMR (250 MHz, CDCl3)
major conformer δ ) 1.02 (t, J ) 7.4 Hz, 3 H, CH3), 2.01 (m,
1 H, CHH′), 2.43 (m, 1 H, CHH′), 3.11 (dd, J ) 9.0, 6.0 Hz, 1
H, CH), 7.16 (dd, J ) 8.0, 1.2 Hz, 1 H), 7.25 (td, J ) 8.2, 1.3
Hz, 1 H), 7.37 (m, 4 H), 7.52 (m, 1 H), 7.65 (d, J ) 7.8, 1.2 Hz,
1 H), 9.02 (br s, 1 H, NH) ppm; minor conformer (disctinct
signals) δ ) 0.76 (t, J ) 7.4 Hz, 1 H, CH3), 1.40 (m, 2 H, CH2),
3.72 (m, 1 H, CH), 9.42 (br s, 1 H, NH) ppm; 13C NMR (62.5
MHz, CDCl3) major conformer δ ) 12.4, 19.6, 46.9, 121.8,
124.3, 124.8, 127.0, 128.5, 128.6, 128.9, 129.7, 132.5, 136.0,
137.2, 137.7, 173.8 ppm; IR (film) υ ) 3201, 1672 cm-1; HRMS
(CI) calcd for C16H16NO [(M + H)+]: 238.1232; found: 238.1262.
7,12-Dih yd r o-in d olo[3,2-d ][1]b en za zep in -6(5H )-on e
(p a u llon e) 3a . Compound 3a was synthesized in the same
manner as above for 5a from 10a (200 mg, 0.81 mmol) using
procedure a with a reflux time of 6 h. 3a was obtained as a
white powder (103 mg, 51%); mp > 350 °C.12
6-Am in o-7H-d iben z[b,d ]a zep in e 11a . A solution of 8a (53
mg, 0.25 mmol) in 2-methoxyethanol (0.5 mL)/water (0.4 mL)/
concd sulfuric acid (0.1 mL) was heated to 120 °C for 1 h. After
cooling, the reaction mixture was poured onto ice and neutral-
ized with concd aqueous sodium hydroxide. The resulting
aqueous solution was extracted with ethyl acetate, the gath-
ered organic layers were dried over MgSO4, and the solvents
were evaporated under vacuum. The residue was purified by
preparative thin-layer chromatography (silica gel, dichlo-
romethane/methanol 85/15), to afford 11a as a white solid (21
mg, 39%); 1H NMR (300 MHz, CDCl3) δ ) 3.18 (d, J ) 12 Hz,
1 H), 3.27 (d, J ) 12.9 Hz, 1 H), 4.61 (br s, 2 H), 7.14 (td, J )
7.7, 1.2 Hz, 1 H), 7.19 (m, 2 H), 7.36 (m, 3 H), 7.61 (dd, J )
8.1, 1.2 Hz, 1 H), 7.64 (dd, J ) 7.2, 1.5 Hz, 1 H) ppm; 13C NMR
(75 MHz, CDCl3/CD3OD) δ ) 38.2 (CH2), 122.7 (CH), 125.9
(CH), 126.9 (CH), 127.6 (CH), 127.9 (CH), 128.2 (CH), 128.8
(CH), 129.8 (CH), 131.6 (Cq), 135.8 (Cq), 137.5 (Cq), 145.4 (Cq),
159.7 (Cq) ppm; IR (film) υ ) 3460, 1648, 1580 cm-1; HRMS
(CI) calcd for C14H13N2 [(M + H)+]: 209.1079; found: 209.1051.
6-Am in o-7-d ieth yl-7H-d iben z[b,d ]a zep in e 11b. 11b was
obtained in the same manner as above for 11a from 8b (20
mg, 0.076 mmol), with a heating time of 4 h at 120 °C; white
solid (14 mg, 70%); 1H NMR (250 MHz, CDCl3) δ ) 0.50 (m, 3

Synthesis of Biologically Active Biaryl Lactams
J . Org. Chem., Vol. 67, No. 4, 2002 1207
acetate 95/5, then 9/1), affording 7c as a colorless oil (433 mg,
86%); 1H NMR (300 MHz, CDCl3) δ ) 2.64 (t, J ) 6.9 Hz, 2 H,
CH2), 3.06 (t, J ) 7.2 Hz, 2 H, CH2), 6.97 (td, J ) 7.5, 2.1 Hz,
1 H), 7.31 (m, 2 H), 7.83 (dd, J ) 8.1, 1.2 Hz, 1 H); 13C NMR
(75 MHz, CDCl3) δ ) 17.7 (CH2), 36.4 (CH2), 99.7 (Cq), 118.6
(Cq), 128.8 (CH), 129.1 (CH), 129.8 (CH), 139.7 (CH), 140.3
(Cq) ppm; IR (film) υ ) 3053, 2246 cm-1; HRMS (EI) calcd for
C9H8IN [M+•]: 256.9701; found: 256.9709.
the solvent was evaporated under reduced pressure. The
residue was redissolved in ethyl acetate and precipitated with
heptane, affording lactam 5e as a white powder (65 mg, 25%);
mp 212 °C; 1H NMR (300 MHz, CDCl3) δ ) 2.57 (m, 1 H), 2.74
(m, 1 H), 2.85 (m, 2 H), 7.15 (m, 2 H), 7.31 (m, 6 H), 7.67 (br
s, 1 H) ppm; 13C NMR (75 MHz, CDCl3) δ ) 29.6 (CH2), 34.4
(CH2), 126.3 (CH), 126.8 (CH), 127.8 (CH), 128.3 (CH), 128.5
(CH), 129.5 (CH), 129.7 (CH), 130.4 (CH), 135.8 (Cq), 138.1
(Cq), 138.6 (Cq), 140.7 (Cq), 174.7 (Cq) ppm; IR (film) υ ) 3172,
1667 cm-1; HRMS (LSIMS) calcd for C15H14NO [(M + H)+]:
224.1075; found: 224.1072.
7,8-Dih yd r o-d iben z[b,d ]a zocin -6(5H)-on e 5e. A solution
of compound 8g (260 mg, 1.17 mmol) and sodium hydroxide
(468 mg, 11.7 mmol) in ethanol (8 mL)/water (4 mL) was
refluxed for 8 h. After cooling, ethanol was evaporated under
vacuum, and the aqueous solution was neutralized (pH ) 6-8)
with a 1 N aqueous HCl solution and extracted with ethyl
Ack n ow led gm en t. We thank Dr. C. Thal for his
constant interest and his helpful comments, S. Thoret
for tubulin polymerization and depolymerization assays,
Dr. M.-T. Martin for assistance with NOESY experi-
ments, and C. Gaspard for cytotoxicity assays. This
work was financially supported by the Centre National
de la Recherche Scientifique (France).
1
acetate, affording crude amino acid 17 (183 mg) as an oil; H
NMR (250 MHz, CDCl3) δ ) 2.43 (t, J ) 7.0 Hz, 2 H, CH2),
2.78 (m, 2 H, CH2), 6.01 (br s, 3 H, NH2, CO2H), 6.72 (d, J )
8.0 Hz, 1 H), 6.78 (t, J ) 7.4 Hz, 1 H), 6.98 (d, J ) 7.5, 1.5 Hz,
1 H), 7.14 (m, 2 H), 7.28 (m, 3 H) ppm; 13C NMR (75 MHz,
CDCl3) δ ) 28.1, 34.8, 115.4, 118.4, 126.8, 128.0, 128.5, 129.2,
130.1, 130.4, 138.3, 139.1, 143.3, 178.8 ppm; MS (ESI) m/z 242
[(M + H)+]. To a solution of this oil in dichloromethane (75
mL) at 25 °C under argon were added triethylamine (264 µL,
1.90 mmol) and EDCI‚HCl (160 mg, 0.83 mmol). After stirring
for 24 h, the solution was concentrated under vacuum and
washed twice with a saturated NaHCO3 aqueous solution,
twice with a 1 N HCl aqueous solution, and once with a
saturated NH4Cl aqueous solution. After drying over MgSO4,
Su p p or tin g In for m a tion Ava ila ble: X-ray diffraction
1
data for compound 5c as well as copies of selected H, 13C, and
NOESY NMR spectra are available free of charge via the
Internet at http://pubs.acs.org.
J O0160726