Organometallic reagent-mediated one-pot synthesis of 3,5,6-trisubstituted naphthostyrils

Article abstract of DOI:10.1016/S0040-4039(03)00826-8

A one-pot synthesis of 3,5,6-trisubstituted naphthostyrils is described. Addition of organometallic reagents to β-iodovinyl ketone 1 followed by elimination gave the Z-form β-alkyl vinyl ketone 15. Intramolecular cyclization of 15 under the reaction conditions afforded 3,5,6-trisubstituted naphthostyrils 4.

Full text of DOI:10.1016/S0040-4039(03)00826-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3901–3904
Organometallic reagent-mediated one-pot synthesis of
3,5,6-trisubstituted naphthostyrils
Jin-Jun Liu,* Fred Konzelmann and Kin-Chun Luk
Department of Discovery Chemistry, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA
Received 5 March 2003; revised 24 March 2003; accepted 28 March 2003
Abstract—A one-pot synthesis of 3,5,6-trisubstituted naphthostyrils is described. Addition of organometallic reagents to
b-iodovinyl ketone 1 followed by elimination gave the Z-form b-alkyl vinyl ketone 15. Intramolecular cyclization of 15 under the
reaction conditions afforded 3,5,6-trisubstituted naphthostyrils 4. © 2003 Elsevier Science Ltd. All rights reserved.
hexenone have been studied by a number of groups.9 In
this paper we show that organocuprates and organo-
zinc–copper reagents can be used to introduce alkyl
substituents at the 5-position of naphthostyrils via a
nucleophilic addition to a b-iodovinyl ketone followed
by elimination and an intramolecular Dieckman type
cyclization.
Recently we have developed a novel and convenient
method1 for the synthesis of 3,5,6-trisubstituted naph-
thostyrils which showed potent activity against CDKs.2
The process involves the generation of a b-iodovinyl
ketone, Michael addition of nucleophiles to the b-
iodovinyl ketone and a subsequent base-catalyzed
intramolecular Dieckman type cyclization.
Michael addition reaction in our process was a key step
in which substituent groups were introduced into the
5-position of the final naphthostyril ring system. In our
previous work, amines and alcohols were used as nucle-
ophiles in the key step. In order to expand the scope of
the method, we decided to examine the use of
organometallic reagents as carbon nucleophiles which
would form a new CꢀC bond at the b-position of the
b-iodovinyl ketone to give intermediates 2 or 3. Under
suitable conditions, the excess amount of the reagent
could also serve as a base to catalyze the subsequent
intramolecular cyclization of 2 or 3 to form naph-
thostyril 4 (Scheme 1).
In the first series of experiments, we studied the reac-
tion between our model compound 8 and simple
organometallic reagents (Scheme 2).
Compound 8 was prepared easily from ethynyl alcohol
5, derived from benzaldehyde and ethynylmagnesium
chloride, and N,O-di-protected-5-fluoro-4-iodo-oxin-
dole 6 (Scheme 2). Thus, the cross-coupling reaction
between 5 and 6 in the presence of catalytic amount of
tetrakis-(triphenylphosphine)-palladium(0) and cop-
per(I) iodide in tetrahydrofuran followed by oxidation
with manganese dioxide gave compound 7. Treatment
of 7 with NaI in TFA led to b-iodovinyl ketone 8 in
From the literature it is known that organometallic
reagents, such as Grignard reagents,3 organocopper,4
alkylzinc5 and alkylaluminum compounds,6 could serve
as effective nucleophiles toward Michael acceptors. To
our knowledge, there are only a few examples in which
simple Grignard reagents7 and organocuprates8 were
successfully used as nucleophiles for addition to a b-
iodovinyl ketone, although substitution reactions of
some organometallic reagents with 3-iodo-2-cyclo-
Keywords: trisubstituted naphthostyril; intramolecular cyclization;
CꢀC bond formation; organometallic reagents.
* Corresponding author.
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00826-8

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J.-J. Liu et al. / Tetrahedron Letters 44 (2003) 3901–3904
Encouraged by the results from the model studies, we
then checked the reaction of compound 11 with various
organometallic reagents under similar conditions (Table
1). While Grignard reagents such as CH2ꢁCHCH2MgBr
did not work with 11 as expected (Table 1, 12c), the
reaction of alkylcuprates can be extended to 11 to give
the desired 5-alkyl naphthostyrils as the final products
(Table 1, 12a and 12d). The yield of the final product
decreased dramatically as the size of the alkyl group
increased (12a versus 12d).
A typical procedure using an alkylcuprate is as follows.
Preparation of 6-fluoro-5-methyl-3-(1H-pyrrol-2-yl)-
1H-benzo[cd]indol-2-one (12a): To a suspension of cop-
per(I) iodide (190 mg, 1.0 mmol) in dry THF (2 mL)
was added MeLi (1.4 M solution in ether, 1.42 mL, 2.0
mmol) by injection, under argon, at 0°C and the reac-
tion mixture was allowed to stir for 15 min. To the
colorless solution obtained was added a solution of
(Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrro-2-yl)-pro-
penyl]-1,3-dihydro-indol-2-one (39.6 mg, 0.1 mmol) in
THF (2 mL). After stirring at 0°C for another 45 min,
the reaction mixture was quenched with a saturated
aqueous ammonium chloride solution (10 mL) and
extracted with ethyl acetate (3×20 mL). The combined
organic extracts were successively washed with water
(10 mL) and brine (10 mL), dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo to
give a crude product (28.5 mg) which was further
purified by preparative TLC (SiO2, 20% AcOEt in hex-
anes) to afford 6-fluoro-5-methyl-3-(1H-pyrrol-2-yl)-1H-
benzo[cd]indol-2-one (12.6 mg, 47.4%) as a yellow solid.10
Scheme 2. Reagents and conditions: (a) ethynylmagnesium
chloride (0.5 M in THF, 1.25 equiv.), THF, −65°C to rt, 1.5
h, 98%; (b) 5 (1.3 equiv.), (Ph3P)4Pd (0.08 equiv.), CuI (0.16
equiv.) THF, TEA, rt, 2 h, 65%; (c) MnO2 (10.0 equiv.),
CH2Cl2, rt, overnight, 88%; (d) NaI, TFA, rt, 78%; (e) MeLi
(20.0 equiv.), CuI (10.0 equiv.), THF, 0°C, 1.5 h, 96%; (f)
Zn(Et)2 (7.5 equiv.), CuCN (7.5 equiv.), LiCl (15 equiv.),
−78°C, 1 h, then rt, 15 h, 99%.
good yield. The reactions to synthesize naphthostyrils
were run by slow addition of a THF solution of 8 to a
dry, stirred THF solution of the appropriate
organometallic reagents under argon. The reaction was
then stirred at the same or higher temperature for
several hours. As shown in Scheme 2, the expected 1,4
addition occurred when 8 was treated with Me2CuLi–
LiI or Zn(Et)2–CuCN–LiCl complex. The final product
isolated in almost quantitative yield was the 5-alkyl-
naphthostyril 9 or 10. Thus, the desired intramolecular
cyclization catalyzed by the excess amount of the
organic base did occur under the reaction conditions.
On the other hand, no stable product was identified
from the reaction in which Grignard reagent EtMgBr
was used (EtMgBr, THF, −15°C to reflux).
Dialkylzinc cuprate complex also worked in this case
but gave a rather poor yield. Remarkably, the function-
alized organozinc-copper reagent derived by the activa-
tion of NCCH2CH2ZnBr with CuCN/LiCl11 reacted
with 11 to afford the corresponding 5-alkyl naph-
thostyril in 16% yield (Table 1, 12e). Interestingly, in a
Table 1. One-pot reaction of organometallic reagents to b-iodovinyl ketone 11
Entry
Nucleophile/conditionsa
12 (R=)
Yield (%)
a
b
MeLi (20.0 equiv.), CuI (10.0 equiv.), THF, 0°C, 45 min
Et2Zn (15.0 equiv.), CuCN (1.5 equiv.), LiCl (3.0 equiv.), THF/−78°C, 1.5 h, then rt, 12 h and
reflux for 3 h
Me
Et
47
19
c
d
e
CH2ꢁCHCH2MgBr, THF/0°C, 1 h then reflux for 2 h
sBuLi (20.0 equiv.), CuI (10.0 equiv.), THF, 0°C, 45 min, then rt, 2 h
NCCH2CH2ZnBr (15.0 equiv.), CuCN (1.5 equiv.), LiCl (3.0 equiv.), THF/−5°C, 0.5 h, then rt, 2 NCCH2CH2
h and reflux for 12 h
CH2ꢁCHCH2
s-Bu
0
12
16
fb
1) NCCH2CH2ZnBr (10.0 equiv.), CuCN (10.0 equiv.), LiCl (20.0 equiv.), THF, −5°C, 20 min,
NCCH2CH2
41
then rt, 3 h
2) NaOH aq. rt overnight
a Conditions are not optimized.
b The intermediate was isolated by flash column.12

J.-J. Liu et al. / Tetrahedron Letters 44 (2003) 3901–3904
3903
thostyril, nucleophiles such as a Grignard reagent
which favors 1,2-addition, might not be suitable to
trigger the reaction.17
separate experiment, the intermediate 1,4-addition
product 13a, was isolated for the first time from the
reaction in 41% yield.12 The Z stereochemistry was
suggested by NOE studies.13 Compound 13a readily
underwent intramolecular cyclization upon treatment
with aqueous NaOH solution at room temperature to
form the corresponding naphthostyril quantitatively.
That is consistent with the result from our earlier study
of the cis olefin.14 Thus the 2-step reaction actually gave
a better yield than the one-pot reaction in this case. The
E isomer 13b was not detected from the reaction.
In conclusion, we have found a novel organometallic
reagent mediated one-pot synthesis of 3,5,6-trisubsti-
tuted naphthostyrils. The present findings provide a
useful method for the introduction of a rich variety of
alkyl side chains including functionalized alkyl groups,
into the 5-position of naphthostyrils. Further investiga-
tions using other organometallic reagents are in
progress.
Acknowledgements
1
We thank Mr. Gino Sasso for H NMR spectral analy-
sis and NOE studies, Mr. Vance Bell, Mr. Richard
Szypula, Ms. Theresa Burchfield, and Mr. Michael
Lanyi for mass and IR spectral analysis. We also
acknowledge Dr. John Roberts for providing helpful
discussions.
Although the exact mechanism of the stereoselective
formation of the inversion product 13a is not clear,15 its
isolation provided useful information and strong evi-
dence for the mechanism of this one-pot reaction that
involves addition–elimination–cyclization sequence. In
this process, the iodovinyl ketone 1 reacted with a
nucleophilic species (or an electron-transfer reagent16)
to provide initially the 1,4-addition intermediate 14.
The following elimination reaction should form vinyl
ketones 15 and/or 16. By geometric consideration,11
only the Z-form, vinyl ketone intermediate 15, could go
through the intramolecular cyclization in the presence
of excess base to afford the final product, naphthostyril
4, as shown in Scheme 3.
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Scheme 3. Mechanisms of intramolecular cyclization of b-
iodovinyl ketone 1 to naphthostyrils 4.

3904
J.-J. Liu et al. / Tetrahedron Letters 44 (2003) 3901–3904
1989, 101, 358–360; (c) Negishi, E.-I. Organozinc
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cyanide (1.51 g, 16.9 mmol) and lithium chloride (1.44 g,
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16 mmol) by injection, under argon, at −5°C and the
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same temperature. To the reaction mixture at −5 to 0°C
was added the solution of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-
(1H-pyrro-2-yl)-propenyl]-1,3-dihydro-indol-2-one (0.64
g, 1.6 mmol) in dry THF (20 mL). After stirring at the
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allowed to warm up slowly to room temperature and
stirred for 3 h. The reaction mixture was quenched with
a saturated aqueous ammonium chloride solution (20
mL) and extracted with ethyl acetate (3×30 mL). The
combined organic extracts were successively washed with
water (20 mL) and brine (20 mL), dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo to give
a crude product which was purified by flash column
(SiO2, 20% AcOEt in hexanes) to give 4-(5-fluoro-2-oxo-
2,3-dihydro-1H-indol-4-yl)-6-oxo-6-(1H-pyrrol-2-yl)-hex-
4-enenitrile (0.212 g, 40.8%) as a yellow solid. 13a: 1H
NMR (400 MHz, DMSO-d6): l 11.48 (br.s, 1H), 10.40 (s,
1H), 7.16–7.12 (m, 3H), 7.00 (dd, 1H, J1=9.8 Hz, J2=8.8
Hz), 6.72 (dd, 1H, J1=8.8 Hz, J2=3.9 Hz), 6.24 (m, 1H),
3.47 (d, 1H, J=22.5 Hz), 3.00 (d, 1H, J=22.5 Hz),
2.77–2.50 (m, 4H). IR (thin film) w=3409, 2246, 1706,
1683, 1649. HRMS for C18H14FN3O2 (M++Na) calcd:
346.0962, found: 346.0966.
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10. Spectroscopic data for selected compounds are provided.
1
9: H NMR (400 MHz, DMSO-d6): l 10.76 (s, 1H), 7.82
13. 5 and 10% NOEs between the vinyl proton and the two
protons of the side chain were observed, respectively.
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(m, 2H), 7.66 (s, 1H), 7.50 (m, 3H), 7.22 (dd, 1H,
J1=12.7 Hz, J2=7.8 Hz), 6.88 (dd, 1H, J1=7.8 Hz,
J2=2.9 Hz), 3.22 (q, 2H, J=7.8 Hz), 1.34 (t, 3H, J=7.8
Hz). IR (thin film) w=3415, 1703, 1644, 1466. HRMS
m/z calcd for C19H14FNO [M+]: 291.1059. Found:
1
291.1061. 12a: H NMR (400 MHz, DMSO-d6): l 13.38
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17. There was no change on TLC after 8 or 11 was added to
the THF solution of a Grignard reagent such as EtMgBr
at −15°C and when the reaction mixture was finally
heated up to reflux for 2 h the starting material decom-
posed.
(s, 1H), 11.26 (s, 1H), 8.05 (s, 1H), 7.27 (br.s, 2H), 7.16
(dd, 1H, J1=13.7 Hz, J2=7.8 Hz), 6.99 (dd, 1H, J1=7.8
Hz, J2=2.9 Hz), 6.34 (m, 1H), 2.83 (s, 3H). IR (thin film)
w=3145, 3064, 2927, 1672, 1642. HRMS for C16H11FN2O
(M+) calcd: 266.0855, found: 266.0859. 12e: 1H NMR
(400 MHz, DMSO-d6): l 13.36 (br.s, 1H), 11.34 (s, 1H),
8.16 (s, 1H), 7.28 (m, 2H), 7.21 (dd, 1H, J1=13.7 Hz,
J2=7.8 Hz), 7.02 (dd, 1H, J1=7.8 Hz, J2=2.9 Hz), 6.36
(m, 1H), 3.47 (t, 1H, J=6.8 Hz), 3.00 (t, 1H, J=6.84
Hz). IR (thin film) w=3419, 3171, 2247, 1675, 1643, 1575.
HRMS for C18H12FN3O (M+) calcd: 305.0964, found:
305.0968.
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