Preparation of Polyfunctional Heterocycles Using Highly Functionalized Aminated Arylmagnesium Reagents as Versatile Scaffolds

Article abstract of DOI:10.1021/ol025597x

(Equation Presented) Functionalized Grignard reagents, derived from readily available o-iodoaniline derivatives and obtained via a straightforward iodine-magnesium exchange, can be used to prepare a wide range of polyfunctional indoles, quinolines, and quinazolinones.

Full text of DOI:10.1021/ol025597x

ORGANIC
LETTERS
2002
Vol. 4, No. 11
1819-1822
Preparation of Polyfunctional
Heterocycles Using Highly
Functionalized Aminated Arylmagnesium
Reagents as Versatile Scaffolds
David M. Lindsay, Wolfgang Dohle, Anne Eeg Jensen, Felix Kopp, and
Paul Knochel*
Institut fu¨r Organische Chemie, Ludwig-Maximilians-UniVersita¨t Mu¨nchen,
Butenandtstr. 5-13, Haus F, 81377 Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received January 22, 2002
ABSTRACT
Functionalized Grignard reagents, derived from readily available o-iodoaniline derivatives and obtained via a straightforward iodine−magnesium
exchange, can be used to prepare a wide range of polyfunctional indoles, quinolines, and quinazolinones.
The preparation of polyfunctional heterocycles by using
multicoupling reagents1 as versatile scaffolds has recently
been extensively studied.2 Such polyfunctional scaffolds
allow the synthesis of a broad range of diversely function-
alized heterocycles. Recently, we have reported that various
polyfunctional aryl-, heteroaryl-, and alkenylmagnesium
compounds3 can be prepared using an iodine- or bromine-
magnesium exchange reaction.3,4 Aminated arylmagnesium
compounds recently obtained by these methods5 should be
especially useful for the preparation of nitrogen-containing
heterocycles.6 Herein, we report that readily available func-
tionalized o-iodoanilines or o-iodo-p-phenylenediamines can
be converted, via organomagnesium intermediates, into
polyfunctionalized indoles, quinolines, and quinazolinones.
Thus, treatment of the amidine-protected diiodoamidine7 1a
(3) (a) Rottla¨nder, M.; Boymond, L.; Be´rillon, L.; Lepreˆtre, A.; Varchi,
G.; Avolio, S.; Laaziri, H.; Que´guiner, G.; Ricci, A.; Cahiez, G.; Knochel,
P. Chem. Eur. J. 2000, 6, 767. (b) Abarbri, M.; Thibonnet, J.; Be´rillon, L.;
Dehmel, F.; Rottla¨nder, M.; Knochel,P. J. Org. Chem. 2000, 65, 4618. (c)
Bonnet, V.; Mongin, F.; Tre´court, F.; Que´guiner, G.; Knochel,P. Tetrahedron
Lett. 2001, 42, 5717. (d) Dohle, W.; Lindsay, D. M.; Knochel, P. Org.
Lett. 2001, 3, 2871.
(4) For alternative methods for the preparation of functionalized aryl-
magnesium reagents, see: (a) Lee, J.; Velarde-Ortiz, R.; Guijarro, A.; Wurst,
J. R.; Rieke, R. D. J. Org. Chem. 2000, 65, 5428. (b) Kitagawa, K.; Inoue,
A.; Shinokubo, H.; Oshima,K. Angew. Chem., Int. Ed. 2000, 39, 2481. (c)
Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. J. Org. Chem. 2001,
66, 4333.
(1) (a) Seebach, D.; Knochel, P. HelV. Chim. Acta 1984, 67, 261. (b)
Achyutha Rao, S.; Knochel, P. J. Org. Chem. 1991, 56, 4591. (c) Rottla¨nder,
M.; Palmer, N.; Knochel, P. Synlett 1996, 61, 5743.
(2) (a) Bienayme, H.; Bouzid, K. Angew. Chem., Int. Ed. 1998, 37, 2234.
(b) Gauzy, L.; Le Merrer, Y.; Depezay, J.-C.; Clerc, F.; Mignani, S.
Tetrahedron Lett. 1999, 40, 6005. (c) Lowik, D. W. P. M.; Lowe, C. R.
Tetrahedron Lett. 2000, 41, 1837. (d) Bienayme, H.; Ancel, J.-E.; Meilland,
P.; Simonato, J.-P. Tetrahedron Lett. 2000, 41, 3339. (e) Sun, X.; Janvier,
P.; Zhao, G.; Bienayme, H.; Zhu, J. Org. Lett. 2001, 3, 877. (f) Tietze, L.
F.; Evers, H.; Topken, E. Angew. Chem., Int. Ed. 2001, 40, 903. (g) Abrous,
L.; Hynes, J.; Friedrich, S. R.; Smith, A. B., III; Hirschmann, R. Org. Lett.
2001, 3, 1089. (h) Arrayas, R. G.; Liebeskind, L. S. J. Am. Chem. Soc.
2001, 123, 6185. (i) Neumann, H.; Wangelin, A. J. v.; Go¨rdes, D.;
Spannenberg, A.; Beller, M. J. Am. Chem. Soc. 2001, 123, 8398.
(5) Varchi, G.; Jensen, A. E.; Dohle, W.; Ricci, A.; Cahiez, G.; Knochel,
P. Synlett 2001, 477.
(6) Functionalized heterocycles can also be prepared using various
lithiated aromatic or heterocyclic precursors; see: (a) Snieckus,V. Chem.
ReV. 1990, 90, 879. (b) Green, L.; Chander, B.; Snieckus,V. J. Heterocycl.
Chem. 1999, 36, 1453. (c) Turck, A.; Ple´, N.; Que´guiner, G. Heterocycles
1994, 37, 2149. (d) Mongin, F.; Que´guiner,G. Tetrahedron 2001, 4059. (e)
Turck, A.; Ple´, N.; Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4489.
For recent metal-mediated indole synthesis, see: (f) Wagaw, S.; Yang, B.
H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 10251. (g) Wagaw, S.;
Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 6621.
10.1021/ol025597x CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/30/2002

or the diimine derivative of 2-iodophenylenediamine,8 2, with
i-PrMgCl in THF (-20 °C, 5 min or -10 °C, 3 h, respec-
tively) furnishes the corresponding mono-organomagnesium
derivative in over 90% yield, as estimated by analysis of
reaction aliquots. After transmetalation to the corresponding
copper species with CuCN‚2LiCl9 and allylation with
2-methoxyallyl bromide,10 the desired allylation products 3
and 4 are obtained in 75% and 68% yield, respectively.
Treatment of these allylated products 3 and 4 with HCl in
THF/H2O (25 °C, 30 min) produces the polyfunctional
indoles 5 and 6 in 90% and 71% yield, respectively (Scheme
1).
achieved (i-PrMgCl, -20 °C, 0.5 h), furnishing the poly-
functional arylmagnesium reagent 7 (Scheme 2). After
Scheme 2
Scheme 1
transmetalation into the copper reagent using CuCN‚2LiCl,
reaction with allyl bromide leads after cyclization under
acidic conditions to the indole 10 in 88% yield. Alternatively,
alkylation with ethyl 4-iodobutyrate3d followed by successive
treatment with HCl (rt, 5 min) and ZnCl2 in EtOH (80 °C,
16 h) produces the indole 11 in 53% yield. Finally,
transmetalation of the aryl iodide 3 to the corresponding
arylzinc reagent by reaction with ZnBr2 followed by Negishi
cross-coupling11 with ethyl p-iodobenzoate, using tri-o-
furylphosphine12 (tpf, 10 mol %) and Pd(dba)2 (5 mol %)
leads, after acidic workup, to the functionalized indole 12
in 72% yield (Scheme 2).
Remarkably, the diiodoaniline derivatives of type 1 are
selectively converted to the monomagnesium reagent, since
the increased electron density of the aromatic ring of the
magnesiated intermediate prohibits a further iodine-
magnesium exchange. However, once this magnesium re-
agent has reacted with an electrophile to give product 3, a
second iodine-magnesium exchange can now be readily
Functionalized aminated aryl iodides can also be used for
the preparation of quinolines. Thus, the conversion of the
(7) Compounds 1a-c have been prepared according to literature
procedures; see Supporting Information. (a) Sy, W.-W. Synth. Commun.
1992, 22, 3215, (b) Gottlieb, L.; Meyers, A. I. Tetrahedron Lett. 1990, 31,
4723, (c) Meyers, A. I.; Elsworthy, T. R. J. Org. Chem. 1992, 57, 4732,
(d) Meyers, A. I.; Milot, G. J. Am. Chem. Soc. 1993, 115, 6652, (e) Toste,
D.; McNulty, J.; Still, I. W. J. Synth. Commun. 1994, 24, 1617.
(8) Compound 2 has been prepared according to literature procedures;
see Supporting Information. (a) Sy, W.-W. Synth. Commun. 1992, 22, 3215,
(b) Nicolet, B. H.; Ray, W. L. J. Am. Chem. Soc. 1927, 49, 1804.
(9) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
(11) (a) Negishi, E. Acc. Chem. Res. 1982, 15, 340. (b) Negishi, E.;
Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc. 1980, 102, 3298. (c)
Kobayashi, M.; Negishi, E. J. Org. Chem. 1980, 45, 5223. (d) Tamura, Y.;
Ochiai, H.; Nakamura, T.; Yoshida, Z. Tetrahedron Lett. 1986, 27,
955.
(12) (a) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
(b) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S.
J. Org. Chem. 1994, 59, 5905. (c) Klement, I.; Rottla¨nder, M.; Tucker,
C. E.; Majid, T. N.; Knochel, P.; Venegas, P. Tetrahedron 1996, 52,
7201.
(10) Jacobson, R. M.; Raths, R. A.; McDonald, J. H. J. Org. Chem. 1977,
42, 2545.
1820
Org. Lett., Vol. 4, No. 11, 2002

iodoaniline derivative 13 to the corresponding zinc reagent
is performed by a sequential iodine-magnesium exchange
reaction, followed by a transmetalation with zinc bromide
(Scheme 3). Subsequent Negishi cross-coupling with ethyl
Scheme 4
Scheme 3
a a: i-PrMgBr (1.1 equiv), THF, -20 °C, 30 min; b: R-NdCdO
(1.2-1.4 equiv), 0 °C, 3-6 h, then MeOH; c: HCl (1 equiv), silica
gel, THF, rt, 16 h; d: i-PrMgBr (5 equiv), THF, -20 °C, 5 min;
e: R-NdCdO (15 equiv), -20 °C to 0 °C, 2-3 h; f: ZnCl2 (15
equiv), THF, 60 °C, 16 h; g: TFA/CH2Cl2/H; 9:1:1, 15 min.
by reaction with a range of isocycanates furnishes, after
workup and treatment with silica gel (rt, 16 h), the desired
quinazolinones 21a-h in 72-92% yield (Scheme 4 and
Table 1). The same synthetic sequence has also been
a Yield in the absence of TBAl.
Table 1. Functionalized Quinazolinones of Type 21 Prepared
in Solution Starting from 1a-c or on Solid Phase Starting from
22 via Intermediate Functionalized Magnesium Reagents
2-trifluorosulfonyloxy-1-cyclohexenylcarboxylate 14 (0.7
equiv)13 leads to the heterocycle 15 in 74% yield (Pd(dba)2
(5 mol %); tfp (10 mol %), 25 °C, 16 h). The amide function
of 15 can then be converted to the enol triflate (16) by
reaction with Tf2O and pyridine in CH2Cl2 (0-25 °C, 16 h;
62% yield).14 Palladium(0)-catalyzed cross-coupling of 16
with functionalized arylzinc bromides, such as 17 and 18,
leads to the polyfunctional quinolines 19 and 20 in 71% and
89% yield, respectively (Scheme 3). Interestingly, the yield
of this cross-coupling can be greatly improved by the addition
of tetrabutylammonium iodide (TBAI, 3 equiv).15 This
enhanced reactivity is proposed16 to be due to activation of
the palladium catalyst by the formation of a palladate
species,16 thereby facilitating the oxidative addition to the
carbon-triflate bond.
Finally, by exploiting the electrophilic carbon and di-
methylamino leaving group of the amidine unit, several
diversely functionalized diiodoamidines of type 1 have been
converted, in a one-pot procedure, to quinazolinones of type
21. Thus, formation of the corresponding Grignard reagents
(THF, i-PrMgCl (1.1 equiv), -20 °C, 5-30 min) followed
product of
yield
(%)a
entry
FG
R
type 21
1
2
3
4
5
6
7
8
9
CO2Et
CO2Et
CO2Et
CO2Et
CN
CN
CN
CF3
CO2H
CO2H
CO2H
CO2H
p-ClC6H4
m-CF3C6H4
n-C14H29
21a
21b
21c
21d
21e
21f
21g
21h
21i
21j
21k
21l
88
90
72
75
92
91
86
84
90b,c
89b,c
84b,c
92b,c
CH2CHdCH2
m-CF3C6H4
p-ClC6H4
p-MeOC6H4
2,4-MeC6H3
2,4-MeC6H3
m-CNC6H4
p-MeOC6H4
p-ClC6H4
10
11
12
a Isolated yield of analytically pure product. b HPLC purity (254 nm).
c Solid-phase reaction.
performed successfully on solid phase. Thus, Wang resin
attached ester 2217 was treated with i-PrMgBr (5 equiv, 5
min, -20 °C) and various functionalized isocyanates (15
equiv, 0 °C, 2-3 h). After washing the resin, functionalized
quinazolinones 21i-l can be formed either by direct cleavage
(13) Crisp, G. T.; Meyer, A. G. J. Org. Chem. 1992, 57, 6972.
(14) Robl, J. A. Synthesis 1991, 56.
(15) Piber, M.; Jensen, A. E.; Rottla¨nder, M.; Knochel, P. Org. Lett.
1999, 1, 1324.
(16) (a) Amatore, C.; Azzabi, M.; Jutand, A. J. Am. Chem. Soc. 1991,
113, 8375, (b) Amatore, C.; Jutand, A.; Suarez, A. J. Am. Chem. Soc. 1993,
115, 9531.
(17) Wang resin attached compound 22 was prepared according to
literature procedures starting from compound 1a; see Supporting Informa-
tion. (a) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831,
(b) Sheehan, J. C.; Hess, G. P. J. Am. Chem. Soc. 1955, 77, 1067.
Org. Lett., Vol. 4, No. 11, 2002
1821

and cyclization reaction with TFA/CH2Cl2/H2O 9:1:1 (15-
30 min) or prior use of ZnCl2 (15 equiv, 60 °C, 0.6 M in
THF) in order to form the heterocycle on solid phase without
cleaving it. Further diversity might be introduced in the resin-
attached molecule, by applying one of the two strategies
described above.
Acknowledgment. We thank the DFG (Leibniz-Program)
and the Fonds der chemischen Industrie for financial support.
W.D. thanks the BASF AG for a fellowship. A.E.J. thanks
L’Ore´al (Aubervilliers) for a fellowship. D.M.L. thanks the
Alexander von Humboldt Foundation for a fellowship. We
thank Chemetall GmbH (Frankfurt), the BASF AG (Lud-
wigshafen), OMG (Hanau-Wolfgang), and Degussa AG
(Hanau) for generous gifts of chemicals.
In conclusion, we have shown that the Grignard reagents
derived from readily available o-iodoaniline derivatives can
be used to prepare a wide range of polyfunctional indoles,
quinolines, and quinazolinones, which may be of great
interest for their potential pharmaceutical properties. Exten-
sions of this method for the preparation of more complex
heterocycles is currently underway in our laboratories.18
Supporting Information Available: Experimental pro-
cedures and full characterization of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL025597X
(18) Typical Experimental Procedure. Preparation of the Iodoaryl
Amidine (3). A dry and argon-flushed 50-mL Schlenk flask, equipped with
a septum and a magnetic stirrer, was charged with the diiodoarylamidine
1a (3.81 g, 8.08 mmol) in dry THF (25 mL). The solution was cooled to
-25 °C, and i-PrMgCl (4.1 mL, 2.1 M in Et2O, 8.6 mmol) was added
slowly, keeping the temperature below -20 °C. After 10 min the exchange
was complete (checked by TLC analysis), a solution of CuCN‚2LiCl (8.8
mL, 1 M in THF, 8.8 mmol) was added at -20 °C, and the reaction mixture
was stirred for 30 min at this temperature. Then 2-methoxyallyl bromide
(4.04 g, 45%, 12.0 mmol)10 was added, keeping the temperature below -15
°C. The reaction mixture was stirred then for 1 h at -20 °C, after which
TLC analysis indicated complete conversion. Then the reaction mixture
was quenched by the addition of a 9:1 mixture of saturated NH4Cl(aq) and
25% NH3(aq) (5 mL) and poured into a separatory funnel containing saturated
NH4Cl(aq) (40 mL). The aqueous phase was extracted with ethyl acetate (3
× 40 mL), and the combined organic phases were washed with water (50
mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by flash chromatography (19:5:1 pentane/ether/triethylamine)
yielding 3 as a pale yellow oil (2.52 g, 75% yield). Preparation of the
Polyfunctional Indole (11). A dry and argon-flushed 10-mL Schlenk flask,
equipped with a septum and a magnetic stirrer, was charged with the iodoaryl
amidine 3 (545 mg, 1.3 mmol) in dry THF (2 mL). The solution was cooled
to -25 °C, and i-PrMgBr (1.2 mL, 1.3 M in THF, 1.6 mmol) was added
slowly, keeping the temperature below -20 °C. After 1 h at -20 °C the
exchange was complete (checked by TLC analysis), and a solution of CuCN‚
2LiCl (1.6 mL, 1 M in THF, 1.6 mmol) was added slowly at -20 °C and
stirred for 30 min at this temperature. Ethyl 4-iodobutyrate (578 mg, 2.4
mmol) was added, and the reaction mixture was allowed to warm to room
temperature and stirred then for 16 h. After this time, TLC analysis indicated
complete conversion, and the reaction mixture was quenched and worked
up as described for 3. The residue was purified by flash chromatography
(67:33:1 ether/pentane/triethylamine) to give 318 mg of a pale yellow oil.
This oil was then dissolved in THF (4 mL) and water (4 mL), and
concentrated HCl (0.4 mL) was added. After 5 min of stirring at room
temperature, TLC analysis indicated complete conversion. The reaction
mixture was poured into a separatory funnel containing saturated NaHCO3(aq)
solution (10 mL). The aqueous phase was extracted with ethyl acetate (4
× 10 mL), and the organic phases were washed with water (20 mL), dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was
redissolved in ethanol (5 mL), and dry zinc chloride (325 mg, 2.4 mmol)
was added. The reaction mixture was heated to reflux for 16 h and then
cooled to room temperature, and ethanol was removed in vacuo. The residue
was dissolved in ethyl acetate (10 mL) and poured into water (10 mL).
The organic layer was separated, and the aqueous layer was extracted with
ethyl acetate (4 × 10 mL). The combined organic phase was washed with
water (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The
crude product was then titurated with a few mL of 1:1 pentane/ether to
give 11 as a white powder (224 mg, 53% yield).
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Org. Lett., Vol. 4, No. 11, 2002