Preparation and reactions of heteroarylmethylzinc reagents

Article abstract of DOI:10.1021/ol500790p

We report a general preparation of heteroarylmethylzinc chlorides by direct zinc insertion into heteroarylmethyl chlorides, along with a facile and straightforward synthesis of these heterocyclic chloromethyl precursors. We demonstrate that heteroarylmethylzinc reagents undergo various reactions including cross-couplings, allylations, acylations, and addition reactions to aldehydes, leading to polyfunctional heterocyclic products. Furthermore, these heteroaromatic zinc compounds prove to be versatile reagents for the preparation of various N- and O-heterocycles and give access to an analogue of a CB1 modifier.

Full text of DOI:10.1021/ol500790p

Letter
pubs.acs.org/OrgLett
Preparation and Reactions of Heteroarylmethylzinc Reagents
Nadja M. Barl, Elodie Sansiaume-Dagousset, Gabriel Monzon, Andreas J. Wagner, and Paul Knochel*
́
Department of Chemistry, Ludwig-Maximilians-Universitat, Butenandtstrasse 5-13, 81377 Munich, Germany
̈
S
* Supporting Information
ABSTRACT: We report a general preparation of heteroarylmethyl-
zinc chlorides by direct zinc insertion into heteroarylmethyl chlorides,
along with a facile and straightforward synthesis of these heterocyclic
chloromethyl precursors. We demonstrate that heteroarylmethylzinc
reagents undergo various reactions including cross-couplings,
allylations, acylations, and addition reactions to aldehydes, leading to
polyfunctional heterocyclic products. Furthermore, these heteroar-
omatic zinc compounds prove to be versatile reagents for the
preparation of various N- and O-heterocycles and give access to an
analogue of a CB1 modifier.
inc organometallics are key intermediates in organic
synthesis.1,2 The broad functional group tolerance of the
Scheme 2. Preparation of Zinc Reagent 1a Followed by a
Copper-Mediated Reaction with an Acyl Chloride Leading
to the Ketone 5a
Z
carbon−zinc bond allows the preparation of highly function-
alized zinc reagents. Thus, aryl, heteroaryl, and alkylzinc
compounds are readily prepared and react with a broad range
of electrophiles under appropriate reaction conditions.3
Recently, we have shown that polyfunctional benzylic zincs
are obtained by direct zinc insertion.4 Since heterocyclic
scaffolds are major building blocks for pharmaceuticals and
materials, we envisioned the development of a general
preparation of heteroarylmethylzinc compounds of type 15
(Scheme 1). Herein, we report a practical synthesis of these
Scheme 1. Preparation of Chloromethyl Heterocycles of
Type 2, Their Conversion to Zinc Reagents of Type 1, and
Trapping Reactions Leading to Products of Type 5
pyridine 1a (Scheme 2). Thus, the I/Mg exchange on 6-chloro-
2-fluoro-3-iodopyridine6 (6) with i-PrMgCl·LiCl7 (1.1 equiv)
produces an intermediate magnesium reagent which readily
reacts with methylene(dimethyl)iminium trifluoroacetate 7,8
leading to the benzylic N,N-dimethylamine 3a in 79% yield.
Treatment with ClCO2Et9 affords the 3-(chloromethyl)-
pyridine10 2a in 60% yield. Subsequent LiCl-promoted zinc
insertion furnishes the new pyridylzinc reagent 1a in 85%
yield.11 Although the metalation of 2- and 4-picolines can be
realized with various bases,12 the direct metalation of 3-
picolines is difficult since the resulting cross-conjugated anion is
not delocalized onto the nitrogen, therefore leading to a highly
reactive anion.13 Our new approach provides readily metalated
3-picoline derivatives such as 1a.14 The acylation of 1a with 2,4-
dichlorobenzoyl chloride in the presence of CuCN·2LiCl15
(1.1 equiv) gives 5a in 80% yield (Scheme 2).
heterocyclic zinc chlorides 1 as well as of the corresponding
heteroarylmethyl chlorides (2). These chloromethyl hetero-
arenes 2 are prepared in a straightforward manner from the
N,N-dimethylaminomethyl heteroarenes of type 3 obtained
from readily available heteroaryl organometallics (4). The novel
heteroarylmethylzinc compounds 1 proved to be stable and
practical reagents that react with a wide range of electrophiles
leading to polyfunctional heterocyclic products of type 5
(Scheme 1).
Similarly, the zinc reagent 1a adds rapidly to aldehydes,
leading to the alcohol 5b in 80% yield (entry 1, Table 1). Pd-
catalyzed cross-coupling (3 mol % Pd(dba)2 (dba =
A typical preparation of these new heterocyclic zinc reagents
is shown in the synthesis of the polyfunctional zincated
Received: March 17, 2014
Published: April 11, 2014
© 2014 American Chemical Society
2422
dx.doi.org/10.1021/ol500790p | Org. Lett. 2014, 16, 2422−2425

Organic Letters
Letter
Table 1. Products of Type 5 Obtained by the Reaction of
Heteroarylmethylzinc Reagents 1 Followed by Reaction with
Electrophiles
Figure 1. Zinc reagents of type 1 obtained by direct zinc insertion into
the corresponding chloromethyl derivatives of type 2. Yields were
determined by iodometric titration.11 MOM = methoxymethyl. X =
Cl·LiCl.
dibenzylideneacetone), 6 mol % tfp (tri-o-furylphosphine))16
with 1-bromo-2-iodobenzene leads to 5c in 70% yield (entry 2,
Table 1). Although the preparation of 3-(chloromethyl)-
pyridine can be realized, the corresponding zinc reagent is
unstable and polymerizes rapidly. This can be avoided by
introducing a chlorine substituent in position 6. The resulting
zinc reagent 1b reacts well with aldehydes to afford 5d−e in
89−91% yield (entry 3, Table 1). Pd-catalyzed cross-coupling
of 1b with 3-bromobenzothiophene using 1 mol % PEPPSI-
IPr17 provides 5f in 93% yield (entry 4, Table 1). This reaction
sequence is extended to the preparation of biorelevant uracil
(1c), thiophene (1d), benzothiophene (1e), benzofuran (1f),
7-azaindole (1g), and quinoline (1h) derived zinc reagents in
60−85% yield (Figure 1).18
Thus, the uracil reagent 1c undergoes a copper-mediated
acylation with CuCN·2LiCl15 and affords the uracil derivative
5g in 88% yield (entry 5, Table 1). The thienylzinc reagent 1d
smoothly reacts in a Pd-catalyzed cross-coupling (1 mol %
PEPPSI-IPr17) with 2-bromo-1-chloro-4-(trifluoromethyl)-
benzene to furnish 5h in 72% yield (entry 6, Table 1).
Furthermore, the benzothienylzinc reagent 1e undergoes a
smooth Pd-catalyzed cross-coupling (1 mol % PEPPSI-IPr17)
with aryl halides to give the benzothiophenes 5i,j in 85% yield
each (entries 7 and 8, Table 1). The benzofurylzinc reagent 1f
is allylated using 5 mol % CuCN·2LiCl15 with ethyl (2-
bromomethyl)acrylate19 to provide 5k in 80% yield (entry 9,
Table 1).
Similarly, the 7-azaindolylzinc reagent 1g is readily allylated
with ethyl (2-bromomethyl)acrylate19 and reacts smoothly with
S-benzenesulfonothioate and 4-cyanobenzaldehyde to furnish
the desired products 5l−n in 81−98% yield (entries 10−12,
Table 1). Moreover, the quinolylzinc reagent 1h reacts with 3-
bromocyclohexene (5 mol % CuCN·2LiCl15) to afford 5o in
76% yield (entry 13, Table 1). Pd-catalyzed cross-coupling of
1h (5 mol % PEPPSI-IPr17) with ethyl 4-iodobenzoate
produces the quinoline derivative 5p in 70% yield (entry 14,
Table 1).
The heterocyclic zinc reagents of type 1 are versatile reagents
for the preparation of condensed N-heterocycles such as
furopyridines. These heterocycles are of high interest for
pharmaceutical applications as enzyme inhibitors, receptors and
modifiers.20 Thus, the furopyridine 8a is prepared via a
cyclization reaction starting from the previously prepared
pyridyl alcohol 5b (entry 1, Table 1). Its treatment with NaH
leads to the dihydrofuropyridine 9a in 86% yield. Oxidation
using DDQ21 (DDQ = 2,3-dichloro-5,6-dicyanobenzo-1,4-
quinone) provides 8a in 82% yield (71% yield over two
steps; Scheme 3, A).
a
b
LiCl omitted for sake of clarity. Isolated yield of analytically pure
c
d
product. Obtained by Pd-catalyzed cross-coupling. Obtained by Cu-
mediated acylation. Obtained by Cu-catalyzed allylation.
e
2423
dx.doi.org/10.1021/ol500790p | Org. Lett. 2014, 16, 2422−2425

Organic Letters
Letter
Scheme 3. Preparation of Furopyridines 10a−c Using the
Alcohol 5b and the Benzylic Zinc Reagent 1h and
Preparation of the Tetra-azanaphthalene 10 from the
Benzylic Ketone 5g
Scheme 4. Key Steps in the Synthesis of the CB1 Modifier
Analogue 16 Starting from Pyridine 12
a
It is noteworthy that such functionalized furopyridines may
also be prepared from the appropriate heterobenzylic ketones
by a copper-catalyzed ring closure recently reported by
Ackermann.22 Hence, the copper-mediated acylation of the
heterocyclic zinc reagent 1h with acid chlorides such as benzoyl
chloride or cyclobutanecarbonyl chloride affords 5q,r in 66−
67% yield (Scheme 3, A). Subsequent copper-catalyzed ring
closure (CuI, 10 mol %) using K3PO4 (2 equiv) and N,N′-
dimethylethylenediamine (DMEDA, 30 mol %) furnishes the
furoquinolines 8b,c in 62−65% yield (Scheme 3, A).22
a
LiCl omitted for sake of clarity.
acid30 leads to the CB1 modifier analogue 16 in 73% yield
(46% over two steps; Scheme 4).
Tetra-azanaphthalenes are biorelevant molecules which have
been prepared in a nonstraightforward manner.23 The
ketouracil 5g reacts with hydrazine to provide the aromatized
tetra-azanaphthalene 10 in 70% overall yield after oxidation
In summary, we have developed a general preparation of
various chloromethyl heterocycles as well as their elusive zinc
derivatives. These new organozinc reagents prove to be
versatile organometallic intermediates for the preparation of
numerous polyfunctional heterocycles and give a short access to
furopyridines, furoquinolines, and tetra-azanaphthalenes as well
as to an analogue of the CB1 modifier 11.
24
with Pb(OAc)4 (Scheme 3; B).
As an application toward the preparation of biorelevant
heterocycles, we have prepared an analogue of the CB1
modifier 11 being applicable for various targets in the central
nervous system (Scheme 4).20b Thus, commercially available 2-
bromo-6-fluoropyridine is regioselectively lithiated with LDA
(lithium diisopropylamide; 1.05 equiv). Subsequent iodination
gives 12 in 82% yield.25 I/Mg exchange with i-PrMgCl·LiCl7
(1.0 equiv) produces a Grignard reagent, which readily reacts
with methylene(dimethyl)iminium trifluoroacetate 78 to furnish
the benzylic N,N-dimethylamine 3g in 86% yield (71% yield
over two steps). This aminopyridine is regioselectively
magnesiated with TMPMgCl·LiCl6 (1.2 equiv), and subsequent
chlorination with PhSO2Cl26 gives 3h in 73% yield. Treatment
with ClCO2Et9 (67% yield) and LiCl-promoted zinc insertion
(90% yield) affords the new benzylic zinc reagent 1i in 60%
overall yield. Addition of this pyridylzinc reagent to 2-
thiophenecarboxaldehyde leads after cyclization to the corre-
sponding dihydrofuropyridine 9b in 69% yield. Subsequent
oxidation with DDQ21 provides the furopyridine 8d in 70%
yield (48% yield over two steps). To ensure a high lipophilicity
of 11, we have replaced the 1,1-dimethylheptyl group by the
highly lipophilic adamantyl group.27 Pd-catalyzed cross-
coupling reaction with the adamantylzinc reagent 1328
(1.1 equiv) furnishes 14 in 67% yield. Treatment with sodium
(p-methoxyphenyl)methanolate29 (PMBO-Na) affords the
alkoxy heterocycle 15 in 63% yield. Subsequent deprotection
of the PMB (p-methoxybenzyl) group with trifluoroacetic
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures and characterization data for
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: paul.knochel@cup.uni-muenchen.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The research leading to these results has received funding from
the European Community’s Seventh Framework Programme
(FP7/2007-2013) ERC grant agreement no. 227763. We are
grateful to BASF SE (Ludwigshafen), W. C. Heraeus (Hanau),
and Rockwood Lithium GmbH (Frankfurt) for the generous
gift of chemicals. We thank Dr. A. Metzger (Ludwig-
Maximilians-Universitat Munich, Germany) for preliminary
experiments.
̈
2424
dx.doi.org/10.1021/ol500790p | Org. Lett. 2014, 16, 2422−2425

Organic Letters
Letter
McGowan, D.; Bemis, J. E.; Kayser, F.; Fu, J.; Liu, J.; Jiao, X. Y. U.S.
Patent 7,674,907, 2010.
(21) Taylor, E. C.; Macor, J. E.; Pont, J. L. Tetrahedron 1987, 43,
REFERENCES
■
(1) (a) Handbook of Functionalized Organometallics; Knochel, P., Ed.;
Wiley-VCH: Weinheim, 2005; pp 251−333. (b) Duan, H.; Meng, L.;
Bao, D.; Zhang, H.; Li, Y.; Lei, A. Angew. Chem., Int. Ed. 2010, 49,
6387. (c) Bernhardt, S.; Manolikakes, G.; Kunz, T.; Knochel, P. Angew.
Chem., Int. Ed. 2011, 50, 9205. (d) Zimmer, L. E.; Charette, A. J. Am.
Chem. Soc. 2009, 131, 15633.
5145.
(22) Ackermann, L.; Kaspar, L. T. J. Org. Chem. 2007, 72, 6149.
(23) (a) Mallory, W. R.; Morrison, R. W. J. Org. Chem. 1980, 45,
3919. (b) Styles, V. L.; Morrison, R. W., Jr. J. Org. Chem. 1985, 50,
346.
(2) (a) Negishi, E.-i. Angew. Chem., Int. Ed. 2011, 50, 6738.
(b) Negishi, E.-i. Acc. Chem. Res. 1982, 15, 340.
(24) Kochi, J. K. Org. React. 1972, 19, 279.
(25) The regioselective lithiation of 2-bromo-6-fluoropyridine
proceeds analogously to the known lithiation of 2-chloro-6-
fluoropyridine: Zhou, Q.; Snider, B. B. Org. Lett. 2011, 13, 526.
(26) Chemla, F.; Marek, I.; Normant, J.-F. Synlett 1993, 665.
(27) For a review on the application of adamantane derivatives in
medicinal chemistry, see: Wanka, L.; Iqbal, K.; Schreiner, P. R. Chem.
Rev. 2013, 113, 3516.
(3) (a) Organozinc Reagents; Knochel, P., Jones, P., Eds.; Oxford
University Press: New York, 1999. (b) Knochel, P.; Millot, N.;
Rodriguez, A. L.; Tucker, C. E. Org. React. 2001, 58, 417. (c) Haag, B.;
Mosrin, M.; Hiriyakkanavar, I.; Malakhov, V.; Knochel, P. Angew.
Chem., Int. Ed. 2011, 50, 9794.
(4) (a) Metzger, A.; Piller, F. M.; Knochel, P. Chem. Commun. 2008,
44, 5824. (b) Metzger, A.; Schade, M. A.; Knochel, P. Org. Lett. 2008,
10, 1107.
(5) (a) Murakami, K.; Yorimitsu, H.; Oshima, K. Chem.Eur. J.
2010, 16, 7688. (b) Braendvang, M.; Bakken, V.; Gundersen, L.-L.
Bioorg. Med. Chem. 2009, 17, 6512. (c) Baba, Y.; Toshimitsu, A.;
Matsubara, S. Synlett 2008, 2061.
(6) The iodopyridine 6 was prepared in 76% yield from commercially
available 2-chloro-6-fluoropyridine using TMPMgCl·LiCl (1.1 equiv,
−40 °C, 4 h) followed by iodolysis: (a) Krasovskiy, A.; Krasovskaya,
V.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 2958. (b) Lin, W.;
Baron, O.; Knochel, P. Org. Lett. 2006, 8, 5673. (c) Mosrin, M.;
Knochel, P. Org. Lett. 2008, 10, 2497. (d) Jaric, M.; Haag, B. A.;
Manolikakes, S. M.; Knochel, P. Org. Lett. 2011, 13, 2306.
(28) Samann, C.; Dhayalan, V.; Schreiner, P. R.; Knochel, P. Org.
̈
Lett. 2014, DOI: 10.1021/ol500781j.
(29) (a) Claude, P. C.; Alexandre, F.-R.; Convard, T.; Surleraux, D.
WO 2012/109398, 2012. (b) Berge, J. M.; Brown, P.; Elder, J. S.;
Forrest, A. K.; Hamprecht, D. W.; Jarvest, R. L.; McNair, D. J.;
Sheppard, R. J. U.S. Patent 6,320,051, 2000.
(30) Llinas-Brunet, M.; Bordeleau, J.; Godbout, C.; Leblanc, M.;
Moreau, B.; O’Meara, J. European Patent 2,504,344, 2011.
(7) (a) Boymond, L.; Rottlander, M.; Cahiez, G.; Knochel, P. Angew.
̈
Chem., Int. Ed. 1998, 37, 1701. (b) Sapountzis, I.; Knochel, P. Angew.
Chem., Int. Ed. 2002, 41, 1610. (c) Krasovskiy, A.; Knochel, P. Angew.
Chem., Int. Ed. 2004, 43, 3333.
(8) Kinast, G.; Tietze, L.-F. Angew. Chem., Int. Ed. 1976, 15, 239.
(9) Kashdan, D. S.; Schwartz, J. A.; Rapoport, H. J. Org. Chem. 1982,
47, 2638 and references cited therein.
(10) Zhou, Q.; Snider, B. B. Org. Lett. 2011, 13, 526.
(11) This yield was determined by iodometric titration: Krasovskiy,
A.; Knochel, P. Synthesis 2006, 890.
(12) (a) Kamienski, T.; Gros, P.; Fort, Y. Eur. J. Org. Chem. 2003,
3855. (b) Schlosser, M.; Mongin, F. Chem. Soc. Rev. 2007, 36, 1161.
(c) Duez, S.; Steib, A.; Manolikakes, S. M.; Knochel, P. Angew. Chem.,
Int. Ed. 2011, 50, 7686.
(13) Albrecht, M.; Riether, C. Synlett 1995, 309.
(14) For preliminary results describing unoptimized syntheses of
1a,b, see: (a) Metzger, A. Ph.D. Dissertation, Ludwig-Maximilians
Universitat Munich, Germany, 2010. (b) Wagner, A. J. Ph.D.
̈
Dissertation, Ludwig-Maximilians Universitat Munich, Germany,
̈
2011. (c) Monzo
Universitat Munich, Germany, 2012. For the use of 1b in Pd-
catalyzed acylations, see:. Cho, K.-H.; Kim, S.-H. Bull. Korean Chem.
n, G. Ph.D. Dissertation, Ludwig-Maximilians
Soc. 2013, 34, 983.
(15) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
(16) (a) Negishi, E.-i.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc.
1980, 102, 3298. (b) Kobayashi, M.; Negishi, E.-i. J. Org. Chem. 1980,
45, 5223.
(17) (a) Organ, M. G.; Avola, S.; Dubovyk, I.; Hadei, N.; Kantchev,
E. A. B.; O’Brien, C. J.; Valente, C. Chem.Eur. J. 2006, 12, 4749.
́
(b) Kantchev, E. A. B.; OBrien, C. J.; Organ, M. G. Angew. Chem., Int.
Ed. 2007, 46, 2768. (c) Organ, M. G.; Abdel-Hadi, M.; Avola, S.;
Dubovyk, I.; Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Sayah, M.;
Valente, C. Chem.Eur. J. 2008, 14, 2443.
(18) For further experimental details on the preparation of the
starting materials for 1c, 1g, and 1h, see the Supporting Information.
(19) (a) Rambaud, M.; Villier
J.; Rambaud, M. Org. Synth. 1988, 66, 220.
́ ́
as, J. Synthesis 1984, 406. (b) Villieras,
(20) (a) Arcadi, A.; Cacchi, S.; Di Giuseppe, S.; Fabrizi, G.; Marinelli,
F. Org. Lett. 2002, 4, 2409. (b) Moore, B. M.; Gurley, S.; Mustafa, S.
U.S. Patent 8,476,309, 2013. (c) Nunes, J. J.; Martin, M. W.; White, R.;
2425
dx.doi.org/10.1021/ol500790p | Org. Lett. 2014, 16, 2422−2425