Iron-catalyzed cross-coupling of N-heterocyclic chlorides and bromides with arylmagnesium reagents

Article abstract of DOI:10.1021/ol302136c

A simple, practical iron salt catalyzed procedure allows fast cross-couplings of N-heterocyclic chlorides and bromides with various electron-rich and -poor arylmagnesium reagents. A solvent mixture of THF and tBuOMe is found to be essential for achieving high yields mainly by avoiding homocoupling side reactions.

Full text of DOI:10.1021/ol302136c

ORGANIC
LETTERS
2012
Vol. 14, No. 18
4818–4821
Iron-Catalyzed Cross-Coupling of
N‑Heterocyclic Chlorides and Bromides
with Arylmagnesium Reagents
Olesya M. Kuzmina,† Andreas K. Steib,† Dietmar Flubacher,‡ and Paul Knochel*,†
€
€
Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstr. 5-13,
81377 Mu€nchen, Germany, and Novartis Pharma AG, Novartis Campus,
CH-4056 Basel, Switzerland
Paul.Knochel@cup.uni-muenchen.de
Received August 1, 2012
ABSTRACT
A simple, practical iron salt catalyzed procedure allows fast cross-couplings of N-heterocyclic chlorides and bromides with various electron-rich
and -poor arylmagnesium reagents. A solvent mixture of THF and tBuOMe is found to be essential for achieving high yields mainly by avoiding
homocoupling side reactions.
Fe-catalyzed cross-couplings have received a lot of atten-
tion due to the environmentally friendly properties of iron
salts combined with their moderate prices.1 Whereas alkyl-
aryl,2 alkyl-alkenyl,3 aryl-alkenyl,3b,c,4 and alkynyl5 cou-
pling reactions are well documented, the corresponding
arylÀaryl cross-couplings are much more challenging due
to the formation of homocoupling products2a,6,7 or to the
need for additional copper salts.8 The use of iron fluorides in
combination with carbene ligands improves such arylÀaryl
cross-couplings dramatically as shown by M. Nakamura.9
The cross-coupling of N-heterocyclic halides (chlorides
or bromides) with arylmagnesium reagents is of special
importance due to the potential biological activity of the
resulting arylated heterocycles. For such reactions only a
€
(2) (a) Furstner, A.; Leitner, A. Angew. Chem. 2002, 114, 632. Angew.
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Chem., Int. Ed. 2002, 41, 609. (b) Furstner, A.; Leitner, A.; Mendez, M.;
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Krause, H. J. Am. Chem. Soc. 2002, 124, 13856. (c) Martin, R.; Furstner,
A. Angew. Chem. 2004, 116, 4045. Angew. Chem., Int. Ed. 2004, 43, 3955.
(d) Nagano, T.; Hayashi, T. Org. Lett. 2004, 6, 1297. (e) Nakamura, M.; Ito,
S.; Matsuo, K.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 3686. (f)
Bedford, R. B.;Bruce, D. W.;Frost, R. M.; Goodby, J. W.;Hird, M.Chem.
Commun. 2004, 40, 2822. (g) Nakamura, M.; Ito, S.; Matsuo, K.;
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(j) Furstner, A.; Martin, R.; Krause, H.; Seidel, G.; Goddard, R.; Lehmann,
C. W. J. Am. Chem. Soc. 2008, 130, 8773. (k) Czaplik, W. M.; Mayer, M.;
Jacobi von Wangelin, A. Angew. Chem. 2009, 121, 616. Angew. Chem., Int.
Ed. 2009, 48, 607. (l) Bedford, R. B.; Huwe, M.; Wilkinson, M. C. Chem.
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Chem. 2009, 121, 3013. Angew. Chem., Int. Ed. 2009,48, 2969. (n) Noda, D.;
Sunada, Y.; Hatakeyama, T.; Nakamura, M.; Nagashima, H. J. Am.
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Nakamura, M. Org. Lett. 2009, 11, 4306. (p) Gøgsig, T. M.; Lindhardt,
A. T.; Skrydstrup, T. Org. Lett. 2009, 11, 4886. (q) Kawamura, S.; Ishizuka,
K.; Takaya, H.; Nakamura, M. Chem. Commun. 2010, 46, 6054. (r)
Hatakeyama, T.; Hashimoto, T.; Kondo, Y.; Fujiwara, Y.; Seike, H.;
Takaya, H.; Tamada, Y.; Ono, T.; Nakamura, M. J. Am. Chem. Soc. 2010,
132, 10674. (s) Steib, A. K.; Thaler, T.; Komeyama, K.; Mayer, P.;
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50, 3303. (t) Yamaguchi, Y.; Ando, H.; Nagaya, M.; Hinago, H.; Ito, T.;
Asami, M. Chem. Lett. 2011, 40, 983. (u) Jin, M.; Nakamura, M. Chem.
Lett. 2011, 40, 1012. (v) Hatakeyama, T.; Fujiwara, Y.-i.; Okada, Y.; Itoh,
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†
€
Ludwig-Maximilians-Universitat M€unchen.
‡ Novartis Pharma AG.
(1) For selected reviews on iron-catalyzed reactions, see: (a) Bolm,
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Shinokubo, H.; Oshima, K. Eur. J. Org. Chem. 2004, 2081. (c) Furstner,
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€
€
~
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ꢁ
Thome, I.; Nijs, A.; Bolm, C. Chem. Soc. Rev. 2012, 41, 979.
r
10.1021/ol302136c
Published on Web 09/11/2012
2012 American Chemical Society

few examples have been reported and no general cross-
coupling method has been available.2a,b,9,10 Herein, we
describe an efficient iron-catalyzed cross-coupling be-
tween N-heterocyclic chlorides and bromides with var-
ious arylmagnesium reagents using a simple iron salt as
the catalyst system.
Inpreliminary experiments, we have examined the cross-
coupling between 2-chloropyridine (1a) and PhMgCl (2a)
(Scheme 1). Thus, catalytic amounts (5 mol %) of various
iron salts such as Fe(acac)2, Fe(acac)3, or the related
Fe(TMHD)3 (TMHD = 2,2,6,6-tetramethyl-3,5-heptane-
dionate; entries 1À3 of Table 1) and iron halides such as
FeCl2, FeCl3, FeBr2, or FeBr3 (entries 4À7) as well as
Fe(OTf)3 (entry 8) gave only moderate yields of the desired
cross-coupling product 3a (46À63%) in THF at rt. Also,
the use of iron fluorides and iodide led to only traces
of product at rt (entries 9À11). Polar cosolvents such as
NMP (N-methylpyrrolidone) hampered the cross-coupling
(entry 12). Nonpolar solvents, e.g., n-hexane or toluene,
did not display any considerable improvement (entries
13À14).11 However, ethereal solvents such as diethyl
ether or tBuOMe dramatically increased the GC yield
up to 87% affording after isolation the arylated pyridine
3a in 84% yield (entries 15À16). Since comparable yields
are obtained using tBuOMe or Et2O, we have pursued
our investigations using the industry-friendly solvent
tBuOMe. The use of such ethereal solvents proved to be
a key determinant and allowed us to extend this cross-
coupling to various other N-heterocycles. In order to study
the reaction scope, we have first varied the N-heterocyclic
chlorides or bromides and determined their reactions with
PhMgCl (2a) in tBuOMe at rt.12 Thus, we observed that
Scheme 1. Cross-Coupling of Pyridyl Chloride (1a) with
PhMgCl (2a) in the Presence of Various Fe-Salts
Table 2. Scope of Iron-Catalyzed Cross-Coupling of
N-Heteroarylchlorides/-bromides (1aÀ1j) with PhMgCl (2a)
Table 1. Optimization of the Conditions for Reaction of Pyridyl
Chloride (1a) with PhMgCl (2a) Catalyzed by Fe-Salts
reaction
timeb
yield
(%)c
entry
Fe-salta
solvent
THF
1
Fe(acac)2
Fe(acac)3
Fe(TMHD)3
FeCl2
2 h
46
55
53
56
55
62
63
60
2
THF
2 h
3
THF
2 h
4
THF
5 h
5
FeCl3
THF
2 h
6
FeBr2
THF
2 h
7
FeBr3
THF
1.5 h
5 h
8
Fe(OTf)3
FeF2
THF
9
THF
20 h
20 h
20 h
2 h
tracesd
tracesd
tracesd
traces
10
11
12
13
14
15
16
FeF3
THF
FeI2
THF
FeBr3
THF/NMPe
n-hexane
toluene
Et2O
FeBr3
2 h
53
FeBr3
1.5 h
1.5 h
1.5 h
14
FeBr3
73, 87f (84)f
75, 85f (82)f
FeBr3
t-BuOMe
a 5 mol % of Fe-salt was used. b Reaction time until reaction com-
pletion according to GC analysis. c Calibrated GC yield using undecane
(C11H24) as internal standard. Numbers in brackets indicate isolated
yields d Starting material was not consumed even after 20 h. e A mixture
of THF/NMP (5:1) was used. The reaction of PhMgCl with NMP was
dominant. f 3 mol % of FeBr3 was used.
(3) (a) Tamura, M.; Kochi, J. K. J. Am. Chem. Soc. 1971, 93, 1487. (b)
Fabre, J.-L.; Julia, M.; Verpeaux, J.-N. Tetrahedron. Lett. 1982, 23,
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2469. (c) Scheiper, B.; Bonnekessel, M.; Krause, H.; Furstner, A. J. Org.
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a The reaction was performed on a 1 mmol scale with 3 mol % of
FeBr3 in THF/tBuOMe (ca. 2:5) at rt. b Isolated yield. c GC yield.
Org. Lett., Vol. 14, No. 18, 2012
4819

Table 3. Iron-Catalyzed Cross-couplings of N-Heteroarylchlorides/-bromides with Various Grignard Reagents
a The reaction was performed on a 1 mmol scale with 3 mol % of FeBr3 in THF/tBuOMe (ca. 2:5) at rt. b Isolated yield.
2-bromopyridine (1b) reacted with PhMgCl at a faster rate
for completion than 2-chloropyridine (70 min instead of
90 min) and produced 3a in the same yield (83%, entry 2 of
Table 2). Substituted bromo- or chloropyridines such as
2-chloro-4-picoline (1c) and 2-bromo-5-chloropyridine (1d)
reacted smoothly with similar reaction times leading to
the pyridines 3b and 3c in 78À84% yield (entries 3 and 4).
Interestingly, the presence of a tert-butoxycarbonyl group
in position 3 (1e) dramatically increased the reaction rate
leading to full conversion within 5 min (entry 5). The cross-
coupling product 3d was isolated in 60% yield. No starting
chloride was detected, and the relatively moderate yield
may be due to a polymerization of 1e. The annulation of the
pyridine ring with a benzene moiety also accelerated the
reaction rate, and the cross-couplings of PhMgCl with
(4) (a) Molander, G. A.; Rahn, B. J.; Shubert, D. C.; Bonde, S. E.
Tetrahedron Lett. 1983, 24, 5449. (b) Itami, K.; Higashi, S.; Mineno, M.;
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Y.; Yoshimoto, Y.; Nakamura, M. Angew. Chem. 2011, 123, 11204.
Angew. Chem., Int. Ed. 2011, 50, 10973.
4820
Org. Lett., Vol. 14, No. 18, 2012

2-chloroquinoline (1f) or 1-chloroisoquinoline (1g) were
completed in 5 min and gave the expected phenylated
N-heterocycles 3e and 3f in 88À90% yield (entries 6 and 7).
The cross-coupling was also extended to diazines. Whereas
the 2-chloropyrimidine derivative 1h reacted with PhMgCl
within 2 h providing the arylated pyrimidine 3g in 76%
yield (entry 8), the more sensitive chloropyridazine 1i
and -pyrazine 1j required 3À5 h for the reaction to go to
completion but led to the phenylated products in only
22À24% yields (entries 9 and 10).13
smoothly underwent cross-coupling with 2-chloroquino-
line leading to the 2-arylated quinoline 3x in 84% yield
(entry 15). An amino substituent did not disturb the cross-
coupling, and the Grignard reagent 2n reacted with
1f within 5 min providing the product 3y in 82% yield
(entry 16).
Even though the mechanism of this cross-coupling could
not yet be elucidated, we noticed that the use of Fe(II) or
Fe(III) salt led to similar results. Reducing the Fe(III)
catalyst in situ with iPrMgCl prior to cross-coupling
deactivated the catalytic system and hampered the cou-
pling reaction. The use of an apolar cosolvent such as
tBuOMe was found to be vital to achieving high yields
mainly by avoiding homocoupling products.
In summary, we have developed a new practical iron-
catalyzed sp2Àsp2 cross-coupling between N-heterocyclic
chlorides or bromides and various arylmagnesium reagents.
This cross-coupling reaction tolerates several electron-
withdrawing and -rich functionalities, such as dimethyl-
amino, tert-butoxyoxycarbonyl (OBoc), or methoxy groups.
Further studies to increased the reaction scope as well as
mechanistic investigations are currently underway in our
laboratories.
We have then varied the nature of the Grignard
reagent14 using typical N-heterocyclic chlorides and bro-
mides (1b, 1f, 1g) as electrophiles (Table 3). In all cases, the
Fe-catalyzed cross-couplings were fast (2 min to 5 h) and
led to complete conversion. Both electron-rich and -poor
substituents can be present in the Grignard reagent. We
have examined first the substitution pattern of the aryl-
magnesium reagent and have found that ortho-, meta-, and
para-substituted Grignard reagents can be used. Whereas
m-TolMgBr LiCl (2b) and p-TolMgBr LiCl (2c) react at
3
3
similar rates as the unsubstituted magnesium reagent, the
presence of an ortho-methyl substituent in o-TolMgBr
3
LiCl (2d) reduced the reaction rate (compare entry 3 of
Table 3 with entry 6 of Table 2). However, in all cases
excellent yields (80À93%; entries 1À3 of Table 3) were
obtained. Various electron-poor substituents such as a
trifluoromethyl group (as in 3-trifluoromethyl- magnesium
bromide 2e and in 3,5-ditrifluorophenylmagnesium bro-
mide 2f; entries 4À6), a fluorine group (as in 4-fluo-
rophenylmagnesium bromide 2g; entries 7 and 8), and
a chlorine group (as in 2h; entry 9) were well tolerated in
the cross-couplings providing the expected products in
66À92% yields (entries 4À9). Interestingly, also electron-
rich substituents such as methoxy (see reagents 2i and 2j;
entries 10À12), methylenedioxy (see reagent 2k; entry 13),
and pivalate groups (OPiv; see reagent 2l; entry 14) were
compatible with rapid iron-catalyzed cross-couplings. The
more sensitive Boc-protected Grignard reagent 2m also
Acknowledgment. The research leading to these results
has received funding from the European Research Council
under the European Community’s Seventh Framework
Programme (FP7/2007-2013) ERC Grant Agreement
No. 227763. We thank the Fonds der Chemischen Indus-
trie for financial support and are grateful to BASF AG
and Chemetall GmbH for the generous gift of chemicals.
O.M.K. thanks the Novartis Pharma AG for financial
support.
Supporting Information Available. Experimental pro-
cedures and characterization data of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
ꢂ
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Grignard reagent.
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(11) The low yields in entries 1À14 of Table 1 are due to the fact that
the reaction conversion never reaches 100% for these substrates.
(12) Since PhMgCl is prepared in THF, the cross-coupling reaction is
in fact performed in a mixture of THF and tBuOMe (ca. 2:5).
(13) The use of other heterocyclic halides, such as 3- and 4-chlo-
ropyridine, 2-chlorothiophene, or 2-bromofuran, as well as standard
haloarenes resulted in only low yields.
(14) The Grignard reagents were prepared by LiCl-mediated Mg
insertion; see: Piller, F. M.; Metzger, A.; Schade, M. A.; Haag, B. A.;
Gavryushin, A.; P. Knochel, P. Chem.;Eur. J. 2009, 15, 7192.
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9844. (b) Hatakeyama, T.; Hashimoto, S.; Ishizuka, K.; Nakamura, M.
J. Am. Chem. Soc. 2009, 131, 11949.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 18, 2012
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