Preparation of functionalized aryl iron(II) compounds and a nickel-catalyzed cross-coupling with alkyl halides

Article abstract of DOI:10.1002/anie.200905196

The ortho-ferration of functionalized arenes using tmp2Fe-2MgCl2-4 LiCl furnishes the corresponding diorgano Fell reagents at 258C in high yields. These reagents undergo cross-coupling reactions in the presence of 4-fluorostyrene to give various alkylated arenes. It turned out that Nill impurities present in commercial FeCl2 (98% pure] catalyzed this alkyl-aryl cross-coupling reaction.

Full text of DOI:10.1002/anie.200905196

Angewandte
Chemie
DOI: 10.1002/anie.200905196
Directed Ferration
Preparation of Functionalized Aryl Iron(II) Compounds and a Nickel-
Catalyzed Cross-Coupling with Alkyl Halides**
Stefan H. Wunderlich and Paul Knochel*
Iron-catalyzed cross-coupling reactions of organometallic
reagents have found numerous applications in organic syn-
thesis.[1] Although this method has found wide acceptance,[2]
the mechanism of the cross-coupling is still not completely
elucidated.[3] This goal may be achieved by preparing
stoichiometric amounts of organometallic Fe compounds
and studying their stability and reactivity towards electro-
philes.[4] Although aryl FeII derivatives can be prepared by
ined, and such impurities were found to catalyze this cross-
coupling reaction.
Thus, the reaction of tmpMgCl·LiCl[8] (2 equiv) with
FeCl2·2LiCl[12] (1 equiv) at 08C and further stirring at 258C
for 3 h produces quantitatively tmp2Fe·2MgCl2·4LiCl (1).
This base has excellent solubility in THF (0.5m) and can be
stored in solution without decomposition for at least eight
weeks at 258C. The reaction of 1 with ethyl-3-fluorobenzoate
(2a; 258C, 3 h) leads to the corresponding diaryl FeII species
3a, which reacted smoothly with 1-iodooctane (1.2 equiv) to
provide the 1,2,3-trisubstituted benzoate 5a in 86% yield. The
reaction time was 14 h, but by adding 4-fluorostyrene (4; 10
mol%), the cross-coupling was complete within 7 h at 258C
(88% yield; Table 1, entry 1). 4-Fluorostyrene is known to
promote Ni-catalyzed cross-coupling reactions.[11] It is
assumed that it accelerates the reductive elimination step
through a coordination of the electron-poor olefin to the
metal center.
transmetalation[5] or by direct ferration using
a
tetramethylethylenediamine(tmeda)-stabilized sodium fer-
rate base,[6] no iron base has been reported that allows for
the general preparation of organometallic aryl FeII com-
pounds.
Building on our previous reports on LiCl-solubilized
Mg,[7] Zn,[8] Al,[9] and Mn[10] tmp bases (tmp = 2,2,6,6-tetra-
methylpiperidyl), we now report a new convenient iron(II)
base tmp2Fe·2MgCl2·4LiCl (1), which allows room-temper-
ature ferration of a broad range of functionalized arenes 2 to
diaryl FeII derivatives 3. A subsequent efficient cross-coupling
with alkyl iodides (or bromides) and benzylic chlorides
promoted by 4-fluorostyrene (4)[11] resulted in the formation
of polyfunctional arenes 5 in 60–88% yield (Scheme 1). The
importance of metallic impurities in FeCl2·2LiCl was exam-
Table 1: Influence of the purity of FeCl2 and additives on the cross-
coupling yield.
Entry Additive[a] Yield [%][b]
Entry Additive[a]
Yield [%]
1
2
3
4
5
6
7
8
9
–
–
95[c] (88)
25[d]
10
11
12
13
14
15
16
17
NiCl2, MnCl2
MnCl2, FeCl3
88[d]
18[d]
MnCl2
CoCl2
CuCl2
CuCl
FeCl3
NiCl2
NiCl2,
FeCl3
20[d]
NiCl2, MnCl2, FeCl3 74[d]
34[d]
CuCl2, FeCl3
CuCl2, NiCl2
CuCl2, MnCl2
18[d]
85[d]
26[d]
27[d]
23[d]
Scheme 1. Preparation and reactions of 1. DG: directing group; FG:
functional group.
12[d]
CuCl2, NiCl2, FeCl3 65[d]
CuCl2, MnCl2, FeCl3 17[d]
94[d] (86)
69[d]
[*] S. H. Wunderlich, Prof. Dr. P. Knochel
Ludwig Maximilians-Universitꢀt Mꢁnchen, Department Chemie &
Biochemie
[a] 0.5% of the additive was used. In the case of several additives,
equimolar amounts were used. [b] Yields in brackets refer to yield of
isolated, analytically pure product. [c] FeCl2 with a purity grade of 98%
was used. [d] FeCl2 with a purity grade of 99.998% was used.
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
Fax: (+49)892-1807-7680
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie, the European
Research Council (ERC) and the Deutsche Forschungsgemeinschaft
(DFG) for financial support. We also thank Evonik AG (Hanau),
BASF AG (Ludwigshafen), W. C. Heraeus GmbH (Hanau), and
Chemetall GmbH (Frankfurt) for the generous gift of chemicals.
Although the purity of FeCl2 did not modify the metal-
ation rate leading to 3a, it considerably influences the cross-
coupling step. Thus, we observed that by using FeCl2 with a
purity of 99.998%, the cross-coupling conversion to 5a after a
reaction time of 8 h is only 25% rather than the 95%
achieved using 98% pure FeCl2 (Table 1, entries 1 and 2).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200905196.
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Since atomic absorption analysis revealed that the commer-
Remarkably, this tandem metalation/cross-coupling pro-
cedure could be extended to various organic halides. Thus, the
ferration of ethyl-3-chlorobenzoate (2b) and methyl-3-chlor-
obenzoate (2c) using 1 proceeds within 36 h at 258C, and the
subsequent couplings with an alkyl iodide and a benzylic
chloride, respectively, provide the desired products 5i,j in 71
and 66% yield (Table 3, entries 1 and 2). Similarly, the cyano-
substituted ethyl benzoates 2d,e are metalated at 258C within
18 and 48 h, respectively. Subsequent cross-coupling reactions
with aliphatic iodides furnish the alkylated products 5k,l in 75
and 65% yield (entries 3 and 4). Fluoro-substituted benzoni-
triles are also excellent substrates. Thus, the metalation of 3-
cial sample of 98% pure FeCl2 contains traces of Mn, Ni, Co,
and Cu, small amounts (0.5%) of the corresponding chlorides
were intentionally added to FeCl2 (99.998%).[13]
Whereas FeCl3, CoCl2, MnCl2, CuCl2, and CuCl only
moderately changed the cross-coupling rate (Table 1,
entries 3–7), the addition of 0.5% NiCl2 restored the full
cross-coupling rate observed with 98% pure FeCl2 (entry 8).
Interestingly, combinations of two or three metallic chlorides
produced intermediate cross-coupling rates (entries 9–17). In
conclusion, the presence of 0.25% Ni in commercial FeCl2 is
certainly responsible for the observed cross-coupling reaction
rate. From a practical point of view, FeCl2 (98% pure) has
been used for preparing tmp2Fe (1), and most of the
subsequent cross-coupling reactions were performed in the
presence of 4-fluorostyrene (4; 10 mol%).[11]
Table 3: Preparation of diaryl FeII derivatives and cross-coupling with
various organic halides in the presence of 4 (10 mol%) leading to the
products of type 5.
Starting from ethyl-3-fluorobenzoate (2a), the cross-
coupling of 3a proceeds well with octyl iodide (Table 2,
entry 1). Octyl bromide reacts more slowly, providing after
Entry
Substrate
t [h]
Halide
Product
Yield [%][a]
Table 2: Cross-coupling of 3a with organic halides in the presence of 4
leading to the substitution products 5a–h.
1
2b
36
5i: 71
Entry Substrate
Halide
Product
Yield [%][a]
À
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
Oct I
À
Oct Br
5a: R=Oct
5a: R=Oct
5b: R=iPr
5c: R=cHex
5c: R=cHex
5d: R=Bn
88
74
70
83
60
88[b]
80
2
3
2c
2d
36
18
5j: 66[b]
5k: 75
À
iPr Br
À
cHex I
À
cHex Br
PhCH2Cl
I(CH2)3CO2Et 5e: R=(CH2)3CO2Et
ICH2P(O)(OEt)2 5 f: R=CH2P(O)(OEt)2 68[b]
I(CH2)6Cl
I(CH2)4CH
CH2
5g: R=(CH2)6Cl
5h: R=(CH2)4CH
CH2
85
77
=
=
10
4
5
2e
2 f
48
9
5l: 65
[a] Yield of isolated, analytically pure product. [b] No 4 was added.
5m: 70
20 h at 258C the product 5a in 74% yield (entry 2). Also,
À
À
secondary alkyl iodides and bromides such as iPr Br, cHex I,
À
and cHex Br lead to the corresponding cross-coupling
products 5b,c in 60–83% yield (entries 3–5). In the absence
of 4-fluorostyrene (4), an efficient reaction with benzyl
chloride was observed, furnishing the benzylated arene 5d
in 88% yield (entry 6). Remarkably, various functionalized
alkyl iodides undergo smooth cross-coupling reactions. Thus,
the reaction of 3a with ethyl-4-iodobutyrate (1.2 equiv) leads
to the desired diester 5e in 80% yield (entry 7). Diethyl
iodomethylphosphonate reacts rapidly with 3a at À108C in
the absence of 4-fluorostyrene (4) to give the phosphonate 5 f
in 68% yield (entry 8). Interestingly, the dihalide 1-chloro-6-
iodohexane undergoes only a substitution of the carbon–
iodine bond, providing the benzoate 5g in 85% yield
(entry 9). Surprisingly, the reaction of 3a with 6-iodohex-1-
ene provided only the alkenylated product 5h in 77% yield
without any cyclization product (entry 10).[14]
6
7
2g
2h
18
10
5n: 72[b]
5o: 77
À
Dec I
À
Oct I
8
9
2i
2j
30
60
5p: 85
5q: 66
À
Hex I
[a] Yield of isolated, analytically pure product. [b] No 4 was added.
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Angewandte
Chemie
fluorobenzonitrile (2 f) with 1 (0.75 equiv, 258C) is completed
within 9 h, whereas the metalation of 4-fluorobenzonitrile
(2g) requires 18 h. Alkylation with 6-iodo-2,2-dimethylhex-
anenitrile and diethyl iodomethylphosphonate produces the
functionalized benzonitriles 5m,n in 70 and 72% yield
(entries 5 and 6). Interestingly, the metalation of 1,3-difluor-
obenzene (2h) is completed within 10 h and the reaction with
1-iododecane leads to the alkylated benzene 5o in 77% yield
(entry 7). Moreover, the protected phenols 2i and 2j are
deprotonated by tmp2Fe at 258C within 30 and 60 h,
respectively. After alkylation reactions with 1-iodooctane or
1-iodohexane, the substituted products 5p,q are obtained in
85 and 66% yield (entries 8 and 9).
To gain some mechanistic insight into the reactivity of
organometallic Fe intermediates, we treated tmpMgCl·LiCl
(3.0 equiv) with FeCl3 (1.0 equiv) in THF. Surprisingly,
Mꢀssbauer spectroscopy (see the Supporting Information)
indicated that the product is mainly an FeII amide (70% yield
compared to 95% yield for the preparation of 1 starting from
FeCl2·2LiCl). This reagent 6 has a comparable stability to 1
and induces smooth deprotonation (0.75 equiv, 258C, 3 h) of
ethyl-3-fluorobenzoate (2a), leading to the corresponding
iron(II) derivative. Its cross-coupling with octyl iodide in the
presence of 4-fluorostyrene (4) proceeds with similar rate as
the analogous reaction with FeII base 1 and provides the
corresponding cross-coupling product 5a in 72% yield
(compared to 88% with 1, Table 1, entry 1).
Keywords: cross-coupling · directed metalation · ferration ·
homogeneous catalysis · nickel
.
[1] For reviews, see: a) C. Bolm, J. Legros, J. LePiah, L. Zani, Chem.
Rev. 2004, 104, 6217; b) B. D. Sherry, A. Fꢁrstner, Acc. Chem.
Res. 2008, 41, 1500.
[2] a) A. Fꢁrstner, M. Mꢂndez, Angew. Chem. 2003, 115, 5513;
Angew. Chem. Int. Ed. 2003, 42, 5355; b) A. Fꢁrstner, A. Leitner,
M. Mꢂndez, H. Krause, J. Am. Chem. Soc. 2002, 124, 13856; c) A.
Fꢁrstner, R. Martin, H. Krause, G. Seidel, R. Goddard, C. W.
Lehmann, J. Am. Chem. Soc. 2008, 130, 8773; d) J. Norinder, A.
Matsumoto, N. Yoshikai, E. Nakamura, J. Am. Chem. Soc. 2008,
130, 5858; e) M. Nakamura, K. Matsu, S. Ito, E. Nakamura, J.
Am. Chem. Soc. 2004, 126, 3686; f) G. Cahiez, L. Foulgoc, A.
Moyeux, Angew. Chem. 2009, 121, 3013; Angew. Chem. Int. Ed.
2009, 48, 2969; g) G. Cahiez, V. Habiak, C. Duplais, A. Moyeux,
Angew. Chem. 2007, 119, 4442; Angew. Chem. Int. Ed. 2007, 46,
4364; h) I. Sapountzis, W. Lin, C. C. Kofink, C. Despotopoulou,
P. Knochel, Angew. Chem. 2005, 117, 1682; Angew. Chem. Int.
Ed. 2005, 44, 1654; i) C. Duplais, F. Bures, I. Sapountzis, T. J.
Korn, G. Cahiez, P. Knochel, Angew. Chem. 2004, 116, 3028;
Angew. Chem. Int. Ed. 2004, 43, 2968; j) M. Carril, A. Correa, C.
Bolm, Angew. Chem. 2008, 120, 4940; Angew. Chem. Int. Ed.
2008, 47, 4862; k) O. Bistri, A. Correa, C. Bolm, Angew. Chem.
2008, 120, 596; Angew. Chem. Int. Ed. 2008, 47, 586; l) A. Correa,
M. Carril, C. Bolm, Angew. Chem. 2008, 120, 2922; Angew.
Chem. Int. Ed. 2008, 47, 2880; m) A. Correa, C. Bolm, Angew.
Chem. 2007, 119, 9018; Angew. Chem. Int. Ed. 2007, 46, 8862;
n) R. B. Bedford, M. Huwe, C. M. Wilkinson, Chem. Commun.
2009, 600; o) R. B. Bedford, M. Betham, D. W. Bruce, A. A.
Danopoulos, R. M. Frost, M. Hird, J. Org. Chem. 2006, 71, 1104;
p) A. Guꢂrinot, S. Reymond, J. Cossy, Angew. Chem. 2007, 119,
6641; Angew. Chem. Int. Ed. 2007, 46, 6521.
In summary, we have described a convenient directed
ferration of various polyfunctional aromatics. This metalation
procedure tolerates many functional groups (methyl and ethyl
esters, halogen atoms, nitriles) and proceeds at 258C. More-
over, we reported that the subsequent cross-coupling reaction
with functionalized organic halides is catalyzed by the Ni
impurities of commercial FeCl2. Further studies on the
reaction scope of this cross-coupling are currently underway.
[3] a) A. Fꢁrstner, Angew. Chem. 2009, 121, 1390; Angew. Chem.
Int. Ed. 2009, 48, 1364; b) A. Fꢁrstner, K. Majima, R. Martin, H.
Krause, E. Kattnig, R. Goddard, C. W. Lehmann, J. Am. Chem.
Soc. 2008, 130, 1992; c) A. Fꢁrstner, H. Krause, C. W. Lehmann,
Angew. Chem. 2006, 118, 454; Angew. Chem. Int. Ed. 2006, 45,
440; d) R. Martin, A. Fꢁrstner, Angew. Chem. 2004, 116, 4045;
Angew. Chem. Int. Ed. 2004, 43, 3955.
[4] C. Kishan Reddy, P. Knochel, Angew. Chem. 1996, 108, 1812;
Angew. Chem. Int. Ed. Engl. 1996, 35, 1700.
[5] a) T. Kauffmann, Angew. Chem. 1996, 108, 401; Angew. Chem.
Int. Ed. Engl. 1996, 35, 386; b) H. Bꢁrger, U. Wannagat,
Monatsh. Chem. 1963, 94, 1007.
Experimental Section
1: In a dry and argon-flushed 250 mL Schlenk flask, freshly titrated
tmpMgCl·LiCl (100 mmol, 1.18m, 85 mL) was purged and cooled to
08C. Then, FeCl2·2LiCl (1m in THF, 50 mL, 50 mmol) was added over
5 min. The resulting mixture was stirred for 30 min at 08C, warmed to
258C, and stirred for another 3 h. The resulting solution of 1 was
concentrated in vacuo and was titrated prior to use at 08C with
benzoic acid (0.2m in THF) using 4-(phenylazo)diphenylamine as
indicator. A concentration of 0.5m in THF was obtained (95% yield).
5a: A dry and argon-flushed 25 mL Schlenk tube, equipped with
a magnetic stirring bar and septum was charged with a solution of 2a
(336 mg, 2 mmol) in anhydrous THF (1 mL). Compound 1 (0.5m in
THF, 3.0 mL, 1.5 mmol) was added dropwise, and the reaction
mixture was stirred at 258C for 3 h. Then, 4 (24 mg, 0.2 mmol) was
added and subsequently 1-iodooctane (576 mg, 2.4 mmol). The
mixture was stirred for 7 h at 258C. After standard workup, the
solvent was evaporated in vacuo. The crude product was purified by
column chromatography (SiO2; pentane/diethyl ether 100:1) to give
5a (493 mg, 88% yield) as a colorless liquid.
[6] P. Alborꢂs, L. M. Carrella, W. Clegg, P. Garcꢃ-ꢄlvares, A. R.
Kennedy, J. Klett, R. E. Mulvey, E. Rentschler, L. Russo, Angew.
Chem. 2009, 121, 3367; Angew. Chem. Int. Ed. 2009, 48, 3317.
[7] a) A. Krasovskiy, V. Krasovskaya, P. Knochel, Angew. Chem.
2006, 118, 3024; Angew. Chem. Int. Ed. 2006, 45, 2958; b) W. Lin,
O. Baron, P. Knochel, Org. Lett. 2006, 8, 5673; c) N. Boudet, J. R.
Lachs, P. Knochel, Org. Lett. 2007, 9, 5525; d) N. Boudet, S. R.
Dubbaka, P. Knochel, Org. Lett. 2008, 10, 1715; e) A. H. Stoll, P.
Knochel, Org. Lett. 2008, 10, 113; f) M. Mosrin, P. Knochel, Org.
Lett. 2008, 10, 2497; g) G. C. Clososki, C. J. Rohbogner, P.
Knochel, Angew. Chem. 2007, 119, 7825; Angew. Chem. Int. Ed.
2007, 46, 7681; h) C. J. Rohbogner, G. C. Clososki, P. Knochel,
Angew. Chem. 2008, 120, 1526; Angew. Chem. Int. Ed. 2008, 47,
1503.
[8] a) S. H. Wunderlich, P. Knochel, Angew. Chem. 2007, 119, 7829;
Angew. Chem. Int. Ed. 2007, 46, 7685; b) S. H. Wunderlich, P.
Knochel, Org. Lett. 2008, 10, 4705; c) S. H. Wunderlich, P.
Knochel, Chem. Commun. 2008, 47, 6387; d) M. Mosrin, P.
Knochel, Org. Lett. 2009, 11, 1837.
Received: September 16, 2009
Published online: November 18, 2009
[9] S. H. Wunderlich, P. Knochel, Angew. Chem. 2009, 121, 1530;
Angew. Chem. Int. Ed. 2009, 48, 1501.
Angew. Chem. Int. Ed. 2009, 48, 9717 –9720
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
9719

Communications
[10] S. H. Wunderlich, M. Kienle, P. Knochel, Angew. Chem. 2009,
Angew. Chem. 2005, 117, 3007; Angew. Chem. Int. Ed. 2005, 44,
2947.
121, 7392; Angew. Chem. Int. Ed. 2009, 48, 7256.
[12] I. Solinas, H. D. Lutz, J. Solid State Chem. 1995, 117, 34.
[13] a) S. L. Buchwald, C. Bolm, Angew. Chem. 2009, 121, 5694;
Angew. Chem. Int. Ed. 2009, 48, 5586; b) P.-F. Larsson, A.
Correa, M. Carril, P.-O. Norrby, C. Bolm, Angew. Chem. 2009,
121, 5801; Angew. Chem. Int. Ed. 2009, 48, 5691.
[14] a) V. B. Phapale, D. J. Cardenas, Chem. Soc. Rev. 2009, 38, 1598;
b) V. B. Phapale, D. J. Cardenas, Angew. Chem. 2007, 119, 8946;
Angew. Chem. Int. Ed. 2007, 46, 8790.
[11] a) A. Devasagayaraj, T. Stꢁdemann, P. Knochel, Angew. Chem.
1995, 107, 2952; Angew. Chem. Int. Ed. Engl. 1995, 34, 2723;
b) R. Giovannini, T. Stꢁdemann, G. Dussin, P. Knochel, Angew.
Chem. 1998, 110, 2512; Angew. Chem. Int. Ed. 1998, 37, 2387;
c) R. Giovannini, T. Stꢁdemann, A. Devasagayaraj, G. Dussin, P.
Knochel, J. Org. Chem. 1999, 64, 3544; d) A. E. Jensen, P.
Knochel, J. Org. Chem. 2002, 67, 79; e) T. J. Korn, P. Knochel,
9720 www.angewandte.org
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