Highly selective metalations of pyridines and related heterocycles using new frustrated lewis pairs or tmp-zinc and tmp-magnesium bases with bf 3·oet2

Article abstract of DOI:10.1002/anie.201002031

(Figure Presented) Efficient and selective: Frustrated Lewis pairs based on BF₃·OEt₂ and LiCl-com-plexed tmpMg or tmpZn amides (tmp = 2,2,6,6-tetramethylpiperidyl) allow the efficient and regioselective metalation of various functionalized N heterocycles (see scheme for examples). Moreover, such metalations carried out in the presence or absence of BF ₃·OEt₂ enable a complete switch of regioselectivity, thus allowing complementary fuctionalization.

Full text of DOI:10.1002/anie.201002031

Angewandte
Chemie
DOI: 10.1002/anie.201002031
Frustrated Lewis Pairs
Highly Selective Metalations of Pyridines and Related Heterocycles
Using New Frustrated Lewis Pairs or tmp-Zinc and tmp-Magnesium
Bases with BF3·OEt2**
Milica Jaric, Benjamin A. Haag, Andreas Unsinn, Konstantin Karaghiosoff, and Paul Knochel*
Dedicated to Professor Rolf Huisgen on the occasion of his 90th birthday
The functionalization of pyridines and quinolines is a major
synthetic goal since many of these heterocycles have impor-
tant biological properties[1] or are of interest as new materi-
als.[2] The regioselective functionalization of these heterocy-
frustrated Lewis pairs[13,14] such as tmpMgCl·BF3·LiCl (9)
derived from the strong Lewis base tmp and the strong Lewis
acid BF3·OEt2.
The complexation of 4-phenylpyridine (5a) with BF3·OEt2
(1.1 equiv, 08C, 15 min) furnishes 6. The subsequent addition
of tmpMgCl·LiCl (1; 1.1 equiv, ꢀ408C, 20 min) generates a
metalated pyridine derivative, which after transmetalation
with ZnCl2 and a subsequent Negishi cross-coupling[15] with
ethyl 4-iodobenzoate (7a) affords the 2-arylated pyridine 8a
in 84% yield (Scheme 1).
clic scaffolds has been achieved by direct metalation[3] or
[4]
ꢀ
metal-catalyzed C H activation. The stoichiometric lithia-
tion of unactivated pyridines is often complicated because of
Tchitchibabin-type dimerizations.[5] An elegant solution has
been proposed by Kessar et al., who showed that the
complexation of pyridine with BF3 allows the low-temper-
ature a-lithiation of pyridine[6] and other amino
derivatives.[7] Michl and co-workers described the
BF3-assisted metalation of 3-alkylpyridines with
BF3·OEt2 and lithium tmp zincates.[8] Recently, we
reported the preparation of highly chemoselective
LiCl-complexed 2,2,6,6-tetramethylpiperidyl (tmp)
metal amide bases, such as tmpMgCl·LiCl (1),[9]
tmpZnCl·LiCl (2),[10] tmp2Zn·2MgCl2·2LiCl (3),[11]
and tmp3Al·3LiCl (4),[12] which allow the selective
metalation of sensitive aromatic compounds and
heterocycles. However, attempts to magnesiate,
zincate, or aluminate unactivated pyridines with
such bases proved to be unsatisfactory. For example,
the use of 1 (1.1 equiv, 258C) led to only a partial
magnesiation being observed (less than 40%). This
Scheme 1. BF3-triggered accelerated metalations. [a] Pd cat.: [Pd(dba)2] (5 mol%);
P(2-furyl)3 (10 mol%), ꢀ408C!258C, 12 h. dba=trans,trans-dibenzylideneace-
tone.
led us to consider metalations with the tmp bases 1–4
in the presence of BF3·OEt2. Herein, we report a
ꢀ
convenient regioselective C H activation of various
polyfunctional pyridines and related heterocycles by
a stepwise activation with BF3·OEt2 followed by
metalation with the appropriate tmp base. We also describe
an unexpected alternative metalation method involving new
To clarify the nature of the generated organometallic
intermediate we performed an alternative experiment, in
which 4-phenylpyridine (5a) was treated with a premixed
solution of BF3·OEt2 (1.1 equiv) and tmpMgCl·LiCl
(1; 1.1 equiv, ꢀ408C, 10 min), tentatively written as
tmpMgCl·BF3·LiCl (9). Surprisingly, an efficient metalation
with the reagent 9 occurs within 10 minutes at ꢀ408C.
[*] Dipl.-Chem. M. Jaric, Dipl.-Chem. B. A. Haag, Dipl.-Chem. A. Unsinn,
Prof. Dr. K. Karaghiosoff, Prof. Dr. P. Knochel
Department Chemie, Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
Fax: (+49)89-2180-77680
[16]
Transmetalation with ZnCl2 and a Negishi cross-coupling
reaction[15] with the aryl iodide 7a provides product 8a in
comparable yield (70%). This result implies that the new
frustrated Lewis pair 9 is unexpectedly reactive for the
metalation of pyridines.[13,14]
We have examined the mechanism and scope of this
reaction in more detail. 11B NMR, 19F NMR, and 13C NMR
spectroscopic measurements clearly indicate that the inter-
mediate organometallic species 10 contains a carbon–boron
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie, the European
Research Council (ERC), the Deutsche Forschungsgemeinschaft
(DFG), and SFB 749 for financial support. We also thank BASF AG
(Ludwigshafen), W. C. Heraeus (Hanau), and Chemetall GmbH
(Frankfurt) for the generous gift of chemicals. tmp=2,2,6,6-
tetramethylpiperidyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002031.
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Communications
bond, as depicted in Scheme 1.[17,18] This structure has also
258C, 12 h), the pyridyl ketone 8b in 84% yield (Scheme 3).
The lithiation of 2-methoxypyridine (5c) with lithium super-
bases produces a mixture of products unless a large excess of
been supported by DFT calculations.[19] Thermodynamic
analysis by DFT calculations shows that the structure 10A
ꢀ1
ꢀ
(with a C B bond) is 13.5 kcalmol thermodynamically
ꢀ
more stable than the isomeric structure 10B (with a C Mg
bond; Scheme 2). This finding indicates that otherwise
Scheme 3. Regioselective metalation of N heterocycles with the frus-
trated Lewis pair 9. a) 9 (1.1 equiv), THF, ꢀ408C, 15 min; b) CuCN·2
LiCl (1.1 equiv), ꢀ408C, 30 min; 7b (0.8 equiv), ꢀ408C!258C, 12 h;
c) CuCN·2LiCl (1.1 equiv), ꢀ408C, 30 min; 7c (0.8 equiv), ꢀ408C to
258C, 12 h; d) 9 (1.1 equiv), THF, ꢀ408C, 30 min; e) ZnCl2 (1.1 equiv),
ꢀ408C, 30 min; 7d (0.8 equiv), [Pd(dba)2] (5 mol%), P(2-furyl)3
(10 mol%), ꢀ408C!258C, 12 h; f) 9 (1.1 equiv), THF, ꢀ408C,
10 min; g) I2, (1.5 equiv), ꢀ408C!258C, 10 min.
base is added.[24] However, a regioselective metalation can be
achieved
by
using
the
frustrated
Lewis
pair
tmpMgCl·BF3·LiCl (9) to produce, after acylation with 2-
furoyl chloride (7c), the 2,6-disubstituted pyridine (8c) in
76% yield. The metalation of electron-poor pyridines such as
5d cannot be performed with any conventional lithium base
because of extensive decomposition.[25] The new reagent 9
allows this synthetic problem to be overcome. Thus, treatment
of ethyl nicotinate (5d) with 9 (1.5 equiv, ꢀ408C, 30 min)
furnishes an organometallic intermediate, which undergoes a
smooth Negishi cross-coupling reaction[15] with 1-iodo-3-
(trifluoromethyl)benzene (7d) to give the functionalized
pyridine 8d in 71% yield. Other related sensitive hetero-
cycles, such as 2-(methylthio)pyrazine (5e), are metalated
with 9 (1.1 equiv, ꢀ408C, 10 min) to give 2-iodo-3-(methyl-
thio)pyrazine (8e) in 81% yield after iodolysis (Scheme 3).
To demonstrate the synthetic potential of 9 we have
prepared two biologically active molecules: an antihistaminic
drug, carbinoxamine (11),[26] and the haplophyllum alkaloid,
dubamine (12),[27] in two one-pot procedures (Scheme 4).
Scheme 2. Structure and reactivity of the frustrated Lewis pair 9.
difficult to prepare pyridyltrifluoroborates can be readily
obtained in a one-pot procedure by highly regioselective C H
ꢀ
activations.[16,20,21] The exact structure of the reagent 9 could
not be clearly defined, despite numerous NMR studies.
However, DFT calculations led to the tentative structures
9A and 9B, with both energetically favored.[17] NMR studies
confirm that 9 exists as several species in solution. The
reaction pathways of 9A and 9B in the presence of pyridine
(Py) have been modeled by DFT calculations, which reveal
that 9A and 9B may dissociate in the presence of pyridine to
furnish a Py·BF3 complex (6A) as well as tmpMgCl(thf)2
(1A). The reaction of 6A with 1A proceeds thereafter via
TS-1, which has a particularly low activation barrier (1.9 kcal
molꢀ1), to eventually afford complex 10A.[22] The
alternative pathway involving the direct metalation
of pyridine with 9A or 9B (no prior dissociation)
via TS-2 has comparably a much higher activation
energy (12.4 kcalmolꢀ1). This calculation highlights
the frustrated Lewis pair character of 9 and the
facile reversibility of its formation in the presence
of an appropriate substrate (such as pyridine), and
led us to examine the synthetic utility and reaction
scope of this new class of reagents.
Pyridine
(5b)
similarly
reacts
with
tmpMgCl·BF3·LiCl (9; 1.1 equiv, ꢀ408C, 15 min)
and furnishes, after transmetalation with
CuCN·2LiCl[23] and a subsequent acylation with
4-chlorobenzoyl chloride (7b; 0.8 equiv, ꢀ408C to Scheme 4. One-pot preparation of carbinoxamine (11) and dubamine (12).
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Angewandte
Chemie
Table 1: Switchable, regioselective metalations of N heterocycles with
tmp bases in the presence or absence of BF3·OEt2.
Treatment of 5b with 9 (1.1 equiv, ꢀ408C, 15 min) followed
by the addition of 4-chlorobenzaldehyde (7e) led to
the alcoholate 13, which was treated in situ with
Cl(CH2)2NMe2·HCl (7 f; 1.2 equiv) and NaH (1.2 equiv,
508C, 2 h); this sequence provided carbinoxamine (11) in
72% yield. Similarly, the reaction of quinoline (5 f) with 9
(1.1 equiv, ꢀ408C, 15 min) furnishes the intermediate 14.
Transmetalation with ZnCl2 and a subsequent Negishi cross-
coupling reaction[15] with the aryl iodide 7g affords dubamine
(12) in 79% yield (Scheme 4).
Entry Substrate
TMP base metalation BF3-triggered metalation
(procedure A)[a]
(procedure B)[a]
1
5g
15a: 85%[b]
16a: 83%[c]
During the study of the reaction scope of 9, we realized
that a two-step metalation with prior precomplexation with
BF3·OEt2 and subsequent addition of TMPMgCl·LiCl (1),
TMP2Zn·2MgCl2·LiCl
(3),
or
[(tBu)NCH(iPr)-
2
3
5h
15b: 72%[d,e]
16b: 74%[d,e]
(tBu)]3Al·3LiCl (4a) in a second step is more flexible and
often results in higher yields.[28] This two-step metalation
allows, in a number of cases, a complete switch of regiose-
lectivity by using either tmp-derived bases 1–4 without
BF3·OEt2 (metalation procedure A) or metalation of BF3-
precomplexed N heterocycles (metalation procedure B;
Table 1).
5i
15c: 75%[f,e]
16c: 78%[f,g]
Thus, 2-phenylpyridine (5g) is selectively magnesiated
with 1 (2 equiv, 558C, 30 h) at the ortho position of the phenyl
substituent; a subsequent iodolysis then gives the aryl iodide
15a (85% yield). In contrast, precomplexation with BF3·OEt2
(1.1 equiv, 08C, 15 min) followed by the addition of 1
(1.5 equiv, 08C, 30 h) leads to a selective metalation in
position 6. Iodolysis of the intermediate affords 2-iodopyr-
idine derivative 16a (83% yield). A number of substituted
pyridines (5h–l; entries 2–6) display this remarkable switch in
selectivity. Thus, 3-fluoropyridine (5h) is magnesiated with 1
(1.1 equiv, ꢀ788C, 30 min) at position 2. After transmetala-
tion with ZnCl2 and a Negishi cross-coupling reaction[15] with
ethyl 4-iodobenzoate (7a), the 2,3-disubstituted pyridine 15b
is obtained in 72% yield (entry 2). Precomplexation with
BF3·OEt2 and metalation with 1 (1.1 equiv, ꢀ788C, 30 min)
provides the 4-metalated pyridine, which after cross-coupling
with the aryl iodide 7h furnished the 3,4-disubstituted
pyridine 16b (74% yield; entry 2). This complementary
functionalization is also observed for 3-chloropyridine (5i)
and 3-cyanopyridine (5j), and leads after similar reaction
sequences to the 2,3-disubstituted pyridines 15c and 15d (72
and 75%, respectively) and to the 3,4-disubstituted pyridines
16c and 16d (78 and 79%, respectively; Table 1, entries 3 and
4). The metalation of the electron-poor pyridine 5j is
especially remarkable since such sensitive heterocycles are
prone to polymerization during metalations. Thus, 5j can be
selectively metalated in position 2 by using 3 and furnishes,
after a Negishi cross-coupling reaction,[15] the 2,3-disubsti-
tuted pyridine 15d in 72% yield. Precomplexation with
BF3·OEt2 and zincation with 3 (ꢀ308C, 30 min) provides the
3,4-disubstituted product 16d (79% yield; entry 4) after
cross-coupling. Electron-deficient disubstituted pyridines
such as 3-bromo-4-cyanopyridine (5k) are metalated with 1
(1.1 equiv, ꢀ788C, 1 h), and a copper-mediated allylation[29]
with 3-bromocyclohexene (7i) affords the 1,2,3-trisubstituted
pyridine 15e (65% yield; entry 5). In contrast, selective
zincation occurs in position 4 after precomplexation with
BF3·OEt2 (1.1 equiv, 08C, 15 min) and subsequent reaction
4
5j
15d: 72%[h,e]
16d: 79%[i,e]
5
6
5k
5l
15e: 65%[j]
15 f: 68%[l,g]
16e: 63%[k,g]
16 f: 75%[m]
7
5m
15g: 68%[n,e]
16g: 94%[o,g]
[a] Yield of analytically pure isolated product. [b] 1 (558C, 30 h). [c] 1
(08C, 30 h). [d] 1 (ꢀ788C, 30 min). [e] Obtained by a palladium-catalyzed
cross-coupling with [Pd(dba)2] (5 mol%) and P(2-furyl)3 (10 mol%) at
258C for 12 h. [f] 1 (ꢀ788C, 45 min). [g] Obtained after transmetalation
with CuCN·2LiCl (1.1 equiv). [h] 3 (258C, 12 h). [i] 3 (ꢀ308C, 30 min).
[j] 1 (ꢀ788C, 1 h). [k] 3 (ꢀ788C, 1 h). [l] 4a (258C, 2 h). [m] 1 (08C, 60 h).
[n] 4a (ꢀ788C, 1 h). [o] 1 (08C, 1 h).
with 3. Subsequent allylation then affords the 3,4,5-trisub-
stituted pyridine 16e (63% yield; entry 5). Electron-rich
pyridines such as 2-methoxypyridine (5l) can also be depro-
tonated regioselectively by using in this case the aluminum
base 4a. In the absence of BF3·OEt2 this reaction leads, after
acylation, to the 2,3-substituted pyridine 15 f (68% yield;
entry 6). Precomplexation with BF3·OEt2 followed by metal-
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Communications
M. Nogueras, A. Marchal, J. Cobo, Tetrahedron Lett. 2010, 51,
1107.
ation with 1 and iodolysis provides 2-iodo-6-methoxypyridine
(16 f; 75% yield; entry 6). This regioselectivity has been
extended to functionalized quinoline derivatives. Thus,
6-methoxyquinoline (5m) is aluminated with 4a at posi-
tion 5.[30] After transmetalation with ZnCl2 and a subsequent
Negishi cross-coupling,[15] the 5,6-disubstituted quinoline 15g
is obtained in 68% yield. Precomplexation with BF3·OEt2 and
metalation with 1 leads, after a copper-mediated acylation, to
the 2,6-disubstituted quinoline 16g (94% yield; entry 7). The
regioselectivity of the metalation in the presence of BF3 may
be best explained in the case of 3-substituted pyridines by
assuming that the complexation of BF3 at the pyridine
nitrogen atom leads to a substantial steric hindrance at
position 2, thereby favoring metalation at position 4.
In summary, we have reported a new class of frustrated
Lewis pairs based on BF3·OEt2 and LiCl-complexed tmpMg
or tmpZn amides which allows an efficient, regioselective
metalation of various N heterocycles. This approach consti-
tutes an expeditive preparation of versatile magnesium
chloride heteroaryl trifluoroborates, expanding on the work
of Molander et al.[16,18,21] The metalation of various N hetero-
cycles with or without BF3·OEt2 by using hindered Mg, Zn, or
Al bases (1, 2, or 4a) allows a complementary regioselective
functionalization to generate a range of new polyfunctional
N heterocycles. An extension of this method to other
unsaturated substrates is currently underway.
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Experimental Section
16c (Table 1, entry 3): BF3·OEt2 (780 mg, 5.5 mmol) was added
dropwise to 3-chloropyridine (568 mg, 5.0 mmol) in dry THF (25 mL)
at 08C in a flame-dried Schlenk-flask, flushed with argon. The
resulting mixture was stirred for 15 min at 08C. Then tmpMgCl·LiCl
(1; 5.5 mmol, 4.6 mL, 1.2m in THF) was added dropwise at ꢀ788C
and the mixture stirred for 45 min. CuCN·2LiCl (5.5 mmol, 5.5 mL,
1m in THF) was then added at ꢀ788C. After 30 min, 2-furoyl chloride
(7c; 522 mg, 4 mmol) was added and the reaction mixture was
warmed slowly to 258C and then stirred for 12 h. The reaction mixture
was quenched with saturated NH4Cl solution (20 mL) and NH3
(conc.; 3 mL) before extracting with diethyl ether (3 ꢀ 30 mL).
Purification by flash column (pentane/diethyl ether, 1:1) furnished
pyridine derivative 16c as a brown oil (648 mg, 78%).
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Received: April 6, 2010
Published online: July 7, 2010
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Keywords: boranes · frustrated Lewis pairs · metalation ·
N heterocycles · regioselectivity
.
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[22] The reaction of pyridine with tmpMgCl(thf)2 has also been
modeled (see the Supporting Information).
[23] a) P. Knochel, M. Yeh, S. Berk, J. Talbert, J. Org. Chem. 1988, 53,
2390; b) P. Knochel, S. A. Rao, J. Am. Chem. Soc. 1990, 112,
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[28] Although 9 is conveniently prepared within 5 min at ꢀ408C, a
study of its stability reveals that it decomposes slowly in the
absence of a substrate within a few hours at ꢀ208C.
[29] F. Dꢆbner, P. Knochel, Angew. Chem. 1999, 111, 391; Angew.
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[17] For further details see the Supporting Information.
[18] R. A. Oliveira, R. O. Silva, G. A. Molander, P. H. Menezes,
Magn. Reson. Chem. 2009, 47, 873.
[19] DFT calculations were carried out using the Gaussian03
Rev. B.04 program package with the nonlocal hybrid B3LYP
exchange correlation functionals and the Møller-Plesset second-
order correlation energy correction (MP2). The basis set
denoted as 631SVP consists of the Ahlrich def2-SVP all electron
basis set for Mg atoms and the 6-31G(d,p) basis set for other
atoms. Unless otherwise stated, energies refer to relative zero-
point corrected electronic energies (MP2/631SVP//B3LYP/
631SVP). For full details on the computational study and full
citations, see the Supporting Information.
[20] The pyridyl-2-trifluoroborate 10 was also prepared in an
alternative way: an I/Mg exchange of 2-iodo-4-phenylpyridine
followed by a transmetalation with BF3 and ZnCl2 also furnished
the product 8a in 65% yield.
[21] For an excellent review, see G. A. Molander, B. Canturk, Angew.
Chem. 2009, 121, 9404; Angew. Chem. Int. Ed. 2009, 48, 9240.
[30] The use of an Al base is essential. A mixture of metalated
regioisomers is obtained by using tmpMgCl·LiCl.
Angew. Chem. Int. Ed. 2010, 49, 5451 –5455
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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