TMP-magnesium and TMP-Zinc bases for the regioselective metalation of the cinnoline scaffold

Article abstract of DOI:10.1021/ol5001999

A regioselective functionalization of cinnolines in positions 3 and 8 using metalations has been developed. This involves either the use of a frustrated Lewis pair consisting of BF₃·Et₂O and TMP ₂Mg·2LiCl or the in situ generated base TMP ₂Zn·2MgCl₂·2LiCl. Successive metalations allow the preparation of 3,8-disubstituted cinnolines. Various functionalizations by acylation, allylation, and cross-coupling reactions with aryl halides or alkenyl iodides were carried out successfully.

Full text of DOI:10.1021/ol5001999

Letter
pubs.acs.org/OrgLett
TMP−Magnesium and TMP−Zinc Bases for the Regioselective
Metalation of the Cinnoline Scaffold
Thomas Klatt,† Daniela Sustac Roman,‡ Thierry Leon,† and Paul Knochel*,†
́
†Department of Chemistry, Ludwig-Maximilians-University, Munich, Germany
‡Department of Chemistry, Universite
́
de Montrea
́
l, Montrea
́
l, Queb
́
ec, Canada
S
* Supporting Information
ABSTRACT: A regioselective functionalization of cinnolines
in positions 3 and 8 using metalations has been developed. This
involves either the use of a frustrated Lewis pair consisting of
BF3·Et2O and TMP2Mg·2LiCl or the in situ generated base
TMP2Zn·2MgCl2·2LiCl. Successive metalations allow the
preparation of 3,8-disubstituted cinnolines. Various functional-
izations by acylation, allylation, and cross-coupling reactions
with aryl halides or alkenyl iodides were carried out
successfully.
ue to their bioactivity, nitrogen-containing heterocycles
magnesiation with TMP2Mg·2LiCl (2; 1.1 equiv) leads to a
Dare privileged structures in organic chemistry. They are highly selective metalation at position 3 (>98:2).
Thus, treatment of cinnoline (1) with BF3·OEt2 (1.1 equiv,
0 °C, 15 min) and TMP2Mg·2LiCl (2; 1.1 equiv, −78 °C,
10 min; procedure A) results in C(3)-selective magnesiation,
and after transmetalation with ZnCl2, a Pd-catalyzed Negishi
cross-coupling15 with ethyl 4-bromobenzoate (4a) furnishes
the 3-substituted cinnoline 5a in 74% yield (Table 1, entry 1).
Other aryl bromides and iodides bearing electron-donating or
electron-withdrawing substituents reacted as well, affording the
3-arylated cinnolines 5b−e in 63−75% yield (entries 2−5).
The halogenation of the metalated cinnoline with either
(CBrCl2)2 or iodine provides the bromocinnoline 5f in 55%
yield or the iodocinnoline 5g in 51% yield (entries 6 and 7).
Quenching the magnesiated species with MeSO2Me furnishes
the thioether 5h in 51% yield (entry 8). Additionally, after
transmetalation with ZnCl2 ,the corresponding zincated
cinnoline is readily acylated in the presence of CuCN·2LiCl17
(1.1 equiv). The use of acyl chlorides bearing aryl, alkyl, or
heteroaryl substituents affords the corresponding ketones 5i−k
in 53−58% yield (entries 9−11).
Complementary to the C(3)-selective magnesiation, a regio-
selective zincation of cinnoline (1) in position 8 can also be
achieved. Thus, metalation of 1 with putative TMP2Zn·2MgCl2·
2LiCl18 (3; 1 equiv, 50 °C, 3 h) furnishes the 8-zincated cinnoline
intermediate with high regioselectivity (95:5).19 Subsequent
cross-coupling with 4-iodoanisole (4b) leads to the 8-arylated
cinnoline 6a in 84% yield (Table 2, entry 1). Further examples
illustrating this metalation sequence and cross-coupling with
aryl iodides substituted in the para-, meta- and ortho-position
proceeds in 60−70% yield (entries 2−4). A cross-coupling with
(E)-iodooctene (4l) leads to the cinnoline 6e in 65% yield
present in numerous natural products, pharmaceuticals, and
agrochemicals.1 Among them, 1,2-benzodiazines or cinnolines
have found various applications in materials and optics2 and
have important anticancer,3 anti-inflammatory, and antifungal
properties.4 Consequently, the functionalization of these hetero-
cyclic scaffolds is of special synthetic importance.5
The construction of the cinnoline (1) ring and especially its
derivatives involves lengthy syntheses and the handling of
diazonium species.2,6 More recently, copper-catalyzed prepara-
tions of cinnolines have been reported by Willis7 and Ge.8
There are only a few reports describing the direct metalation
́
of cinnolines. Queguiner showed that 3-, 4-chloro- and 3-, 4-
methoxycinnolines can be lithiated with 2,2,6,6-tetramethylpi-
peridyllithium (TMP-Li) or lithium diisopropylamide (LDA).9
The resulting heteroaryllithium species are sensitive intermediates
that require handling at low temperature to avoid decomposition
by competitive nucleophilic addition reactions.10
Recently, we have reported a range of sterically hindered TMP-
magnesium bases such as TMP2Mg·2LiCl (2) for the selective
magnesiation of unsaturated substrates.11 In addition, TMP-zinc
bases, such as TMP2Zn·2MgCl2·2LiCl (3),12 were developed for
the selective zincation of heterocycles.13 Furthermore, we have
shown that these bases are compatible with strong Lewis acids,
such as BF3·OEt2, forming frustrated Lewis pairs (FLP).14 This
considerably expands the synthetic scope of the original Zn- and
Mg-TMP bases.
Herein, we report that the cinnoline scaffold can be regio-
selectively metalated using these new TMP-bases 2 and 3.
Preliminary results indicated that the reaction of cinnoline (1)
with TMP2Mg·2LiCl (2; 1.0 equiv, −78 °C, 10 min) leads to
a preferential magnesiation at position 3 accompanied by
substantial amounts of metalation at position 8 (ratio = 4:1).
However, the addition of BF3·OEt2 (1.1 equiv) to 1 prior to the
Received: January 20, 2014
Published: February 11, 2014
© 2014 American Chemical Society
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Letter
Table 1. Preparation of C(3)-Substituted Cinnolines by
Magnesiation and Subsequent Quenching with Electrophiles
Table 2. 8-Substituted Products Obtained by Regioselective
Zincation and Subsequent Reaction with Electrophiles
a
b
Isolated yield of analytically pure product. Pd-catalyzed cross-coupling
c
a
b
using 5 mol % of Pd(PPh3)4 and 0.8 equiv of electrophile. Pd-catalyzed
Isolated yield of analytically pure product. Pd-catalyzed cross-
cross-coupling using 2 mol % of Pd(dba)2, 4 mol % of P(o-furyl)3,16
coupling using 2 mol % of Pd(dba)2, 4 mol % of P(o-furyl)3, and
d
c
and 0.8 equiv of electrophile. CuCN·2LiCl (1.1 equiv) was used.
0.8 equiv of electrophile. CuCN·2LiCl (1.1 equiv) was used.
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Using this procedure, 6-cyanocinnoline (7a) undergoes regio-
selective metalation at position 8. The resulting zinc species
reacts with various electrophiles to afford the functionalized
cinnoline derivatives 8a−c in 59−72% yield (Table 3, entries 1−3).
The mild metalation conditions also tolerate the presence of
an ester group in substrate 7b. After metalation and subsequent
cross-coupling with the alkenyl iodide 4p, the 6,8-disubstituted
cinnoline 8d is obtained in 57% yield (entry 4).
Table 3. Preparation of Disubstituted Cinnoline Derivatives
Finally, a double functionalization via successive metalation
can be achieved, and the 3-functionalized cinnolines (5f, 5h; see
Table 1) can be readily zincated (procedure B) affording the
corresponding 3,8-disubstituted cinnolines (8e,f) in 48−65%
yield (entries 5 and 6). Additionally, 8-substituted cinnoline 6e
undergoes a second metalation and a subsequent cross-coupling
with 4-iodoanisole (4b) to furnish the corresponding disubsti-
tuted cinnoline 8g in 68% yield (entry 7).
The observed regioselectivity in the case of a metalation at
position 3 is best explained by assuming a complexation of BF3
at the most sterically accessible nitrogen N(2). This coordination
acidifies the proton in position 3 sufficiently so that a de-
protonation occurs exclusively in this position (Scheme 1).
Scheme 1. BF3·OEt2- and MgCl2-Triggered Selective
Metalations of Cinnoline (1) at Positions 3 and 8 Using
TMP2Mg·2LiCl (2) and TMP2Zn·MgCl2 (3)
By using the much less active TMP2Zn·2MgCl2·2LiCl (3),
position 3 is now only activated by MgCl2 (instead of
BF3·OEt2) due to complexation at N(2). This may not be
sufficient activation to initiate the deprotonation at position 3,
and coordination of zinc from 3 at N(1) directs the zincation at
position 8.21
In conclusion, we have developed a new general method for
the regioselective metalation of the cinnoline scaffold by
implementation of two complementary metalation procedures
(BF3·OEt2 and TMP2Mg·2LiCl (2) or TMP2Zn·2MgCl2·2LiCl
(3)) allowing either a magnesiation at C(3) or a selective
zincation at C(8). Additionally, a second selective metalation
of prefunctionalized cinnoline derivatives can be performed,
leading to highly functionalized compounds. Extension of this
method to the metalation of related heterocycles is currently
underway in our laboratories.
a
b
Isolated yield of analytically pure product. Pd-catalyzed cross-
coupling using 2 mol % of Pd(dba)2, 4 mol % of P(o-furyl)3, and
c
0.8 equiv of electrophile. Pd-catalyzed cross-coupling using 2 mol %
of Pd(dba)2, 4 mol % of P(o-furyl)3, and 0.7 equiv of electrophile.
ASSOCIATED CONTENT
* Supporting Information
■
S
(E/ > 99:1; entry 5). Copper(I)-mediated allylation with ethyl
2-(bromomethyl)acrylate20 (4m) or 3-bromocyclohexene (4n)
affords the allylated cinnolines 6f−g in 53−61% yield (entries 6
and 7). Bromination and iodination of the 8-zincated cinnoline
furnishes the sensitive halogenated derivatives 6h−i in 46−52%
yield (entries 8 and 9).
Functionalized cinnolines bearing a cyano or an ester group
such as 7a,b can be readily prepared6b and zincated using in situ
generated TMP2Zn·2MgCl2·2LiCl (3; 1.0 equiv, 25 °C, 1 h;
procedure B).
Experimental details and full spectroscopic data for all 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.
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(15) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc.
1980, 102, 3298. (b) Kobayashi, M.; Negishi, E. J. Org. Chem. 1980,
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(18) For the in situ zincation cinnoline 1 was premixed with ZnCl2
(1.0 equiv) followed by the addition of TMPMgCl·LiCl (2.0 equiv).
(19) Zincation with the in situ generated base leads to slightly higher
yields of metalated species than by using the preformed base.
(20) Villieras, J.; Rambaud, M. Synthesis 1982, 924.
ACKNOWLEDGMENTS
■
The research leading to these results has received funding from
the European Research Council under the European
Community’s Seventh Framework Programme (FP7/2007−
2014) ERC grant agreement no. 227763. We thank the Fonds
der Chemischen Industrie for financial support. We also thank
Heraeus Holding GmbH (Hanau), Rockwood Lithium
(Frankfurt), and BASF SE (Ludwigshafen) for the generous
gift of chemicals. We thank Dr. K. Groll for his support. D.S.R.
thanks FRQNT for a scholarship.
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