The Diverse One-Pot Reactions of 2-Quinolylzincates: Homologation, Electrophilic Trapping, Hydroxylation, and Arylation Reactions

Article abstract of DOI:10.1002/ejoc.201801192

2-Quinolylzincates were efficiently produced from the regioselective metalation reactions of quinoline with various organozincates as key intermediates. The four different types of title reactions of these intermediates under the presented reaction conditions allowed for the facile formation of the corresponding C-2 functionalized quinolines, which are not successfully accessed through typical zincation methods.

Full text of DOI:10.1002/ejoc.201801192

A Journal of
Accepted Article
Title: The diverse one-pot reactions of 2-quinolylzincates:
homologation, electrophilic trapping, hydroxylation, and arylation
reactions.
Authors: Hye Jin Jeong, Suyeon Chae, Keunhong Jeong, and
SungKeon Namgoong
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801192
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10.1002/ejoc.201801192
European Journal of Organic Chemistry
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The diverse one-pot reactions of 2-quinolylzincates:
homologation, electrophilic trapping, hydroxylation, and arylation
reactions
Hye Jin Jeong,[a] Suyeon Chae,[a] Keunhong Jeong [b] and Sung Keon Namgoong*[a]
Abstract: 2-Quinolylzincates were efficiently produced from the
regioselective metalation reactions of quinoline with various
organozincates as key intermediates. The four different types of title
reactions of these intermediates under the presented reaction
conditions allowed for the facile formation of the corresponding C-2
functionalized quinolines which are not successfully accessed
through typical zincation methods.
Introduction
2-Functionalized quinoline scaffolds are one of the most
promising N-heterocyclic nuclei that occupy a crucial role in
many bioactive compounds.[1] Consequently the directed C-2
Scheme 1. The diverse C-2 functionalization strategies of quinoline.
metalation of quinolines are an important strategy for syntheses
2-quinolylzincate as a sole intermediate at 45 ℃ in 80% yield,
unlike the case employing anhydrous ZnCl2. This initial finding is
unknown and of particular interest, as there is no precedent for
the regioselective formation of 2-quinolyzincate molecule, an
ate-complex, in the field of organozincate chemistry. Therefore,
we systematically examined the zincation reactions of Q with
LiR2TMPZn·2MX (R: alkyl or phenyl groups, MX: LiCl or MgCl2)
under various reaction conditions and herein report the
subsequent results.
of regioselective functionalized quinolines. The use of highly
active TMP (2,2,6,6-tetramethylpiperidyl) base for direct
metalation can be a way to complete such a protocol.[2] Few
examples for the functionalization of quinolines via C-2
metalation
reaction
have
been
previously
reported:
Zr(TMP)4/BF3-induced metalation and subsequent arylation[3];
transmetalated arylation and nucleophilic addition to active
carbonyl compounds employing TMPMgCl·BF3.[4] In general,
these arylation strategies of quinoline can be achieved by the
Negishi cross-coupling reactions[5] of either commercially
available expensive 2-haloquinoline or its derivative, 2-
quinolylzinc halide with appropriate coupling partners. However,
the other metalation strategy using LitBu2TMPZn was not
successful, resulting in the formation of ca 3:7 ratio for 2-:8-
zincated quinoline (Q).[6]
Results and Discussion
The present work is summarized in Table 1. The C-2 zincation
strategy began with the deprotonation reactions of Q with
various TMP-zincates (2.2 equiv). TMP-zincate is normally
formed by the sequential reactions of ZnCl2 with 2RLi (or
2RMgCl) and lithium 2,2,6,6-tetramethylpiperidinide (LiTMP).
Consequently, TMP-zincate has two equiv of LiCl or MgCl2. N-
Heteroaryl compounds, such as quinoline and isoquinoline
requires 2.2 equiv of TMP-zincates to completely deprotonate at
specific positions of those compounds (see Experimental
Section and Supporting Information).
First of all, a zincation reaction employing slightly hydrated
ZnCl2 is not suitable as a scientific method due to the fact that
the ZnCl2 comes into contact with a variable amount of H2O,
meaning that it can fail to record reproducible yields. In fact, the
water in ZnCl2 reacts with RLi and is completely converted into
LiOH in the preparation process of LitBu2TMPZn. Therefore,
LiOH may play an important role of showing high regioselectivity
in the presented reaction. Indeed, an initial addition of LiOH
(powder type, 5~20 mol% in THF) into the LitBu2TMPZn·2LiCl
solution and subsequent addition of Q proved to be effective and
reproducible for the formation of 2-quinolylzincate, recorded 80%
yield (Table 1, entry 1; MX: LiCl).
We have widely studied the regioselective C-2 zincation for Q
to obtain 2-quinolylzincate, a negatively charged ate-complex,
as a key intermediate. In general, the reactivity of this zincate
intermediate is very different from that of the neutral 2-
quinolylzinc halide easily prepared by the reaction of 2-
haloquinoline with activated zinc. It is a particularly useful
molecule since various functionalized quinolines can be
prepared from this single ate-intermediate via diverse one-pot
reactions:
homologation[7],
electrophilic
trapping[4b,6]
,
hydroxylation[8], and cross-coupling reactions[6,9] (Scheme 1).
As a result, for a number of attempts for directed zincation
reactions of Q, the use of LitBu2TMPZn·2LiCl (2.2 equiv) derived
from slightly hydrated ZnCl2 (H2O content: 5~20 mol%) afforded
[a]
[b]
Department of Chemistry, Seoul Women’s University,
Seoul 01797, Korea
E-mail: sknam@swu.ac.kr
Department of Chemistry, Korea Military Academy,
Seoul 01805, Korea
E-mail: doas1mind@gmail.com
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801192
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The 1H NMR study related with the deuterium labeling
experiment in this application is displayed at Figures 1, S1 and
S2. It indicated that the formation yields for 2- and 8-
deuterioquinoline[10] were slowly varied from 33:66 to exactly
80:0 according to the increase in the reaction temperature from
25℃ to 45℃. The remaining 20% was recovered as Q (Figures
1(b), 1(d) and S1). The reaction time depends on the amount of
LiOH added. It was 15 h and 18 h for the respective uses of 20
mol and 5 mol LiOH. Eventually, 20 mol of LiOH was
applied in this reaction for the optimum C-2 zincation of Q (Table
1). The amount of unreacted Q was gradually increased
according to the addition of more than 20 mol of LiOH to the
reaction mixture. In the absence of LiOH, the zincation of Q was
observed at 8- and 2-position with equal amounts (1:1) at 45 °C,
even for a prolonged reaction time (72 h) (Figures 1(c)). These
data do not reflect the thermodynamic correlation between 2-
and 8-quinolylzincate. Therefore, the use of LiOH predominantly
affects the regioselective C-2 zincation for Q under anhydrous
reaction conditions.
Table 1. The regioselective formation of 2-deuterioquinoline (2Qd) via 2-
quinolylzincates from quinoline.[a,b]
MX (2Qd:8Qd, % yield)[c]
[f]
Entry
R
LiCl/LiOH[d,e]
80:0
MgCl2
99:0
96:0[g]
96:0
96:0
-
1
2
3
4
5
tBu
iPr
Bu
Me
Ph
81:0
Figure 1. Deuterium labelling experiments of 2- and 8-quinolylzincates
(LitBuQTMPZn∙2MX) under various reaction conditions: (a) Q as a reference
80:0
molecule (300 Hz, , H-2: 8.95 and H-8: 8.13 ppm); (b) MX: LiCl, 3 h at 25 ℃,
80:0
(2Qd:8Qd, % yield), 33:66; (c) MX: LiCl, 72 h at 45 ℃, (2Qd:8Qd, % yield),
50:50; (d) LiOH (20 mol%) added, MX: LiCl, 15 h at 45 ℃, (2Qd:8Qd, % yield),
80:0; (e) MX: MgCl2, 3 h at 25 ℃, (2Qd:8Qd, % yield), 99:0.
21:79
[a] Reaction conditions: Q (0.80 mmol), LiR2TMPZn·2MX (1.8 mmol) and THF
(10 mL) under N2. [b] Quenching of 2-quinolylzincates with D2O (1 mL). [c]
Determined by 1H NMR spectroscopic analyses. [d] Pre-addition of LiOH (0.16
mmol, 20 mol%) into Q/THF solution and subsequent addition of TMP-Zincate.
[e] Reaction time: 15 h at 45 ℃. [f] Reaction time: 3 h at 25 ℃. [g] MX: MgCl2
or MgCl2∙LiCl.
reactions (R: iPr, Bu, and Me, Table 1, entries 2-4; MX: LiCl,
Figure S1). However, this C-2 zincation strategy was
unsuccessful in the case of a Ph ligand, resulting in the
preferential formation for C-8 zincated Q (Table 1, entry 5; MX:
LiCl, Figure S1).
The addition of the hydroxide ion into tri-coordinated 2- and 8-
quinolylzincates in the presented reaction conditions may
reversibly form tetra-coordinated quinolylzincate complexes.[11]
The hydroxide group from these complexes can selectively
transfer a proton to more basic 8-quinolyl ligand than 2-quinolyl
ligand and facilitates the conversion of 8-quinolylzincate into 2-
quinolylzincate through the repeated processes of C-8
reprotonation/C-2 deprotonation. It is still unclear why 20% of Q
always remains unreactive following the reaction. A similar result
was obtained in the other alkyl ligands-bearing zincation
A continuous effort was then initiated to determine an
optimum condition for improving the limited yields of 2-
quinolylzincates. As a result, the selection of LiR2TMPZn·2MgCl2
(2.2 equiv, R: tBu, iPr, Bu, and Me) were successful in almost
quantitatively producing 2-quinolylzincates without the use of
LiOH (Table 1, entries 1-4; MX: MgCl2, Figures 1(e) and S2). As
for the case concerned with iPr ligand, the use of LiiPr2TMPZn
including either MgCl2 or MgCl2·LiCl was also effective for the C-
2 zincation. Surprisingly, the zincations in this series occurred at
the C-2 position only, even at initial stages and were completed
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10.1002/ejoc.201801192
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within 3 h at 25℃. It was quite remarkable that the simple
replacement of LiCl with MgCl2 in this application demonstrated
of the nucleophilic alkyl ligand to the 2-position of
2Qzm·B(OMe)3 complex. Moreover, the steric hindrance
between the alkyl and TMP-Zn groups caused by 1,2-migration
facilitated further elimination of (MeO)2BZnTMP to quickly
produce 1a-1d. For the formation mechanism of 1e[13], it was
very similar to that of 1a-1d, except for the elimination of
HZnTMP/BF3 through the aqueous work-up process
(Scheme2).[7b]
a
perfect C-2 regioselectivity even though the mode of
deprotonative metalation is unclear.
2-Quinolylzincates to apply for the following title reactions are
divided into two different ate-complexes. The first one is 2-
quinolylzincates·2LiCl·LiOH (LiRQTMPZn·2LiCl·LiOH, R: alkyl,
2Qzl). 2Qzl contains 2 equiv of LiCl and 20 mol% of LiOH as an
additive. The other one is 2-quinolylzincates·2MgCl2
(LiRQTMPZn·2MgCl2, R: alkyl, 2Qzm). On the other hand,
2Qzm includes only 2 equiv of MgCl2. These two zincates, 2Qzl
or 2Qzm, were prepared by the deprotonation reactions of Q
with the prepared TMP-zincates containing either LiCl or MgCl2
in the presence or absence of 20 mol% LiOH (see Experimental
Section and Supporting Information).
All of the reactions were completed within an hour after the
addition of B(OMe)3 (5 equiv) in this series. The metal ion of
MgCl2 coordinates with the oxygen atom of B(OMe)3. At the
same time, one of its chloride ions presumably coordinates with
the electrophilic boron atom. The double dual coordination
between MgCl2 and B(OMe)3 may lead to the production of the
1:2 complex (2MgCl2:4B(OMe)3), unlike the previous 1:1 dual
coordination complex in the case of Iq series.[7a] This bulky 1:2
complex cannot coordinate to the nitrogen atom of 2Qzm, so the
additional 1 equiv of B(OMe)3 (total 5 equiv) was necessary to
complete the reaction. On the other hand, a 1.2 equivalent of
B(OMe)3 was sufficient for a successful homologation in Iq
series. Therefore, it is indicated that the interactive functions of
MgX2 (X: Cl or Br) with B(OMe)3 in 2-quinolyl and 1-isoquinolyl
zincate series are considerably different.
The first application strategy employing 2-quinolylzincates is to
prepare 2-homologated quinolines. This preparation method
normally includes the following two-step reactions: nucleophilic
addition of alkyl or aryl anion to Q and an additional oxidation of
2-substituted-1,2-dihydroquinoline.[12] On the basis of the
excellent C-2 zincation results of
Q
and our previous
[7a]
homologation results for isoquinoline (Iq)
,
the one-pot
homologation strategy started from the B(OMe)3-induced
reactions of 2-quinolylzincates·2MgCl2 (2Qzm) (for iPr ligand:
2MgCl2·2LiCl) under anhydrous condition. The corresponding
homologation reactions described here can avoid such required
two-step reactions. The formation mechanisms[7b] for 1a-1e[12,13]
are illustrated (Scheme 2) and the present work is summarized
(Table 2).
The present evaluation of the 1,2-migratory ability of the alkyl
ligands in 2Qzm revealed that most alkyl ligands were the
effective 1,2-migrating groups in this series (Table 2, entries 1-3).
Table 2. The B(OMe)3-induced homologation reactions of 2Qzm.[a].
Entry
Product/R
Yield(%)[b]
1
2
1a/tBu
1b/iPr
1c/Bu
1d/Me
1e/Ph
94
75[c]
85
3
4[d]
5
50
63[e]
[a] Reaction conditions: B(OMe)3 (4.0 mmol), 2Qzm (0.80 mmol) and THF (10
mL) under N2 for 1 h at 25 ℃. [b] Isolated yield by column chromatography. [c]
B(OMe)3 (5.6 mmol) used. [d] 2Qzm possessing Me ligand instead of TMP
ligand. [e] Reaction conditions: Q∙BF3 pre-complex (0.80 mmol),
LiPh2TMPZn∙2LiCl (1.8 mmol) and THF (10 mL) under N2 for 1 h at 25 ℃.
Scheme 2. The proposed formation mechanisms for 1a-1e.
The following formation mechanism for 1a-1d is proposed,
proceeding through a three-step process: (1) coordination of
B(OMe)3 with the sp2-nitrogen of 2Qzm, (2) 1,2-migratory
addition of the alkyl ligand from 2Qzm·B(OMe)3 complex and
subsequent cleavage of B-OMe bond, and (3) reformation of the
aromatic ring through loss of (MeO)2BZnTMP at 1,2-position
from precursor.[7b] The B(OMe)3 plays an important role in
enhancing electrophilicity at the 2-carbon, stimulating movement
For the case of iPr ligand, it is noted that 2Qzm containing
2MgCl2·2LiCl, instead of 2MgCl2, was only effective for 1,2-
migratory addition. However, this homologation strategy was
partially successful in the reaction for methyl ligand, probably
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10.1002/ejoc.201801192
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due to its weak nucleophilic nature (Table 2, entry 4). As for the
case of Ph ligand, the alternative preparation method employing
the reaction of Q·BF3 pre-complex[7a] with LiPh2TMPZn (2.2
equiv) was only successful in the generation of 1e (Table 2,
entry 5). However, the 1,2-migratory ability of the alkyl ligands in
1-isoquinolyl zincate was also quite different from that in 2Qzm.
The corresponding homologation reactions (R: Me and Ph) of Iq
did not work at all due to both the inactive nature of the Me
ligand and its preferential attack to B(OMe)3 prior to 1,2-
migratory addition of Ph ligand. The butylation of Iq recorded
only 37% yield.[7a]
Product
5
was almost quantitatively generated by the
hydroxylation reactions including these three kinds of alkyl
ligands when the limited conversion yields of Q into 2Qzl (Table
1, entries 1-3, ca 80%) are considered (Table 4, entries 1-3 for
5). Of particular note is that the corresponding reactions of
Table 4. The synthesis of 5 from Q via 2Qzl.
The second application strategy employing 2Qzm aims to
synthesize another functionalized quinolines (2-4) by
electrophilic trapping reactions (Table 3, R: tBu).
Entry
R
Yield(%)[a,b]
1
2
3
tBu
iPr
Bu
80
77
80
Table 3. The electrophilic trapping reactions of 2Qzm.[a]
[a] Isolated yield by column chromatography. [b] Reaction conditions:
LiR2TMPZn∙2LiCl (1.8 mmol), LiOH (0.16 mmol), Q (0.80 mmol) and THF (10
mL) under N2 for 15 h at 45 ℃; TBHP (2.0 mmol) for 1 h at 25 ℃.
Entry
R
E+
D2O
D2O
I2
Product/E
2/D
Yield(%)[b]
99[c]
96[c]
98
1
2
3
4
5
6
tBu
iPr
tBu
iPr
tBu
iPr
2Qzm did not work at all. Although the role of MgCl2 is unclear,
its presence is a critical factor in unsuccessful hydroxylation
reactions. Similar results were also observed in the production
2/D
3/I
reactions of isocarbostyril[8] (1-hydroxyisoquinoline as
a
tautomer) proceeding in the same manner as mentioned above
from Iq even if these data are not described here.
I2
3/I
94
PhCHO
PhCHO
4/PhCHOH
4/PhCHOH
86
According to previously published results[8] not including Q,
the directed hydroxylations for a couple of aryl cuprates/zincates
should proceed in the presence of stoichiometric/catalytic
amount of CuCN, whereas those in this application did not
require the use of CuCN. Moreover, the C-2 hydroxylation of Q
is yet to be reported because its regioselective C-2 zincation
was unsuccessful.
80
[a] Reaction conditions: E+ (4.0 mmol), 2Qzm (0.80 mmol) and THF (10 mL)
under N2 for 1 h at 25 ℃. [b] Isolated yield by column chromatography. [c]
Product
2 obtained as an inseparable mixture with unreacted Q after
purification by column chromatography.
The proposed reaction mechanism for the formation of 5
proceeds through a three-step process from 2Qzl (R: tBu): (1)
production of A by the addition of TBHP anion to tBuZnQ and
the subsequent reformation of TMP-zincate, (2) 1,2-migration of
2-quinolyl group to an oxygen atom of tBuO2 ligand followed by
the addition of resulting tBuO group to a Zn atom, and (3) final
rapid hydrolytic cleavage of QO–Zn bond from B (Scheme 3).
Quenching the 2Qzm formation reaction with D2O almost
quantitatively produced 2-deuterioquinoline[14] (2) as an
inseparable mixture with unreacted Q (Table 3, entry 1). The
1
yield of 2 was determined via H NMR spectroscopic analysis.
When 2Qzm was treated with I2, 2-iodoquinoline (3)[6] was
obtained in 98% yield (Table 3, entry 3). Treatment of 2Qzm
with PhCHO gave the addition product, α-phenyl-2-
quinolylmethanol (4)[15] in 86% yield (Table 3, entry 5). The
employment of iPr ligand, instead of tBu ligand, in this
application also showed similar results (Table 3, entries 2, 4 and
6).
In general, zincate complex is not susceptible to oxidation,
unlike
cuprate
complex.[8]
Nonetheless,
2-
quinolylzincate·2LiCl·LiOH (2Qzl, R: tBu, iPr and Bu, LiOH: 20
mol% as an additive) was partially converted into carbostyril
(
5)[16] (2-hydroxyquinoline as a tautomer) under O2 atmospheric
condition in 39% yield. The third application strategy employing
2Qzl aims to develop an efficient C-2 hydroxylation method. As
a result of this study, the reactions of 2Qzl with TBHP (tert-butyl
hydroperoxide, 2.5 equiv)[8] resulted in the better formation of 5.
Scheme 3. The proposed formation mechanism for 5 from 2Qzl.
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In addition, the hydroxylation mechanism applying O2 gas
involves an additional single-step process for the generation of
the identical intermediate A: Zn-O bond formation through the
insertion of O2 between Zn-tBu bond of 2Qzl (Scheme 3).[17]
A DFT calculation (see Supporting Information, p11-14) with
thermodynamic properties was performed to examine the stable
structures of A and B, as shown in Scheme 3. Both TMP and
tBuO2 ligands were replaced by Me2N and MeO2 groups as the
chemical models, respectively. After investigating the four
possible intermediate structures with Li+ (A’, A’’, B’, and B’’), the
5-membered ring complex for A’ and 4-membered ring complex
for B’ showed the most stable structures, which were more
stable than the other possible structures, 4-membered ring
complex (A’’) and skewed 6-membered ring complex (B’’) by as
much as 14.2 kcal/mol and 5.3 kcal/mol, respectively (Scheme
4). Therefore, the migration reaction in Scheme 3 would be
processed from A to B by being thermodynamically stabilized as
much as 87.0 kcal/mol.
expensive 2-haloquinolines as coupling partners were applied
for C-2 arylations of Q in the presence of specific catalysts.[1b,18]
Our previous C-2 arylation results employing 2Qzm (R: tBu)
were similar to those of the above described arylations.
Accordingly, the conversion of the ate-complex, 2Qzm, into the
neutral tert-butylquinolylzinc (tBuZnQ) is necessary to avoid
such side reactions. The use of tert-butyl bromide (tBuBr, 2.2
equiv) entirely converted 2Qzm to tBuZnQ and offered excellent
arylation results in this application. It is noted that the E2
reaction of tBuBr with TMP base from 2Qzm can quickly afford
tBuZnQ within 5 min. The C-2 arylations of Q are successfully
achieved by the present method under mild conditions without
specific catalysts and the resulting work is summarized in Table
4.
All of the Pd(0)-catalyzed one-pot C-2 arylation reactions of Q
via tBuZnQ with various aryl iodides gave the corresponding
products, 1e[1b] and 6a-6d[19] within 1 h in excellent yields (Table
5, entries 1-5).
Table 5. The Pd(0)-catalyzed arylation reactions of 2Qzm via tBuZnQ.[a]
Entry
ArI
Product
1e
Yield(%)[b]
93
1
2
3
4
5
6
6a
90
6b
96
6c
84
6d
93[c]
82[d]
6e
[a] Reaction conditions: 2Qzm (R: tBu, 0.80 mmol), tBuBr (1.8 mmol) and THF
(10 mL) under N2 for 5 min at 25 ℃; ArI (0.96 mmol) and (Ph3P)4Pd (0.04
mmol) for 1 h at 25 ℃. [b] Isolated yield by column chromatography. [c]
Pd(dba)2 (0.04 mmol) used as a Pd(0) catalyst. [d] Syringe pump injection of
corresponding ArI (0.96 mmol) to a mixture of tBuZnQ (0.80 mmol), THF (10
mL) and (Ph3P)4Pd (0.08 mmol) for 12 h at 25 ℃.
Scheme 4. Optimized stable intermediates (A and B in Scheme 3) and their
energy differences between proposed intermediates including possible Li+
coordination in the structures.
Finally, the Pd-catalyzed cross-coupling reactions of
arylzincates[6,9] with aryl halides normally failed to record good
yields even under harsh reaction conditions. This is presumably
attributable to the side reactions of aryl halides under the given
reaction conditions such as those dehalogenation reactions
caused by tBu ligand and deprotonative zincation reactions
induced by TMP base from zincates. As an alternative method,
the Suzuki-Miyaura cross-coupling reactions including very
The tBu group of tBuZnQ probably enhances the
nucleophilicity[20] of Q ligand, such that it can undergo rapid
arylation reactions. Especially, the chemoselective arylation of Q
was successful in the formation of 6a[1b] under the presented
reaction condition (Table 5, entry 2). The other arylation reaction
to afford the bioactive haplophyllum alkaloid, dubamine (6e)[1c,4a]
required prolonged injection time of the corresponding aryl
iodide (1.2 equiv) to the reaction mixture by syringe pump for 12
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Lithium
tert-butyl(quinolin-2-yl)(2,2,6,6-tetramethylpiperidin-1-
h, mainly due to the formation of homo-coupling side product
(Table 5, entry 6). Although the C-1 arylation results for Iq are
not described here, these were comparable to the results of Q.
yl)zincate∙2MgCl2 (2Qzm, R: tBu).
tBuMgCl (1.0M in THF, 3.6 mL, 3.6 mmol) was added to a solution of
ZnCl2 (0.26 g, 1.8 mmol) in THF (3 mL) at -78 ℃ under N2. The mixture
was stirred for 30 min at 25 ℃ to give the solution of tBu2Zn∙2MgCl2. The
prepared LiTMP solution (3.2 mL, 1.8 mmol) was added to the
corresponding tBu2Zn∙2MgCl2 solution at -78 ℃. The reaction mixture
was stirred for 30 min at 25 ℃ to generate LitBu2TMPZn∙2MgCl2. Finally,
quinoline (0.1 mL, 0.80 mmol) was added to the LitBu2TMPZn∙2MgCl2
solution under N2 atmosphere. The resulting mixture was then stirred for
3 h at 25 ℃ to produce 2Qzm (0.80 mmol).
Conclusions
In conclusion, the diverse C-2 functionalized quinolines were
efficiently produced from the key intermediates, either 2Qzm or
2Qzl via one-pot homologation, electrophilic trapping,
hydroxylation and cross-coupling reactions under the presented
reaction conditions. These types of reactions were generally
applicable to the synthetic methods for 2-functionalized
quinolines in the field of organozincate chemistry. Such synthetic
methods can be also applicable to the preparation of other
2-tert-Butylquinoline (1a).
B(OMe)3 (0.46 mL, 4.0 mmol) was added to the solution of 2Qzm (R: tBu,
9.9 mL, 0.80 mmol) and stirred for 1 h at 25 ℃. The reaction was
quenched with distilled water (6 mL) at 0 ℃. THF was evaporated under
reduced pressure and the resulting mixture was diluted with CH2Cl2 (6
mL). The organic layer was washed with H2O (6 mL), dried over MgSO4,
and concentrated under reduced pressure. The crude reaction mixture
was purified by column chromatography (ethyl acetate:hexane, 1:4) to
afford 1a as a pale-yellow oil. Yield 94% (140 mg). 1H NMR (300 MHz,
CDCl3) δ 8.10 (d, J = 8.7 Hz, 2 H), 7.79 (d, J = 8.1 Hz, 1 H), 7.73-7.67 (m,
1 H), 7.57-7.47 (m, 2 H), 1.50 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ
169.25, 147.39, 135.89, 129.37, 129.00, 127.22, 126.44, 125.63, 118.23,
38.13, 30.15 ppm.
functionalized
N-heterocycles.
The
specific
formation
mechanisms for compounds 1a–1e and 5 were proposed in
detail. In addition, The DFT calculation study also suggested the
stable structures of the intermediates A and B formed in the
process of hydroxylation reaction of quinoline.
2-Iodoquinoline (3).
I2 (1.0 g, 4.0 mmol) was added to the solution of 2Qzm (R: tBu, 9.9 mL,
0.8 mmol) and stirred for 1 h at 25 ℃. The reaction was quenched with
Experimental Section
distilled water (6 mL) at 0 ℃. THF was evaporated under reduced
pressure and CH2Cl2 (6 mL) was added to the resulting mixture. The
organic layer was washed with H2O (6 mL), dried over MgSO4, and
concentrated under reduced pressure. The crude reaction mixture was
purified by column chromatography (ethyl acetate:hexane, 1:2) to give 3
as a yellow solid. Yield 98% (201 mg). (m.p. 52 ℃; lit. m.p. 52-53 ℃). 1H
NMR (300 MHz, CDCl3) δ 8.01 (d, J = 8.7 Hz, 1 H), 7.74-7.65 (m, 4 H),
7.55-7.52 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ 149.51, 137.11, 131.94,
130.31, 128.76, 127.87, 127.16, 127.09, 119.12 ppm.
General: All of the reagents used in this work were purchased from
Sigma-Aldrich, Tokyo chemical industry and Alfa aesar companies. The
reactions were performed under anhydrous conditions. All the reaction
glassware was flame-dried for at least 1 h and purged with N2. The THF
solvent was distilled from sodium/benzophenone under N2 atmospheric
condition. All the synthetic compounds were characterized by 1H and 13
C
NMR spectroscopic analyses. The NMR spectra were recorded on
Brucker AvanceⅢ 300. The CDCl3 was used as solvent unless otherwise
stated (CDCl3 peak 1H NMR: δ 7.28 ppm, 13C NMR: δ 77.0 ppm). All
coupling constants (J) are reported in hertz (Hz). The following
abbreviations are used: brs = broad singlet, s = singlet, d = doublet, t =
triplet, q = quartet, qt = quintet, st = sextet, spt = septet, and m = multiplet.
Thin layer chromatography was performed with Silica gel 60 F254 and
compounds were visualized under UV light at 254 nm. All of the products
were isolated by flash column chromatography (Silica gel 60, 0.063-
0.200 mm). The representative procedures for the prepared compounds
are as follows; the synthetic procedures and corresponding spectral data
for all of the compounds prepared in this work are described in the
supporting information, p7-10.
Carbostyril (5).
tert-Butyl hydroperoxide (0.40 mL, 2.0 mmol) was added to the solution
of 2Qzl (R: tBu, 11mL, 0.80 mmol) at 25 ℃ and stirred for 1 h. The
reaction mixture was diluted with CH2Cl2 (10 mL), and then quenched
with distilled water (4 mL) at 0 ℃. The organic layer was separated, dried
over MgSO4, and concentrated under reduced pressure. The crude
reaction mixture was purified by column chromatography (ethyl
acetate:hexane, 4:1) to give 5 as a white solid. Yield 80% (93 mg). (m.p.
188-190 ℃; lit. m.p. 192-194 ℃). 1H NMR (300 MHz, CDCl3) δ 11.8 (brs,
1 H), 7.84 (d, J = 9.6 Hz, 1 H), 7.61-7.40 (m, 3 H), 7.28-7.23 (m, 1 H),
6.73 (d, J = 9.3 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 164.64, 141.14,
138.53, 130.70, 127.70, 122.73, 121.28, 119.92, 116.38 ppm.
2-(4-Bromophenyl)quinoline (6a).
Lithium 2,2,6,6-tetramethylpiperidinide (LiTMP).
tert-Butyl bromide (0.21 mL, 1.8 mmol) was added to the solution of
2Qzm (R: tBu, 9.9 mL, 0.80 mmol). The mixture was stirred for 5 min at
25 ℃. (Ph3P)4Pd (5.0 mg, 0.04 mmol) in THF (1 mL), and 1-bromo-4-
iodobenzene (0.28 g, 0.96 mmol) in THF (1 mL) was added to the
reaction mixture. The reaction mixture was stirred for 1 h at 25 ℃. The
BuLi (2.0M in cyclohexane, 0.90 mL, 1.8 mmol) was added to a solution
of 2,2,6,6-tetramethylpiperidine (0.31 mL, 1.8 mmol) in THF (2 mL) at -
78 ℃ under N2 atmosphere. The mixture was stirred for 30 min at 0 ℃ to
give LiTMP (1.8 mmol).
reaction was quenched with saturated aqueous NH4Cl (6 mL) at 0 ℃.
THF was evaporated under reduced pressure and CH2Cl2 (6 mL) was
added to the resulting mixture. The organic layer was washed with H2O
(6 mL), dried over MgSO4, and concentrated under reduced pressure.
The crude reaction mixture was purified by column chromatography
(ethyl acetate:hexane,1:10) to produce 6a as a yellow solid. Yield 90%
Lithium
tert-butyl(quinolin-2-yl)(2,2,6,6-tetramethylpiperidin-1-
yl)zincate∙2LiCl·LiOH (2Qzl, R: tBu, LiOH: 20 mol% as an additive).
tBuLi (1.7M in pentane, 2.2 mL, 3.6 mmol) was added to a solution of
ZnCl2 (0.26 g, 1.8 mmol) in THF (5 mL) at -78 ℃ under N2. The mixture
was stirred at 25 ℃ for 30 min to give tBu2Zn∙2LiCl. The prepared LiTMP
solution (3.2 mL, 1.8 mmol) was added to the solution of tBu2Zn∙2LiCl at
-78 ℃. The reaction mixture was stirred for 30 min at 25 ℃ to generate
LitBu2TMPZn∙2LiCl. Lithium hydroxide (4.0 mg, 0.16 mmol) in THF (1
mL) was added to the corresponding LitBu2TMPZn∙2LiCl solution at 25 ℃.
Finally, quinoline (0.1 mL, 0.80 mmol) was added to the resulting mixture
and then stirred for 15 h at 45 ℃ to afford 2Qzl (0.80 mmol).
1
(206 mg). (m.p. 115 ℃; lit. m.p. 117-119 ℃). H NMR (300 MHz, CDCl3)
δ 8.26 (d J = 8.7 Hz, 1 H), 8.18 (d, J = 8.7 Hz, 1 H), 8.10-8.06 (m, 2 H),
7.88-7.84 (m, 2 H), 7.79-7.76 (m, 1 H), 7.70-7.66 (m, 2 H), 7.59-7.54 (m,
1 H); 13C NMR (75 MHz, CDCl3) δ 156.07, 148.24, 138.51, 137.03,
132.00, 129.89, 129.70, 129.12, 127.52, 127.25, 126.55, 123.94, 118.55
ppm.
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10.1002/ejoc.201801192
European Journal of Organic Chemistry
FULL PAPER
[19] For the compound 6a, see reference 1b). The compounds 1e, 6b, and
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Acknowledgements
This work was supported by a research grant from Seoul
Women’s University (2018).
Keywords: Nitrogen heterocycles • Regioselectivity • Zincates•
Quinoline • Regioselective C-2 zincations • One-pot reactions •
Functionalized quinolines
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10.1002/ejoc.201801192
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
The diverse C-2 functionalizations of
quinoline are successfully achieved
via 2-quinolylzincate intermediates
by the four different types of title
reactions.
Functionalized quinolines
Hye Jin Jeong, Suyeon Chae,
Keunhong Jeong and Sung Keon
Namgoong*[a]
Page No. – Page No.
The diverse one-pot reactions of 2-
quinolylzincates: homologation,
electrophilic trapping,
hydroxylation, and arylation
reactions
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