Trimethyl borate/magnesium halide complex-induced one-pot homologation reactions of isoquinoline with dialkyl-TMP-zincate

Article abstract of DOI:10.1016/j.tetlet.2012.05.002

Novel one-pot homologation reactions of isoquinoline with lithium dialkyl-TMP-zincate?2MgBrCl/trimethyl borate are described. 1-Alkylisoquinolines (2, 3A, 4A, 5A, 6, and 7) and 1-alkyl-3,4- dihydroisoquinolines (3B, 4B, and 5B) are easily prepared under t

Full text of DOI:10.1016/j.tetlet.2012.05.002

Tetrahedron Letters 53 (2012) 3594–3598
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Tetrahedron Letters
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Trimethyl borate/magnesium halide complex-induced one-pot
homologation reactions of isoquinoline with dialkyl-TMP-zincate
⇑
Hye Ji Seo, Sung Keon Namgoong
Department of Chemistry, Seoul Women’s University, 621 Hwarangno, Nowon-gu, Seoul 139-774, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel one-pot homologation reactions of isoquinoline with lithium dialkyl-TMP-zincateÁ2MgBrCl/tri-
methyl borate are described. 1-Alkylisoquinolines (2, 3A, 4A, 5A, 6, and 7) and 1-alkyl-3,4-dihydroiso-
quinolines (3B, 4B, and 5B) are easily prepared under the presented reaction conditions. The role of
the B(OMe)3/MgBrCl complex is examined in these homologation reactions. The specific reaction mech-
anisms, including 1,2-migration of the alkyl ligands from 1-isoquinolylzincates, are proposed. The migra-
tory aptitudes of ligands of 1-isoquinolylzincates are also discussed.
Received 2 April 2012
Revised 24 April 2012
Accepted 2 May 2012
Available online 7 May 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Trimethyl borate
Magnesium halide
Isoquinoline
Dialkyl-TMP-zincate
Homologation
Di-tert-butyl(2,2,6,6-tetramethylpiperidino)zincate (TMP-zincate)
is a useful deprotonating agent for the directed ortho metalation
(DoM) reaction of isoquinoline and other heteroaryl compounds.1
It is also an efficient t-butylating agent for the homologation reac-
tions of benzophenone2 and isoquinoline.3
TMP-zincate is normally formed by the sequential reactions of
ZnCl2 with 2tBuLi (or 2tBuMgBr) andlithium 2,2,6,6-tetramethylpipe-
ridinide (LiTMP). Consequently, TMP-zincate has two equivalents of
LiCl or MgBrCl. Our previous study on trimethyl borate-induced
one-pot homologation reactions of isoquinoline (Iq) with TMP-zin-
cateÁ2LiCl showed that 1-t-butylisoquinoline 1A4 and 1-t-butyl-3,4-
dihydroisoquinoline 1B5 were selectively prepared according to the
choice of two separate work-up methods under the identical reaction
condition (Scheme 1).3 The reaction mechanisms for the formation of
1A and 1B proceeded through 5- and 6-step processes, involving 1,2-
Scheme 1. Result for the reactions of isoquinoline with Li(tBu2TMPZn)Á2X and
B(OMe)3 in THF. Reagents and conditions: (a) excess H2O, 30 min, 96%; (b)
ventilation, 1 h, 94%.
whereas the other strategy using zincateÁ2MgBrCl/B(OMe)3 can
be generally applied to synthetic methods for most of the other
1-alkylisoquinoline derivatives.
t
migratory addition of a Bu ligand from 1-isoquinolylzincate.3 Re-
As key structural units in many important natural products7 and
pharmaceuticals,8,9 isoquinoline derivatives such as 1-alkylisoquin-
oline and 1-alkyl-3,4-dihydroisoquinoline are typically obtained
through Pomeranz–Fritsch reaction10 and Bischler–Napieralski
reaction.11 These types of reactions normally require more than a
single step to prepare the expected products, together with drastic
reaction conditions. In contrast, the zincate reactions
described herein offer the advantage of successfully achieving the
homologations of Iq through one-pot reaction under mild condi-
tion. Furthermore, this method allows the production of each
1-alkylisoquinoline and its 3,4-reduced derivative under the
identical reaction condition and selective control of work-up meth-
ods when an alkyl ligand is the sec-alkyl group. This result is of par-
ticular interest as there is no precedent for a generally applicable
cently, the corresponding reactions of TMP-zincateÁ2MgBrCl did not
afford the products 1A and 1B at all. Instead, the reactant, Iq was
quantitatively isolated.6 The simple replacement of LiCl with MgBrCl
in this application demonstrated a remarkable difference in the 1,2-
migratory ability of the tBu ligand. On the other hand, this tendency
is completely reversed in the results obtained for several different al-
i
kyl ligand-bearing zincate reactions (R: Et and Pr) of LiCl versus
MgBrCl.6
The homologation strategy employing zincateÁ2LiCl/B(OMe)3 is
limited to the preparation of 1-t-butylisoquinoline derivatives,
⇑
Corresponding author. Tel.: +82 2 970 5658; fax: +82 2 970 5972.
E-mail address: sknam@swu.ac.kr (S.K. Namgoong).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.002

H. J. Seo, S. K. Namgoong / Tetrahedron Letters 53 (2012) 3594–3598
3595
and 1-Iz) in THF within 3 h as shown in Scheme 2. Subsequent tri-
i
methyl borate-induced reactions of 1-IzX (R: Et and Pr, X: 2LiCl)
were unsuccessful, leading to the sole recovery of Iq.
On the other hand, the corresponding reactions of 1-IzY (R: Et
i
and Pr, Y: 2MgBrCl) produced the desired products 2, 3A, and 3B
in good yields (Scheme 2 and Table 1, entries 3–5). Those reactions
were completed within 3 h and did not produce any products with-
out adding B(OMe)3 to the reaction mixture of 1-IzY. A minimum
requirement (1.2 equiv) of B(OMe)3 was necessary to complete
the reaction. As for the zincate reactions including sterically less
hindered primary alkyl ligands, such as ethyl (Et), propyl (Pr), and
butyl (Bu) groups, 1-alkylisoquinolines (A) were only observed
and no reductive alkylation products (B) were detected, regardless
of the choice of the two separate work-up procedures. The following
two experimental work-up conditions can be recommended based
on these results: quickly quench the reaction and work-up the reac-
tion mixture with an excess of H2O comparable to the solvent (THF)
volume (W in Table 1), and slowly supply moisture for the reaction
mixture through ventilation for 1 hour (V in Table 1).The reaction
mixture is ventilated by removal of a sealing septum from the reac-
tion flask. The reaction of 1-IzY (R: Et) with B(OMe)3 generated 212
as the single major product (Scheme 2 and Table 1, entry 3).
As for the cases concerned with sterically more hindered sec-
ondary alkyl and cycloalkyl ligands, such as isopropyl (iPr), cyclo-
Scheme 2. Synthetic scheme for 1-alkylisoquinoline derivatives. Reagents and
conditions: (a) Li(R2TMPZn)Á2LiCl (2.2 equiv), THF, rt, 3 h; (b) Li(R2TMPZn)Á2MgBrCl
(2.2 equiv), THF, rt, 3 h; (c) Li(R2TMPZn) (2.2 equiv), THF, rt, 3 h; (d) B(OMe)3
(1.2 equiv), 3 h; (e) ventilation, 1 h; (f) excess H2O, 5–30 min.
hexyl (cHx), and cyclopentyl (cPt) groups,
A and B can be
selectively formed as the major products according to the adopted
work-up method. This pattern is very similar to that of the case for
t
the Bu ligand as illustrated in Scheme 1 (Table 1, entries 1 and 2,
Table 1
X: LiCl).3 Thus, the respective work-up methods for the isopropyl-
zincate reaction facilitated the generation of each of 3A13 and 3B14
(Scheme 2 and Table 1, entries 4 and 5; Y: MgBrCl). The 1-IzY reac-
tions possessing sec-alkyl ligands always produced A or B as the
minor products below 10% yields under the respective work-up
The conversion of isoquinoline into products A and Ba
t
conditions (Table 1, entries 4–9), unlike the case of the Bu ligand.
Entry/
product
R
Work-up
Yieldc (A:B, %)
The presented results of the 1-IzY reactions contrast with those
of the 1-IzX reactions in Scheme 2 and Table 1 (entries 1–5). These
results pose two curious questions: what are the functions of LiCl
and MgBrCl in the reactions of 1-IzX and 1-IzY with B(OMe)3;
and how are A and B formed together under each different work-
up condition? The latter question is addressed later by the reaction
mechanism illustrated in Scheme 3.
conditionb
X: LiCl Y: MgBrCl X/Y freed
1/1A
2/1B
3/2
tBu
tBu
Et
V
W
W or V
V
W
V
W
V
94:03
0:963
NR
NR
NR
—
NRe
NR
64:0
77:8
10:75
72:6
10:75
67:4
—
—
28:0
26:10
8:25
—
—
—
—
—
4/3A
5/3B
6/4A
7/4B
8/5A
9/5B
10/6
11/7
12/8
iPr
iPr
cHxf
cHx
cPtg
cPt
Pr
To elucidate the functions of such inorganic salts in this applica-
tion, the following experiments were carried out. First, the salt-free
reactions of 1-Iz with B(OMe)3 were investigated (Scheme 2 and
Table 1, entries 3–5). 1-Iz was prepared by the deprotonation reac-
tion of Iq with Li(R2TMPZn) which can be obtained from the reac-
tion of the commercially available R2Zn (R: Et and iPr) with LiTMP.
These salt-free reactions were partially successful, leading to the
production of 2–3B in 25–28% yields, whereas the corresponding
reactions of 1-IzX (X: LiCl) were not at all. These poor yields of
2–3B were attributed to the predominant nucleophilic addition
of R from excess Li(R2TMPZn) (1.2 equiv) to B(OMe)3 over the
1,2-migration of R from 1-Iz. The results for the 1-IzX reactions,
however, showed that the 1,2-migration of alkyl ligands was com-
pletely inhibited in the presence of LiCl. LiCl initially forms the
coordinative complex with B(OMe)3 prior to the coordination of
B(OMe)3 with the sp2-nitrogen of 1-IzX. This complex, possibly
B(OMe)3Á(LiCl)n (n = 1 or 2), is extremely electrophilic and hence
predominantly undergoes nucleophilic attack by the labile alkyl
ligands (Et and iPr) from excess Li(R2TMPZn). Therefore, the forma-
tion reactions of products 2–3B could not proceed at all. Nonethe-
—
—
—
—
W
5:66
W or V
W or V
W or V
42(52)h:0
Bu
Me
37:03,i 38:0
—
—
NR
NR
a
Reactions carried out in anhydrous THF at rt.
W: rapid work-up of the reaction mixture with excess water; V: ventilation of
b
the reaction mixture by removal of a sealing septum from the reaction flask.
c
The isolated yield of A and B after purification by column chromatography.
The reaction yield in the absence of LiCl and MgBrCl.
d
e
NR: No reaction occurred.
f
cHx: Cyclohexyl.
g
cPt: Cyclopentyl.
h
The yield for the reaction of the IqÁBF3 complex with Li(Pr2TMPZn)Á2Y.
i
The overall yield for the butylzincate reaction before/after addition of B(OMe)3.
one-pot homologation method of Iq in organozincate chemistry.
Therefore, we specially examined the B(OMe)3-induced homologa-
tion reactions of isoquinoline with various Li(R2TMPZn)Á2MgBrCl
compounds and herein report the subsequent results.
The present work is outlined in Scheme 2 and summarized in
Table 1. The one-pot homologation strategy began with the DoM
reaction of Iq with various lithium dialkyl-TMP-zincates
(2.2 equiv). Regioselective metalation reactions quantitatively pro-
duced the lithium 1-isoquinolylzincate intermediates (1-IzX, 1-IzY,
t
less, the excellent results for the Bu ligand (Table 1, entries 1 and
2; X: LiCl) is unusual. The tBu ligand proved to be the powerful 1,2-
t
migrating group in the formation reactions of 1A and 1B. The Bu
ligand is not labile, so that it cannot undergo nucleophilic addition
to the B(OMe)3ÁLiCl complex.

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H. J. Seo, S. K. Namgoong / Tetrahedron Letters 53 (2012) 3594–3598
Scheme 3. Proposed mechanisms for the formation of 2–7 from 1-IzY.
The other experiment was to investigate the substitution effect
yields of only ca 5–10%. These yields were slightly improved to
ca 30–40% when 8 equiv of B(OMe)3 were used in this application.
The homologation strategy employing MgCl2 required the use of a
large amount of B(OMe)3/THF and therefore, was not efficient. Its
precipitation was not observed in THF when MgBrCl was substi-
tuted with MgBr2. Its 1-IzY reaction (R: Et) produced 2 in 45% yield,
which was lower than that of the MgBrCl reaction (Table 1, entry
3). In general, the corresponding reactions of MgBr2 need ZnBr2,
which is relatively expensive as compared to ZnCl2. Based on the
combined experimental results of 1-IzY, the homologation strategy
employing MgBrCl was demonstrated to be the best among the
three strategies described above.
The coordination pattern of MgBrCl with B(OMe)3 is expected to
be different from the case of LiCl even though the exact structures
of these coordinative complexes are not clear. The metal ion of
MgBrCl coordinates with the oxygen atom(s) of B(OMe)3 in a sim-
ilar manner to that of LiCl. At the same time, one of its halide ions
presumably coordinates with the electrophilic boron atom, unlike
the case of LiCl. The dual coordination between MgBrCl and
of MgBrCl with MgCl2 and MgBr2 under the identical reaction con-
dition. Both MgCl2 and MgBr2 (2.2 equiv for Iq) were generated by
the reactions of ZnCl2/2RMgCl and ZnBr2/2RMgBr, respectively.
When MgBrCl was replaced by MgCl2, this method failed to pro-
duce reproducible yields of 3A and 3B due to the limited solubility
of MgCl2 in THF. A considerable amount of precipitated MgCl2 was
i
observed during the preparation of Pr2Zn. It was gradually dis-
solved in the THF as the amount of B(OMe)3 added to the reaction
mixture was increased. This indicated that a coordinative complex
was formed between the insoluble MgCl2 and B(OMe)3 and that
this complex became soluble in THF. In this regard, a similar result
is observed in the literature method for preparing the complex,
Mg(OEt)2ÁB(OMe)3.15 Mg(OEt)2 was practically insoluble in alcohol
solvents and most of Mg(OEt)2 became soluble in alcohols after the
addition of B(OMe)3 to the reaction mixture, resulting in the for-
mation of the 1:1 complex. This complex formation reaction was
noticeably exothermic. However, the use of B(OMe)3 (1.2 equiv)
was not effective for the formation of 3A and 3B, and recorded

H. J. Seo, S. K. Namgoong / Tetrahedron Letters 53 (2012) 3594–3598
3597
B(OMe)3 may lead to the production of the 1:1 complex like the
complex, Mg(OEt)2ÁB(OMe)3.15 This complex is not only less elec-
trophilic but also more sterically hindered than the LiCl complex,
and is presumably not susceptible to nucleophilic attack by alkyl
ligands from excess zincates, leading to stable formation of the
subsequent complex between 1-IzY and MgBrClÁB(OMe)3. In this
application of the tBu ligand, the steric hindrance between the bo-
rate complex and 1-(tBuTMPZn) group of 1-IzY is too large to allow
access of this complex to the ring nitrogen atom, which prevents
any production of 1A or 1B (entries 1 and 2).
B(OMe)3ÁY (Y: MgBrCl) with the sp2-nitrogen of 1-IzY, (2) 1,2-
migratory addition of the alkyl ligand from C, and (3) subsequent
reformation of the aromatic ring through loss of the (MeO)2BZnTMP
group from D. The B(OMe)3ÁY complex plays an important role in
enhancing electrophilicity at the 1-carbon, and stimulating move-
ment of the nucleophilic alkyl ligand to the corresponding position
of 1-IzY. The elimination pattern of (MeO)2BZnTMP is similarly ob-
served in the formation mechanisms of 1-butylisoquinoline and 2-
t-butylquinoline, as previously reported.3 1-IzY possessing sec-al-
kyl ligands can be partially converted into A type of minor products
(3A, 4A, and 5A) due to the insufficient steric hindrance between R
(iPr, cHx, and cPt) and ZnTMP groups of D, even under the work-up
condition (W) applied for excess H2O.
As for both reductive alkylation and alkylation mechanisms for
the major production of B (3B, 4B, and 5B) and A (3A, 4A, and 5A),
these mechanisms involve the same pathways as those previously
reported for the formation of compounds 1A and 1B.3 The produc-
tion mechanism for B proceeds through a 4-step process from C:
(1) 1,2-migratory addition of R from C, (2) further migration of
the ZnTMP group to a 3-carbon, (3) rapid hydrolytic cleavage (W)
of C-Zn bond, and (4) final C-B bond cleavage at the 4-position of
intermediate G. The steric repulsion between the sec-alkyl and
ZnTMP groups caused by 1,2-migration facilitated further migra-
tion of the ZnTMP group to quickly produce F.
The following mechanism for major formation of A involves a 3-
step process from F: (1) production of H by nucleophilic addition of
hydroxide ion to a boron atom, (2) preferential benzylic CAB bond
cleavage via internal electrophilic substitution (SEi),23 and (3) sub-
sequent re-aromatization through elimination of HZnTMP from I.
The ventilation work-up method (V) allowed the production of
the hydroxide ion derived from H2O and predominated the prefer-
ential hydroxide ion-promoted CAB bond cleavage at a 4-carbon
prior to CAZn bond cleavage at a 3-carbon of H, thereby generating
the precursor I.3,23
Finally, the mechanism for minor formation of B (3B, 4B, and
5B) is proposed in Scheme 3, proceeding through a 5-step process
from E: (1) production of J by nucleophilic addition of hydroxide
ion to a boron atom, (2) preferential CAB bond cleavage followed
by re-coordination of borate moiety with sp2-nitrogen, (3) rear-
rangement of the ZnTMP group to an oxide ion of borate moiety
through cyclic transition state from K, (4) repeated nucleophilic
addition of hydroxide ion to a boron atom of L, and (5) final hydro-
lytic cleavage of the C-B bond of M. The species E is not completely
transformed into F due to the limited steric hindrance between the
sec-R and ZnTMP groups. Thus, the remaining species E is con-
verted into K via J under ventilation condition (V). A re-coordina-
tion of borate moiety with K followed by formation of a 5-
membered cyclic structure possibly facilitates intramolecular rear-
rangement of the ZnTMP group, which is then transformed into the
more stable conjugated species L. The hydrolytic cleavage of the
CAB bond from M leads to the formation of reductive alkylation
products B (3B, 4B, and 5B) as minor products in 5–10% yields,
even under ventilation condition. Consequently, each of the two
separate work-up methods allowed minor production of A or B
in this application, as illustrated in Scheme 3.
This MgBrCl complex was exclusively applied to other homolo-
gation reactions as shown in Table 1 (entries 6–12). The results for
the cHx and cPt ligands were analogous to that of the iPr ligand and
also showed the expected products 4A16, 4B17, 5A,18 and 5B19 in
good yields (entries 6–9). Although compound 5A was specified
in the literature,18 its spectral data remain unknown.20 The yields
for the Pr and Bu ligands (42% and 38% yields, entries 10 and 11,
respectively) were relatively lower than that of 2 (entry 3). As they
are probably more labile than the Et ligand, these ligands undergo
an easier nucleophilic addition to the B(OMe)3 complex. The reac-
tions for the Pr and Bu ligands required a rapid work-up within
5 min, unlike the reactions for the other ligands. Otherwise, an
inseparable mixture of products was formed for the prolonged
work-up time (30 min). The alternative preparation method3
employing the IqÁBF3 complex and Li(Pr2TMPZn)Á2MgBrCl im-
proved the yield of 621 (52%, entry 10), even though the yields of
the corresponding reactions for the other ligands were still low
in the range of 18–41%. However, this method afforded only the
single major product 6 and was not sensitive to the prolonged
work-up time. Especially, product 722 was initially formed from
the reaction for Bu ligand/LiCl3 in ca 20% yield, even without
B(OMe)3.On the other hand, this product was not generated in
the corresponding reaction of MgBrCl without the presence of
B(OMe)3 (entry 11). This result indicates that MgBrCl acts to re-
strict direct addition of the labile Bu ligand from excess Li(-
Bu2TMPZn) into isoquinoline.
Finally, this homologation strategy was unsuccessful in the
reactions for methyl and aryl ligands. 1-IzY possessing the methyl
ligand demonstrated inactivity for the 1,2-migratory addition and,
therefore, was not converted into product 822 at all (entry 12; X
and Y). The Me ligand does not seem to be sufficiently nucleophilic
to facilitate 1,2-migratory addition. Although the results are not
shown in Table 1, the aryl (Ph and 4-Cl-Ph, Y) ligands also proved
extremely labile as in the previously reported example (Ph, X).3
Such arylzincate reactions gave the 1:1 IqÁtriarylborane complexes
as the major products instead of the desired products. All the spec-
tral data of the prepared compounds (2–4B and 5B–7) were iden-
tical to those in the reference data.12–14,16–19,21,22 The structure of
compound 5A was also confirmed by IR, NMR, and high resolution
mass spectroscopic analyses.20
This present evaluation of the 1,2-migratory ability of the li-
gands in 1-IzY revealed a migratory aptitude in the following order:
sec-R (alkyl group) > pri-R >> Me. The order of a migratory aptitude
for tert-alkyl (tBu) ligand could not be defined in this series because
its inactive nature was attributed to the steric hindrance of
t
MgBrClÁB(OMe)3 complex, unlike the case of Me ligand. The Bu
In conclusion, one-pot homologation reactions of isoquinoline
were efficiently achieved in the presence of the trimethyl borate/
MgBrCl complex via directed ortho metalation and a 1,2-migratory
addition reaction. The role of the B(OMe)3/MgBrCl complex in the
presented reactions was explained by the selected experimental
results. These types of homologation reactions were generally
applicable to the synthetic method for 1-alkylisoquinoline deriva-
tives in the field of zincate chemistry. The migratory aptitude of
the ligands was clearly determined by evaluating the 1,2-migra-
tory ability of the ligands in 1-IzY. The specific formation mecha-
nisms for compounds 2–7 were also suggested.
group was the most effective 1,2-migrating group in a series of li-
gands in 1-IzX. These two ligands, iPr and Et, were extremely labile
in this series, and hence predominantly underwent nucleophilic
addition to the B(OMe)3ÁLiCl complex. In addition, the Me ligand
was the most non-transferring alkyl group for the 1,2-migratory
addition and the nucleophilic addition to B(OMe)3 in both series.
The reaction mechanisms for the formation of 2–7 are proposed
in Scheme 3, and proceed through 3- to 7-step processes from 1-
IzY. The following mechanism is for the major production of A (2,
6, and 7) possessing primary alkyl groups: (1) coordination of

3598
H. J. Seo, S. K. Namgoong / Tetrahedron Letters 53 (2012) 3594–3598
9. Ortqvist, P.; Peterson, S. D.; Akerblom, E.; Gossas, T.; Sabnis, Y. A.; Fransson, R.;
Acknowledgments
Lindeberg, G.; Danielson, U. H.; Karlen, A.; Sandstrom, A. Bioorg. Med. Chem.
2007, 15, 1448–1474.
The authors are very grateful to the Molecular Imaging Research
Center (Korea Institute of Radiological & Medical Sciences, Seoul
139–706) for the kind support of their NMR facilities. This work
was supported by a special research grant from Seoul Women’s
University (2012).
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D.; Hodgetts, K. J. Bioorg. Med. Chem. Lett. 2008, 18, 891–896.
(d, J = 8.2 Hz, 1H, Ph), 7.84–7.81 (m, 1H, Ph), 7.70–7.65 (m, 1H, Ph), 7.63–7.57
(m, 1H, Ph), 7.50–7.49 (d, J = 5.4 Hz, 1H, Ph), 4.10–4.00 (qt, J = 8.3 Hz, 1H, CH),
2.20–2.04 (m, 4H, 2CH2), 1.98–1.76 (m, 4H, 2CH2); 13C NMR (75 MHz, CDCl3) d
164.7, 141.8, 136.2, 129.6, 127.4, 127.2, 126.8, 125.2 118.9, 43.0, 32.8, 26.1
ppm; HRMS (CI) m/z calcd for C14H16N (MH+): 198.1283; found: 198.1284.
21. Kido, K.; Watanabe, Y. Heterocycles 1980, 14, 1151–1154.
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