Concise synthesis of multisubstituted isoquinolines from pyridines by regioselective diels-alder reactions of 2-silyl-3,4-pyridynes

Article abstract of DOI:10.1002/chem.201404633

A four-step regioselective synthesis of multisubsti-tuted isoquinoline derivatives from 3-bromopyridines was developed by the Diels-Alder (DA) reactions of 2-silyl-3,4-pyridynes with furans, followed by functional-group transformations. In particular, the silyl group at the C2-position of the 3,4-pyridynes played two important roles: firstly, it functioned as the directing group for the DA reaction, and secondly, it served to introduce diverse substituents at the C1-position of the isoquinolines by electrophilic ipso-substitution.

Full text of DOI:10.1002/chem.201404633

DOI: 10.1002/chem.201404633
Full Paper
&
Synthetic Methods
Concise Synthesis of Multisubstituted Isoquinolines from
Pyridines by Regioselective Diels–Alder Reactions of 2-Silyl-3,4-
pyridynes
Takashi Ikawa,*[a] Hirohito Urata,[b] Yutaka Fukumoto,[a] Yuta Sumii,[a] Tsuyoshi Nishiyama,[b]
and Shuji Akai*[a]
Abstract: A four-step regioselective synthesis of multisubsti-
tuted isoquinoline derivatives from 3-bromopyridines was
developed by the Diels–Alder (DA) reactions of 2-silyl-3,4-
pyridynes with furans, followed by functional-group transfor-
mations. In particular, the silyl group at the C2-position of
the 3,4-pyridynes played two important roles: firstly, it func-
tioned as the directing group for the DA reaction, and sec-
ondly, it served to introduce diverse substituents at the C1-
position of the isoquinolines by electrophilic ipso-substitu-
tion.
Introduction
Isoquinolines are abundant in biologically active natural and
non-natural compounds,[1,2] many of which are currently used
as therapeutic agents, such as antibiotics,[2a] antineoplastics,[2b]
and antispasmodics.[2c] Therefore, the synthesis of isoquinolines
has attracted considerable attention from both synthetic and
biological perspectives. Although diverse synthetic methods
for isoquinolines have been reported,[3–6] most of them are
based on the construction of a pyridine ring on benzene;[4,5a,c–i]
for example, the ring closure at the C1-position of isoquinoline,
in the Pictet–Spengler[4] and Bischler–Napieralski reactions,[4]
and at the C4-position, in the Pomeranz–Fritsch reaction[4]
(Figure 1). In contrast, the “reverse approach”, the construction
of a benzene ring on pyridine, has not been investigated in de-
tail.[5b,6] Therefore, the development of an effective methodolo-
gy for this reverse approach is important to synthesize struc-
turally diverse substituted isoquinolines.
Figure 1. Comparison between traditional approaches and this work for the
syntheses of isoquinolines.
groups have reported a total of three regioselective DA reac-
tions. Guitiꢀn and co-workers developed a Cl-atom-directed re-
gioselective DA reaction for the total synthesis of ellipticine.[6d,f]
Recently, Goetz and Garg reported that a OSO2NMe2 moiety
and a Br atom on 3,4-pyridyne could be used as directing
groups for DA reactions with furan.[6i] These electron-withdraw-
ing directing groups were transformed into other substituents,
such as amino and aryl, and H groups by transition-metal-cata-
lyzed reactions. However, the regioselectivity of the products
and the number of substituents accessed from them were not
sufficient, and the generality of these reactions has not been
investigated in detail. Therefore, to make the reverse approach
more practical, a new methodology, which utilizes another
powerful and versatile directing group, is required.
The Diels–Alder (DA) reaction of 3,4-pyridynes[6–8] with
dienes, such as furans, is classified as the reverse approach and
may be a powerful tool for the synthesis of isoquinolines; how-
ever, this reaction suffers from severe regioselectivity problems
(Figure 1).[6] To the best of our knowledge, only two research
[a] Dr. T. Ikawa, Y. Fukumoto, Y. Sumii, Prof. Dr. S. Akai
Graduate School of Pharmaceutical Sciences
Osaka University
1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan)
Fax: (+81)6-6879-8212, (+81)6-6879-8210
E-mail: ikawa@phs.osaka-u.ac.jp
akai@phs.osaka-u.ac.jp
[b] H. Urata, T. Nishiyama
School of Pharmaceutical Sciences,
University of Shizuoka
52-1 Yada, Suruga-ku, Shizuoka 422-8526 (Japan)
Herein, we demonstrate that inductively electron-donating
groups (M) such as silyl[9] and stannyl, can be used as directing
groups for the first time and the DA reactions of such 3,4-pyri-
dynes can be achieved with moderate-to-excellent regioselec-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404633.
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tivity (Figure 1). Moreover, the silyl groups of the DA adducts
worked to introduce diverse substituents (R) at the C1-position
of isoquinolines. Thus, the overall process results in the four-
step synthesis of diverse multisubstituted isoquinoline deriva-
tives from readily available 3-bromopyridines.
Table 1. Regioselectivity in the DA reactions of various 3,4-pyridynes 3,
obtained from pyridines 2, with 2-butylfuran 4A.[a]
Results and Discussion
We designed new precursors, 3-iodo-2,4-bis(triethylsilyl)pyri-
dine (2a)[10] and 3-iodo-2-(tributylstannyl)-4-(triethylsilyl)pyri-
dine (2b), to afford 3,4-pyridynes, possessing the directing silyl
(3a)[9] or stannyl group (3b) at the C2-position, by treatment
with a fluoride ion. After intensive trials, 2a and 2b were syn-
thesized from commercially available 3-bromopyridine 1a
(Scheme 1). Thus, the in situ double triethylsilylation of 1a
Entry
M
2, 3
Time
[h]
D-5A/P-5A[b]
5A
Yield
[%][c]
1
SiEt3
SiEt3
Si(Bu)3
Sn(Bu)3
H
2a, 3a
2a’, 3a
2c, 3c
2b, 3b
2d, 3d
2e, 3e
2 f, 3 f
9
6
25
11
9
2.3:1
2.3:1
2.4:1
2.8:1
1.0:1
1.1:1
1:1.5
5Aa
5Aa
5Ac
5Ab
5Ad
5Ae
5Af
93 (82)[d]
78 (77)[d]
77 (70)[d]
83 (71)[d]
48
92 (77)[d]
61 (56)[d]
2[e]
3
4
5
6
7
tBu
OMe
8
16
[a] Conditions: 1.0 equiv of pyridine 2, 7.0 equiv of furan 4A, 1.5 equiv of
1
CsF in MeCN (0.40m) at 608C for 4–24 h. [b] Determined by H NMR spec-
troscopy. [c] Total NMR yield of distal-5A and proximal-5A. [d] Total isolat-
ed yield of distal-5A and proximal-5A. [e] 2,4-Bis(triethylsilyl)-3-bromopyr-
idine 2a’ was used instead of 2a.
The above-mentioned results are significant because no se-
lectivity was observed for the reactions of unsubstituted 3d
(distal-5Ad/proximal-5Ad=1:1, entry 5) and 2-tert-butyl-3,4-
pyridyne 3e (distal-5Ae/proximal-5Ae=1.1:1, entry 6). The re-
action of 2-methoxy-3,4-pyridyne 3 f preferentially afforded
proximal-5Af with low selectivity (distal-5Af/proximal-5Af=
1:1.5, entry 7). As expected, the electron-donating inductive ef-
fects of the silyl and stannyl groups of 3a–c afforded the distal
adducts, which is opposite to the case of 2-methoxypyridyne
3 f.
Scheme 1. Synthesis of new precursors, 2,4-bis(triethylsilyl)-3-iodopyridine
(2a) and 3-iodo-2-(tributylstannyl)-4-(triethylsilyl)pyridine (2b).
using excess amounts of lithium diisopropylamide (LDA) and
Me3SiCl afforded 2,4-bis(triethylsilyl)-3-bromopyridine 2a’.[11]
The transformation of 2a’ to 2a was achieved by a Br/Li ex-
change followed by I2 quenching (76% over two steps). On the
other hand, the sequential C4-silylation and C2-stannylation af-
forded 2b’ regioselectively; the iodination of 2b’ afforded 2b
(24% in three steps).[12]
The effects of methoxy (3g) and tBu (3h) groups at the C6-
position of 3,4-pyridyne on the regioselectivity were insignifi-
cant (distal-5A/proximal-5A=2.5:1 for 5Ag and 1.7:1 for 5Ah)
(Table 2, entries 1 and 2).
The generation of 3,4-pyridynes 3a–f from the correspond-
ing pyridines 2a–f, and the regioselectivity of their DA reac-
tions with 2-butylfuran 4A, were examined by using CsF in
MeCN at 608C (Table 1). The reaction of 2-(triethylsilyl)-3,4-pyri-
dyne 3a,[13] generated from 2a, preferentially afforded distal-
5Aa (distal-5Aa/proximal-5Aa=2.3:1, Table 1, entry 1). Nota-
bly, although precursor 2a has silyl groups at the C2- and C4-
positions, 3,4-pyridyne 3a was obtained with excellent chemo-
selectivity.[12] The precursor 2a, bearing a 3-iodo group, was
necessary to achieve a high yield (93% yield, obtained by NMR
spectroscopy) of distal- and proximal-5Aa; when the 3-bromo
analogue, 2a’, was used the total yield of 5Aa slightly de-
creased (78%, obtained by NMR spectroscopy) owing to the
protodesilylation of 2a’ (entry 2). The regioselectivity of 3,4-
pyridyne 3c bearing a bulkier tributylsilyl group at the C2-posi-
tion (distal-5Ac/proximal-5Ac=2.4:1, entry 3) was similar to
that of 3a, whereas a similar reaction of 2-(tributylstannyl)-3,4-
pyridyne 3b afforded slightly higher regioselectivity (distal-
5Ab/proximal-5Ab=2.8:1, entry 4). However, the silyl group is
more attractive because of its significantly low toxicity com-
pared to that of the stannyl group.
Next, the substrate scope and limitation of the DA reactions
of 3a with various furans 4 were investigated. The total isolat-
ed yields were moderate to excellent (60–92%, Table 2, en-
tries 3–11), and all reactions afforded distal-5a as the major
product. The regioselectivity increased according to the bulki-
ness of the R2 and R3 groups (entries 3–7); the highest regiose-
lectivity was obtained by using 2-stannylfuran 4F (distal-5Fa/
proximal-5Fa=14:1, entry 7). Interestingly, the distal products
were preferentially obtained from the reactions with furans
(4G and 4H) bearing an electron-withdrawing substituent
(R2 =CO2Me and COMe) at the C2-position, even though the
regioselectivity decreased (entries 8 and 9). In these cases, the
protection of the carbonyl groups as an acetal significantly in-
creased the distal selectivity and yield (entries 10 and 11).
The reaction of pyridyne 3a with C2-substituted pyrrole 4K
afforded distal-5Ka with high regioselectivity (distal-5Ka/proxi-
mal-5Ka=8.8:1, total 87% yield) [Eq. (1)]. This type of cycload-
dition product, 5Ka, containing an azabicyclo[2.2.1]heptane
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Table 2. Substrate scope and limitation of the regioselective DA reactions
of 2-silyl-3,4-pyridynes 3 with various furans 4.[a]
Entry R1
2, 3
R2
R3
4
D-5/P-5[b]
5
Yield [%][c]
1
2
3
4
5
6
7[f]
8
OMe 2g, 3g nBu
H
H
H
H
4A
4A
4B
4C
2.5:1
1.7:1
2.0:1
7.8:1
4.3:1
5Ag 86
5Ah 95[b]
5Ba 66
5Ca 92[d]
5Da 65
5Ea 88[e]
5Fa 89
5Ga 60
5Ha 62
tBu
H
2h, 3h nBu
2a, 3a Me
H
2a, 3a tBu
H
2a, 3a Me
Me 4D
H
H
H
H
2a, 3a SiMe3
2a, 3a Sn(Bu)3
2a, 3a CO2Me
2a, 3a COMe
H
H
H
H
4E >4.5:1
4F
4G
4H
14:1
1.3:1
1.8:1
9
10
11
H
H
2a, 3a
H
H
4I
9.5:1
4.2:1
5Ia 79
5Ja 63
2a, 3a CH(OEt)2
4J
Scheme 2. Transformations of distal-5Aa to multisubstituted isoquinolines
(6a–6g, 7a’, and 7b). TBAF=tetrabutylammonium fluoride; HMPA=hexa-
methylphosphoramide.
[a] Conditions: 1.0 equiv of 2, 7.0 equiv of 4, 1.5 equiv of CsF in MeCN
(0.40m) at 608C for 2–24 h. [b] Determined by 1H NMR spectroscopy.
[c] Total isolated yield of distal-5 and proximal-5. [d] Total isolated yield of
distal-5Ca (58%), desilylated distal-5Ca’ (17%, M=H), and proximal-5Ca’
(17%, M=H). [e] Total isolated yield of distal-5Ea (72%), desilylated 5Ea’
(2.4%, M=H), and 5Ea’’ (14%, R2 =H). [f] 3.0 equiv of CsF was used.
skeleton can be used for the synthesis of functionalized alka-
loids or other analogues.[14]
Figure 2. Electron densities and internal angles of 2-substituted pyridynes
(3a and 3 f) and 2-methylfuran 4B.[17]
and 3e are shown in the Supporting Information). The distor-
tion and electronic property strongly indicate that the C3-posi-
tion of 3a is more electrophilic than the C4-position, and the
C4-position of 4B is more nucleophilic than the C2-position
(for details, see the Supporting Information).[18] Therefore, the
delocalization of electrons between the C3-position of 3a and
the C4-position of 4B, and that between the C4-position of 3a
and the C2-position of 4B, may be the major driving force for
the distal selective DA reaction. In a similar manner, the ob-
served opposite proximal selectivity in the case of 3 f can be
explained by the distortion[6i,9f] and electronic properties[18] of
3 f (i.e., the C4-position of 3 f is more electrophilic). The prop-
erties of 3a and 3b can be attributed to the electron-donating
inductive effects of the Si and Sn atoms, respectively, and
those of 3 f can be attributed to the electron-withdrawing in-
ductive effect of the O atom (Allred–Rochow electronegativi-
ties: O, 3.5; C, 2.5; Si, 1.7; Sn, 1.7).[19]
As a typical example, the DA adduct, distal-5Aa, was further
transformed into various substituted isoquinolines 6a–6g, 7a’,
and 7b (Scheme 2). The 1,4-epoxide of 5Aa[15] was opened by
treatment with trimethylsilyl triflate (Me3SiOTf), followed by
quenching with H2O, to afford 8-hydroxyisoquinoline 6a. In
contrast, the same reaction without quenching with H2O af-
forded 7a’. The deoxygenative cleavage[15a] of the 1,4-epoxide
by using Fe2(CO)9 afforded 1-(triethylsilyl)isoquinoline 7b, the
silyl group of which was converted to an iodo (6b), oxo (6c),
amino (6d), aryl (6e), alkyl (6 f), or H (6g) group.[16] Therefore,
the overall process provides a new method for the four-step,
regioselective synthesis of various substituted isoquinoline de-
rivatives (6 and 7) from 3-bromopyridine 1.
Finally, the origin of the regioselectivity of the DA reactions
of 3,4-pyridynes was analyzed by density-functional-theory
(DFT) and natural-bond-orbitals (NBO) calculations (Figure 2).[17]
The structures of 3a, 3 f, and 4B were optimized by DFT
[B3LYP/6-31G(d)], and the electron densities of their reacting
orbitals were calculated by NBO5.0 (for reference, those of 3d
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period shown in Tables 1 and 2 and cooled to RT. H2O and Et2O
were added to the reaction mixture, and the aqueous phase was
extracted three times with Et2O. The combined organic phase was
washed with a saturated aqueous NaCl solution. The organic phase
was dried over anhydrous Na2SO4, and the solvent was removed
under reduced pressure. The residue was subjected to 1H NMR
analysis for calculating the ratio and total yield of the two re-
gioisomers (distal- and proximal-5) using naphthalene as the inter-
nal standard. The crude product was purified by flash column chro-
matography on silica gel (hexane, a mixture of hexane and EtOAc,
or CH2Cl2) to afford distal- and proximal-5.
Conclusion
We have demonstrated that various substituted isoquinoline
derivatives could be synthesized in four steps starting from
commercially available 3-bromopyridines. The silyl group at-
tached at the C2-position of 3,4-pyridynes functions as an ef-
fective directing group for the regioselective DA reaction of
3,4-pyridynes with furans and also acts as a versatile functional
group for further ipso-substitution, affording diverse substitu-
ents. The regioselectivity control by the 2-silyl group can be at-
tributed to its electronic effect, as explained by theoretical
studies. Further investigations, including the improvement of
regioselectivities, the synthetic applications, and detailed
mechanistic studies of the DA reactions with furans bearing
electron-withdrawing groups are underway.
Acknowledgements
This work was supported by the JSPS KAKENHI Grant Number
23790017, 25460018, and Platform for Drug Discovery, Infor-
matics, and Structural Life Science from the MEXT. We thank
University of Shizuoka, the Uehara Memorial Foundation, and
Hoansha foundation for financial support. We also acknowl-
edged National Institute of Biomedical Innovation for sharing
a Bruker NMR instrument.
Experimental Section
Synthesis of 3-iodo-2,4-bis(triethylsilyl)pyridine 2a (Scheme
1)
A flame-dried flask with a stir bar was charged with 3-bromopyri-
dine 1a (1.0 equiv), capped with a three-way stopcock, and evacu-
ated and back-filled with Ar. Anhydrous THF (0.50m) was added by
a syringe, and the mixture was cooled to À788C. A freshly pre-
pared 0.80m LDA (4.5 equiv) solution of THF was slowly added to
the flask through a cannula over 5 min at À788C, and the mixture
was stirred for 10 min. Et3SiCl (4.5 equiv) was added at À788C, and
the reaction mixture was warmed up to RT and stirred for 2 h. H2O
and Et2O were added to the reaction mixture, and the aqueous
phase was extracted three times with Et2O. The combined organic
phase was washed with a saturated aqueous NaCl solution. The or-
ganic phase was dried over anhydrous Na2SO4, and the solvent
was removed under reduced pressure. The crude product was puri-
fied by flash column chromatography on silica gel (hexane/
EtOAc=100:1 with 1% Et3N) to afford 3-bromo-2,4-bis(triethylsilyl)-
pyridine 2a’. Another flame-dried flask with a stir bar was charged
with 2a’ (1.0 equiv), capped with a three-way stopcock, and evacu-
ated and back-filled with Ar. Anhydrous THF (0.30m) was added by
a syringe, and the mixture was cooled to À788C. A 1.6m nBuLi so-
lution (1.5 equiv) in hexane was slowly added by a syringe over
10 min under stirring, and the reaction mixture was stirred at
À788C for 10 min. A 1.0m iodine solution (1.1 equiv) in THF was
slowly added to the flask by a syringe over 5 min. The reaction
mixture was warmed to RT and stirred for 30 min. 5% Na2S2O3 and
Et2O were added to the reaction mixture, and the aqueous phase
was extracted three times with Et2O. The combined organic phase
was washed with a saturated aqueous NaCl solution. The organic
phase was dried over anhydrous Na2SO4, and the solvent was re-
moved under reduced pressure. The crude product was purified by
flash column chromatography on silica gel (hexane/EtOAc=70:1
with 1% Et3N) to afford precursor 2a.
Keywords: cycloaddition · furans · isoquinolines · pyridynes ·
silyl groups
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furan 4 (Tables 1 and 2)
CsF (1.5 equiv) was flame-dried under reduced pressure in a reac-
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flask through a cannula. The mixture was stirred at 608C for the
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Received: July 28, 2014
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Published online on October 13, 2014
Chem. Eur. J. 2014, 20, 16228 – 16232
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