Synthesis of 1,3,4-trisubstituted isoquinolines by iodine-mediated electrophilic cyclization of 2-alkynyl benzyl azides

Article abstract of DOI:10.1002/anie.200701392

(Chemical Equation Presented) The I's have it: A series of 2-alkynyl benzyl azides have been smoothly converted into 1,3,4-trisubstituted isoquinolines in moderate to excellent yields by an iodonium-mediated synthesis (see scheme). Depending on the struct

Full text of DOI:10.1002/anie.200701392

Communications
DOI: 10.1002/anie.200701392
Synthetic Methods
Synthesis of 1,3,4-Trisubstituted Isoquinolines by Iodine-Mediated
Electrophilic Cyclization of 2-Alkynyl Benzyl Azides**
Dirk Fischer, Hisamitsu Tomeba, Nirmal K. Pahadi, Nitin T. Patil, and Yoshinori Yamamoto*
Isoquinolines are an important class of alkaloids commonly
found in natural products.[1] Their biological activities have
resulted in them often being used as building blocks in
pharmaceutical compounds,[2] as chiral ligands for transition-
metal catalysts,[3] and their iridium complexes in organic light-
emitting diodes (OLEDs).[4]
Scheme 2. PtBr2-catalyzed synthesis of isoquinolines.
A general and flexible approach to this class of hetero-
cycles is highly desirable for the syntheses of delicate natural
products as well as for the fine-tuning of the biological and/or
physical properties of the compounds for final application.
Although many ways have been developed to synthesize
isoquinolines, classical methods such as the Pomernanz–
Fritsch reaction have considerable drawbacks, for example,
the use of strong acids and elevated temperature,[5] which are
not suitable for sensitive substrates. In recent years, new
transition-metal-catalyzed reactions have been developed to
synthesize substituted isoquinolines from phenylacetylene
substrates (Scheme 1).[6] These reactions have proven to be
undergo the transformation shown in Scheme 1. This has
prompted us to develop a new mild method to synthesis 1,3,4-
trisubstituted isoquinolines.
After considering the pathway of the transformation, we
focused our attention on using azides as the leaving group
most likely to achieve high yields and conversions. To gain
access to 1,3,4-trisubstituted isoquinolines, we considered
using an electrophile as a reaction mediator, since it would be
incorporated into the final product. The iodonium ion is well
suited for this purpose, and it offers clear potential for the
further introduction of molecular diversity at C4.
Initial cyclization studies of 1a using five equivalents of
iodine and five equivalents of K3PO4 as a base in CH2Cl2
provided the desired isoquinoline 2a in an excellent yield of
95% (Table 1, entry 1). Compounds 1a and 1 f were used as
model substrates to optimize the reaction conditions. The
reactions were always carried out for 24 h to ensure complete
Scheme 1. Transition-metal-catalyzed synthesis of isoquinolines. dba=
trans,trans-benzylideneacetone.
Table 1: Iodine-mediated synthesis of isoquinolines.
extremely efficient in the synthesis of a wide variety of 3,4-
substituted isoquinolines and other carbo- and heterocycles.[7]
It is, however, not possible to synthesize 1,3,4-trisubstituted
isoquinolines by these methods.
During our research into forming functionalized indenes
by using platinum as a catalyst,[8] we observed in one case the
formation of a 1,3-substituted isoquinoline (Scheme 2).[9]
Only aldimine-type substrates are currently known to
Entry
1
R1
R2
X
Yield[a] [%] 2 Yield[a] [%] 3
1[b]
2[b]
3[b,d]
4[b]
5[c]
1a Ph
H
H
H
H
CH 95
CH 94
CH 95
CH 82
CH 69
–
–
–
–
–
–
–
1b p-OMePh
1c p-CF3Ph
1d 1-cyclohexenyl
1e Ph
1 f Ph
1g Ph
1h Ph
1i
1j
[*] Dr. D. Fischer, H. Tomeba, Dr. N. K. Pahadi, Dr. N. T. Patil,
Prof. Dr. Y. Yamamoto
Me
Department of Chemistry
Graduate School of Science
TohokuUniversity
Sendai 980-8578 (Japan)
Fax: (+81)22-795-6784
6[c]
Hex CH 73
Ph
H
H
H
7[c]
CH 68[e]
N
CH
CH
8[b]
9[b]
10[b]
92
–
–
–
2-pyridinyl
H
86
56[f]
E-mail: yoshi@mail.tains.tohoku.ac.jp
[**] We thank the Japanese Society for the Promotion of Science and the
Center of Excellence for financial support.
[a] Yield of isolated product. [b] I2 (5 equiv), K3PO4 (5 equiv), CH2Cl2
(0.1m), 24 h, RT. [c] I2 (5 equiv), NaHCO3 (1 equiv), CH2Cl2 (0.1m), 24 h,
RT. [d] Reaction time 72 h. [e] Two side products were formed, which
could not be separated; yield determined by NMR spectroscopic
analysis. [f] The crystal structure is shown in the Supporting Information.
Hex=n-hexyl.
Supporting information for this article (including general exper-
imental procedures, spectroscopic data for all new compounds, and
crystal structural data for 3j) is available on the WWW under http://
www.angewandte.org or from the author.
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Chemie
conversion. The use of CH2Cl2 as the solvent and five
equivalents of iodine at room temperature gave the best
results. Other solvents, less iodine, or a different temperature
either did not improve the yield or even lowered it.
The choice of base used in the reactions was found to
depend on the substrate: of the different bases tested, K3PO4
and NaHCO3 gave the best results for primary and secondary
azides, respectively, while using Al2O3 or NEt3, for example,
resulted in lower yields or even inhibited the reaction
completely.
substituted isoquinolines and isoquinolines. Similar to the 2-
pyridine substrate 1i, a cation in position 2’ is less favored in
the case of alkyl-substituted substrates, and thus the forma-
tion of 2 will be hindered. Initial experiments showed that
under the original reaction conditions the products 2 and 3
were formed in a ratio of approximately 1:4 (R1 = Me).
Attempts to transform the bis-iodine adduct 3 into isoquino-
line 2 by prolonged heating or abstraction of iodide by silver
resulted only in decomposition of 3.
To prevent the formation of product 3, we investigated the
use of electrophiles with less nucleophilic counterions. While
ICl led to a mixture of iodo- and chloro-substituted isoquino-
lines and N-bromosuccinimide (NBS) gave no conversion, the
Barluenga reagent (Py2IBF4/HBF4) in CH2Cl2 at À788C and
N-iodosuccinimide (NIS) in (CH2Cl)2 at 508C produced the
desired isoquinoline 2 as a single product. The alkyl-
substituted isoquinolines were formed in moderate to fair
yields (Table 2). In general, the use of the Barluenga reagent
For primary azides (R1 = aryl) the originally selected
reaction conditions gave the best results with excellent yields
of around 95% (entries 1–3); a longer reaction time of 72 h
was required to achieve full conversion in the case of the
electron-deficient substrate 1c. The reaction even proceeded
very smoothly with R1 = 1-cyclohexenyl to give 2d in a yield
of 82% (entry 4).
For secondary azides, and using the weaker base NaHCO3
(entries 5–7), the yields of the trisubstituted isoquinolines
2e–g ranged from 68 to 73%. In the case of 1g, two
uncharacterized side products were formed, which could not
be separated from 2g. Therefore, the yield of 2g had to be
determined by NMR spectroscopy.
Table 2: Py2IBF4- or NIS-mediated synthesis of isoquinolines.
We were also interested in incorporating additional
nitrogen atoms into the product. Replacing the carbon atom
at position X (Table 1) with a nitrogen atom did not affect the
cyclization reaction, it still proceeded very smoothly and
afforded the 7,8-substituted 1,6-naphthyridine 2h in a yield of
92% (entry 8). However, only the bis-iodine product 3i was
obtained from the 2-pyridine-substituted substrate 1i
(entry 9). The structure of the axial chiral product 3i was
determined by X-ray crystal-structure analysis of 3j (entry 10,
see also the Supporting Information) and by comparison of
the 1H NMR spectral data.
The formation of bis-iodine product 3i was unexpected,
but can be explained by a plausible reaction pathway. The
I+ ion initially coordinates at the alkyne, thereby activating
the triple bond towards nucleophilic ring closure of the azide
at the C2’ carbon atom. Subsequent elimination of N2 and H+
then results in the formation of isoquinoline 2 (Scheme 3).[10]
Entry
1
R1
R2
Yield[a] [%] Py2IBF4 Yield[b] [%] NIS
1
2
3
4
5
1k Me
1l
1m t-butyl
1n CH2TMS
1o Ph
H
H
H
H
55
67
42
66
n-butyl
71 (I2, 21 days)[c]
69
62
CH2OAc 62
18[d]
[a] Py2IBF4 (2 equiv), HBF4 in Et2O (2 equiv), CH2Cl2, À788C, Ar; yield of
isolated product. [b] NIS (5 equiv), NaHCO3 (1 equiv), (CH2Cl)2 (0.1m),
508C, Ar; yield of isolated product. [c] I2 (5 equiv), NaHCO3 (1 equiv),
CH2Cl2 (0.1m), 21 days, RT, 96% conversion. [d] 80% conversion.
TMS=trimethylsilyl.
under acidic conditions produced the desired isoquinolines in
higher yields then when NIS was used under basic conditions.
This finding may result from the shorter reaction time and
lower reaction temperature required. However, the yield of
substrate 1l under the two reaction conditions was almost
identical (Table 2, entry 2). In contrast, the yield of the
methyl-substituted isoquinoline 2k decreased significantly
from 55% (Py2IBF4) to 42% (NIS, entry 1). I2 was used as the
electrophile for substrate 1m, which bears the bulky tert-butyl
substituent, since the bis-iodine adduct 3m was not formed.
Product 2m was formed in a good yield of 71% with 96%
conversion after 21 days at room temperature (entry 3).
The easily accessible substrates 1n and 1o were tested as
examples of substrates bearing functional groups. Both
substrates were converted into the corresponding isoquino-
lines 2n and 2o in reasonable yields of 69% and 62%,
respectively, when Py2IBF4 was used (entries 4 and 5). The
yield of substrate 1n dropped slightly to 62% when NIS was
used, while substrate 1o was not compatible to the reaction
Scheme 3. Plausible reaction pathway.
The proximity of the pyridinyl substituent to the reaction
center enables the basic nitrogen atom to coordinate to the
iodonium ion, thereby holding it close to the C2’ carbon atom
À
and preventing the azide from forming the new C2’ N bond.
Instead, IÀ is added at the C1’ carbon atom to form the bis-
iodine adduct 3. If a nitrogen atom is incorporated into the
aromatic system of the benzyl azide itself (1h), the reaction
proceeds smoothly in 92% yield (entry 8).
Besides the formation of 3-aryl- and 3-alkenyl-substituted
isoquinolines, we were interested in the formation of 3-alkyl-
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Communications
Kletsas, W. Li, Z. Han, V. Papadopoulos, Biochem. Pharmacol.
2004, 67, 1927 – 1932; c) U. R. Mach, A. E. Hackling, S. Per-
achon, S. Ferry, C. G. Wermuth, J.-C. Schwartz, P. Sokoloff, H.
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conditions employed, and gave 2n in a yield of only 18% after
80% conversion (entries 4 and 5).
On considering the obtained results, it becomes clear that
the substrates must satisfy certain requirements for the
iodine-mediated cyclization: R1 needs to be either a transi-
tion-state-stabilizing (Table 1, entries 1–8) or
a bulky
[3] See, for example: a) B. A. Sweetman, H. Müller-Bunz, P. J.
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(Table 2, entry 3) substituent; otherwise different iodine
sources have to be used (Table 2, entries 1, 2, 4, 5). Only
when R1 contained a coordinating substituent or was unsub-
stituted (Table 1, entries 9 and 10) did the reaction not
proceed at all.
In conclusion, we have presented a general and flexible
approach to highly substituted isoquinoline building blocks,
which can be further functionalized. Depending on the nature
of the substrate employed, acidic, basic, or neutral reaction
conditions can be used, which makes this method compatible
with sensitive, highly functionalized molecules. Additional
studies on this method to broaden the scope even further is
currently underway.
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Experimental Section
Azide 1e (7.22 mg, 0.29 mmol) was dissolved in CH2Cl2 (0.1m) and
NaHCO3 (1 equiv) added. Iodine (5 equiv) was added and the
solution stirred in the dark for 24 h. After complete conversion (as
evident by TLC) the reaction was quenched with Na2S2O3 solution,
the product extracted with ethyl acetate, dried over MgSO4, and
purified by column chromatography (SiO2) to yield 6.9 mg (69%) of
2e.
Barluenga reagent (Py2IBF4, 2 equiv) was dissolved in CH2Cl2
(0.16m) cooled to À788C under argon and then HBF4 (54% in Et2O;
2 equiv) added. The solution was transferred to a solution of azide 1o
(25 mg, 82 mmol) in CH2Cl2 (1.33m) at À788C. After 1 h, the reaction
was quenched with Na2S2O3 solution, the product extracted with ethyl
acetate, dried over MgSO4, and purified by column chromatography
(SiO2) to yield 20.1 mg (61%) of 2o.
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[9] N. K. Pahadi, PhD thesis, Tohoku University, 2005.
[10] A similar reaction pathway as described takes place: D. J. Gorin,
N. R. Davis, F. D. Toste, J. Am. Chem. Soc. 2005, 127, 11260 –
11261.
Received: March 31, 2007
Published online: May 22, 2007
Keywords: azides · cyclization · heterocycles · iodine ·
.
isoquinolines
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Dewally, C. Slomianny, J.-C. Ameisen, F. DeBels, S. Tomavo,
Antimicrob. Agents Chemother. 2002, 46, 3197 – 3207; b) D.
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