Synthesis of Pyridoisoindoles through Diazotization Followed by Intramolecular Cyclization from Pyridinylarylacetates in One Pot

Article abstract of DOI:10.1002/adsc.201500433

A robust synthetic method for a variety of pyridoisoindoles from pyridinylarylacetates has been developed through diazotization using 4-methylbenzenesulfonyl azide and 1,8-diazabicyclo[5.4.0]undec-7-ene followed by intramolecular cyclization via eliminati

Full text of DOI:10.1002/adsc.201500433

FULL PAPERS
DOI: 10.1002/adsc.201500433
Synthesis of Pyridoisoindoles through Diazotization Followed by
Intramolecular Cyclization from Pyridinylarylacetates in One Pot
Cheol-Eui Kim,a Yonghyeon Baek,a Sung Hong Kim,b and Phil Ho Leea,*
a
National Creative Research Initiative Center for Catalytic Organic Reactions, Department of Chemistry, Kangwon
National University, Chuncheon 200-701, Republic of Korea
Fax: (+82)-33-259-5667; e-mail: phlee@kangwon.ac.kr
Analysis Research Division Daegu Center, Korea Basic Science Institute, Daegu 702-701, Republic of Korea
b
Received: May 1, 2015; Revised: June 17, 2015; Published online: September 10, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500433.
Abstract: A robust synthetic method for a variety of also took place efficiently with diazo substrates to
pyridoisoindoles from pyridinylarylacetates has been produce pyridoisoindoles in good to excellent yields
developed through diazotization using 4-methylben- under metal-free conditions or catalytic conditions
zenesulfonyl azide and 1,8-diazabicyclo[5.4.0]undec- [1.0 mol% copper(II) trifluoromethanesulfonate,
7-ene followed by intramolecular cyclization via 258C].
elimination of a nitrogen molecule under copper(II)
trifluoromethanesulfonate-catalyzed conditions in Keywords: carbenes; copper; metal-free conditions;
a one-pot process. The intramolecular cyclization pyridinylarylacetates; pyridoisoindoles
Introduction
Pyridoisoindoles are key priviledged scaffolds in ni-
trogen-containing heterocyclic compounds, which are
widely found in pharmaceuticals,[1] natural products,[2]
fluorescent materials,[3] and dyes.[4] Accordingly, the
development of synthetic methods for preparing pyri-
doisoindoles having a variety of functional groups
represents a considerable task and a significant chal-
lenge.[5] Although some functionalizations of pyridoi-
soindole derivatives have been reported, only a limited
number of synthetic methods has been described. To
date, some of the most general synthetic methods re-
ported in the literature contain an approach through
reduction, bromination, and cyclization followed by
dehydrobromination from ethyl 2-(2-pyridyl)ben-
zoates [Eq. (1), Scheme 1],[6] intramolecular photo-
chemical cyclization of 2-bromo-N-benzylpyridinium
salts [Eq. (2)],[7] multi-component reactions of pyri-
dines, a-bromo carbonyl compounds, and silylaryl tri-
flates [Eq. (3)],[8] Fe-catalyzed reaction of 2-arylpyri-
dines with 2-bromoacetophenones [Eq. (4)],[9] Rh-cat-
À
alyzed direct oxidative C H acylation of 2-arylpyri-
dines with terminal alkynes or g-substituted tert-prop-
argyl alcohols [Eq. (5)],[10] and aryne annulations
involving pyridines [Eq. (6)].[11] Thus, a robust synthe-
sis of pyridoisoindole derivatives has been continu-
ously needed. Especially, it is very significant to intro-
duce a wide range of functional groups onto pyrido- ducing pyridoisoindoles.
Scheme 1. Previously reported synthetic methods for pro-
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Table 1. Reaction optimization.[a]
Entry Cat. [mol%]
Temp. [oC]
t
Yield [%][b]
1
2
–
–
–
–
25
50
80
80
25
25
25
15 h
15 h
2 (83)[c]
83
3
30 min 88
4[d]
5
30 min 92 (91)[e]
Scheme 2. Synthesis of pyridoisoindoles from pyridinylaryl-
acetates in one pot.
CuCl (5)
CuI (5)
Cu(OAc)2 (5)
5 min
5 min
2 h
5 min
5 min
5 min
90
87
80
87
97
97
6
7
8
9
10
11
12[d]
13[f]
Cu(hfacac)2 (5) 25
Cu(OTf)2 (5)
Cu(OTf)2 (3)
Cu(OTf)2 (1)
Cu(OTf)2 (1)
Cu(OTf)2 (1)
25
25
25
25
25
isoindoles and to prepare 6-ethoxycarbonylpyridoi-
soindoles. Moreover, preparation of pyridoisoindole
derivatives having other nitrogen heterocycles besides
pyridine provides a synthetic challenge.[5,12]
20 min 97
20 min 97 (94)[e]
20 min 96
Since carbene species have an intrinsically electro-
philic nature, they can react with a variety of nucleo-
philes.[13] In this regard, we recently reported
a number of synthetic approaches to carbocycles as
well as azaheterocycles containing pyrroles, dihydro-
pyrroles, dihydroazepines, bicyclic N,O-acetals, pyra-
zines, and fluorenes[14] and Rh-catalyzed N-sulfonyl-
aminoalkenylation of azulenes[15] using imino Rh-car-
benoids generated in situ from N-sulfonyltriazoles.[16]
[a]
Reactions were carried out with 1a (0.2 mmol) in DCE
(1.0 mL) under a nitrogen atmosphere.
NMR yield using CH2Br2 as an internal standard.
NMR yield of 1a.
Under air.
Isolated yield.
[b]
[c]
[d]
[e]
[f]
2,6-Di-tert-butylpyridine (2.0 mol%) was added.
These results stimulated us to explore the feasibility celerated and 2a was obtained in 88% yield after
of the synthesis of pyridoisoindoles using carbene in- 30 min (entry 3), indicating that the present reaction
termediates. Consequently, we envisioned that an in- is very sensitive to temperature. Eventually, 2a was
tramolecular cyclization from treatment of aryl diazo- produced in 92% yield in DCE at 808C after 30 min
acetates having a pyridine moiety with a transition under metal-free conditions (entry 4). Next, a variety
metal catalyst would take place to produce pyrido- of copper catalysts was examined to access this cy-
isoindoles. Herein, we demonstrate an efficient syn- clized product under extremely mild conditions
thetic method for a wide range of pyridoisoindoles (258C). A wide range of copper catalysts such as
from pyridinylaryl diazocetates under Cu-catalytic or CuCl, CuI, Cu(OAc)2, Cu(hfacac)2, and Cu(OTf)2 was
metal-free conditons (Scheme 2). Moreover, these examined to disclose that Cu(OTf)2 (1.0 mol%) was
transformations are achieved through diazotization of the catalyst of choice, affording pyridoisoindole (2a)
pyridinylarylacetates using TsN3 and DBU followed in 97% yield at 258C for 20 min (entries 5–12). To
by intramolecular cyclization via elimination of a ni- check the possibility of cyclization by a protic acid,
trogen molecule under Cu(OTf)2-catalyzed conditions we attempted the cyclization in the presence of 2,6-di-
in a one-pot process.
tert-butylpyridine (2.0 mol%) as a proton scavenger
and found that 2a was produced in 96% yield
(entry 13). This result indicates that the present cycli-
zation reaction proceeds by Cu catalysis.
Results and Discussion
Next, the scope of substrates was examined with
First, we attempted an intramolecular cyclization with the two optimal conditions (metal-free and Cu-cata-
ethyl 2-diazo-2-[2-(pyridin-2-yl)phenyl]acetate (1a)[17] lyzed) in hand (Scheme 3). First, metal-free condi-
obtained from diazotization of ethyl 2-[2-(pyridin-2- tions were applied to a large number of pyridinylaryl
yl)phenyl]acetate with TsN3 in the presence of DBU diazoacetates (1). Electronic variation of substituents
(Table 1).[18] This reaction did not proceed in DCE at at the aryl moiety of 1 had little effect on the reaction
258C (entry 1). However, when the reaction was car- efficiency. In fact, pyridoisoindole products bearing
ried out at 508C for 15 h, the desired pyridoisoindole electron-donating substituents such as methyl (2b, 2c,
(2a) was produced in 83% yield under a nitrogen at- and 2d) and methoxy (2e) on the aryl ring were pro-
mosphere (entry 2). At 808C, the cyclization was ac- duced in good to excellent yields ranging from 80%
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Synthesis of Pyridoisoindoles through Diazotization
dinylaryl diazoacetate (1f) having electron-donating
methoxy as well as electron-withdrawing fluoro group
underwent the intramolecular cyclization, affording
the corresponding pyridoisoindole 2f in 78% yield.
Chloro-substituted diazo substrates were also cyclized
to give rise to pyridoisoindoles 2g (81%) and 2h
(94%). Substrates having strong electron-withdrawing
groups such as nitro and trifluoromethyl groups are
applicable to the present transformation, providing
the corresponding pyridoisoindoles (2i and 2j). A
diazo compound (1k) possessing the biphenyl moiety
turned out to be compatible with the reaction condi-
tions, providing 2k in 98% yield. However, naphtha-
len-2-yl-substituted substrate (1l) was less reactive
and the pyridoisoindole 2l was obtained in 63% yield.
Diazo substrates substituted on the pyridine ring
were also employed in the intramolecular cyclization.
When a methyl group was substituted at the 3- or 6-
position of pyridine (1m and 1n), the pyridoisoindoles
(2m and 2n) were produced in excellent yields. The
intramolecular cyclization took place efficiently with
diazo substrates (1o and 1p) having 5-methoxy- and
5-fluoropyridinyl moieties to furnish 2o and 2p in
94% yield. Also, the cyclization of a substrate bearing
an acetyl group proceeded smoothly, producing pyri-
doisoindole 2q in 89% yield under metal-free condi-
tions.
Second, Cu(OTf)2-catalyzed cyclization conditions
which are more reactive than the metal-free ones
were applied to a wide range of pyridinylaryl diazoa-
cetates (1). Likewise to the metal-free conditions, the
presence of various substituents on the aryl group did
not influence the efficiency of the reaction. The cycli-
zation reaction was amenable with respect to sub-
strates having substituents such as methyl, methoxy,
fluoro, chloro, nitro, and trifluoromethyl to provide
the products 2b–2j in good to excellent yields ranging
from 86% to 99% in DCE at 258C within 30 min. In
contrast to the metal-free conditions, the naphthalen-
2-yl-substituted substrate (1l) was smoothly cyclized
to produce the pyridoisoindole 2l in 82% yield, indi-
cating that catalytic conditions are more reactive than
metal-free ones. A variety of substrates having sub-
stituents such as methyl, methoxy, fluoro, and acetyl
on the pyridine side was also readily used in the intra-
molecular cyclization process and the desired pyridoi-
soindoles were produced in good to excellent yields.
Diazo ester (1r) having a pyridinyl-substituted thio-
phene moiety underwent the intramolecular cycliza-
tion, leading to the formation of ethyl thieno[2,3-a]in-
dolizine-4-carboxylate (2r) in 61% yield (entry 1,
Table 2). However, the Cu-catalyzed reaction deliv-
ered 2r in 20% yield because the thiophene moiety
having a sulfur atom probably poisoned the catalyst
(entry 2). Pyrimidinylaryl diazoacetate (1s) also
Scheme 3. Substrate scope of pyridinylaryl diazoacetates.
to 90% at 808C. The structure of 2d was confirmed worked well, leading to the formation of pyrimidoi-
by X-ray crystallography.[19] To our satisfaction, pyri- soindole 2s in 86% yield under metal-free conditions
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Table 2. Cyclization of substrates having thiophenyl and pyr-
imidinyl moieties.
[a]
Reactions were carried out with 1 (0.2 mmol) in DCE
(1.0 mL) at 808C.
Reactions were carried out with 1 (0.2 mmol) in the pres-
[b]
Scheme 4. Synthesis of pyridoisoindoles from pyridinylaryl-
ence of Cu(OTf)2 (1.0 mol%) in DCE (1.0 mL) at 258C.
acetates in one pot.[a]
(entry 3). This compound was also obtained in 80% diazoacetates 1.[17] When diazoacetates 1 were treated
yield in DCE at 258C for 10 min in the presence of with the copper catalyst, copper carbenoid A was gen-
Cu(OTf)2 (1.0 mol%) (entry 4).
erated through the elimination of a nitrogen mole-
In addition, because the preparation of diazo com- cule.[20] Then, nucleophilic attack of the pyridine
pounds 1 is a very simple,[17] it was feasible that this moiety to the carbene provides the copper-bound
cyclization could be performed directly from pyridiny- zwitterionic intermediate B and the release of an elec-
larylacetates in a one-pot fashion (Scheme 4). Pyridi- tron pair from the anionic copper of B provides pyri-
nylphenylacetate (3a, 0.20 mmol), tosyl azide doisoindoles 2 (pathway a). Heating of diazoacetates
(2 equiv.), DBU (2 equiv.), and acetonitrile (1.0 mL) 1 to 808C produces carbene intermediate C through
were placed in a reaction vessel, and the reaction mix- the evolution of nitrogen gas. Nucleophilic attack of
ture was stirred at 258C. After consumption of 3a the pyridine moiety affords nitrogen ylide D and sub-
after 12 h, the reaction mixture was treated with sequent resonance delivered the pyridoisoindoles 2
1.0 mol% Cu(OTf)2 and, then, it was successively (pathway b). In addition to the free carbene pathway
stirred at 808C. After chromatographic separation, b under 808C conditions, pathway c cannot be ruled
the pyridoisoindole 2a was produced in 59% yield. out.
These results suggest that TsN3 as well as DBU re-
maining in the reaction mixture after the first diazoti-
zation step have an effect on the formation and reac- Conclusions
tivity of the carbenoid. Although diazotization fol-
lowed by the intramolecular cyclization in one pot In summary, we have developed a robust synthetic
was influenced to some extent by the electronic method for a wide range of pyridoisoindoles from
nature of the substrate, methyl- and chloro-substitut- pyridinylarylacetates in one pot through diazotization
ed pyridoisoindoles 2d and 2g were obtained in good using TsN3 and DBU followed by intramolecular cyc-
yields. The substrates having thiophenyl and pyrimi- lization via elimination of a nitrogen molecule under
dinyl moieties were smoothly converted to the corre- Cu(OTf)2-catalyzed conditions. Also, the intramolecu-
sponding pyridoisoindoles 2r and 2s in one pot.
lar cyclization took place efficiently with diazo sub-
A plausible reaction pathway for the preparation of strates to furnish pyridoisoindoles in good to excellent
pyridoisoindoles 2 from pyridinylarylacetates (3) in yields under metal-free conditions or Cu(OTf)2-cata-
one pot is shown in Scheme 5. First, 3 was diazotized lyzed conditions at room temperature.
with TsN3 and DBU, leading to the formation of
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Synthesis of Pyridoisoindoles through Diazotization
Scheme 5. A plausible mechanism.
evaporated, and the residue was purified by column chroma-
tography to give the corresponding ethyl 2-diazo-2-[2-(pyri-
din-2-yl)aryl]acetate.
Experimental Section
General Methods
Ethyl
2-diazo-2-[2-(pyridin-2-yl)phenyl]acetate
(1a):
Reactions were carried out in oven-dried glassware under
air or N2 atmosphere. Cu(hfacac)2, Cu(OTf)2, Cu(OAc)2,
CuI, and CuCl were purchased. Commercially available re-
agents were used without purification. DCE and MeCN
were dried with CaH2. Caution: 4-Methylbenzenesulfonyl
azide and diazo compounds are potential explosives. Many
of these compounds are sensitive to heat, light, shock, and
metal catalysts. Therefore, precautions should be taken in
preparation, storage, and use. All reaction mixtures were
stirred magnetically and were monitored by thin-layer chro-
matography using silica gel precoated glass plates, which
were visualized with UV light and then developed using
either iodine or a solution of anisaldehyde. Flash column
chromatography was carried out using silica gel (230–400
yield: 246 mg (92%); Rf =0.3 (ether:dichloromethane:hex-
ane=1:2:3); yellow oil; 1H NMR (400 MHz, CDCl3): d=
8.71–8.69 (m, 1H), 7.75 (td, J=1.82, 11.57 Hz, 1H), 7.61–
7.56 (m, 2H), 7.49–7.45 (m, 1H), 7.44–7.40 (m, 2H), 7.24
(ddd, J=1.12, 4.88, 7.56 Hz, 1H), 4.15 (q, J=7.10 Hz, 2H),
1.19 (t, J=7.10 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
166.1, 158.5, 149.9, 139.4, 136.8, 130.8, 130.7, 128.9, 128.5,
123.6, 123.3, 122.0, 61.1, 14.4; IR (film): n=2981, 2089, 1696,
1585, 1369, 1173, 1035, 989, 756; HR-MS (FAB): m/z=
268.1089 [M+H]+, calcd. for C15H13N3O2: 268.1087.
Ethyl 2-diazo-2-[3-methyl-2-(pyridin-2-yl)phenyl]acetate
(1b): yield: 211 mg (78%); Rf =0.3 (THF:hexane=1:5);
yellow oil; 1H NMR (400 MHz, CDCl3): d=8.74–8.72 (m,
1H), 7.78 (td, J=11.6 Hz„ J=1.8 Hz, 2H), 7.43 (d, J=
7.7 Hz, 1H), 7.35 (t, J=7.7 Hz, 1H), 7.30–7.26 (m, 3H), 4.18
(q, J=7.1 Hz, 2H), 2.13 (s, 3H), 1.22 (t, J=7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=166.4, 158.3, 150.4, 140.0,
137.3, 136.8, 130.5, 128.8, 124.5, 124.2, 122.2, 61.1, 20.4, 14.0;
1
mesh). H NMR (400 MHz) and 13C NMR (100 MHz) spec-
tra were recorded on NMR spectrometers. Deuterated
chloroform was used as the solvent and chemical shift
values (d) are reported in parts per million relative to the
1
residual signals of this solvent [d=7.26 for H (chloroform-
IR (film): n=3062, 2980, 1732, 1461, 1157, 989, 754 cmÀ1
;
d), d=77.16 for 13C (chloroform-d)]. Infrared spectra were
recorded on an FT-IR spectrometer as either a thin film
pressed between two sodium chloride plates or as a solid
suspended in a potassium bromide disk. Mass spectra were
obtained from the KBSI on a high resolution mass spec-
trometer. Melting points were determined in open capillary
tubes.
HR-MS (FAB): m/z=282.1247 [M+H]+, calcd. for
C16H15N3O2: 282.1242.
Ethyl 2-diazo-2-[5-methyl-2-(pyridin-2-yl)phenyl]acetate
(1c): yield: 211 mg (75%); Rf =0.3 (THF:hexane=1:5);
yellow oil; 1H NMR (400 MHz, CDCl3): d=8.69 (dq, J=
4.9 Hz, J=0.9 Hz, 1H), 7.74 (td, J=11.6 Hz„ J=1.8 Hz,
2H), 7.50–7.45 ( m, 2H), 7.41 (s, 1H), 7.25–7.21 (m, 2H),
4.15 (q, J=7.1 Hz, 2H), 2.42 (s, 3H), 1.19 (t, J=7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=166.2, 158.6, 149.8,
138.9, 136.8, 136.6, 131.3, 130.6, 129.4, 123.2, 121.7, 61.0,
21.2, 14.4; IR (film): n=2979, 1698, 1436, 1191, 788,
768 cmÀ1; HR-MS (FAB): m/z=282.1240 [M+H]+, calcd.
for C16H15N3O2: 282.1242.
Synthetic Prodedure for Ethyl 2-Diazo-2-[2-(pyridin-
2-yl)aryl]acetate[17]
In a dried 25-mL round-bottom flask, ethyl 2-[2-(pyridin-2-
yl)phenyl]acetate (2.5 mmol) and tosyl azide (5.0 mmol,
2 equiv.) were dissolved in MeCN (6.5 mL) under air. After
5 min, DBU (5.0 mmol, 2 equiv.) was added. The reaction
mixture was stirred for 12 h at 258C. The solvent was then
Ethyl 2-diazo-2-[4-methyl-2-(pyridin-2-yl)phenyl]acetate
(1d): yield: 197 mg (70%); Rf =0.3 (ether:dichloromethane:
1
hexane=1:2:5); yellow oil; H NMR (400 MHz, CDCl3): d=
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8.70 (dq, J=4.9 Hz, J=0.9 Hz, 1H), 7.74 (td, J=11.6 Hz,
J=1.8 Hz, 2H), 7.48–7.46 (m, 2H), 7.42 (d, J=0.8 Hz, 1H),
7.29–7.25 (m, 2H), 4.15 (q, J=7.1 Hz, 2H), 2.41 (s, 3H),
1.18 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
158.7, 149.9, 139.6, 138.8, 136.7, 131.4, 131.0, 129.9, 123.4,
122.0, 120.5, 61.1, 21.3, 14.5; IR (film): n=2978, 1659, 1429,
1295, 810, 769 cmÀ1; HR-MS (FAB): m/z=282.1241 [M+
H]+, calcd. for C16H15N3O2: 282.1242.
1H), 7.55–7.52 (m, 1H), 7.38–7.34 (m, 1H), 4.25 (q, J=
7.1 Hz, 2H), 1.27 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=164.7, 156.4, 150.3, 146.6, 138.7, 137.5, 131.5,
130.3, 126.1, 123.6, 123.4, 123.1, 61.7, 14.4; IR (film): n=
3081, 1700, 1518, 1337, 910, 888, 794 cmÀ1; HR-MS (FAB):
m/z=313.0940 [M+H]+, calcd. for C15H12N4O4: 313.0937.
Ethyl 2-diazo-2-[2-(pyridin-2-yl)-5-(trifluoromethyl)phe-
nyl]acetate (1j): yield: 235 mg (70%); Rf =0.3 (ether:di-
Ethyl 2-diazo-2-[5-methoxy-2-(pyridin-2-yl)phenyl]acetate
(1e): yield: 190 mg (64%); Rf =0.3 (ether:dichloromethane:
chloromethane:hexane=1:2:5);
yellow
oil;
1H NMR
(400 MHz, CDCl3): d=8.74–8.72 (m, 1H), 7.94 (s, 1H), 7.82
(td, J=1.78, 7.73 Hz, 1H), 7.69–7.64 (m, 2H), 7.50 (dt, J=
0.89, 7.86 Hz, 1H), 7.31 (ddd, J=1.08, 4.88, 7.60 Hz, 1H),
4.20 (q, J=7.11 Hz, 2H), 1.23 (t, J=7.12 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=165.5, 157.2, 150.2, 142.1, 137.1,
131.3, 131.1 (q, J=32.79 Hz), 127.6 (q, J=3.87 Hz), 124.9 (q,
J=3.58 Hz), 125.0, 123.8 (J=q, 272.59 Hz), 123.4, 122.7,
61.4, 14.4; IR (film): n=2984, 2099, 1702, 1504, 1467, 1343,
1312, 900, 794, 744; HR-MS (FAB): m/z=336.0957 [M+
H]+, calcd. for C16H12F3N3O2: 336.0960.
1
hexane=1:2:5); yellow oil; H NMR (400 MHz, CDCl3): d=
8.68 (dq, J=4.8 Hz, J=0.9 Hz, 1H), 7.73 (td, J=11.6 Hz„
J=1.8 Hz, 2H), 7.52 (d, J=8.6 1H), 7.44 (dt, J=7.9 Hz, J=
0.9 Hz, 1H), 7.23–7.20 (m, 1H), 7.16 (d, J=2.4 Hz, 1H),
7.00 (dd, J=8.6 Hz, J=2.6 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H),
3.87 (s, 3H), 1.21 (t., J=7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=166.0, 159.9, 158.3, 149.8, 136.6, 131.9, 124.8,
123.2, 121.5, 115.4, 114.5, 61.0, 55.5, 14.4; IR (film): n=2977,
2832, 1659, 1185, 1213, 1185, 839, 789 cmÀ1; HR-MS (FAB):
m/z=298.1188 [M+H]+, calcd. for C16H15N3O3: 298.1191.
Ethyl 2-diazo-2-[3-fluoro-4-methoxy-2-(pyridin-2-yl)phe-
nyl]acetate (1f): yield: 173 mg (55%); Rf =0.5 (ethyl acet-
ate:hexane=1:5); yellow oil; 1H NMR (400 MHz, CDCl3):
d=8.72 (dq, J=4.9 Hz, J=0.9 Hz, 1H), 7.78 (td, J=
11.6 Hz„ J=1.8 Hz, 1H), 7.44–7.42 (m, 1H), 7.34–7.28 (m,
2H), 7.07 (t, J=8.6 Hz, 1H), 4.12 (q, J=7.1 Hz, 2H), 3.94
(s, 3H), 1.18 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=166.3, 152.8, 151.4, 150.0, 149.0, 148.2 (d, J=
11.5 Hz), 136.6, 129.2 (d, J=13.2 Hz), 127.1 (d, J=4.1 Hz),
125.7 (d, J=2.2 Hz), 122.8, 117.3 (d, J=2.5 Hz), 113.5 (d,
J=2.5 Hz), 61.1, 56.6, 14.5; IR (film): n=2981, 1728, 1696,
1271, 1218, 912, 750 cmÀ1; HR-MS (FAB): m/z316.1093 [M+
H]+, calcd. for C16H14FN3O3: 316.1097.
Ethyl 2-diazo-2-[4-(pyridin-2-yl)-[1,1’-biphenyl]-3-yl]ace-
tate (1k): yield: 206 mg (60%); Rf =0.3 (ether:dichlorome-
thane:hexane=1:2:5); yellow oil; 1H NMR (400 MHz,
CDCl3): d=8.73 (dq, J=4.9 Hz, J=0.9 Hz, 1H), 7.84 (s,
1H), 7.78 (td, J=11.6 Hz, J=1.8 Hz, 1H), 7.66–7.63 (m,
4H), 7.53 (dt, J=7.9 Hz, J=1.0 Hz, 1H), 7.49–7.45 (m, 2H),
7.40–7.36 (m, 1H), 7.28–7.25 (m, 1H), 4.18 (q, J=7.1 Hz,
2H), 1.21 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=166.2, 158.3, 150.0, 141.9, 140.1, 138.2, 136.9, 131.3, 129.6,
129.0, 127.9, 127.3, 127.28, 124.1, 123.4, 122.1, 61.2, 14.6; IR
(film): n=3057, 2979, 1696, 1660, 1185, 997, 887, 761 cmÀ1
;
HR-MS (FAB): m/z=344.1399 [M+H]+, calcd. for
C21H17N3O2: 344.1399.
Ethyl 2-diazo-2-[3-(pyridin-2-yl)naphthalen-2-yl]acetate
(1l): yield: 165 mg (52%); Rf =0.2 (THF:hexane=1:10);
yellow oil; 1H NMR (400 MHz, CDCl3): d=8.74–8.72 (m,
1H), 8.09 (s, 1H), 8.06 (s, 1H), 7.89–7.85(m, 2H), 7.79 (td,
J=1.82, 7.71 Hz, 1H), 7.58 (dt, J=0.97, 7.86 Hz, 1H), 7.55–
7.48 (m, 2H), 7.29–7.26 (m, 1H), 4.14 (q, J=7.06 Hz, 2H),
1.17 (t, J=7.08 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
166.3, 158.7, 149.8, 137.4, 136.8, 133.2, 132.9, 130.5, 130.3,
128.1, 127.8, 127.1, 127.0, 123.5, 122.1, 121.4, 61.1, 14.5; IR
(film): n=2980, 2087, 1585, 1564, 1476, 1426, 1369, 889, 784;
HR-MS (FAB): m/z=318.1240 [M+H]+, calcd. for
C19H15N3O2: 318.1242.
Ethyl 2-[4-chloro-2-(pyridin-2-yl)phenyl]-2-diazoacetate
(1g): yield: 187 mg (62%); Rf =0.3 (ether:dichloromethane:
1
hexane=1:2:8); yellow oil; H NMR (400 MHz, CDCl3): d=
8.72–8.70 (m, 1H), 7.79 (td, J=1.80, 7.72 Hz, 1H), 7.58–7.55
(m, 2H), 7.48 (dt, J=0.93, 7.82 Hz, 1H), 7.43 (dd, J=2.32,
8.48 Hz, 1H), 7.29 (ddd, J=1.09, 4.89, 7.59 Hz, 1H), 4.17 (q,
J=7.11 Hz, 2H), 1.21 (t, J=7.10 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=166.5, 157.2, 150.1, 140.7, 137.0,
134.4, 132.1, 130.7, 129.1, 123.3, 122.6, 122.3, 61.3, 14.5; IR
(film): n=2981, 2088, 1693, 1584, 1462, 1284, 1173, 884, 791;
HR-MS (FAB): m/z=302.0698 [M+H]+, calcd. for
C15H12ClN3O2: 302.0696,
Ethyl
2-diazo-2-[2-(3-methylpyridin-2-yl)phenyl]acetate
Ethyl 2-[5-chloro-2-(pyridin-2-yl)phenyl]-2-diazoacetate
(1h): yield: 181 mg (60%); Rf =0.3 (ether:dichloromethane:
hexane=1:2:3); yellow oil; H NMR (400 MHz, CDCl3): d=
(1m): yield: 208 mg (74%); Rf =0.3 (ethyl acetate:hexane=
1:3); yellow oil; H NMR (400 MHz, CDCl3): d=8.52 (dd,
1
1
J=4.8 Hz, J=1.1 Hz, 1H), 7.64–7.59 (m, 2H), 7.47–7.38 (m,
2H), 7.35–7.32 (m, 1H), 7.22–7.19 (m, 1H), 4.20 (q, J=
7.1 Hz, 2H), 2.13 (s, 3H), 1.23 (t, J=7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=166.0, 157.7, 147.4, 139.3, 138.2,
131.8, 130.4, 129.9, 128.6, 128.1, 124.1, 122.7, 61.0, 19.0, 14.5;
8.71–8.69 (m, 1H), 7.76 (td, J=1.77, 11.58 Hz, 1H), 7.65 (d,
J=1.92 Hz, 1H), 7.50 (d, J=8.32 Hz, 1H), 7.45 (d, J=
7.88 Hz, 1H), 7.38 (dd, J=2.08, 8.32 Hz, 1H), 7.28–7.25 (m,
1H), 4.18 (q, J=7.10 Hz, 2H), 1.21 (t, J=7.12 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=165.5, 157.5, 150.0, 137.4,
137.0, 134.8, 132.0, 130.3, 128.4, 125.5, 123.3, 122.3, 61.3,
14.5; IR (film): n=2981, 2095, 1697, 1590, 1464, 1290, 1173,
1044, 880, 788; HR-MS (FAB): m/z=302.0699 [M+H]+,
calcd. for C15H12ClN3O2: 302.0697.
IR (film): n=3057, 2981, 1696, 1445, 1066, 989, 781 cmÀ1
;
HR-MS (FAB): m/z=282.1246 [M+H]+, calcd. for
C16H15N3O2: 282.1242.
Ethyl
2-diazo-2-[2-(6-methylpyridin-2-yl)phenyl]acetate
(1n): yield: 214 mg (76%); Rf =0.3 (ether:dichloromethane:
1
Ethyl
2-diazo-2-[4-nitro-2-(pyridin-2-yl)phenyl]acetate
hexane=1:2:5); yellow oil; H NMR (400 MHz, CDCl3): d=
(1i): yield: 203 mg (65%); Rf =0.3 (ether:dichloromethane:
hexane=1:2:3); yellow oil; H NMR (400 MHz, CDCl3): d=
8.76–8.75 (m, 1H), 8.39–8.38 (m, 1H), 8.29–8.25 (m, 1H),
7.95 (d, J=8.8 Hz, 1H), 7.86 (tt, J=11.6 Hz, J=1.6 Hz,
7.65 (t, J=7.7 Hz, 1H), 7.60–7.55 (m, 2H), 7.46–7.39 (m,
2H), 7.27 (d, J=8.1 Hz, 1H), 7.12 (d, J=7.7 Hz, 1H), 4.16
(q, J=7.1 Hz, 2H), 2.60 (s, 3H), 1.20 (t, J=7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=166.4, 58.6, 157.9, 140.0,
1
2908
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Adv. Synth. Catal. 2015, 357, 2903 – 2912

FULL PAPERS
Synthesis of Pyridoisoindoles through Diazotization
137.0, 131.1, 130.7, 128.8, 128.7, 123.7, 121.6, 120.3, 61.1,
24.7, 14.5; IR (film): n=3063, 2980, 1698, 1573, 1286, 995,
802, 711 cmÀ1; HR-MS (FAB): m/z=282.1246 [M+H]+,
calcd. for C16H15N3O2: 282.1242.
oacetate derivative 1 (0.2 mmol) in 0.5 mL of DCE was
added. The reaction mixture was stirred at 258C and then
evaporated. The residue was purified by column chromatog-
raphy to give the corresponding ethyl pyrido[2,1-a]isoindole-
6-carboxylate.
Ethyl 2-diazo-2-[2-(5-methoxypyridin-2-yl)phenyl]acetate
(1o): yield: 190 mg (64%); Rf =0.3 (ethyl acetate:hexane=
1
1:3); yellow oil; H NMR (400 MHz, CDCl3): d=8.40–8.39
(m, 1H), 7.60–7.53 (m, 2H), 7.45–7.38 (m, 3H), 7.30–7.27
(m, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.91 (s, 3H), 1.22 (t, J=
7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=166.3, 154.6,
150.8, 139.2, 137.4, 131.0, 130.6, 128.6, 123.7, 123.6, 121.3,
61.1, 55.8, 14.6; IR (film): n=3049, 2983, 1639, 1453, 1184,
985, 826, 738 cmÀ1; HR-MS (FAB): m/z=298.1191 [M+H]+,
calcd. for C16H15N3O3: 298.1191.
Synthetic Procedure B for Pyrido[2,1-a]isoindoles
To a dried test tube, diazoacetate derivative 1 (0.2 mmol)
was added in 1.0 mL of DCE under air. The reaction mix-
ture was stirred at 808C, and then evaporated. The residue
was purified by column chromatography to give the corre-
sponding ethyl pyrido[2,1-a]isoindole-6-carboxylate.
Ethyl
pyrido[2,1-a]isoindole-6-carboxylate[8b]
(2a):
Ethyl
2-diazo-2-[2-(5-fluoropyridin-2-yl)phenyl]acetate
Method A yield: 45 mg (94%); Method B yield: 44 mg
(1p): yield: 211 mg (74%); Rf =0.3 (THF:hexane=1:10);
yellow oil; 1H NMR (400 MHz, CDCl3): d=8.55 (t, J=
1.7 Hz, 1H), 7.60–7.53 (m, 2H), 7.50–7.40 (m, 4H), 4.16 (q,
J=7.1 Hz, 2H), 1.21 (t, J=7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=165.9, 159.7, 157.2, 154.7 (d, J=
4.2 Hz), 138.5, 138., 137.8, 130.9, 130.6, 129.0, 28.6, 124.2 (d,
J=4.1 Hz), 123.6 (d. J=18.4 Hz), 123.62, 61.1, 14.4; IR
(film): n=2982, 1698, 1476, 1236, 910, 740 cmÀ1; HR-MS
(FAB): m/z=285.0911 [M]+, calcd. for C15H12FN3O2:
285.0914.
(91%); Rf =0.4 (THF:hexane=1:5); yellow solid; mp 65–
1
688C; H NMR (400 MHz, CDCl3): d=9.99 (d, J=6.67 Hz,
1H), 8.27 (d, J=8.52 Hz, 1H), 8.13–8.08 (m, 2H), 7.57–7.53
(m, 1H), 7.31–7.25 (m, 2H), 7.21 (td, J=1.53, 10.40 Hz,
1H), 4.50 (q, J=7.12 Hz, 2H), 1.52 (t, J=7.10 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=162.6, 132.8, 131.0, 128.2,
127.6, 121.7, 120.8, 119.9, 119.5, 118.7, 117.5, 117.3, 104.0,
59.6, 14.9; IR (film): n=2978, 1663, 1436, 1325, 1186, 1112,
1045, 765 cmÀ1; HR-MS (EI): m/z=239.0948, calcd. for
C15H13NO2: 239.0946.
Ethyl
2-[2-(5-acetylpyridin-2-yl)phenyl]-2-diazoacetate
Ethyl 10-methylpyrido[2,1-a]isoindole-6-carboxylate (2b):
Method A; yield: 47 mg (92%); Method B yield: 46 mg
(90%); Rf =0.5 (THF:hexane=1:5); yellow solid; mp 75–
(1q): yield: 161 mg (52%); Rf =0.2 (ether:dichloromethane:
1
hexane=1:2:3); yellow oil; H NMR (400 MHz, CDCl3): d=
9.24 (dd, J=2.2 Hz, J=0.7 Hz, 1H), 8.32 (dd, J=8.2 Hz, J=
2.3 Hz, 1H), 7.63–7.60 (m, 3H), 7.53–7.44 (m, 2H), 4.15 (q,
J=7.1 Hz, 2H), 2.29 (s, 3H), 1.19 (t, J=7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=196.6, 162.7, 150.2, 138.6,
136.5, 131.1, 130.9, 130.4, 129.8, 128.8, 124.0, 123.3, 61.0,
26.9, 14.5; IR (film): n=3061, 2981, 1688, 1590, 1373, 1022,
758, 698 cmÀ1; HR-MS (FAB): m/z=310.1189 [M+H]+,
calcd. for C17H15N3O3: 310.1191.
1
788C; H NMR (400 MHz, CDCl3): d=10.11 (d, J=6.69 Hz,
1H), 8.31 (d, J=8.68 Hz, 1H), 8.21 (d, J=8.48 Hz, 1H),
7.46 (dd, J=6.94, 8.46 Hz, 1H), 7.35–7.31 (m, 1H), 7.26–7.22
(m, 1H), 7.06 (dt, J=0.90, 6.84 Hz, 1H), 4.51 (q, J=
7.12 Hz, 2H), 2.89 (s, 3H), 1.53 (t, J=7.12 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=162.7, 133.2, 132.0, 131.5,
127.8, 127.5, 122.3, 121.6, 120.0, 117.9, 117.7, 116.7, 104.2,
59.6, 21.8, 14.9; IR (film): n=2977, 1660, 1428, 1314, 1213,
1121, 1039, 785, 710 cmÀ1; HR-MS (EI): m/z=253.1100,
calcd. for C16H15NO2: 253.1103.
Ethyl
2-diazo-2-[2-(pyridin-2-yl)thiophen-3-yl]acetate
(1r): yield: 208 mg (76%); Rf =0.4 (THF:hexane=1:10);
yellow oil; 1H NMR (400 MHz, CDCl3): d=8.66–8.64 (m,
1H), 7.75 (dt, J=11.7 Hz„ J=1.8 Hz, 1H), 7.52 (d, J=
8.0 Hz, 1H), 7.45 (d, J=5.3 Hz, 1H), 7.30 (d, J=5.2 Hz,
1H), 7.21–7.18 (m, 1H), 4.30 (q, J=7.1 Hz, 2H), 1.22 (t, J=
7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=166.0, 151.9,
149.8, 136.9, 136.5, 127.0, 122.1, 121.4, 61.5, 14.6; IR (film):
n=3081, 2980, 1696, 1272, 1112, 838, 740 cmÀ1; HR-MS
(FAB): m/z=274.0650 [M+H]+, calcd. for C13H11N3O2S:
274.0650.
Ethyl 2-diazo-2-[3-methyl-2-(pyrimidin-2-yl)phenyl]ace-
tate (1s): yield: 248 mg (88%); Rf =0.2 (ether:dichlorome-
thane:hexane=1:2:5); yellow oil; 1H NMR (400 MHz,
CDCl3): d=8.88 (d, J=4.9 Hz, 2H), 7.44–7.36 (m, 2H),
7.29–7.25 (m,2H), 4.13 (q, J=7.1 Hz, 2H), 2.21 (s, 3H), 1.19
(t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=167.0,
166.1, 157.4, 157.1, 138.4, 137.3, 130.7, 129.1, 128.5, 124.1,
119.1, 61.1, 20.3, 14.5; IR (film): n=3037, 2980, 1696, 1556,
1408, 1165, 807, 738 cmÀ1; HR-MS (FAB): m/z=283.1192
[M+H]+, calcd. for C15H14N4O2: 283.1195.
Ethyl 8-methylpyrido[2,1-a]isoindole-6-carboxylate (2c):
Method A yield: 46 mg (90%); Method B yield: 41 mg
(80%); Rf =0.5 (THF:hexane=1:5); yellow solid; mp 69–
1
728C; H NMR (400 MHz, CDCl3): d=9.97 (d, J=6.64 Hz,
1H), 8.10 (dt, J=1.13, 8.50 Hz, 1H), 8.06 (s, 1H), 8.01 (d,
J=8.36 Hz, 1H), 7.32–7.28 (m, 1H), 7.19 (td, J=1.44,
10.44 Hz, 1H), 7.12 (dd, J=1.28, 8.36 Hz, 1H), 4.52 (q, J=
7.10 Hz, 2H), 2.58 (s, 3H), 1.53 (t, J=7.10 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=162.6, 138.2, 132.9, 131.5,
127.7, 123.1, 121.7, 119.2, 118.9, 117.2, 117.0, 116.8, 103.6,
59.5, 22.7, 15.0; IR (film): n=2978, 1160, 1437, 1323, 1191,
1173, 1114, 1046, 766 cmÀ1; HR-MS (EI): m/z=253.1104,
calcd. for C16H15NO2:253.1103.
Ethyl 9-methylpyrido[2,1-a]isoindole-6-carboxylate (2d):
Method A yield: 47 mg (92%); Method B yield: 45 mg
(89%); Rf =0.5 (ether:dichloromethane:hexane=1:2:5);
1
yellow solid; mp 100–1048C; H NMR (400 MHz, CDCl3):
d=9.90 (d, J=6.48 Hz, 1H), 8.13 (d, J=8.56 Hz, 1H), 8.0
(d, J=8.40 Hz, 1H), 7.80 (dd, J=0.70, 1.38 Hz, 1H), 7.35
(dd, J=1.36, 8.60 Hz, 1H), 7.23–7.17 (m, 1H), 7.13 (td, J=
1.42, 10.32 Hz, 1H), 4.48 (q, J=7.10 Hz, 2H), 2.51 (s, 3H),
1.50 (t, J=7.12 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
162.5, 132.3, 130.5, 130.2, 129.3, 127.5, 121.1, 119.7, 119.0,
118.3, 117.4, 117.0, 103.8, 59.3, 21.7, 14.9; IR (film): n=2978,
Synthetic Procedure A for Pyrido[2,1-a]isoindoles
In a dried test tube, Cu(OTf)2 (0.002 mmol) was dissolved in
DCE (0.5 mL) under air. To the above stirred solution, diaz-
Adv. Synth. Catal. 2015, 357, 2903 – 2912
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asc.wiley-vch.de
2909

FULL PAPERS
Cheol-Eui Kim et al.
1659, 1430, 1296, 1115, 1047, 809, 740 cmÀ1; HR-MS (EI): m/
z=253.1099, calcd. for C16H15NO2:253.1103.
1.38, 10.53 Hz, 1H), 4.54 (q, J=7.13 Hz, 2H), 1.53 (t, J=
7.16 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=162.1, 141.3,
134.5, 132.5, 128.7, 124.6, 122.3, 120.1, 119.1, 118.07, 118.03,
116.8, 105.6, 60.3, 14.8; IR (film): n=2985, 1656, 1603, 1495,
1327, 1188, 1087, 1049, 768 cmÀ1; HR-MS (EI): m/z=
284.0794, calcd. for C15H12N2O4: 284.0797.
Ethyl 8-methoxypyrido[2,1-a]isoindole-6-carboxylate (2e):
Method A yield: 48 mg (90%); Method B yield: 48 mg
(90%); Rf =0.3 (THF:hexane=1:5); yellow solid; mp 95–
988C; 1H NMR (400 MHz, CDCl3): d=9.91 (s, 1H), 8.01
(dt, J=1.19, 8.58 Hz, 1H), 7.97 (dd, J=0.46, 8.86 Hz, 1H),
7.62 (s, 1H), 7.31–7.26 (m, 1H), 7.14 (td, J=1.42, 10.43 Hz,
1H), 6.92 (dd, J=2.30, 8.86 Hz, 1H), 4.50 (q, J=7.10 Hz,
2H), 3.96 (s, 3H), 1.53 (t, J=7.10 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=162.5, 160.3, 133.1, 132.7, 127.8,
122.2, 120.8, 116.7, 116.1, 113.8, 113.7, 103.9, 98.7, 59.4, 55.2,
14.9; IR (film): n=2977, 1660, 1481, 1324, 1213, 1112, 1045,
Ethyl 8-(trifluoromethyl)pyrido[2,1-a]isoindole-6-carbox-
ylate (2j): Method A yield: 61 mg (99%); Method B yield:
57 mg (93%); Rf =0.1 (THF:hexane=1:10); yellow solid;
1
mp 129–1328C; H NMR (400 MHz, CDCl3): d=9.94 (d, J=
6.84 Hz, 1H), 8.51 (s, 1H), 8.10 (d, J=8.32 Hz, 2H), 7.38
(dd, J=1.38, 8.85 Hz, 1H), 7.35–7.31 (m, 1H), 7.26 (td, J=
1.50, 10.41 Hz, 1H), 4.51 (q, J=7.10 Hz, 2H), 1.53 (t, J=
7.12 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=162.1, 132.1,
129.6 (q, J=31.51 Hz), 127.7, 124.9 (q, J=272.40 Hz), 122.3,
120.3, 119.4, 118.2, 118.0, 117.9 (q, J=5.65 Hz), 116.5 (q, J=
3.04 Hz), 104.8, 60.0, 14.8; IR (film): n=3397, 1676, 1458,
1310, 1187, 1113, 1060, 768 cmÀ1; HR-MS (EI): m/z=
307.0816, calcd. for C16H12F3NO2: 307.0820.
839 cmÀ1
C16H15NO3:269.1052.
;
HR-MS (EI): m/z=269.1053, calcd. for
Ethyl
10-fluoro-9-methoxypyrido[2,1-a]isoindole-6-car-
boxylate (2f): Method A yield: 52 mg (91%); Method B
yield: 45 mg (78%); Rf =0.4 (THF:hexane=1:5); yellow
1
solid; mp 110–1148C; H NMR (400 MHz, CDCl3): d=9.91
(d, J=6.72 Hz, 1H), 8.27 (d, J=8.48 Hz, 1H), 7.94 (d, J=
9.04 Hz, 1H), 7.34 (dd, J=8.02, 8.98 Hz, 1H), 7.30–7.26 (m,
1H), 7.22 (td, J=1.60, 10.41 Hz, 1H), 4.49 (q, J=7.12 Hz,
2H), 4.02 (s, 3H), 1.51 (t, J=7.12 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=162.3, 146.9 (d, 250.14 Hz), 139.6 (d,
J=8.52 Hz), 129.9 (d, 3.73 Hz), 128.0 (d, J=4.18 Hz), 127.3,
121.7,120.6 (d, 5.83 Hz), 119.8, 117.6, 115.7 (d, J=4.71 Hz),
109.3 (d, J=14.11 Hz), 104.6, 59.7, 59.0 (d, 1.19 Hz), 14.9;
Ethyl 8-phenylpyrido[2,1-a]isoindole-6-carboxylate (2k):
Method A yield: 62 mg (98%); Method B yield: 62 mg
(98%); Rf =0.3 (ether:dichloromethane:hexane=1:2:5);
1
yellow solid; mp 108–1128C; H NMR (400 MHz, CDCl3):
d=9.95 (d, J=6.60 Hz, 1H), 8.47 (s, 1H), 8.09 (dd, J=0.56,
8.48 Hz, 1H), 8.05 (dt, J=1.07, 8.42 Hz, 1H), 7.76–7.73 (m,
2H), 7.51–7.47 (m, 3H), 7.40–7.36 (m, 1H), 7.27–7.22 (m,
1H), 7.16 (td, J=1.46, 10.39 Hz, 1H), 4.50 (q, J=7.10 Hz,
2H), 1.51 (t, J=7.12 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=162.5, 142.2, 141.0, 132.7, 131.4, 128.9, 127.74, 127.72,
127.3, 121.8, 120.9, 119.9, 118.0, 117.9, 117.5, 117.2, 104.3,
59.6, 14.9; IR (film): n=2978, 1661, 1441, 1324, 1186, 1117,
1047, 883, 761 cmÀ1; HR-MS (EI): m/z=315.1259, calcd. for
C21H17NO2: 315.1259.
IR (film): n=2989, 1650, 1436, 1276, 1218, 1097, 802 cmÀ1
;
HR-MS (EI): m/z=287.0958, calcd. for C16H14FNO3:
287.0958.
Ethyl 9-chloropyrido[2,1-a]isoindole-6-carboxylate (2g):
Method A yield: 47 mg (86%); Method B yield: 44 mg
(81%); Rf =0.3 ether:dichloromethane:hexane=1:2:8);
1
yellow solid; mp 128–1318C; H NMR (400 MHz, CDCl3):
Ethyl benzo[f]pyrido[2,1-a]isoindole-6-carboxylate (2l):
Method A yield: 47 mg (82%); Method B yield: 36 mg
(63%); Rf =0.3 (THF:hexane=1:5); orange solid; mp 129–
d=9.90 (d, J=6.76 Hz, 1H), 8.13 (d, J=8.96 Hz, 1H), 8.01
(dt, J=1.21, 8.62 Hz, 1H), 7.98 (dd, J=0.48, 1.84 Hz, 1H),
7.42 (dd, J=1.92, 8.96 Hz, 1H), 7.30–7.26 (m, 1H), 7.21 (td,
J=1.48, 10.41 Hz, 1H), 4.48 (q, J=7.12 Hz, 2H), 1.51 (t, J=
7.12 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=162.2, 131.7,
128.9, 128.8, 127.6, 126.2, 121.9, 121.4, 118.9, 118.6, 117.7,
117.6, 104.1, 59.8, 14.9; IR (film): n=3421, 2981, 1661, 1428,
1
1328C; H NMR (400 MHz, CDCl3): d=10.18 (s, 1H), 8.71
(s, 2H), 8.38–8.35 (m, 1H), 8.02 (t, J=9.30 Hz, 2H), 7.48–
7.35 (m, 4H), 4.58 (q, J=7.10 Hz, 2H), 1.60 (t, J=7.10 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=162.5, 134.1, 133.4,
129.7, 128.7, 128.5, 128.4, 127.8, 125.6, 123.3, 121.8, 120.4,
119.2, 118.3, 117.9, 116.3, 102.5, 59.4, 15.1; IR (film): n=
1184, 1121, 1043, 839, 766 cmÀ1
; HR-MS (EI): m/z=
273.0555, calcd. for C15H12ClNO2: 273.0557.
2977, 1660, 1504, 1454, 1280, 1185, 1108, 1043, 758 cmÀ1
;
Ethyl 8-chloropyrido[2,1-a]isoindole-6-carboxylate (2h):
Method A yield: 53 mg (97%); Method B yield: 51 mg
(94%); Rf =0.3 (THF:hexane=1:10); yellow solid; mp 63–
HR-MS (EI): m/z=289.1100, calcd. for C19H15NO2:
289.1103.
Ethyl 1-methylpyrido[2,1-a]isoindole-6-carboxylate (2m):
Method A yield: 43 mg (85%); Method B yield: 50 mg
(98%); Rf =0.4 (THF:hexane=1:5); yellow solid; mp 82–
1
678C; H NMR (400 MHz, CDCl3): d=9.91 (d, J=6.80 Hz,
1H), 8.16 (d, J=1.36 Hz, 1H), 8.02 (dt, J=1.18, 8.52 Hz,
1H), 7.94 (dd, J=0.56, 8.64 Hz, 1H), 7.32–7.28 (m, 1H),
7.21 (td, J=1.46, 10.43 Hz, 1H), 7.16 (dd, J=1.86, 8.62 Hz,
1H), 4.49 (q, J=7.10 Hz, 2H), 1.52 (t, J=7.12 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=162.2, 134.2, 132.5, 131.3,
127.7, 122.4, 121.6, 120.8, 119.0, 117.5, 117.4, 116.7, 103.7,
59.8, 14.9; IR (film): n=2977, 1665, 1436, 1319, 1184, 1114,
1
878C; H NMR (400 MHz, CDCl3): d=9.98 (d, J=6.84 Hz,
1H), 8.34 (dt, J=0.91, 8.50 Hz, 1H), 8.24 (dt, J=0.89,
8.42 Hz, 1H), 7.55–7.51 (m, 1H), 7.28–7.24 (m, 1H), 7.13 (t,
J=6.98 Hz, 1H), 7.07 (dt, J=0.93, 7.02 Hz, 1H), 4.51 (q, J=
7.12 Hz, 2H), 2.87 (s, 3H), 1.53 (t, J=7.12 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=162.6, 131.8, 131.3, 130.6,
127.4, 125.6, 123.2, 122.2, 120.7, 119.8, 119.4, 116.7, 104.0,
59.6, 20.9, 14.9; IR (film): n=2976, 1660, 1446, 1326, 1206,
1076, 775, 709 cmÀ1; HR-MS (EI): m/z=253.1101, calcd. for
C16H15NO2: 253.1103.
Ethyl 4-methylpyrido[2,1-a]isoindole-6-carboxylate (2n):
Method A yield: 45 mg (88%); Method B yield: 48 mg
(94%); Rf =0.3 (ether:dichloromethane:hexane=1:2:5);
yellow oil; 1H NMR (400 MHz, CDCl3): d=8.24 (d, J=
998, 762 cmÀ1
; HR-MS (EI): m/z=273.0559, calcd. for
C15H12ClNO2:273.0557.
Ethyl 9-nitropyrido[2,1-a]isoindole-6-carboxylate (2i):
Method A yield: 55 mg (97%); Method B yield: 53 mg
(93%); Rf =0.2 (ether:dichloromethane:hexane=1:2:8);
1
orange solid; mp 198–2028C; H NMR (400 MHz, CDCl3):
d=10.09 (d, J=7.0 Hz, 1H), 9.13 (dd, J=0.54, 2.02 Hz,
1H), 8.36–8.27 (m, 3H), 7.58–7.54 (m, 1H), 7.43 (td, J=
2910
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Synthesis of Pyridoisoindoles through Diazotization
1
8.52 Hz, 1H), 8.09 (d, J=8.20 Hz, 1H), 8.05 (d, J=8.40 Hz,
1H), 7.56–7.52 (m, 1H), 7.30 (t, J=7.74 Hz, 1H), 7.27–7.23
(m, 1H), 7.08 (d, J=7.08 Hz, 1H), 4.48 (q, J=7.10 Hz, 2H),
2.80 (s, 3H), 1.51 (t, J=7.12 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=161.1, 138.7, 135.3, 133.1, 128.2, 122.5, 120.6,
119.7, 119.6, 119.2, 118.8, 114.9, 105.3, 60.0, 23.5, 15.0; IR
(film): n=2977, 1672, 1443, 1376, 1317, 1185, 1089, 1037,
yellow solid; mp 138–1418C; H NMR (400 MHz, CDCl3):
d=10.15 (d, J=6.72 Hz, 1H), 8.52 (dd, J=1.74, 4.14 Hz,
1H), 8.13 (d, J=8.48 Hz, 1H), 7.50 (dd, J=6.94, 8.46 Hz,
1H), 7.20 (dd, J=4.16, 7.08 Hz, 1H), 7.11 (dt, J=0.89,
6.90 Hz, 1H), 4.51 (q, J=7.12 Hz, 2H), 3.02 (s, 3H), 1.53 (t,
J=7.12 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=162.2,
143.2, 140.3, 134.5, 132.8, 132.2, 129.3, 122.7, 117.0, 116.2,
111.9, 101.3, 59.9, 20.5, 14.9; IR (film): n=2977, 1655, 1432,
1325, 1243, 1207, 1122, 1044, 715 cmÀ1; HR-MS (EI): m/z=
254.1053, calcd. for C15H14N2O2: 254.1055.
749 cmÀ1
;
HR-MS (EI): m/z=253.1100, calcd. for
C16H15NO2: 253.1103.
Ethyl 3-methoxypyrido[2,1-a]isoindole-6-carboxylate (2o):
Method A yield: 52 mg (96%); Method B yield: 51 mg
(94%); Rf =0.4 (THF:hexane=1:5); yellow solid; mp 77–
1
808C; H NMR (400 MHz, CDCl3): d=9.63 (s, 1H), 8.19 (d,
Synthetic Procedure for Pyridoisoindoles from Ethyl
2-[2-(Pyridin-2-yl)aryl]acetates in One Pot
J=8.44 Hz, 1H), 7.95 (dd, J=0.70, 8.14 Hz, 1H), 7.88 (d,
J=9.24 Hz, 1H), 7.49–7.45 (m, 1H), 7.24–7.20 (m, 1H),
6.99–6.96 (m, 1H), 4.48 (q, J=7.10 Hz, 2H), 3.92 (s, 3H),
1.52 (t, J=7.12 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
162.7, 152.8, 130.7, 128.8, 127.1, 120.8, 119.7, 119.0, 118.8,
117.3, 115.4, 110.6, 104.6, 59.5, 56.0, 14.9; IR (film): n=2987,
1632, 1496, 1429, 1305, 1184, 1051, 874, 742 cmÀ1; HR-MS
(EI): m/z=269.1051, calcd. for C16H15NO3: 269.1052.
In a dried long test tube, ethyl 2-(2-(pyridin-2-yl)phenyl)ace-
tate (0.2 mmol) and tosyl azide (0.4 mmol, 2 equiv.) were
dissolved in MeCN (1.0 mL) under air. After 5 min, DBU
(0.4 mmol, 2 equiv.) was added. The reaction mixture was
stirred for 12 h at 258C and, then, Cu(OTf)2 (0.002 mmol)
was added to the mixture. The mixture was stirred at 808C
until the diazoacetate derivative was completely consumed
on TLC monitoring. Then, the solvent was removed under
reduced pressure and the residue was purified by silica gel
flash column chromatography to give ethyl pyridoisoindole-
6-carboxylates.
Ethyl 3-fluoropyrido[2,1-a]isoindole-6-carboxylate (2p):
Method A yield: 50 mg (98%); Method B yield: 48 mg
(94%); Rf =0.3 (ether:dichloromethane:hexane=1:2:5);
1
yellow solid; mp 105–1098C; H NMR (400 MHz, CDCl3):
d=9.89 (d, J=4.84 Hz, 1H), 8.20 (d, J=8.44 Hz, 1H), 8.01–
7.97 (m, 2H), 7.53–7.49 (m, 1H), 7.29–7.25 (m, 1H), 7.14–
7.09 (m, 1H), 4.49 (q, J=7.12 Hz, 2H), 1.51 (t, J=7.12 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=162.4, 156.3 (d, J=
239.68 Hz), 130.9, 129.8, 127.7, 121.4, 119.8, 119.0, 118.9,
117.6 (d, J=9.42 Hz), 115.0 (d, J=44.35 Hz), 112.1 (d, J=
24.47 Hz), 105.4, 59.8, 14.8; IR (film): n=2988, 1641, 1454,
1336, 1184, 1103, 1041, 826, 755 cmÀ1; HR-MS (EI): m/z=
257.0850, calcd. for C15H12FNO2: 257.0852.
Synthetic Procedure for Ethyl 2-[2-(pyridin-2-yl)aryl]-
acetate[18]
A mixture of 2-phenylpyridine (0.2 mmol), [Cp*RhCl2]2
(1 mg, 2 mmol, 1.0 mol%), and AgF (1 mg, 10 mmol,
5.0 mol%) was stirred in EtOH (2 mL) for 1 h under air. 5-
Diazo-2,2-dimethyl-1,3-dioxane-4,6-dione
(0.24 mmol,
Ethyl 3-acetylpyrido[2,1-a]isoindole-6-carboxylate (2q):
Method A yield: 50 mg (89%); Method B yield: 50 mg
(89%); Rf =0.4 (ether:dichloromethane:hexane=1:2:3);
1.2 equiv.) was added in one pot, and the solution was
stirred at 758C for 12 h. The mixture was cooled to room
temperature, filtered through a pad of Celite, and concen-
trated under reduced pressure. The residue was then puri-
fied by flash column chromatography to give the ethyl 2-[2-
(pyridin-2-yl)aryl]acetate.
Ethyl 2-[4-methyl-2-(pyridin-2-yl)phenyl]acetate (3d):
Rf =0.3 (ether:dichloromethane:hexane=1:2:5); brown oil;
1H NMR (400 MHz, CDCl3): d=8.65 (dq, J=4.9 Hz, J=
1.0 Hz, 1H), 7.73 (td, J=11.6 Hz, J=1.8 Hz, 2H), 7.47 (dt,
J=7.9 Hz, J=1.0 Hz, 1H), 7.27 (s, 1H), 7.26–7.21 (m, 2H),
7.20–7.18 (m, 1H), 4.05 (q, J=7.1 Hz, 2H), 3.77 (s, 2H),
2.39 (s, 3H), 1.16 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=172.2, 159.7, 149.1, 140.4, 137.1, 136.5, 131.3,
130.7, 129.5, 129.4, 124.1, 121.8, 60.6, 39.0, 21.2, 14.3; IR
(film): n=2979, 1732, 1563, 1158, 794, 749 cmÀ1; HR-MS
(EI): m/z=255.1261, calcd. for C16H17NO2: 255.1259.
Ethyl 2-[4-chloro-2-(pyridin-2-yl)phenyl]acetate (3g): Rf =
0.2 (ether:dichloromethane:hexane=1:2:5); yellow oil;
1H NMR (400 MHz, CDCl3): d=8.66–8.65 (m, 1H), 7.77 (td,
J=1.81, 7.73 Hz, 1H), 7.47–7.45 (m, 2H), 7.35 (dd, J=2.22,
8.22 Hz, 1H), 7.30–7.27 (m, 2H), 4.04 (q, J=7.13 Hz, 2H),
3.78 (s, 2H), 1.16 (t, J=7.14 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=171.5, 158.2, 149.2, 142.0, 136.8, 133.1, 132.8,
131.2, 129.9, 128.6, 124.0, 122.4, 60.8, 38.8, 14.2; IR (film):
n=2980, 2167, 1731, 1586, 1559, 1469, 1293, 1159, 1032, 884,
1
orange solid; mp 128–1328C; H NMR (400 MHz, CDCl3):
d=10.65 (s, 1H), 8.24 (d, J=8.60 Hz, 1H), 8.11 (dd, J=
0.82, 9.02 Hz, 1H), 8.07 (dt, J=0.95, 8.30 Hz, 1H), 7.81 (dd,
J=1.56, 9.0 Hz, 1H), 7.59–7.54 (m, 1H), 7.31–7.27 (m, 1H),
7.31–7.27 (m, 1H), 4.52 (q, J=7.12 Hz, 2H), 2.73 (s, 3H),
1.55 (t, J=7.12 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
195.6, 162.6, 133.0, 132.2, 130.9, 129.1, 127.5, 121.8, 120.2,
119.9, 119.4, 118.5, 117.3, 105.2, 60.0, 26.4, 14.8; IR (film):
n=2980, 1685, 1445, 1281, 1183, 1111, 1040, 764 cmÀ1; HR-
MS (EI): m/z=281.1049, calcd. for C17H15NO3: 281.1052.
Ethyl thieno[2,3-a]indolizine-4-carboxylate (2r): Method
A yield: 10 mg (20%); Method B yield: 30 mg (61%); Rf =
0.6 (ether:dichloromethane:hexane=1:2:5); white solid; mp
78–838C; 1H NMR (400 MHz, CDCl3): d=9.71 (d, J=
7.08 Hz, 1H), 7.66 (dt, J=1.05, 8.90 Hz, 1H), 7.50 (d, J=
5.12 Hz, 1H), 7.45 (d, J=5.12 Hz, 1H), 7.16–7.12 (m, 1H),
6.95 (td, J=1.17, 10.45 Hz, 1H), 4.44 (q, J=7.10 Hz, 2H),
1.46 (t, J=7.12 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
161.3, 140.9, 131.4, 129.5, 128.5, 121.4, 118.4, 117.2, 116.3,
113.9, 104.3, 59.7, 14.8; IR (film): n=2977, 1670, 1416, 1338,
1217, 1093, 761 cmÀ1; HR-MS (EI): m/z=245.0513, calcd.
for C13H11N2O2S: 245.0510.
Ethyl
10-methylpyrimido[2,1-a]isoindole-6-carboxylate
(2s): Methoid A yield: 41 mg (80%); Method B yield: 44 mg
(86%); Rf =0.3 (ether:dichloromethane:hexane=1:2:5);
793 cmÀ1
C15H12ClNO2: 275.0713.
;
HR-MS (EI): m/z=275.0714, calcd. for
Adv. Synth. Catal. 2015, 357, 2903 – 2912
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2911

FULL PAPERS
Cheol-Eui Kim et al.
Ethyl 2-[2-(pyridin-2-yl)thiophen-3-yl]acetate (3r): Rf =
0.4 (THF:hexane=1:10); yellow oil; 1H NMR (400 MHz,
CDCl3): d=8.61 (dq, J=4.8 Hz, J=0.9 Hz 1H), 7.69 (dt, J=
11.6 Hz„ J=1.8 Hz, 1H), 7.61 (dt, J=8.0 Hz, J=1.0 Hz,
1H), 7.32 (d, J=5.2 Hz, 1H), 7.16 (ddd, J=7.4 Hz, J=
4.8 Hz, J=1.1 Hz, 1H), 7.06 (d, J=5.2 Hz, 1H), 4.16 (q, J=
7.1 Hz, 2H), 4.00 (s, 3H), 1.23 (t, J=7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=171.4, 153.0, 149.5, 139.5, 136.7,
132.0, 131.4, 125.5, 122.0, 121.8, 60.9, 35.5, 14.3; IR (film):
n=3077, 2980, 1731, 1584, 1251, 917, 839, 740 cmÀ1; HR-MS
(EI): m/z=247.0665, calcd. for C13H13NO2S: 247.0667.
[7] a) A. Fozard, C. K. Bradsher, J. Org. Chem. 1967, 32,
2966; b) A. Fozard, C. Bradsher, Tetrahedron Lett.
1966, 3341.
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Larock, J. Org. Chem. 2012, 77, 2743.
Ethyl 2-[3-methyl-2-(pyrimidin-2-yl)phenyl]acetate (3s):
Rf =0.4 (ethyl acetate:hexane=1:3); brown oil; 1H NMR
(400 MHz, CDCl3): d=8.86 (d, J=4.9 Hz, 2H), 7.32–7.26
(m, 2H), 7.22 (d, J=7.6 Hz, 1H), 4.01 (q, J=7.1 Hz, 2H),
3.49 (s, 2H), 2.16 (s, 3H), 1.15 (t, J=7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=171.4, 167.7, 157.1, 139.0, 136.4,
132.4, 129.6, 128.8, 128.5, 119.1, 60.7, 39.6, 20.3, 14.2; IR
(film): n=3031, 2979, 1733, 1557, 1411, 1248, 1033, 821,
[12] a) C. Mayor, C. Wentrup, J. Am. Chem. Soc. 1975, 97,
7467; b) C. Wentrup, Chimia 1977, 31 258; c) S. Chu-
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Wiley, New York, 1998; b) M. M. Díaz-Requejo, P. J.
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Duffy, M. Ratnikov, L. Zhou, Chem. Rev. 2010, 110,
704; d) H. M. L. Davies, D. Morton, Chem. Soc. Rev.
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759 cmÀ1
;
HR-MS (EI): m/z=256.1212, calcd. for
C15H16N2O2: 256.1212.
Acknowledgements
[14] a) C.-E. Kim, S. Park, D. Eom, B. Seo, P. H. Lee, Org.
Lett. 2014, 16, 1900; b) C.-E. Kim, Y. Park, S. Park,
P. H. Lee, Adv. Synth. Catal. 2015, 357, 210; c) B. Seo,
W. Jeon, J. Kim, S. Kim, P. H. Lee, J. Org. Chem. 2015,
80, 722; d) T. Ryu, Y. Baek, P. H. Lee, J. Org. Chem.
2015, 80, 2376; e) S. Kim, J. Mo, J. Kim, T. Ryu, P. H.
Lee, Asian J. Org. Chem. 2014, 3, 926; f) S. Shin, Y.
Park, C.-E. Kim, J.-Y. Son, P. H. Lee, J. Org. Chem.
2015, 80, 5859; g) W. Choi, J. Kim, T. Ryu, K.-B. Kim,
P. H. Lee, Org. Lett. 2015, 17, 3330; h) S. Kim, J. E.
Kim, J. Lee, P. H. Lee, Adv. Synth. Catal. 2015, 345,
DOI: 10.1002/adsc.201500636.
This work was supported by the National Research Founda-
tion of Korea (NRF) grant funded by the Korea government
(MSIP) (2014001403).
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