Synthesis of isoquinoline-3-carboxylates and benzocyclobutanes via reaction of 2-amidoacrylate esters with arynes

Article abstract of DOI:10.1055/s-2008-1072723

A mild and general method for the synthesis of a variety of 2-substituted isoquinoline 3-carboxylates and benzocyclobutanes from the reaction of 2-amidoacrylate esters with arynes has been developed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072723

LETTER
1159
Synthesis of Isoquinoline-3-Carboxylates and Benzocyclobutanes via Reaction
of 2-Amidoacrylate Esters with Arynes
S
ynthesis of Iso
o
quinoline-3-
m
Carboxylate
s
and
B
enzoc
B
s
lackburn, Yeeman K. Ramtohul*
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada & Co., Inc., P.O. Box 1005,
16711 Trans Canada Highway, Kirkland, Quebec, H9H 3L1, Canada
Fax +1(514)4284900; E-mail: yeeman_ramtohul@merck.com
Received 1 January 2008
(Scheme 1). Using deuterium labeling experiments we
Abstract: A mild and general method for the synthesis of a variety
showed that the reaction with trideuterated b-enamino es-
of 2-substituted isoquinoline 3-carboxylates and benzocyclobu-
tanes from the reaction of 2-amidoacrylate esters with arynes has
been developed.
ter 2 proceeded via an intramolecular deuterium transfer
of the zwitterionic species 3 to generate the ortho-deuter-
ated aryl product 4.
Key words: arynes, isoquinoline heterocycles, benzocyclobutanes,
annulations, 2-amidoacrylate esters
While investigating the substrate scope of this reaction,
we observed that simple N-vinyl amides react with the
benzyne precursor 1, presumably via the zwitterionic in-
termediate 6 to produce a mixture of E- and Z-arylated
product 7 (3:2 ratio) in 63% yield (Scheme 2). Interesting-
ly, when the N–H proton is replaced by a methyl 8, the an-
ion 9 adds to the iminium carbon to generate the
benzocyclobutane product 10 in a low yield of 33% to-
gether with unreacted starting material 8.
In recent years, the use of arynes to generate 1,2-function-
alized arenes has seen a growing interest in the field of or-
ganic synthesis.1,2 This emergence of aryne chemistry is
largely due to the development of a mild and general
method for generating arynes from ortho-silyl aryltriflates
and fluoride anion.3 Due to its electrophilicity, a wide va-
riety of anionic and uncharged nucleophiles readily add to
arynes to generate substituted arenes. Typical examples
include addition of amines, sulfonamides, carbamates,
phenols, carboxylic acids,4 b-ketoesters,5 malonate es-
ters,6 and a-cyanocarbonyl compounds.7 We recently re-
ported an efficient method for the C-arylation of b-
enamino esters and ketones8 with benzyne precursor 1
We envisioned that if the N–H proton of 5 is made suffi-
ciently acidic so that it is deprotonated by cesium fluoride,
then instead of protonation, the intermediate anion could
react with the amide carbonyl to generate annulated aro-
matic ring systems. To this end, 2-phenylacetamidoacry-
late ester 11a (Scheme 3) was reacted with benzyne
precursor 1 at 80 °C and we were pleased to see that iso-
i) CsF (2.5 equiv),
MeCN, r.t., 6 h
ii) H2O quench
NH2
ND2
D
CO2Me
D
OTf
CO2Me
N
CO2Me
+
D
D
80 %
TMS
D
3
1
2
4
Scheme 1
CsF (2.5 equiv),
MeCN, r.t.,
18 h
O
O
Ph
1 +
N
N
N
H
63%
H
H
5
7 E/Z = 3:2
O
6
CsF (2.5 equiv),
MeCN, r.t.,
18 h
O
+
1
N
N
33%
N
8
O
10
9
O
Scheme 2
SYNLETT 2008, No. 8, pp 1159–1164
x
x.
x
x.
2
0
0
8
Advanced online publication: 16.04.2008
DOI: 10.1055/s-2008-1072723; Art ID: S00208ST
© Georg Thieme Verlag Stuttgart · New York

1160
T. Blackburn, Y. K. Ramtohul
LETTER
CsF (2.5 equiv),
MeCN, 80 °C
4 h
CO2Me
O
1
+
+
CO2Me
NH
N
N
H
CO2Me
Ph
O
11a
Ph
13a 31%
12a 51%
CsF
Ph
– H2O
H
H
CO2Me
N
CO2Me
CO2Me
+
N
N
O
O
Cs
Ph
HO
Ph
Cs
Ph
14
15
16
17
Scheme 3
quinoline-3-carboxylate9 12a and benzocyclobutane 13a followed by a subsequent reaction with acetonitrile,10 it
were isolated in 51% and 31% yield, respectively. We hy- should be noted that no such reaction was observed in our
pothesize that the reaction proceeds via an initial nucleo- case, presumably due to the 1,3-substituents which make
philic addition of acrylate anion 15 onto benzyne 14 to the nitrogen atom more hindered and less reactive.
generate intermediate 16. Subsequent electrophilic cy-
The isoquinoline 12a and benzocyclobutane 13a can be
clization on the carbonyl generates hemi-aminal interme-
separated by flash column chromatography over silica gel
diate 17, which after dehydration would afford
using a gradient elution of ethyl acetate and hexanes. In-
terestingly, after isolation of product 12a and 13a, we ob-
served that an additional 10% of the isoquinoline 12a
(Table 1, entry 1) was isolated when the silica gel column
isoquinoline 12a. Alternatively, the anion 16 could also
react at the imine carbon thereby generating the benzocy-
clobutane 13a. The possibility of benzocyclobutane 13a
being an intermediate in the reaction could be ruled out
was flushed with a more polar solvent system, such as
because treatment of 13a under the reaction conditions in
100% ethyl acetate. The amount of this additional product
12a gradually increases from 10% to 23% with decreasing
temperature (80 °C to r.t., entries 1–4). We speculate that
this additional product might be derived from a polar in-
the presence of cesium fluoride, base (cesium carbonate)
or acid (trifluoroacetic acid) did not produce any isoquin-
oline 12a. Although simple unsubstituted isoquinolines
are known to react with benzyne at the nitrogen position
termediate such as the hemi-aminal derivative 17, which
Table 1 Optimization of Reaction Conditionsa
CO2Me
+
O
F
CO2Me
NH
1
+
N
N
H
CO2Me
conditions
Ph
O
13a
11a
12a
Ph
Ph
Entry
Solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
F– Source
CsF
Temp (°C)
Time (h)
Reaction quench
H2O
Yield of 12a (%)b Yield of 13a (%)b
1
2
80
60
40
r.t.
6
4
51 + 10c
48 + 12c
46 + 15c
42 + 23c
41 + 17c
60 + 3c
64
31
27
23
21
18
23
24
2
CsF
4
H2O
3
CsF
6
H2O
4
CsF
18
18
18
18
18
4
H2O
5
CsF
H2O
6
CsF
r.t.
r.t.
r.t.
r.t.
r.t.
HCl (1 N)
TFAd
7
CsF
8
CsF
TFAd
12
9
THF
TBAF
KF/18-C-6
TFAd
25
13
16
10
THF
18
TFAd
45
a Reaction conditions: o-silyl aryltriflate 1 (0.5 mmol), acrylate 11a (0.4 mmol), and fluoride source (1 mmol) in 0.2 M solvent in a sealed vial.
b Isolated yield.
c Additional product 12a isolated after flushing SiO2 column with 100% EtOAc.
d Five equivalents of TFA were used.
Synlett 2008, No. 8, 1159–1164 © Thieme Stuttgart · New York

LETTER
Synthesis of Isoquinoline-3-Carboxylates and Benzocyclobutanes
1161
Table 2 Reaction of Substituted 2-Amidoacrylate Esters with Benzynea,15
i) CsF, MeCN,
r.t., 18 h
ii) TFA quench
CO2Me
+
O
CO2Me
NH
1
N
+ R
N
H
CO2Me
O
11
12
R
13
R
Entry
1
R of 11
Yield of 12 (%)b
Yield of 13 (%)b
64
24
11a
2
3
4
5
59
64
62
51
21
22
18
21
MeO
11b
11c
O
O
F
11d
11e
O
6
7
8
66
69
56
25
24
22
11f
11g
11h
O
F
9
42
66
12
22
H
11i
10
Me
11j
11
42
11
11k
a Reaction conditions: o-silyl aryltriflate 1 (0.5 mmol), acrylate 11 (0.4 mmol), and CsF (1 mmol) in 0.2 M MeCN in a sealed vial stirred at r.t.
for 18 h then quench with TFA (2 mmol).
b Isolated yield.
slowly dehydrates over the slightly acidic silica gel. So, temperature is lowered from 80 °C to room temperature
by quenching the reaction mixture with acid (1 N HCl or (entries 1–4). Further temperature lowering had no addi-
TFA, entries 6 and 7) we were able to convert almost all tional improvement on the yield or selectivity of the reac-
the suspected polar intermediate 17 into isoquinoline 12a. tion. However, using THF as the solvent with CsF and
In addition, a slight decrease in the amount of benzocy- other reported sources of fluoride for generating aryne
clobutane 13a was observed (from 31% to 23%) as the
Synlett 2008, No. 8, 1159–1164 © Thieme Stuttgart · New York

1162
T. Blackburn, Y. K. Ramtohul
LETTER
Table 3 Reaction of 2-Phenylacetamidoacrylate Ester 11a with Substituted Benzynea
i) CsF, MeCN,
r.t., 18 h
ii) TFA quench
CO2Me
+
OTf
R
R
CO2Me
NH
+
11a
R
N
TMS
O
14
16
15
Ph
Ph
Entry
1
R of 14
Yield of 15 (%)b
Yield 16 (%)b
OTf
40
11
TMS
OTf
14a
14b
14c
14d
O
2
3
4
52
66
28
20
22
9
O
TMS
OTf
MeO
MeO
F
TMS
OTf
F
TMS
OTf
5
11
14
TMS
14e
CO2Me
OTf
CO2Me
NH
N
6c
OMe
TMS
OMe
O
OMe
Ph
Ph
14f
15f, 52%
16f, 16%
a Reaction conditions: o-silyl aryltriflate 14 (0.5 mmol), acrylate 11a (0.4 mmol), and CsF (1 mmol) in 0.2 M MeCN in a sealed vial stirred at
r.t. for 18 h then quench with TFA (2 mmol).
b Isolated yield.
c Structure of products was determined by NOE.
such as TBAF3 or KF/18-crown-611 had a deleterious ef- also be accommodated (entries 9–11). However, one lim-
fect on the yield (entries 8–10).
itation is the stability of some of the acrylates such as 11e
and 11k which tend to polymerize on standing and they
had to be used right away after synthesis. This might ex-
plain the slightly lower yield of the corresponding iso-
quinoline product (entries 5 and 11).
With the optimal condition set at room temperature
(Table 1, entry 7), we began investigating the substrate
scope with a variety of substituted 2-amidoacrylate esters
11a–k (Table 2) which can readily be accessed over two
steps starting from serine methyl ester.12 A variety of aro- We next examined the annulation of substituted arynes
matic substrates substituted with electron-donating and with 2-phenylacetamidoacrylate ester (11a). As shown in
electron-withdrawing groups worked well, affording Table 3, reaction with arynes bearing an electron-donat-
good yield of the isoquinoline products (entries 2–4). ing group works well giving good yield of the correspond-
Even bulky substituent such as naphthalene (entry 5) is ing isoquinolines (entries 2 and 3). However, arynes with
tolerated giving a reasonable yield of the corresponding electron-withdrawing group (entry 4) gave a low yield the
isoquinoline. Substrates substituted with a phenoxy group isoquinoline product, presumably due to the high electro-
also afforded good yield of the isoquinoline products (en- philicity and reactivity of the aryne which makes the reac-
tries 6 and 7). Aliphatic substitutions on the substrates can tion nonselective. When 3,6-dimethyl-substituted aryne
Synlett 2008, No. 8, 1159–1164 © Thieme Stuttgart · New York

LETTER
Synthesis of Isoquinoline-3-Carboxylates and Benzocyclobutanes
1163
i ) CsF, MeCN,
r.t., 18 h
ii) TFA quench
MeO
MeO
CO2Me
MeO
MeO
CO2Me
+
+
14c 11c
N
O
NH
O
17 66%
18 21%
O
O
O
48% HBr, ∆
ref. 14
HO
HO
CO2H
N
O
O
19
hIGFBP-3
Ki = 72 10 nM
Scheme 4
precursor 14e was used, a poor yield of the desired iso-
quinoline product was isolated (entry 5) which might be
due to steric hindrance of the two methyl substituents. Fi-
nally, reaction with unsymmetrical benzyne precursor 14f
proceeded with high regioselectivity affording the corre-
sponding isoquinoline 15f and benzocyclobutane 16f.
This regioselectivity which is presumably due to steric
and electronic effect of the methoxy group has been re-
ported previously13 and it further substantiates a benzyne
mechanism rather than a [4+2]- or [2+2]-cycloaddition
mechanism leading to isoquinoline 15f and benzocyclo-
butane 16f, respectively.
Acknowledgment
The authors gratefully acknowledge Chun Sing Li, Nicolas Lachan-
ce, Jean-Philippe Leclerc, and Erich Grimm (Merck Frosst) for their
helpful discussion and Dan Sorensen for NMR experiments. We
also thank Merck Frosst and Queen’s University (Co-op internship
for T.B.).
References and Notes
(1) For reviews on the use of arynes in organic synthesis, see:
(a) Peña, D.; Pérez, D.; Guitián, E. Angew. Chem. Int. Ed.
2006, 45, 3579. (b) Kessar, S. V. Comprehensive Organic
Synthesis, Vol. 4; Trost, B. M.; Fleming, I., Eds.; Pergamon
Press: New York, 1991, 483–515.
(2) (a) For the application of arynes in total synthesis, see:
Tambar, U. K.; Ebner, D. C.; Stoltz, B. M. J. Am. Chem. Soc.
2006, 128, 11752. (b) Sato, Y.; Tamura, T.; Mori, M.
Angew. Chem. Int. Ed. 2004, 43, 2436.
To demonstrate the usefulness of this methodology for
rapid analogue synthesis of biologically active com-
pounds, we have used this reaction in the formal synthesis
of a potent insulin-like growth-factor (IGF) inhibitor 19
(Ki = 72 10 nM)14 that inhibits the binding of IGF to hu-
man-IGF binding protein-3 (hIGFBP-3). As shown in
Scheme 4, reaction of acrylate 11c with benzyne precur-
sor 14c proceeded smoothly to afford isoquinoline 17 to-
gether with benzocyclobutane 18 in 66% and 21% yield,
respectively. The isoquinoline 17 could be demethylated
with 48% HBr to produce inhibitor 19 as reported previ-
ously.14
(3) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett.
1983, 1211.
(4) Liu, Z. J.; Larock, R. C. J. Org. Chem. 2006, 71, 3198; and
references therein.
(5) Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127,
5340.
(6) Yoshida, H.; Watanabe, M.; Ohshita, J.; Kunai, A. Chem.
Commun. 2005, 3292.
(7) Yoshida, H.; Watanabe, M.; Ohshita, J.; Kunai, A.
Tetrahedron Lett. 2005, 46, 6729.
In summary, we have developed a mild and general meth-
od for the synthesis of 2-substituted isoquinoline 3-car-
boxylates and benzocyclobutanes from the reaction of 2-
amidoacrylate esters with arynes. The reaction presum-
ably proceeds via a nucleophilic addition of the acrylate to
the aryne followed by an electrophilic cyclization and a fi-
nal dehydration to generate the isoquinoline. This meth-
odology provides a facile and direct access to a variety of
biologically interesting substituted isoquinoline 3-carbox-
ylates. Further studies to expand the substrate scope are in
progress.
(8) Ramtohul, Y. K.; Chartrand, A. Org. Lett. 2007, 9, 1029.
(9) During the preparation of this manuscript, Stoltz reported a
similar transformation whereby only the isoquinoline-3-
carboxylates were obtained using Bu4NPh3SiF2 (TBAT) as
the fluoride source in THF, see: Gilmore, C. D.; Allan, K.
M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 1558.
(10) Jeganmohan, M.; Cheng, C.-H. Chem. Commun. 2006,
2454.
(11) Yoshida, H.; Watanabe, M.; Ohshita, J.; Kunai, A. Chem.
Commun. 2005, 3292.
(12) Avenoza, A.; Cativiela, C.; Busto, J. H.; Fernández-Recio,
M. A.; Peregrina, J. M.; Rodríguez, F. Tetrahedron 2001, 57,
548.
(13) (a) Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T.
Angew. Chem. Int. Ed. 2002, 41, 3247. (b) Yoshida, H.;
Fukushima, H.; Ohshita, J.; Kunai, A. J. Am. Chem. Soc.
2006, 128, 11040.
Synlett 2008, No. 8, 1159–1164 © Thieme Stuttgart · New York

1164
T. Blackburn, Y. K. Ramtohul
LETTER
(14) (a) Zhu, Y.-F.; Wilcoxen, K.; Gross, T.; Connors, P.; Strack,
N.; Gross, R.; Huang, C. Q.; McCarthy, J. R.; Xie, Q.; Ling,
N.; Chen, C. Bioorg. Med. Chem. Lett. 2003, 13, 1927.
(b) Chen, C.; Zhu, Y.-F.; Liu, X.-J.; Lu, Z.-X.; Xie, Q.; Ling,
N. J. Med. Chem. 2001, 44, 4001.
carboxylate (13j).
Methyl 1-methylisoquinoline-3-carboxylate (12j): solid (53
mg, 66%). 1H NMR (500 MHz, acetone-d6): d = 8.38 (s, 1
H), 8.23 (d, J = 8.23 Hz, 1 H), 8.07 (d, J = 8.03 Hz, 1 H),
7.84–7.74 (m, 2 H), 3.93 (s, 3 H), 2.94 (s, 3 H). 13C NMR
(126 MHz, acetone-d6): d = 22.4, 52.4, 123.0, 126.5, 129.4,
129.5, 130.2, 131.5, 136.3, 141.6, 159.6, 166.7. HRMS (ESI,
MH+): m/z calcd for C12H12NO2: 202.0862; found: 202.0863.
Methyl 7-(acetylamino)bicyclo[4.2.0]octa-1,3,5-triene-7-
carboxylate (13j): solid (19 mg, 22%). 1H NMR (500 MHz,
acetone-d6): d = 8.38 (s, 1 H), 7.33–7.28 (m, 1 H), 7.25–7.14
(m, 3 H), 3.91 (d, J = 14.18 Hz, 1 H), 3.62 (s, 3 H), 3.24 (d,
J = 14.18 Hz, 1 H), 1.92 (s, 3 H). 13C NMR (126 MHz,
acetone-d6): d = 22.2, 43.2, 52.5, 64.1, 123.3, 124.2, 128.2,
130.4, 144.1, 144.9, 170.9, 171.9. 1H–1H COSY (500 MHz,
acetone-d6): correlation of the cyclobutane methylene
protons at d = 3.62 and 3.24. 1H–13C HMQC (500 MHz,
acetone-d6): correlation of the cyclobutane methylene
protons at d = 3.62 and 3.24 with the methylene carbon at
d = 43.2. HRMS (ESI, MH+): m/z calcd for C12H14NO3:
220.0968; found: 220.0971.
(15) Representative Experimental Procedure
To a mixture of methyl 2-acetamidoacrylate (11j, 57.3 mg,
0.4 mmol, 1 equiv) and CsF (152 mg, 1 mmol, 2.5 equiv) in
dry MeCN (2 mL, 0.2 M) was added o-silyl aryltriflate (1)
(121 mL, 0.5 mmol, 1.25 equiv) in an oven-dried 4 mL glass
vial. The vial was capped under nitrogen and the mixture
was stirred at r.t. overnight (ca. 18 h). The reaction mixture
was quenched with HCl (1 N) or TFA (154 mL, 2 mmol, 5
equiv) and the solvent was evaporated. The residue was
diluted with NaHCO3 (2 mL, 5%) and extracted with EtOAc
(3 × 1 mL). The combined EtOAc extracts were dried over
Na2SO4 and concentrated. The crude product was purified by
CombiFlash chromatography (ISCO) on silica gel column
using a gradient elution of 30–80% EtOAc–hexanes to
afford methyl 1-methylisoquinoline-3-carboxylate (12j) and
methyl 7-(acetylamino)bicyclo[4.2.0]octa-1,3,5-triene-7-
Synlett 2008, No. 8, 1159–1164 © Thieme Stuttgart · New York

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