Palladium-catalyzed double carbonylation-based diversity-oriented synthesis of 3,4-dihydroisoquinoline-1-carboxamides

Article abstract of DOI:10.1016/j.tet.2015.05.102

Abstract A novel palladium-catalyzed double carbonylation approach toward the synthesis of 3,4-dihydroisoquinoline-1-carboxamides is reported. The method developed involves an initial palladium-catalyzed double carbonylation of an N-protected alkylamine a

Full text of DOI:10.1016/j.tet.2015.05.102

Tetrahedron xxx (2015) 1e7
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium-catalyzed double carbonylation-based diversity-oriented
synthesis of 3,4-dihydroisoquinoline-1-carboxamides
,
Hisashi Masui a, Natsumi Ishizawa a, Shinichiro Fuse b, Takashi Takahashi a
*
a Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama, Kanagawa 245-0066, Japan
b Chemical Resources Laboratory, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8503, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A
novel palladium-catalyzed double carbonylation approach toward the synthesis of 3,4-
dihydroisoquinoline-1-carboxamides is reported. The method developed involves an initial palladium-
catalyzed double carbonylation of an N-protected alkylamine aryliodide to afford an -keto carbox-
Received 15 April 2015
Received in revised form 25 May 2015
Accepted 27 May 2015
Available online xxx
a
amide intermediate, which on subsequent deprotection undergoes intramolecular imine formation to
afford the benzo-azacyclic product.
Ó 2015 Published by Elsevier Ltd.
Keywords:
Benzo-azacycles
Double carbonylation
1,2,3,4-Tetrahydroisoquinoline
Isoindole
a
-Amino esters
1. Introduction
Benzo-azacycles,
compounds
harboring
a
1,2,3,4-
tetrahydroisoquinoline (THIQ)-1-carboxamide structural motif, at-
tract significant attention owing to their biological activities.1 The
THIQ-1-carboxamide (Fig. 1, red color) structural motif can be
found in bioactive compounds such as peroxisome proliferator-
activated receptor
d (PPAR d
) agonist,2 opioid antagonist,3 farne-
syl transferase inhibitor,3a,4 and Rho kinase II (ROCK-II) selective
inhibitor.5 Since the THIQ-1-carboxamides can be construed as
conformationally constrained analogues of phenyl alanine (tyro-
sine) or a surrogate of proline, they are often used as building
blocks in the synthesis of modified peptides.
Two routes have been predominantly used for the synthesis of
substituted THIQ-1-carboxamides (Scheme 1, methods A and B).
Method
A is based on the modification of 3,4-dihydrois
oquinoline.1c,d,6 Recently, an Ugi type reaction between 3,4-
dihydroisoquinoline N-oxides and isocyanides in the presence of
TMSCl, has been used to synthesize THIQ-1-carboxamides.7 In the
second method (method B), substituted phenethylamines are
coupled with glyoxylate derivatives to yield the corresponding
THIQ-1-carboxlic acid; here, the piperidine ring of the THIQ moiety
is formed as a result of PicteteSpengler or BischlereNapieralski
reactions.8 The intermediate substituted 3,4-dihydroisoquinoline
Fig. 1. Bioactive compounds containing the THIQ-1-carboxamide structural motif (red
* Corresponding author. E-mail address: ttak@hamayaku.ac.jp (T. Takahashi).
color).
http://dx.doi.org/10.1016/j.tet.2015.05.102
0040-4020/Ó 2015 Published by Elsevier Ltd.
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2
H. Masui et al. / Tetrahedron xxx (2015) 1e7
Table 1
Optimization of conditions for the double carbonylation reactiona
Entry
Base
Phosphine
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
TMG
DABCO
DBU
TMG
TMG
TMG
TMG
TMG
t-Bu3PHBF4
t-Bu3PHBF4
t-Bu3PHBF4
t-Bu3PHBF4
CataCXium A
CataCXium A
PPh3
DMF
DMF
DMF
THF
DMF
THF
72
43
40
46
81
37
37
35
DMF
THF
PPh3
a
Reaction conditions: 1a (1.00 equiv), Pd(OAc)2 (0.100 equiv), H-Gly-OMe
(1.50 equiv), base (3.00 equiv), and phosphine (0.300 equiv) in solvent at room
temperature for 18 h under carbon monoxide (30 atm).
b
Isolated yield.
Scheme 1. Methods for the synthesis of THIQ-1-carboxamides.
Schemes for the synthesis of substituted iodobenzenes (1b, 1c,
and 1d) are shown in Scheme 2. An alkyl chain of 1, 2, or 3 carbon(s)
connects the protected amine with the phenyl moiety in these
structures. The benzyl amine derivative 1b is prepared from iodo-
benzylamine 313 in two steps: reductive amination of 3 with
derivative is eventually reduced to afford the THIQ-1-carboxamide
derivative.9
Development of a divergent route using readily available start-
ing materials remains an important challenge toward the con-
struction of THIQ-1-carboxamides. Herein, we report a novel
palladium-catalyzed double carbonylation approach toward the
synthesis of 3,4-dihydroisoquinoline-1-carboxamides (Scheme 1,
method C). Double carbonylation10,11 of substituted aryliodide us-
ing palladium catalysts followed by subsequent intramolecular
cyclization as a result of imine formation are the highlights of this
method. Considering that the 3,4-dihydroisoquinones can readily
be converted to THIQs,9 this method then presents a formal syn-
thesis of THIQ-1-carboxamides. Such a synthetic methodology can
allow for the rapid synthesis of structurally diverse THIQ-1-
carboxamides.
2. Results and discussion
The key double carbonylation of iodobenzene 1a (details for
synthesis of 1a, see Experimental section) with glycine methyl ester
is presented in Table 1. When tert-butyl phosphine tetra-
fluoroborate, tetramethyl guanidine (TMG), and N,N-dime-
thylformamide (DMF) are employed as the ligand, base, and
solvent, respectively, a good yield of the a-keto carboxamide 2a is
obtained (Table 1, entry 1). Use of other bases, such as 1,4-
diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]-7-
undecene (DBU), significantly reduces the yield (Table 1, entries 2
and 3). The nature of the solvent proves to be critical for the success
of the double carbonylation. Reaction conducted in tetrahydrofuran
(THF) provides the desired product only in moderate yields (Table 1,
entries 4, 6, and 8), while comparable reaction in DMF affords
better yields of 2a. Optimal yield (81%) of 2a is obtained in the
presence of the highly electron-donating phosphine ligand cata-
CXium A,12 the base TMG, and the solvent DMF (Table 1, entry 5).
Scheme 2. Synthesis of alkylamine-substituted iodobenzenes 1be1d.
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H. Masui et al. / Tetrahedron xxx (2015) 1e7
3
benzaldehyde followed by tert-butyloxycarbonyl (Boc) protection
of the resulting secondary amine. Phenethylamine derivative 1c is
synthesized from the amine 4.14 Compound 1d is prepared by
transforming 2-iodobenzylbromide (5). Alkylation of 5 with ethyl
malonate and subsequent decarboxylation affords 6 in a good
yield.15 Reduction of the ethyl ester moiety in 6 to the primary al-
cohol and its subsequent substitution with the protected amine
under Mitsunobu conditions16 affords the desired compound 1d.
Double carbonylations of the synthesized iodobenzenes proceed
smoothly under the determined optimal conditions. Compounds
1b, 1c, and 1d readily react with carbon monoxide in the presence
of primary and secondary amines to afford a-keto carboxamides in
excellent yields (Fig. 2, 7e11).
Fig. 3. Intramolecular imination of a-keto carboxamides 7e11.
4. Experimental section
4.1. General
NMR spectra were recorded on a JEOL Model ECA-500 in-
strument or a JEOL Model ECP-400. Chemical shifts are reported in
parts per million (ppm) relative to the signal for the internal
standard tetramethylsilane (0.0 ppm) or the solvent CDCl3
(7.26 ppm, 1H NMR; or 77.1 ppm, 13C NMR) peaks. Data for 1H NMR
spectra are reported as follows: chemical shift (
coupling constant (Hz), and integration. 13C NMR spectrum data are
reported as follows: chemical shift ( ppm), and where applicable,
d ppm), multiplicity,
d
multiplicity and coupling constants. Multiplicities are reported
using the following abbreviations: s, singlet; d, doublet; t, triplet; q,
quartet; sp, septet; m, multiplet; br, broad; and J, coupling con-
stants in hertz. Only the strongest and/or structurally relevant IR
peaks are reported (cmꢀ1). All reactions were monitored by thin-
layer chromatography performed using 0.2 mm E. Merck silica gel
plate (60F-254). The reactants and products were visualized using
UV light (254 nm), or by heating after treatment with p-anisalde-
hyde solution, ceric sulfate solution, or 10% ethanolic phospho-
molybdic acid. Column chromatography separations were
performed using silica gel (Merck). ESI-TOF mass spectra were ac-
quired on a Waters LCT PremierTM XE. HRMS (ESI-TOF) were
calibrated using a standard curve obtained using leu-enkephalin.
Fig. 2. Double carbonylation of iodobenzene analogues 1be1d. Reaction conditions:
substrate (1.00 equiv), Pd(OAc)2 (0.100 equiv), amine (1.50 equiv), TMG (3.00 equiv),
and cataCXium A (0.300 equiv) in DMF at room temperature for 18 h under carbon
monoxide (30 atm).
With these a-keto carboxamide in hand, intramolecular imine
formation was pursued. On treatment with trifluoroacetic acid
(TFA), compounds 7, 8, 9, 10, and 11 readily yielded the desired
products 12, 13, 14, 15, and 16, respectively. Although isoindole-1-
carboxamide derivative 12 was obtained in low yields (34%; at-
tributed to its instability; Fig. 3, 12), other products, 3,4-
dihydroisoquinoline-1-carboxamide derivatives 13e15 and ben-
zoazepine-1-carboxamide derivative 16 were obtained in excellent
yields.
(2-Iodophenyl)methanamine
hydrochloride
(3),13
2-(2-
iodophenyl)ethanamine hydrochloride (4),14 and ethyl 3-(2-
iodophenyl)propanoate (6)15 were prepared according to litera-
ture procedures.
3. Conclusion
In summary, we have developed a novel diversity-oriented
synthetic methodology for the generation of 3,4-dihydro
isoquinoline-1-carboxamides and its analogues. This method in-
volves the initial palladium-catalyzed double carbonylation of an
N-protected alkylamine aryliodide and an amine partner to afford
4.2. N-(Bis-tert-butoxycarbonyl)-2-iodobenzylamine (1a)
To a solution of Cs2CO3 (3.62 g, 11.1 mmol, 1.10 equiv) in DMF
(11.1 mL) were added Boc2NH (2.41 g, 11.1 mmol, 1.10 equiv) and 2-
iodobenzylbromide (3.00 g, 10.1 mmol, 1.00 equiv) at room tem-
perature. After being stirred at the same temperature for 16 h, the
reaction mixture was poured into water and the aqueous layer was
extracted with two portions of diethyl ether. The combined organic
layer was washed with brine, dried over Na2SO4, filtered, and
the intermediate
a-keto carboxamide, which on subsequent
deprotection undergoes intramolecular imine formation to afford
the benzo-azacyclic product. Since 3,4-dihydroisoquinolines can
readily be reduced to THIQs, this synthetic methodology allows for
the rapid synthesis of structurally diverse THIQ-1-carboxamides.
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4
H. Masui et al. / Tetrahedron xxx (2015) 1e7
concentrated in vacuo. The residue was purified by column chro-
matography on silica gel (12% ethyl acetate in hexane) to give N-
98.0, 80.3, 80.2, 54.9, 54.4, 50.1, 49.8, 28.4. IR (neat): 2975, 1690,
1585, 1564, 1450, 1406, 1364, 1242, 1157, 1122, 1011, 880, 744,
697 cmꢀ1. HRMS (ESI-TOF) calcd for C19H22NO2I [MþH]þ 424.0774,
found 424.0795.
(bis-tert-butoxycarbonyl)-2-iodobenzylamine
(1a)
(4.81
g,
11.1 mmol, quant.) as a colorless oil. 1H NMR (400 MHz, CDCl3)
d
7.81 (d, J¼7.7 Hz, 1H), 7.31 (dd, J¼7.7, 7.7 Hz, 1H), 7.08 (d, J¼7.7 Hz,
1H), 6.94 (dd, J¼7.7, 7.7 Hz, 1H), 4.77 (s, 2H), 1.43 (s, 18H). 13C NMR
(100 MHz, CDCl3)
d
152.2,140.2,139.2,128.4,128.3,125.7, 96.9, 82.8,
4.5. N-(Bis-tert-butoxycarbonyl)-2-(2-iodophenyl)ethan-
54.9, 27.9. IR (chloroform solution): 2934, 1790, 1715, 1586, 1566,
amine (1c)
1417, 1368, 1228, 1146, 1047, 1013, 961, 933, 894, 855, 747 cmꢀ1
.
HRMS (ESI-TOF) calcd for C17H25NO4I [MþH]þ 434.0828, found
To a stirred suspension of 2-(2-iodophenyl)ethanamine hydro-
chloride (4) (284 mg, 1.00 mmol, 1.00 equiv) in THF (4.00 mL) and
water (2.00 mL) were added Na2CO3 (122 mg) and Boc2O (436 mg,
2.00 mmol, 2.00 equiv) at 0 ꢁC. After being stirred at the room
temperature for 1 h, the reaction mixture was extracted with two
portions of ethyl acetate. The combined organic layer was washed
with brine, dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was used for the next reaction without further
purification.
434.0807.
4.3. General procedure for the optimization of double car-
bonylative amidation conditions
N-(Bis-tert-butoxycarbonyl)-2-iodobenzylamine
(1a)
(1.00 equiv), Pd(OAc)2 (0.100 equiv), phosphine (0.300 equiv), H-
Gly-OMe$HCl (1.50 equiv), and base (3.00 equiv) in solvent (1.16 mL)
were added to a glass vessel at room temperature under Ar atmo-
sphere. The vessel was placed in autoclave, which was purged with
CO three times before applying a pressure (30 atm). After being
stirred at 60 ꢁC for 18 h, the reaction mixture was filtered through
a pad of CeliteÒ. The filtrate was poured into 1 M HCl and the
aqueous layer was extracted with two portions of Et2O. The com-
bined organic layer was washed with saturated aqueous NaHCO3
and brine, dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography on silica gel
(40% ethyl acetate in hexane) to give methyl 2-(2-((bis-tert-
butoxycarbonylaminomethyl)phenyl)-2-oxoacetamido)acetate
(2a) as a pale yellow oil.
To a solution of the residue in CH3CN (3.00 mL) were added
DMAP (122 mg, 1.00 mmol, 1.00 equiv) and Boc2O (655 mg,
3.00 mmol, 3.00 equiv) at room temperature. After being stirred at
the same temperature for 8 h, the reaction mixture was poured into
water and the aqueous layer was extracted with two portions of
ethyl acetate. The combined organic layer was washed with brine,
dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (15% ethyl
acetate in hexane) to give N-(bis-tert-butoxycarbonyl)2-(2-
iodophenyl)ethanamine (1c) (643 mg, 1.44 mmol, quant.) as a col-
orless oil. 1H NMR (400 MHz, CDCl3)
d
7.80 (dd, J¼1.0, 7.7 Hz, 1H),
7.26 (ddd, J¼1.0, 7.7, 7.7 Hz, 1H), 7.20 (dd, J¼1.0, 7.7 Hz, 1H), 7.04
(ddd, J¼1.0, 7.7, 7.7 Hz, 1H), 3.84 (t, J¼7.2 Hz, 2H), 3.03 (t, J¼7.2 Hz,
1H NMR (400 MHz, CDCl3)
d
8.05 (d, J¼8.2 Hz, 1H), 7.72e7.64 (m,
1H), 7.59e7.46 (m, 1H), 7.48e7.31 (m, 2H), 5.05 (s, 2H), 4.18 (d,
J¼5.8 Hz, 2H), 3.81 (s, 3H), 1.40 (s, 18H). 13C NMR (100 MHz, CDCl3)
2H), 1.46 (s, 9H). 13C NMR (100 MHz, CDCl3)
d 152.2, 141.9, 139.4,
130.3, 128.4, 128.2, 100.7, 82.2, 46.0, 40.0, 28.0, 27.9. IR (chloroform
solution): 3319, 2979, 1790, 1733,1589, 1563, 1468, 1367, 1255, 1142,
1013, 857, 750 cmꢀ1. HRMS (ESI-TOF) calcd for C18H27NO4I [MþH]þ
448.0985, found 448.0962.
d
189.7, 169.3, 162.1, 152.4, 141.1, 133.2, 132.3, 131.5, 126.5, 126.3,
82.6, 52.4, 47.6, 41.1, 27.8. IR (chloroform solution): 3320, 2982,
1749,1681,1602,1574,1529,1481,1451,1369,1306,1230,1112,1036,
935, 853 cmꢀ1. HRMS (ESI-TOF) calcd for C22H31N2O8 [MþH]þ
451.2080, found 451.2043.
4.6. N-(Bis-tert-butoxycarbonyl)-3-(2-iodophenyl)propan-1-
4.4. tert-Butyl benzyl(2-iodobenzyl)carbamate (1b)
amine (1d)
To a solution of (2-iodophenyl)methanamine hydrochloride (3)
(539 mg, 2.00 mmol, 1.00 equiv) in CH2Cl2 (6.00 mL) were added
To a solution of ethyl 3-(2-iodophenyl)propanoate (6) (1.80 g,
5.92 mmol, 1.00 equiv) in THF (17.8 mL) was added DIBAL-H (1.0 M
solution in hexane, 14.8 mL, 14.8 mmol, 2.50 equiv) at ꢀ50 ꢁC. After
being stirred at the same temperature for 30 min, the reaction
mixture was quenched with MeOH and 10% aqueous Rochelle salt
and the aqueous layer was extracted with two portions of ethyl
acetate. The combined organic layer was washed with brine, dried
over MgSO4, filtered, and concentrated in vacuo. The residue was
used for the next reaction without further purification.
To a solution of the residue in THF (17.8 mL) were added Boc2NH
(1.54 g, 7.10 mmol, 1.20 equiv), triphenylphosphine (1.86 g,
7.10 mmol, 1.20 equiv), and DEAD (2.2 M solution in toluene,
3.23 mL, 7.10 mmol, 1.20 equiv) at 0 ꢁC. After being stirred at the
same temperature for 3 h, the reaction mixture was concentrated in
vacuo. The residue was purified by column chromatography on
silica gel (15% ethyl acetate in hexane) to give N-(bis-tert-butox-
benzaldehyde (243
mL, 2.40 mmol, 1.20 equiv) and sodium tri-
acetoxyborohydride (636 mg, 3.00 mmol, 1.50 equiv) at room
temperature. After being stirred at the same temperature for 3 h,
the reaction mixture was quenched with saturated NaHCO3 aq and
the aqueous layer was extracted with two portions of ethyl acetate.
The combined organic layer was washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo. The residue was used
for the next reaction without further purification.
To a solution of the residue (280 mg, 0.866 mmol, 1.00 equiv) in
CH2Cl2 (2.60 mL) were added DMAP (2.12 mg, 0.0173 mmol,
0.0200 equiv) and Boc2O (208 mg, 0.953 mmol, 1.10 equiv) at room
temperature. After being stirred at the same temperature for 16 h,
the reaction mixture was quenched with 1 M HCl and the aqueous
layer was extracted with two portions of ethyl acetate. The com-
bined organic layer was washed with brine, dried over MgSO4, fil-
tered, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (10% ethyl acetate in hexane)
to give tert-butyl benzyl(2-iodobenzyl)carbamate (1b) (477 mg,
1.13 mmol, 58% in two steps) as a colorless oil. 1H NMR (500 MHz,
ycarbonyl)-3-(2-iodophenyl)propan-1-amine
(1d)
(1.61
g,
7.80
3.49 mmol, 49%) as a colorless oil. 1H NMR (500 MHz, CDCl3)
d
(d, J¼8.0 Hz, 1H), 7.26 (dd, J¼7.4, 7.4 Hz, 1H), 7.20 (d, J¼6.3 Hz, 1H),
6.87 (dd, J¼7.4 Hz, 1H), 3.66 (t, J¼7.4 Hz, 2H), 2.71 (t, J¼8.0 Hz, 2H),
1.90e1.85 (m, 2H), 1.49 (s, 18H). 13C NMR (125 MHz, CDCl3)
d 152.5,
CDCl3)
1H), 4.51 (d, J¼10.9 Hz, 1H), 4.39 (d, J¼10.9 Hz, 1H), 1.54e1.47 (m,
9H). 13C NMR (125 MHz, CDCl3)
155.9, 139.7, 139.5, 137.8, 137.6,
128.8, 128.7, 128.5, 128.4, 128.3, 128.0, 127.9, 127.4, 127.3, 127.1, 98.2,
d
7.83 (d, J¼8.0 Hz, 1H), 7.37e7.10 (m, 7H), 6.97 (t, J¼7.5 Hz,
144.2, 139.5, 129.3, 128.4, 127.9, 100.6, 82.2, 46.0, 38.2, 29.6, 28.1. IR
(neat): 2977, 1740, 1692, 1456, 1436, 1392, 1365, 1290, 1244, 1173,
1137, 1117, 1040, 1009, 855, 748, 647 cmꢀ1. HRMS (ESI-TOF) calcd for
d
C
19H29NO4I [MþH]þ 462.1141, found 462.1188.
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H. Masui et al. / Tetrahedron xxx (2015) 1e7
5
4.7. Methyl (2-(2-((benzyl(tert-butoxycarbonyl)amino)
methyl)phenyl)-2-oxoacetyl)glycinate (7)
temperature under Ar atmosphere. The vessel was placed in auto-
clave, which was purged with CO three times before applying
a pressure (30 atm). After being stirred at 60 ꢁC for 18 h, the re-
action mixture was filtered through a pad of CeliteÒ. The filtrate
was poured into 1 M HCl and the aqueous layer was extracted with
two portions of diethyl ether. The combined organic layer was
washed with saturated aqueous NaHCO3 and brine, dried over
MgSO4, filtered, and concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel (40% ethyl acetate in
hexane) to give 1-(2-(2-(bis-tert-butoxycarbonyl)aminoethyl)phe-
nyl)-2-morpholinoethane-1,2-dione (9) (835 mg, 1.81 mmol,
quant.) as a white solid. Mp 46e49 ꢁC. 1H NMR (500 MHz, CDCl3)
tert-Butyl benzyl(2-iodobenzyl)carbamate (1b) (216 mg,
0.500 mmol, 1.00 equiv), Pd(OAc)2 (11.2 mg, 0.0500 mmol,
0.100 equiv), cataCXium A (53.8 mg, 0.150 mmol, 0.300 equiv), H-
Gly-OMe$HCl (94.2 mg, 0.750 mmol, 1.50 equiv), and tetramethyl
guanidine (188 mL, 1.50 mmol, 3.00 equiv) in DMF (2.50 mL) were
added to a glass vessel at room temperature under Ar atmosphere.
The vessel was placed in autoclave, which was purged with CO
three times before applying a pressure (30 atm). After being stirred
at 60 ꢁC for 18 h, the reaction mixture was filtered through a pad of
CeliteÒ. The filtrate was poured into 1 M HCl and the aqueous layer
was extracted with two portions of Et2O. The combined organic
layer was washed with saturated aqueous NaHCO3 and brine, dried
over MgSO4, filtered, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (40% ethyl acetate
in hexane) to give methyl (2-(2-((benzyl(tert-butoxycarbonyl)
d
7.73 (d, J¼8.0 Hz, 1H), 7.49 (dd, J¼7.4, 7.4 Hz, 1H), 7.35 (dd, J¼7.4,
7.4 Hz, 1H), 7.26 (d, J¼7.4 Hz, 1H), 3.95 (t, J¼7.4 Hz, 2H), 3.79e3.76
(m, 4H), 3.65 (t, J¼5.1 Hz, 2H), 3.47 (t, J¼5.1 Hz, 2H), 3.33 (t,
J¼6.3 Hz, 2H), 1.40 (s, 18H). 13C NMR (125 MHz, CDCl3)
d 193.2,
166.0, 152.6, 142.4, 133.9, 133.4, 133.3, 131.6, 127.0, 82.2, 67.0, 66.8,
46.3, 46.2, 41.7, 33.9, 28.1. IR (neat): 2975, 1743, 1702, 1675, 1645,
1570, 1451, 1365, 1353, 1300, 1268, 1231, 1147, 1112, 977, 924, 837,
747, 712, 650 cmꢀ1. HRMS (ESI-TOF) calcd for C24H35N2O7 [MþH]þ
463.2444, found 463.2477.
amino)methyl)phenyl)-2-oxoacetyl)glycinate
0.413 mmol, 83%) as a pale yellow oil. 1H NMR (500 MHz, CDCl3)
7.95 (br s, 1H), 7.54 (dd, J¼7.5, 7.5 Hz, 2H), 7.38e7.12 (m, 7H), 4.64
(br s, 2H), 4.38 (br s, 2H), 4.13 (d, J¼5.8 Hz, 2H), 3.78 (s, 3H), 1.43 (s,
9H). 13C NMR (125 MHz, CDCl3)
189.9, 169.3, 161.8, 156.1, 137.7,
(7)
(182
mg,
d
d
4.10. 2-(2-(2-(Bis-tert-butoxycarbonyl)aminoethyl)phenyl)-N-
133.2, 132.2, 128.5, 127.6, 127.3, 126.6, 80.3, 52.6, 50.1, 47.9, 41.2,
28.3. IR (neat): 2977, 1752, 1669, 1600, 1573, 1524, 1451, 1408, 1365,
1246, 1204, 1160, 1030, 933, 883, 749, 699, 666 cmꢀ1. HRMS (ESI-
TOF) calcd for C24H29N2O6 [MþH]þ 441.2026, found 441.2027.
octyl-2-oxoacetamide (10)
A
solution of N-(bis-tert-butoxycarbonyl)2-(2-iodophenyl)
ethanamine (1c) (400 mg, 0.894 mmol, 1.00 equiv), Pd(OAc)2
(20.1 mg, 0.0894 mmol, 0.100 equiv), cataCXium A (96.2 mg,
4.8. Methyl 2-(2-(2-(2-((bis-tert-butoxycarbonyl)amino)ethyl)
0.268 mmol, 0.300 equiv), n-octylamine (133
mL, 1.34 mmol,
phenyl)-2-oxoacetamido)acetate (8)
1.50 equiv), and tetramethyl guanidine (336 mL, 2.68 mmol,
3.00 equiv) in DMF (4.47 mL) was added to a glass vessel at room
temperature under Ar atmosphere. The vessel was placed in auto-
clave, which was purged with CO three times before applying
a pressure (30 atm). After being stirred at 60 ꢁC for 18 h, the re-
action mixture was filtered through a pad of CeliteÒ. The filtrate
was poured into 1 M HCl and the aqueous layer was extracted with
two portions of diethyl ether. The combined organic layer was
washed with saturated aqueous NaHCO3 and brine, dried over
MgSO4, filtered, and concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel (40% ethyl acetate in
hexane) to give 2-(2-(2-(bis-tert-butoxycarbonyl)aminoethyl)phe-
nyl)-N-octyl-2-oxoacetamide (10) (373 mg, 0.739 mmol, 83%) as
A
solution of N-(bis-tert-butoxycarbonyl)2-(2-iodophenyl)
ethanamine (1c) (100 mg, 0.224 mmol, 1.00 equiv), Pd(OAc)2
(5.03 mg, 0.0224 mmol, 0.100 equiv), cataCXium A (24.0 mg,
0.0671 mmol, 0.300 equiv), H-Gly-OMe$HCl (42.2 mg, 0.336 mmol,
1.50 equiv), and tetramethyl guanidine (84.2
mL, 0.671 mmol,
3.00 equiv) in DMF (1.16 mL) was added to a glass vessel at room
temperature under Ar atmosphere. The vessel was placed in auto-
clave, which was purged with CO three times before applying
a pressure (30 atm). After being stirred at 60 ꢁC for 18 h, the re-
action mixture was filtered through a pad of CeliteÒ. The filtrate
was poured into 1 M HCl and the aqueous layer was extracted with
two portions of diethyl ether. The combined organic layer was
washed with saturated aqueous NaHCO3 and brine, dried over
MgSO4, filtered, and concentrated in vacuo. The residue was puri-
fied by TLC (33% ethyl acetate in hexane) to give methyl 2-(2-(2-(2-
((bis-tert-butoxycarbonyl)amino)ethyl)phenyl)-2-oxoacetamido)
acetate (90.4 mg, 0.195 mmol, 87%) as a colorless oil. 1H NMR
a colorless oil. 1H NMR (500 MHz, CDCl3)
d
7.91 (d, J¼8.0 Hz, 1H),
7.46 (dd, J¼7.4, 7.4 Hz, 1H), 7.31 (dd, J¼7.4, 7.4 Hz, 1H), 7.28 (d,
J¼7.4 Hz, 1H), 7.16 (br s, 1H), 3.88 (t, J¼7.4 Hz, 2H), 3.38 (t, J¼6.9 Hz,
2H), 3.10 (t, J¼7.4 Hz, 2H), 1.66e1.48 (m, 2H), 1.44 (s, 18H), 1.42e1.27
(m, 10H), 0.87 (t, J¼7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 191.8,
162.5, 152.5, 140.7, 133.4, 132.7, 132.1, 132.0, 126.1, 82.3, 47.2, 39.7,
33.3, 31.8, 29.3, 29.2, 28.1, 27.0, 22.7,14.2. IR (neat): 2927,1780,1745,
1668, 1520, 1455, 1366, 1271, 1256, 1235, 1172, 1143, 1118, 855, 752,
663 cmꢀ1. HRMS (ESI-TOF) calcd for C28H45N2O6 [MþH]þ 505.3278,
found 505.3292.
(400 MHz, CDCl3)
d
7.92 (d, J¼7.7 Hz, 1H), 7.60 (t, J¼5.8 Hz, 1H), 7.47
(t, J¼7.7 Hz, 1H), 7.33 (d, J¼7.7 Hz, 1H), 7.29 (t, J¼7.7 Hz, 1H), 4.18 (d,
J¼5.8 Hz, 2H), 3.90 (t, J¼6.8 Hz, 2H), 3.80 (s, 3H), 3.11 (t, J¼6.8 Hz,
2H), 1.44 (s, 18H). 13C NMR (100 MHz, CDCl3)
d 190.4, 169.3, 162.5,
152.5, 140.9, 132.9, 132.2, 132.0, 126.1, 82.2, 52.5, 47.1, 41.2, 33.2,
28.0. IR (chloroform solution): 3328, 2981, 1747, 1600, 1524, 1479,
1440, 1368, 1123, 1036, 934, 854, 769 cmꢀ1. HRMS (ESI-TOF) calcd
for C23H33N2O8 [MþH]þ 465.2237, found 465.2236.
4.11. Methyl (2-(2-(3-(bis-tert-butoxycarbonyl)aminopropyl)
phenyl)-2-oxoacetyl)glycinate (11)
A
solution of N-(bis-tert-butoxycarbonyl)-3-(2-iodophenyl)
4.9. 1-(2-(2-(Bis-tert-butoxycarbonyl)aminoethyl)phenyl)-2-
morpholinoethane-1,2-dione (9)
propan-1-amine (1d) (103 mg, 0.224 mmol, 1.00 equiv), Pd(OAc)2
(5.03 mg, 0.0224 mmol, 0.100 equiv), cataCXium A (24.0 mg,
0.0671 mmol, 0.300 equiv), H-Gly-OMe$HCl (42.2 mg, 0.336 mmol,
A
solution of N-(bis-tert-butoxycarbonyl)2-(2-iodophenyl)
1.50 equiv), and tetramethyl guanidine (84.2 mL, 0.671 mmol,
ethanamine (1c) (800 mg, 1.79 mmol, 1.00 equiv), Pd(OAc)2
(40.1 mg, 0.179 mmol, 0.100 equiv), cataCXium A (193 mg,
3.00 equiv) in DMF (1.16 mL) was added to a glass vessel at room
temperature under Ar atmosphere. The vessel was placed in auto-
clave, which was purged with CO three times before applying
a pressure (30 atm). After being stirred at 60 ꢁC for 18 h, the re-
action mixture was filtered through a pad of CeliteÒ. The filtrate
0.537 mmol, 0.300 equiv), morpholine (234
1.50 equiv), and tetramethyl guanidine (672
m
m
L, 2.69 mmol,
L, 5.37 mmol,
3.00 equiv) in DMF (8.95 mL) was added to a glass vessel at room
Please cite this article in press as: Masui, H.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.102

6
H. Masui et al. / Tetrahedron xxx (2015) 1e7
was poured into 1 M HCl and the aqueous layer was extracted with
two portions of diethyl ether. The combined organic layer was
washed with saturated aqueous NaHCO3 and brine, dried over
MgSO4, filtered, and concentrated in vacuo. The residue was puri-
fied by TLC (33% ethyl acetate in hexane) to give methyl (2-(2-(3-
(bis-tert-butoxycarbonyl)aminopropyl)phenyl)-2-oxoacetyl)glyci-
nate (11) (89.0 mg, 0.186 mmol, 83%) as a colorless oil. 1H NMR
0.343 mmol, 96%) as a colorless oil. 1H NMR (500 MHz, CDCl3)
d 7.41
(dd, J¼7.4, 7.4 Hz, 1H), 7.36 (d, J¼7.4 Hz, 1H), 7.31 (dd, J¼7.4, 7.4 Hz,
1H), 7.22 (d, J¼7.4 Hz, 1H), 3.90e3.73 (m, 6H), 3.66e3.55 (m, 2H),
3.49e3.41 (m, 2H), 2.83 (t, J¼8.0 Hz, 2H). 13C NMR (125 MHz, CDCl3)
d
165.9, 163.0, 136.9, 132.0, 128.0, 127.5, 126.0, 66.9, 66.8, 46.9, 46.8,
41.8, 25.2. IR (neat): 2853, 1639, 1616, 1572, 1464, 1440, 1388, 1362,
1303, 1269, 1214, 1197, 1111, 1066, 1018, 995, 931, 895, 848, 794, 739,
718, 699, 670, 583 cmꢀ1. HRMS (ESI-TOF) calcd for C14H17N2O2
[MþH]þ 245.1290, found 245.1295.
(500 MHz, CDCl3)
(dd, J¼7.7, 7.7 Hz, 1H), 7.29e7.25 (m, 2H), 4.16 (d, J¼5.8 Hz, 2H), 3.78
(s, 3H), 3.61 (t, J¼7.4 Hz, 2H), 2.78 (t, J¼7.7 Hz, 2H), 1.90e1.83 (m,
d
7.85 (d, J¼8.0 Hz, 1H), 7.58 (t, J¼5.8 Hz, 1H), 7.45
2H), 1.46 (s, 18H). 13C NMR (125 MHz, CDCl3)
d 190.3, 169.4, 162.2,
4.15. N-Octyl-3,4-dihydroisoquinoline-1-carboxamide (15)
152.5, 143.9, 132.9, 132.3, 132.1, 130.7, 125.7, 82.1, 52.6, 46.2, 41.2,
31.0, 30.9, 28.0. IR (neat): 2979, 1742, 1675, 1599, 1523, 1479, 1438,
1392, 1366, 1295, 1248, 1203, 1177, 1139, 987, 934, 851, 754, 734,
703, 664 cmꢀ1. HRMS (ESI-TOF) calcd for C24H35N2O8 [MþH]þ
479.2393, found 479.2423.
To a solution of 2-(2-(2-(bis-tert-butoxycarbonyl)aminoethyl)
phenyl)-N-octyl-2-oxoacetamide (10) (83.7 mg, 0.166 mmol,
1.00 equiv) in CH2Cl2 (571
mL) was added trifluoroacetic acid
(143 L) at room temperature. After being stirred at the same
m
temperature for 1 h, the reaction mixture was concentrated in
vacuo. The residue was purified by TLC (50% ethyl acetate in hex-
ane) to give N-octyl-3,4-dihydroisoquinoline-1-carboxamide (15)
(42.2 mg, 0.147 mmol, 89%) as a colorless oil. 1H NMR (500 MHz,
4.12. Methyl (2-benzyl-2H-isoindole-1-carbonyl)glycinate (12)
To a solution of methyl (2-(2-((benzyl(tert-butoxycarbonyl)
amino)methyl)phenyl)-2-oxoacetyl)glycinate
0.0454 mmol, 1.00 equiv) in CH2Cl2 (720 L) was added trifluoro-
acetic acid (180 L) at room temperature. After being stirred at the
(7)
(20.0
mg,
CDCl3)
d
8.10 (d, J¼6.3 Hz, 1H), 7.68 (br s, 1H), 7.40 (dd, J¼7.4, 7.4 Hz,
m
1H), 7.33 (dd, J¼6.3, 6.3 Hz, 1H), 7.20 (d, J¼7.4 Hz, 1H), 3.81 (s, 2H),
3.39 (s, 2H), 2.78 (s, 2H), 1.59 (s, 2H), 1.36e1.10 (m, 10H), 0.87 (t,
m
J¼6.3 Hz, 3H). 13C NMR (125 MHz, CDCl3)
d 164.0, 161.2, 138.2, 132.2,
same temperature for 1 h, the reaction mixture was concentrated in
vacuo. The residue was purified by TLC (33% ethyl acetate in hex-
ane) to give methyl (2-benzyl-2H-isoindole-1-carbonyl)glycinate
(12) (5.00 mg, 0.0155 mmol, 34%) as a colorless oil. 1H NMR
129.1, 127.3, 127.2, 126.0, 39.7, 31.8, 29.5, 29.3, 29.2, 27.0, 26.9, 25.8,
22.7, 14.1. IR (neat): 2924, 2853, 1668, 1609, 1570, 1519, 1454, 1376,
1236, 1199, 1134, 1023, 937, 890, 799, 750, 720, 692, 608 cmꢀ1
.
HRMS (ESI-TOF) calcd for C18H27N2O [MþH]þ 287.2123, found
(500 MHz, CDCl3)
d
7.87 (d, J¼9.2 Hz, 1H), 7.60 (d, J¼8.6 Hz, 1H),
7.36e7.21 (m, 5H), 7.17 (d, J¼6.8 Hz, 2H), 7.05 (t, J¼8.0 Hz, 1H), 6.53
287.2128.
(br s, 1H), 5.89 (s, 2H), 4.29 (d, J¼5.2 Hz, 2H), 3.81 (s, 3H). 13C NMR
(125 MHz, CDCl3)
d 171.0, 162.1, 137.7, 128.8, 127.8, 127.5, 126.0,
4.16. Methyl (4,5-dihydro-3H-benzo[c]azepine-1-carbonyl)
125.0, 123.9, 121.7, 120.9, 119.5, 118.4, 53.4, 52.5, 41.5. IR (neat):
2925, 1747, 1697, 1639, 1517, 1496, 1455, 1434, 1395, 1358, 1290,
1206, 1178, 1075, 1030, 724, 702, 627 cmꢀ1. HRMS (ESI-TOF) calcd
for C19H19N2O3 [MþH]þ 323.1396, found 323.1393.
glycinate (16)
To a solution of methyl (2-(2-(3-(bis-tert-butoxycarbonyl)ami-
nopropyl)phenyl)-2-oxoacetyl)glycinate (11) (47.9 mg, 0.100 mmol,
1.00 equiv) in CH2Cl2 (400
mL) was added trifluoroacetic acid
4.13. Methyl (3,4-dihydroisoquinoline-1-carbonyl)glycinate
(13)
(100 L) at room temperature. After being stirred at the same
m
temperature for 1 h, the reaction mixture was concentrated in
vacuo. The residue was purified by TLC (33% ethyl acetate in hex-
ane) to give methyl (4,5-dihydro-3H-benzo[c]azepine-1-carbonyl)
glycinate (16) (26.3 mg, 0.101 mmol, quant.) as a pale yellow solid.
To a solution of methyl 2-(2-(2-(2-((bis-tert-butoxycarbonyl)
amino)ethyl)phenyl)-2-oxoacetamido)acetate (8) (20.0 mg,
Mp 86e89 ꢁC. 1H NMR (500 MHz, CDCl3)
d 8.10 (br s, 1H), 7.47 (d,
0.0431 mmol, 1.00 equiv) in CH2Cl2 (860
mL) was added trifluoro-
acetic acid (860 L) at room temperature. After being stirred at the
m
J¼7.4 Hz, 1H), 7.34 (dd, J¼7.4, 7.4 Hz, 1H), 7.31 (dd, J¼7.4, 7.4 Hz, 1H),
7.21 (d, J¼7.4 Hz, 1H), 4.17 (d, J¼5.8 Hz, 1H), 3.78 (s, 3H), 3.40 (t,
J¼6.3 Hz, 1H), 2.51 (t, J¼7.4 Hz, 1H), 2.37e2.29 (m, 2H). 13C NMR
same temperature for 1 h, the reaction mixture was concentrated in
vacuo. The residue was purified by TLC (33% ethyl acetate in hex-
ane) to give methyl (3,4-dihydroisoquinoline-1-carbonyl)glycinate
(13) (13.7 mg, 0.0556 mmol, quant.) as a colorless oil. 1H NMR
(125 MHz, CDCl3)
d 170.2, 164.0, 163.8, 140.6, 131.8, 130.3, 129.5,
128.4, 126.0, 52.4, 49.9, 41.3, 34.1, 30.3. IR (neat): 2940, 1752, 1665,
1610, 1510, 1471, 1453, 1435, 1365, 1303, 1256, 1211, 1193, 1178, 1039,
982, 955, 882, 749 cmꢀ1. HRMS (ESI-TOF) calcd for C14H17N2O3
[MþH]þ 261.1239, found 261.1244.
(400 MHz, CDCl3)
d
8.18 (d, J¼7.7 Hz, 1H), 7.92 (br s, 1H), 7.38 (ddd,
J¼1.5, 7.7, 7.7 Hz, 1H), 7.31 (dd, J¼7.7, 7.7 Hz, 1H), 7.19 (d, J¼7.7 Hz,
1H), 4.18 (d, J¼5.8 Hz, 2H), 3.81 (t, J¼7.7 Hz, 2H), 3.79 (s, 3H), 2.74 (t,
J¼7.7 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d 170.1, 164.4, 159.2, 137.9,
131.4, 128.4, 127.2, 127.0, 126.1, 52.4, 47.2, 41.1, 25.7. IR (chloroform
solution): 3379, 2953, 1751, 1675, 1611, 1520, 1436, 1371, 1204, 970,
755 cmꢀ1; HRMS (ESI-TOF) calcd for C13H15N2O3 [MþH]þ 247.1083,
found 247.1085.
Acknowledgements
The authors would like to thank Dr. Hiroshi Tanaka for HRMS
analysis.
4.14. (3,4-Dihydroisoquinolin-1-yl)(morpholino)methanone
(14)
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Please cite this article in press as: Masui, H.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.102