A tandem Heck-aza-Michael addition protocol for the one-pot synthesis of isoindolines from unprotected amines

Article abstract of DOI:10.1039/c2ob25854d

A palladacycle-catalyzed tandem Heck-intramolecular aza-Michael reaction protocol has been developed for the one-pot synthesis of 1-substituted isoindolines from N-unprotected 2-bromobenzylamines and acrylates with high yields.

Full text of DOI:10.1039/c2ob25854d

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PAPER
A tandem Heck–aza-Michael addition protocol for the one-pot synthesis of
isoindolines from unprotected amines†
Ke Chen and Sumod A. Pullarkat*
Received 4th May 2012, Accepted 21st June 2012
DOI: 10.1039/c2ob25854d
A palladacycle-catalyzed tandem Heck-intramolecular aza-Michael reaction protocol has been developed
for the one-pot synthesis of 1-substituted isoindolines from N-unprotected 2-bromobenzylamines and
acrylates with high yields.
Introduction
Due to their widespread occurrence in nature, diverse biological
activity and interesting chemical properties, isoindolines (1),1
1-substituted isoindolines (2),2 1,3-disubstituted isoindolines (3),3
3-substituted isoindolinones (4)4 (Fig. 1) and their analogs are
Fig. 1 Common isoindoline and isoindolinone scaffolds.
highly attractive organic compounds that have shown potential in
organic synthesis and medicinal chemistry. Therefore, the devel-
opment of new and highly efficient strategies for the generation
consequently limited, especially with respect to substituents on
of these intricate heterocyclic molecular architectures is of great
nitrogen, and extra chemical waste was inevitably generated
during the protection–deprotection steps. Notable attempts to cir-
cumvent these issues include a Pd-catalyzed intramolecular
α-arylation of α-amino acid esters reported by Buchwald and
interest and remains a preeminent goal in organic synthesis.
However, when compared to their congeners, access to 1- and
1,3-substituted isoindolines (2, 3) has been hampered by the fact
that very few synthetic methods have been developed for their
Gaertzen using biaryl based phosphines allowing incorporation
synthesis. The access to 3-substituted isoindolinones via tandem
of phenyl and methyl moieties on nitrogen (eqn (1))2a and a
oxidative C–H functionalization–aza Michael addition of benza-
mide was reported by Li et al.5 using 4 mol% of [RhCp*Cl2] in
formal double arylation of azomethines with 10 mol% phospho-
ric acid catalysts reported recently by Gong et al. yielding disub-
a sealed tube under nitrogen and by Falck and Zhu6 using Pd-
stituted isoindolines (although no variation of substituent on
(OAc)2 with bathophenanthroline ligand. Fustero et al. reported
the synthesis of 1-substituted isoindolines via aza-Michael
nitrogen could be achieved) (eqn (2)).10
However, there is no precedent in the literature for the syn-
thesis of 1-substituted isoindolines using easily accessible unpro-
addition using the N-protected amide (generated using the
Hoveyda–Grubbs catalyst) with 20 mol% of diarylprolinols.7 A
tected amines as substrates, a protocol that would also allow the
metal-free one-pot Brønsted acid catalyzed Friedel–Crafts/base-
incorporation of various substituents on the nitrogen atom. A
catalyzed aza-Michael addition reaction of indoles with N-pro-
tected N-tosyliminoenoates using 10 mol% phosphoric acid cata-
major hindrance to the development of such a method is the fact
that the electron deficient alkenes involved need to be consumed
rapidly by the Heck process so as to avoid an intermolecular
aza-Michael proceeding as the first step.
lyst leading to 1,3-isoindolines has been reported by Enders
et al.3d Jarvo and Williams, and Pfeffer et al. had also reported
methods that yield 1-substituted and 1,3-disubstituted isoindo-
lines and related heterocycles from protected imines8 and
As efficient and versatile precatalysts, palladacycle 5 and its
amines.9 However, such methods usually require use of expens-
derivatives, (Fig. 2), have been extensively employed in the
Heck reaction as well as in other coupling reactions.11 Recently,
ive starting materials/catalysts, high catalyst loadings and/or the
requirement for protection of nitrogen with Cbz, Boc, Ts etc.
The structural versatility of the isoindolines thus obtained was
we had reported the application of similar palladacycles in asym-
metric hydrophosphination reactions12 and in domino alkyl-
ation–cyclization protocols for indole synthesis.13 We have also
used palladacycle 7 as catalyst in a tandem allylic amination–
Division of Chemistry and Biological Chemistry, School of Physical &
allylation reaction for the one-pot synthesis of hitherto inaccess-
Mathematical Sciences, Nanyang Technological University, Singapore
ible 2-allylanilines.14
637371, Singapore. E-mail: sumod@ntu.edu.sg; Tel: +65-63168906
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob25854d
In line with our continuing interest in the catalytic application
of these palladacycles, we herein investigate their efficacy in a
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ð1Þ
ð2Þ
2-bromobenzylamines with tert-butyl acrylate and good to high
yields were achieved in all cases (Scheme 1).
Significantly, the presence of electron-donating or electron-
withdrawing moieties on the amines had no impact on the
tandem Heck reaction–aza-Michael addition sequence (10a–f vs.
10g–h). The presence of either meta- or para-substituent groups
on the amines also had no significant effect on the yields and
rates (10a, 10c, 10f, 10g, 10h vs. 10d, 10e). Furthermore, the
reaction proceeded smoothly and provided good yields for 2-bro-
mobenzylamines incorporating tert-butyl as the N-substituent.
When compared to tert-butyl and n-butyl acrylates, relatively
lower yields were observed for methyl and ethyl acrylates (10j,
10k). This may be attributed to their relatively low boiling
points. A good result was obtained for the use of acrylamides
(10m). However, the aza-Michael addition occurred prior to the
Heck reaction when more active terminal enones were used. A
preliminary attempt to employ available chiral variants of the
palladacycles12,13 in an asymmetric version of this reaction did
not yield satisfactory results in terms of enantioselectivity.
As aforementioned, the overall process for the formation of
1-substituted isoindolines from 2-bromobenzylamines and acry-
lates involves two general transformations: the Heck reaction and
the aza-Michael addition. Thus, the overall reaction could either
proceed via Heck reaction followed by an intramolecular aza-
Michael addition (Path A, Scheme 2) or by an intermolecular
aza-Michael addition followed by intramolecular arylation (Path
B, Scheme 2). To obtain insights into the reaction mechanism,
intermediate 11 (Scheme 3) was prepared via Heck reaction fol-
lowed by reductive amination from the starting material
2-bromobenzaldehyde. When 11 was treated with 2 mol% of
palladacycle 6 at the optimum conditions established previously,
the 1-substituted isoindoline product was obtained. To gain a
better mechanistic understanding of the palladacycle catalyzed
aza-Michael addition, we conducted the controlled experiment
for the intermediate 11 under the optimum conditions in the
absence of 6 (Scheme 3).
Fig. 2 Structures of palladacycles used in this study.
tandem Heck-intramolecular aza-Michael reaction sequence for
the formation of isoindolines incorporating an ester substituent at
the 1-position. The ester moiety is an attractive substituent
because it can be easily transformed into other functionalities.
This work also assumes significance in view of recent studies
demonstrating that isoindolines can be easily converted into the
corresponding isoindoles.15
Results and discussion
In order to test the feasibility of the protocol, 2-bromobenzyl-
amine 8 (easily prepared via the reductive amination of 2-bromo-
benzaldehyde in good yields) was subjected to the tandem Heck
reaction with acrylate 9 and a subsequent intramolecular aza-
Michael addition (Table 1). The dimeric palladacycle 5 was
employed as catalyst. Use of 2 mol% of 5 gave a higher yield
and reactivity than 1 mol% (Table 1, entry 1 vs. entry 2). The
addition of 20 mol% of tetrabutylammonium bromide acceler-
ated the reaction rate and increased the conversions obtained for
the final product (Table 1, entry 1 vs. entry 4).
No product however, was obtained when the reaction was con-
ducted at 90 °C for 24 h in DMF (Table 1, entry 5) and 130 °C
was found to be the optimum temperature. The presence of a tri-
phenylphosphine ligand in complex 6 enhanced the activity and
conversion rate drastically, and the reaction only required 12 h
for completion instead of 24 h for complex 5 (Table 1, entry 6
vs. entry 3 and entry 7 vs. entry 4). The palladacycle complex 7,
which was efficient in our hands for the one-pot synthesis of
2-allylanilines, was, however, inefficient in this scenario (Table 1,
entry 8). A detailed screening of solvents and bases indicated
that DMF and (n-Bu)4NBr are best suited for this protocol. The
choice of base is critical since it needs to help promote the intra-
molecular aza-Michael reaction but should not promote it to
such an extent that an intermolecular aza-Michael takes
precedence over the Heck process. With the optimum
conditions established, we proceeded to screen various
The result showed that the aza-Michael addition was promoted
to give the isoindoline only in the presence of palladacycle 6
(Scheme 3). Thus, it is clear that the formation of isoindoline fol-
lowed a two step sequence consisting of a palladacycle-catalyzed
Heck reaction followed by a palladacycle-catalyzed aza-Michael
addition.
To ascertain the possibility for Path B occurring, compound
12 was prepared and subjected to the same reaction conditions.
The results showed that no isoindoline product was formed
(Scheme 4).
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Table 1 Optimization of conditionsa
Entry
Catalyst
Temp (°C)
Product yieldb (%)
1
2 mol% 5
1 mol% 5
2 mol% 5
2 mol% 5
2 mol% 5
2 mol% 6
2 mol% 6
2 mol% 7
130
130
130
130
90
130
130
130
95
70
50
30
N.R
96
75
2
3c
4d
5
6c
7d
8
N.R
a Unless otherwise indicated, all reactions were performed using 2-bromobenzylamine (1 mmol), acrylate (1.2 mmol), catalyst (2 mol%), (n-Bu)4NBr
(0.2 equiv) and NaOAc (1.4 equiv) in DMF (3 mL) for 24 h. b Isolated yield; c for 12 h. d Without (n-Bu)4NBr.
Scheme 1 Palladacycle-catalyzed one-pot tandem Heck reaction–aza-Michael addition protocol. Unless otherwise indicated, all reactions were per-
formed at 130 °C using 2-bromobenzylamines (1 mmol), acrylates (1.2 mmol), catalyst (2 mol%), (n-Bu)4NBr (0.2 equiv) and NaOAc (1.4 equiv) in
DMF (3 mL) for 12 h. Yields shown are isolated yields.
has hitherto not been possible. Further studies on the scope of
this novel process and the synthetic use of the heterocycles are
currently underway.
Conclusions
In conclusion, we have successfully developed a palladacycle-
catalyzed tandem Heck–aza-Michael addition reaction at low cat-
alyst loading for the one-pot synthesis of 1-substituted isoindo-
lines. This protocol avoids the formation of chemical waste
during the conventional protection and deprotection of amines
by allowing the direct use of unprotected amines as starting
materials. Furthermore it allows the incorporation of a wide
range of substituents on the nitrogen atom of isoindolines, which
Experimental
General experimental
Unless otherwise stated, all reactions were performed under an
argon atmosphere. Unless specified, all reagents and starting
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(10 mL) was added amine (1.2 mmol) and anhydrous MgSO4,
and the mixture was stirred at room temperature for 12 h. After
the aldehyde was converted completely, MgSO4 was filtered off
and the filtrate was concentrated and dissolved in MeOH
(10 mL), the solution was treated with NaBH4 (38 mg, 1 mmol)
to give crude compound 8. After standard work-up, the crude
product was purified by column chromatography (Eluent: from
Hex to EA–Hex = 1 : 30) to give the intermediate 8.
Specific experimental
N-(2-Bromobenzyl)-4-methylaniline (8a). Pale yellow solid;
95% (262 mg) isolated yield; mp: 58–60 °C. 1H NMR
(500 MHz, CDCl3): δ 7.57 (d, J = 7.9 Hz, 1H), 7.42 (d, J =
7.9 Hz, 1H), 7.25–7.28 (m, 1H), 7.12–7.15 (m, 1H), 7.00 (d, J =
8.1 Hz, 2H), 6.55 (d, J = 8.1 Hz, 2H), 4.39 (s, 2H), 4.08 (brs,
1H), 2.45 (s, 3H); 13C NMR (125 MHz, CDCl3): δ;
145.4, 138.4, 132.7, 129.7, 129.2, 128.6, 127.5, 126.9, 48.7,
20.4. HRMS (ESI): Calcd for C14H15 BrN (M+ + H): 276.0388,
found 276.0389.
Scheme 2 Plausible mechanistic pathways.
N-(2-Bromobenzyl)aniline (8b). Pale yellow oil; 94%
(246 mg) isolated yield. 1H NMR (400 MHz, CDCl3): δ 7.58 (d,
J = 7.9 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.25–7.29 (m, 1H),
7.12–7.20 (m, 3H), 6.74 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 8.1 Hz,
2H), 4.42 (s, 2H), 4.20 (brs, 1H); 13C NMR (100 MHz, CDCl3):
δ; 147.7, 138.2, 132.8, 129.3, 129.1, 128.7, 127.5, 123.2, 117.7,
112.9, 48.4; HRMS (ESI): Calcd for C13H13BrN (M+ + H):
262.0231, found 262.0235.
Scheme 3 Role of catalyst in the aza-Michael addition step (Path A).
N-(2-Bromobenzyl)-4-methoxyaniline (8c). Pale yellow oil;
1
92% (269 mg) isolated yield. H NMR (500 MHz, CDCl3): δ
7.57 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.25–7.28
(m, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 8.4 Hz, 2H), 6.59
(d, J = 8.4 Hz, 2H), 4.37 (s, 2H), 3.97 (brs, 1H), 3.74 (s, 3H);
13C NMR (125 MHz, CDCl3): δ; 152.3, 141.9, 138.4, 132.8,
129.3, 128.6, 127.5, 123.3, 114.9, 114.2, 55.7, 49.3; HRMS
(ESI): Calcd for C14H15BrNO (M+ + H): 292.0337, found
292.0330.
Scheme 4 Intramolecular arylation of 12.
materials were purchased from commercial sources and used as
received. Solvents were purified following standard literature
procedures. Analytical thin layer chromatography (TLC) was
performed using pre-coated silica gel plate. Visualization was
achieved by UV light (254 nm). Flash chromatography was per-
formed using silica gel and a gradient solvent system (EtOAc:
n-hexane as eluent). 1H and 13C NMR spectra were measured on
400 and 500 MHz spectrometers and the residual solvent peak
was used as an internal reference: proton (chloroform δ 7.26),
carbon (chloroform δ 77.0). Chemical shifts (ppm) were
recorded with tetramethylsilane (TMS) as the internal reference
standard. Multiplicities are given as: s (singlet), brs (broad
singlet), d (doublet), t (triplet), dd (doublet of doublets) or m
(multiplet). The number of protons (n) for a given resonance is
indicated by nH and coupling constants are reported as a J value
in Hz. High resolution mass spectra (HRMS) were obtained on a
LC/HRMS mass spectrometer (Waters Q-Tof Premier Mass
Spectrometer).
N-(2-Bromobenzyl)-3-methylaniline (8d). Pale yellow oil;
1
90% (249 mg) isolated yield. H NMR (400 MHz, CDCl3): δ
7.59 (dd, J = 7.9, 1.1 Hz, 1H), 7.43 (dd, J = 7.6, 1.4 Hz, 1H),
7.29 (dd, J = 7.5, 1.1 Hz, 1H), 7.15 (td, J = 7.8, 1.7 Hz, 1H),
7.08 (t, J = 7.7 Hz, 1H), 4.41 (s, 2H), 4.12 (brs, 1H), 2.29 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 147.7, 139.1, 138.3,
132.7, 129.2, 129.1, 128.6, 127.5, 123.2, 118.7, 113.7, 110.0,
48.4, 21.6; HRMS (ESI): Calcd for C14H15BrN (M+ + H):
276.0388, found 276.0391.
N-(2-Bromobenzyl)-3-methoxyaniline (8e). Pale yellow oil;
1
92% (269 mg) isolated yield. H NMR (400 MHz, CDCl3): δ
7.57 (dd, J = 7.9, 1.2 Hz, 1H), 7.41 (dd, J = 7.7, 1.5 Hz, 1H),
7.27 (td, J = 7.5, 1.2 Hz, 1H), 7.14 (td, J = 7.5, 1.5 Hz, 1H),
7.09 (t, J = 8.1 Hz, 1H), 6.30 (ddd, J = 8.2, 2.4, 0.8 Hz, 1H),
6.25 (ddd, J = 8.1, 2.2, 0.7 Hz, 1H), 6.18 (t, J = 2.3 Hz, 1H),
4.40 (s, 2H), 4.22 (brs, 1H), 3.76 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ; 160.8, 149.1, 138.1, 132.8, 130.0, 129.1, 128.7,
127.5, 123.2, 106.0, 102.8, 99.0, 55.1, 48.3; HRMS (ESI):
Calcd for C14H15BrNO (M+ + H): 292.0337, found 292.0338.
General procedure for the preparation of intermediates. To a
solution of 2-bromobenzaldehyde (185 mg, 1 mmol) in ether
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N-(2-Bromobenzyl)-4-phenoxyaniline (8f). Pale yellow oil;
91% (322 mg) isolated yield. H NMR (400 MHz, CDCl3): δ
tert-Butyl
2-(2-phenylisoindolin-1-yl)acetate
(10b). Pale
1
1
yellow oil; 92% (285 mg) isolated yield. H NMR (500 MHz,
CDCl3): δ 7.29–7.38 (m, 6H), 6.76–6.80 (m, 3H), 5.47 (d, J =
8.4 Hz, 1H), 4.77 (d, J = 13.2 Hz, 1H), 4.57 (d, J = 13.2 Hz,
1H), 3.05 (dd, J = 15.3, 1H), 2.48 (dd, J = 15.3, 8.6 Hz, 1H),
1.45 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 170.9, 145.6,
141.6, 137.2, 129.5, 127.5, 127.3, 122.7, 122.4, 116.4, 112.2,
80.7, 60.2, 53.8, 39.8, 28.0; HRMS (ESI): Calcd for C20H24NO2
(M+ + H): 310.1807, found 310.1812.
7.59 (dd, J = 8.0, 1.2 Hz, 1H), 7.44 (dd, J = 7.6, 1.4 Hz, 1H),
7.25–7.31 (m, 3H), 7.15 (td, J = 7.8, 1.7 Hz, 1H), 6.99–7.03 (m,
1H), 6.88–6.94 (m, 4H), 6.60–6.62 (m, 2H), 4.40 (s, 2H), 4.13
(brs, 1H); 13C NMR (100 MHz, CDCl3): δ 158.9, 148.0, 144.3,
138.1, 132.8, 129.5, 129.2, 128.8, 127.6, 123.3, 122.0, 121.1,
117.2, 114.0, 49.0; HRMS (ESI): Calcd for C19H17BrNO
(M+ + H): 354.0494, found 354.0493.
4-(2-Bromobenzylamino)benzonitrile (8g). Yellow solid; 90%
(258 mg) isolated yield; mp: 111–113 °C. H NMR (400 MHz,
tert-Butyl 2-(2-(4-methoxyphenyl)isoindolin-1-yl)acetate (10c).
Pale white solid; 95% (322 mg) isolated yield; mp: 100–102 °C.
1H NMR (400 MHz, CDCl3): δ 7.30–7.36 (m, 4H), 6.94 (d, J =
8.9 Hz, 2H), 6.72 (d, J = 8.9 Hz, 2H), 5.40 (d, J = 8.6 Hz, 1H),
4.74 (dd, J = 13.0, 3.0 Hz, 1H), 4.50 (d, J = 13.0 Hz, 1H), 3.80
(s, 3H), 3.02 (dd, J = 15.2, 2.6 Hz, 1H), 2.45 (dd, J = 15.2, 8.7
Hz, 1H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 171.0,
151.3, 141.8, 140.3, 137.4, 127.4, 127.2, 122.6, 122.3, 115.2,
113.1, 80.7, 60.5, 55.8, 54.3, 39.8, 28.0; HRMS (ESI): Calcd for
C21H26NO3 (M+ + H): 340.1913, found 340.1915.
1
CDCl3): δ 7.59 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 8.6 Hz, 2H),
7.25–7.33 (m, 2H), 7.14–7.18 (m, 1H), 6.58 (d, J = 8.6 Hz, 2H),
4.84–4.85 (brs, 1H), 4.44 (d, J = 6.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3): δ; 150.8, 136.5, 133.6, 133.0, 129.1, 128.8,
127.6, 123.2, 120.3, 111.4, 99.1, 47.5; HRMS (ESI): Calcd for
C14H12 Br N2 (M+ + H): 287.0184, found 287.0181.
N-(2-Bromobenzyl)-4-nitroaniline (8h). Yellow oil; 90%
1
(276 mg) isolated yield; mp: 177–179 °C. H NMR (400 MHz,
CDCl3): δ 8.09 (d, J = 9.2 Hz, 2H), 7.61 (d, J = 7.9 Hz, 1H),
7.27–7.33 (m, 2H), 7.17–7.21 (m, 1H), 6.57 (d, J = 9.2 Hz, 2H),
4.97 (brs, 1H), 4.51 (d, J = 6.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3): δ 152.7, 136.2, 133.2, 129.4, 129.0, 127.8, 126.4,
123.4, 111.5, 47.9. HRMS (ESI): Calcd for C13H12 Br N2O2
(M+ + H): 307.0082, found 307.0085.
tert-Butyl
2-(2-m-tolylisoindolin-1-yl)acetate
(10d). Pale
1
yellow oil; 93% (300 mg) isolated yield. H NMR (400 MHz,
CDCl3): δ 7.27–7.37 (m, 4H), 7.19–7.23 (m, 1H), 6.57–6.61 (m,
3H), 5.44 (d, J = 8.6 Hz, 1H), 4.75 (dd, J = 13.2, 2.8 Hz, 1H),
4.55 (d, J = 13.2 Hz, 1H), 3.04 (dd, J = 15.2, 2.6 Hz, 1H), 2.45
(dd, J = 15.2, 8.6 Hz, 1H), 2.37 (s, 3H), 1.43 (s, 9H); 13C NMR
(100 MHz, CDCl3): δ 170.9, 145.7, 141.6, 139.2, 137.3, 129.3,
127.5, 127.2, 122.7, 122.4, 117.4, 113.0, 109.5, 80.7, 60.2, 53.9,
39.9, 28.0, 21.9; HRMS (ESI): Calcd for C21H26NO2 (M+ + H):
324.1964, found 324.1959.
N-(2-Bromobenzyl)-2-methylpropan-2-amine (8i). Pale yellow
1
oil; 95% (230 mg) isolated yield. H NMR (400 MHz, CDCl3):
δ 7.51 (dd, J = 8.0, 0.8 Hz, 1H), 7.45 (dd, J = 7.6, 1.4 Hz, 1H),
7.27 (td, J = 7.6, 0.8 Hz, 1H), 7.09 (dd, J = 8.0, 1.4 Hz, 1H), 3.80
(s, 2H), 1.20 (s, 9H); 13C NMR (100 MHz, CDCl3): δ; 140.4,
132.7, 130.5, 128.4, 127.6, 124.0, 50.9, 47.3, 29.1; HRMS (ESI):
Calcd for C11H17BrN (M+ + H): 242.0544, found 242.0543.
tert-Butyl 2-(2-(3-methoxyphenyl)isoindolin-1-yl)acetate (10e).
Pale yellow oil; 95% (322 mg) isolated yield. 1H NMR
(400 MHz, CDCl3): δ 7.21–7.38 (m, 5H), 6.35–6.41 (m, 2H),
6.32 (s, 1H), 5.44 (d, J = 8.5 Hz, 1H), 4.74 (dd, J = 13.2, 2.7
Hz, 1H), 4.56 (d, J = 13.2 Hz, 1H), 3.85 (s, 3H), 3.06 (dd, J =
15.3, 2.7 Hz, 1H), 2.48 (dd, J = 15.3, 8.5 Hz, 1H), 1.44 (s, 9H);
13C NMR (100 MHz, CDCl3): δ 170.8, 161.0, 146.9, 141.5,
137.1, 130.2, 127.5, 127.3, 122.6, 122.4, 105.4, 101.5, 98.7,
80.7, 60.3, 55.1, 53.9, 39.8, 28.0; HRMS (ESI): Calcd for
C21H26NO3 (M+ + H): 340.1913, found 340.1924.
General procedure for the tandem Heck–aza-Michael addition
reaction. A solution of 8 (1 mmol), 9 (1.2 mmol), N(nBu)4Br
(65 mg, 0.2 mmol), NaOAc (115 mg, 1.4 mmol) and catalyst 6
(11 mg, 0.02 mmol) in DMF (3 mL) was heated to 130 °C under
argon for 12 h. Upon completion, the crude reaction mixture was
poured into water (30 mL), the organic layer was extracted with
dichloromethane (15 mL) and washed with water (3 × 5 mL),
dried over anhydrous MgSO4 and concentrated to give crude
product. The residue was purified by column chromatography
(Eluent: from Hex to EA–Hex = 1 : 30) to give product 10 in
88–96% yield.
tert-Butyl 2-(2-(4-phenoxyphenyl)isoindolin-1-yl)acetate (10f).
Pale white solid; 94% (377 mg) isolated yield; mp: 94–97 °C.
1H NMR (400 MHz, CDCl3): δ 7.28–7.38 (m, 6H), 7.01–7.07
(m, 3H), 6.97 (d, J = 8.1 Hz, 2H), 6.74 (d, J = 8.9 Hz, 2H), 5.44
(d, J = 8.5 Hz, 1H), 4.77 (dd, J = 12.9, 2.8 Hz, 1H), 4.56 (d, J =
12.9 Hz, 1H), 3.04 (dd, J = 15.2, 2.7 Hz, 1H), 2.50 (dd, J =
15.2, 8.6 Hz, 1H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3): δ
170.8, 159.2, 147.0, 142.5, 141.6, 137.2, 129.5, 127.6, 127.3,
122.7, 122.4, 121.9, 121.5, 117.1, 113.0, 80.8, 60.5, 54.2, 39.8,
28.0; HRMS (ESI): Calcd for C26H28NO3 (M+ + H): 402.2069,
found 402.2072.
Specific experimental
tert-Butyl 2-(2-p-tolylisoindolin-1-yl)acetate (10a). Pale white
1
solid; 95% (307 mg) isolated yield; mp: 73–75 °C. H NMR
(400 MHz, CDCl3): δ 7.29–7.39 (m, 4H), 7.16 (d, J = 8.2 Hz,
2H), 6.70 (d, J = 8.2 Hz, 2H), 5.45 (d, J = 8.6 Hz, 1H), 4.76
(dd, J = 13.1, 2.9 Hz, 1H), 4.54 (d, J = 13.1 Hz, 1H), 3.06 (dd,
J = 15.3, 2.4 Hz, 1H), 2.47 (dd, J = 15.3, 8.6 Hz, 1H), 2.30 (s,
3H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 171.0, 143.5,
141.7, 137.4, 130.0, 127.5, 127.2, 125.5, 122.7, 122.4, 112.3,
80.7, 60.2, 53.9, 39.8, 28.0, 20.3; HRMS (ESI): Calcd for
C21H26NO2 (M+ + H): 324.1964, found 324.1967.
tert-Butyl 2-(2-(4-cyanophenyl)isoindolin-1-yl)acetate (10g).
Pale yellow oil; 91% (304 mg) isolated yield. 1H NMR
(500 MHz, CDCl3): δ 7.55 (d, J = 8.2 Hz, 2H), 7.32–7.36 (m,
4H), 6.71 (d, J = 8.2 Hz, 2H), 5.47 (d, J = 8.2 Hz, 1H),, 4.76 (d,
J = 13.5 Hz, 1H), 4.60 (d, J = 13.1 Hz, 1H), 2.93 (dd, J = 15.0,
1.6 Hz, 1H), 2.53 (dd, J = 15.0, 8.2 Hz, 1H), 1.39 (s, 9H); 13C
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NMR (125 MHz, CDCl3): δ 170.1, 148.3, 140.4, 136.0, 133.8,
128.1, 127.8, 122.7, 122.5, 120.5, 112.2, 98.3, 81.2, 60.4, 53.7,
39.6, 28.0; HRMS (ESI): Calcd for C21H23N2O2 (M+ + H):
335.1760, found 335.1776.
(400 MHz, CDCl3): δ 7.44 (d, J = 6.9 Hz, 2H), 7.25–7.33 (m,
3H), 7.12 (d, J = 8.3 Hz, 2H), 6.68 (d, J = 8.3 Hz, 2H),
5.67–5.69 (m, 1H), 4.76 (dd, J = 13.2, 2.8 Hz, 1H), 4.54 (d, J =
13.2 Hz, 1H), 3.05 (dd, J = 15.8, 2.8 Hz, 1H), 3,00 (s, 3H), 2.81
(s, 3H), 2.46 (dd, J = 15.5, 9.0 Hz, 1H), 2.29 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 171.1, 143.6, 142.6, 137.1, 130.0, 127.34,
127.27, 125.4, 123.2, 122.3, 112.3, 60.3, 53.9, 37.8, 37.2, 35.3,
20.2; HRMS (ESI): Calcd for C19H22N2ONa (M+ + Na):
317.1630, found 317.1642.
tert-Butyl 2-(2-(4-nitrophenyl)isoindolin-1-yl)acetate (10h).
Yellow solid; 94% (333 mg) isolated yield; mp: 143–146 °C. 1H
NMR (400 MHz, CDCl3): δ 8.19 (d, J = 9.3 Hz, 2H), 7.32–7.34
(m, 4H), 6.68 (d, J = 9.3 Hz, 2H), 5.50–5.53 (m, 1H), 4.81 (dd,
J = 13.7, 2.2 Hz, 1H), 4.66 (d, J = 13.7 Hz, 1H), 2.95 (dd, J =
15.4, 2.9 Hz, 1H), 2.59 (dd, J = 15.4, 8.2 Hz, 1H), 1.38 (s, 9H);
13C NMR (100 MHz, CDCl3): δ 169.9, 150.1, 140.1, 137.6,
135.7, 128.2, 127.9, 126.4, 122.7, 122.5, 111.1, 81.3, 60.7, 54.0,
39.6, 27.9; HRMS (ESI): Calcd for C20H23N2O4 (M+ + H):
355.1658, found 355.1666.
tert-Butyl 3-(2-((p-tolylamino)methyl)phenyl)acrylate (11).
1
Pale yellow oil. H NMR (500 MHz, CDCl3): δ 7.94 (d, J =
15.8 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.42 (d, J = 6.9 Hz, 1H),
7.28–7.34 (m, 2H), 6.99 (d, J = 8.3 Hz, 2H), 6.55 (d, J =
8.3 Hz, 2H), 6.33 (d, J = 15.8 Hz, 1H), 4.41 (s, 2H), 3.81 (brs,
1H), 2.24 (s, 3H), 1.51 (s, 9H); 13C NMR (125 MHz, CDCl3): δ
166.1, 145.6, 140.2, 138.2, 133.4, 129.9, 129.7, 128.9, 127.7,
127.0, 126.8, 122.2, 113.0, 80.6, 46.4, 28.1, 20.4. HRMS (ESI):
Calcd for C21H26NO2 (M+ + H): 324.1964, found 324.1968.
tert-Butyl 2-(2-tert-butylisoindolin-1-yl)acetate (10i). Pale
1
yellow oil; 88% (255 mg) isolated yield. H NMR (400 MHz,
CDCl3): δ 7.15–7.21 (m, 4H), 4.77 (d, J = 8.4 Hz, 1H),
4.13–4.24 (m, 2H), 2.76 (dd, J = 15.2, 2.7 Hz, 1H), 2.52 (dd,
J = 15.2, 8.6 Hz, 1H), 1.42 (s, 9H), 1.14 (s, 9H); 13C NMR
(100 MHz, CDCl3): δ 171.4, 143.7, 139.8, 126.8, 126.7, 122.4,
121.9, 80.1, 61.0, 54.6, 53.3, 46.7, 28.1, 26.9; HRMS (ESI):
Calcd for C18H28NO2 (M+ + H): 290.2120, found 290.2124.
tert-Butyl 3-(benzyl(2-bromobenzyl)amino)propanoate (12).
1
Pale yellow oil. H NMR (400 MHz, CDCl3): δ 7.17–7.31 (m,
9H), 3.53 (s, 4H), 2.74 (t, J = 8.0 Hz, 1H), 2.38 (t, J = 8.0 Hz,
1H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 172.0, 139.4,
128.8, 128.2, 126.9, 80.2, 58.0, 49.4, 33.9, 28.1. HRMS (ESI):
Calcd for C21H27 Br NO2 (M+ + H): 404.1225, found 404.1219.
Methyl 2-(2-p-tolylisoindolin-1-yl)acetate (10j). Pale yellow
oil; 90% isolated yield. 1H NMR (400 MHz, CDCl3): δ
7.28–7.34 (m, 4H), 7.13 (d, J = 8.3 Hz, 2H), 6.67 (d, J =
8.3 Hz, 2H), 5.46–5.49 (m, 1H), 4.75 (dd, J = 13.1, 3.1 Hz, 1H),
4.53 (d, J = 13.1 Hz, 1H), 3.72 (s, 3H), 3.15 (dd, J = 15.6,
2.9 Hz, 1H), 2.48 (dd, J = 15.6, 8.8 Hz, 1H), 2.29 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 172.1, 143.4, 141.5, 137.4, 130.1,
127.6, 127.3, 125.7, 122.5, 112.3, 60.0, 53.9, 51.7, 38.5, 20.3;
HRMS (ESI): Calcd for C18H20NO2 (M+ + H): 282.1494, found
282.1497.
Acknowledgements
This research was supported by the Ministry of Education,
Singapore (MOE2009-T2-2-065).
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1
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1
96% (310 mg) isolated yield. H NMR (400 MHz, CDCl3): δ
7.27–7.33 (m, 4H), 7.13 (d, J = 8.2 Hz, 2H), 6.68 (d, J =
8.2 Hz, 2H), 5.46–5.48 (m, 1H), 4.75 (dd, J = 13.1, 2.9 Hz, 1H),
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15.5, 2.8 Hz, 1H), 2.49 (dd, J = 15.5, 8.9 Hz, 1H), 2.29 (s, 3H),
1.56–1.63 (m, 2H), 1.31–1.40 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H);
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130.0, 127.6, 127.3, 125.6, 122.5, 122.4, 112.3, 64.4, 60.1, 53.9,
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