Palladium-Catalyzed Carbonylative Synthesis of Isoindolinones from Benzylamines with TFBen as the CO Source

Article abstract of DOI:10.1021/acs.joc.8b02862

A palladium-catalyzed C-H carbonylation of benzylamines for the synthesis of isoindolinone scaffolds has been developed. This protocol is conducted under gas-free conditions by using benzene-1,3,5-triyl triformate (TFBen) as a convenient CO surrogate, fur

Full text of DOI:10.1021/acs.joc.8b02862

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Article
Palladium-Catalyzed Carbonylative Synthesis of Isoindolinones
from Benzylamines with TFBen as the CO Source
Luyang Fu, Jun Ying, Xinxin Qi, Jin-Bao Peng, and Xiao-Feng Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02862 • Publication Date (Web): 08 Jan 2019
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The Journal of Organic Chemistry
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Palladium-Catalyzed Carbonylative Synthesis of Isoindolinones from
Benzylamines with TFBen as the CO Source
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Lu-Yang Fu,a Jun Ying,*a Xinxin Qi,a Jin-Bao Peng,a and Xiao-Feng Wu*a,b
a Department of Chemistry, Zhejiang Sci-Tech University, Xiasha Campus, Hangzhou 310018, People’s Republic of China
b Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Straβe 29a, 18059 Rostock, Germany.
Supporting Information Placeholder
R2
N
R2
R3
PdCl2, Cu(OAc)2
26 examples
up to 95% yield
R3
R1
N
R1
H
TFBen, toluene/DMSO, 110 °C
O
OCHO
Gas-free conditions
Broad substrate scope
High yields
OHCO
OCHO
TFBen
ABSTRACT: A palladium-catalyzed C-H carbonylation of benzylamines for the synthesis of isoindolinone scaffolds has been developed.
This protocol is conducted under gas-free conditions by using benzene-1,3,5-triyl triformate (TFBen) as a convenient CO surrogate,
furnishing a variety of isoindolinone derivatives in moderate to high yields (up to 95%).
Introduction
via C-H carbonylation of benzylamines using Pd(OAc)2 and
Cu(OAc)2 in an atmosphere of CO gas containing air (Scheme 2,
eq c).12 Very recently, Wang, Li and their co-workers developed a
palladium-catalyzed
benzylamine to synthesis the corresponding sterically hindered
benzolactams under atmospheric pressure of CO.13b
Isoindolinone scaffold is a class of important motif frequently
found in pharmaceuticals and bioactive natural products (Scheme
1).1 For instance, Lenalidomide is one of the novel drug agents
used to treat multiple myeloma.2 Pazinaclone shows excellent
sedative and anxiolytic properties by acting as a partial agonist at
GABA-A benzodiazepine receptors.3 Nuevamine, a representative
example of natural isoindolinone alkaloids, whose analogues
possess potential and promising biological activities such as anti-
inflammatory, anti-microbial, anti-tumoral and so on.4 Due to the
potent applications, many procedures have been developed for
their construction. The achieved methods include lactamization of
o-(aminomethyl)benzoic acids,5 monoreduction of phthalimides,6
Bischler-Napieralski-type cyclization of carbamates from
benzylamines,7 and metal-catalyzed carbonylation of benzylamine
derivatives.8-15
carbonylation
of
α,α-disubstituted
.
Scheme 1. Representative Pharmaceuticals and Natural
Products of Isoindolinones.
Cl
OMe
O
O
N
MeO
N
N
N
O
Nuevamine
N
Pazinaclone
O
O
O
O
O
Benzylamine is an attractive precursor to the establishment of
the isoindolinone core via carbonylation with carbon monoxide
(CO) or its surrogates in the presence of metal catalysts (Scheme
2). Over the past decades, tremendous work on metal-catalyzed
carbonylation of 2-aminomethylaryl halides or 2-aminomethylaryl
tosylates have been reported (Scheme 2, eq a).8-10 Recently, metal-
catalyzed direct C-H carbonylation of benzylamines have been
realized as well.11-15 Zhao and Shi disclosed a Ru(II)-catalyzed C-H
carbonylation of benzylamines with isocyanate as a CO source
(Scheme 2, eq b).11 In this reaction, oxalyl amide as a directing
group was required in the coordination of the Ru center and
activation of ortho-C-H of a benzylamine. Orito and co-workers
developed a synthetic protocol to the isoindolinone ring systems
N
O
O
NH
CO2H
Me
O
NH2
N
Indoprofen
Lenalidomide
O
MeO
OH
N
HOOC
OH
Erinacerin D
To avoid the use of flammable CO gas in carbonylative
reactions, various CO surrogates have been developed.16 Among
them, TFBen, developed by our group,17 is a solid, safe and
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convenient CO source. Herein, we report a Pd-catalyzed C-H
carbonylation of benzylamines with TFBen as the CO source,
producing a series of isoindolinones.
12
13d
14e
K2S2O8 as oxidant
Mo(CO)6 as CO source
HCOOH/Ac2O as CO source
0
57
67
1
2
3
4
5
6
7
8
aReaction conditions: 1a (0.5 mmol), TFBen (2.0 equiv), catalyst
(10 mol %), oxidant (1.5 equiv), Et3N (2.0 equiv), PivOH (2.0
equiv), solvent (2.2 mL), 110 oC, 20 h. bYields were determined by
Scheme 2. Carbonylative Synthesis of Isoindolinones from
Benzylamines.
c
GC with dodecane as an internal standard. Isolated yield.
dMo(CO)6 (1.0 equiv), DBU (2.0 equiv). HCOOH (2.0 equiv),
Ac2O (2.0 equiv), Et3N (2.0 equiv).
Carbonylation of substituted benzylamines
e
R
[M]
N
N
R
H
a)
[CO]
X
9
O
X = I, Br, Cl, OTs
With the optimal reaction conditions in hand, we began
exploring the scope of C-H carbonylation of benzylamines. First,
various substituted benzylamines were tested and the results were
summarized in Scheme 3. Benzylamines with electron-donating
substituents could undergo the reaction smoothly to give the
desired products 2b-2d in excellent yields (86-93%). It was found
that para-Me substituted benzylamine 1c gave the products 2c and
2c’ with a ratio of 1:2.6. The observed regioselectivity could be
attributed to the steric hindrance of C-H activation site. Other
tested functional groups including methoxy, fluoro and chloro can
be well tolerated as well and gave the corresponding products in
good yields 2e-2g. The reaction with electron-withdrawing
substituted benzylamines also afforded moderate to good yields
(51-86%) of products 2h-2j. Similar to 1c, the reaction with di-
substituted benzylamines provided two regiomers. A ratio of 1:3.7
in 89% yield was observed for the products 2k and 2k’ in the
reaction with di-Me substituted benzylamine. Di-OMe substituted
benzylamine gave the expected products 2l and 2l’ in 95% yield
with a ratio of 1:3.3. For compound 1m, the reaction proceeded
well to produce the regiomers 2m and 2m’ with 1:1.4 ratio in 92%
yield. Additionally, thiophene and pyridine analogue of amines
were tested as well, but very low yield of the desired products were
obtained. In the case of free benzylamine, mainly N-
benzylformamide was formed.
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C-H carbonylation of benzylamines
R2
N
R2
O
[Ru]
OA
N(iPr)2
R1
OA =
OA
N
R3
R1
b)
c)
N
C
O
H
O
O
R2
[Pd]
R1
N
N
O
R2
R1
H
CO (1 atm), Cu(OAc)2, air
This work
OCHO
R2
N
R2
R3
[Pd]
TFBen, oxidant
R3
R1
N
R1
H
OHCO
OCHO
O
TFBen
Results and Discussion
Initially, benzylamine 1a was chosen as a substrate for the model
reaction.13 After extensive study of the reaction conditions, the
desired isoindolinone product 2a was obtained in 83% yield in the
presence of PdCl2. The reaction employed TFBen as the CO
source and Cu(OAc)2 as the oxidant (Table 1, entry 1). The use of
other Pd catalysts instead of PdCl2 gave similar results (Table 1,
entries 2-5). Et3N and PivOH were likely to tune the acidity of the
reaction system and promote the activation of C-H bond. Without
the addition of Et3N and PivOH, the yield was remarkably
decreased to 47% (Table 1, entry 6). When toluene or DMSO was
used instead of their mixed solvent system, reduced yields of the
product 2a were achieved (Table 1, entry 7 and 8). Moreover, a
series of other oxidants were examined and the reaction gave much
lower yields or no product (Table 1, entries 9-12). Finally, using
other CO surrogates instead of TFBen decreased the reaction yield
(Table 1, entry 13 and 14). Here 2 equivalents of TFBen is needed
to maintain the CO concentration in the reaction media.
Scheme 3. Scope of Substituted Benzylamines.a
Table 1. Study on Reaction Conditions.a
PdCl2 (10 mol %)
Cu(OAc)2 (1.5 equiv)
Et3N (2.0 equiv)
Bu
N
H
N
Bu
+
TFBen
PivOH (2.0 equiv)
toluene/DMSO (10:1) (2.2 mL)
110 °C, 20 h
(2.0 equiv)
O
1a
2a
entry
1
variations from the standard conditions
none
yield (%)b
83 (81c)
63
2
3
4
5
Pd(PPh3)2Cl2 as catalyst
Pd(OAc)2 as catalyst
Pd(cinnamyl)Cl2 as catalyst
PdBr2 as catalyst
78
68
81
47
75
71
25
16
6
7
8
9
without Et3N and PivOH
toluene instead of mixed solvent
DMSO instead of mixed solvent
CuO as oxidant
10
11
Ag2O as oxidant
BQ as oxidant
10
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The Journal of Organic Chemistry
Then, a couple of N-substituted benzylamines were investigated
PdCl2 (10 mol %)
Cu(OAc)2 (1.5 equiv)
Et3N (2.0 equiv)
Bu
1
2
3
4
5
6
7
8
N
(Scheme 5). The reaction with N-linear alkyl substituents gave
moderate to good yields of products 2s and 2t. N-iPr substituted
benzylamine was converted to the isoindolinone product 2u in 57%
yield. Compounds with the carbocycle unit were successfully
transformed to the expected products 2v and 2w in high yields.
Also, the reaction with N-benzyl substituted benzylamine
proceeded well in an excellent yield (2x, 95%). For substrates
containing functional groups such as methoxyl and cyano, 64% and
43% yield of products 2y and 2z were achieved, respectively.
N
Bu
+
TFBen
H
PivOH (2.0 equiv)
toluene/DMSO (10:1) (2.2 mL)
110 °C, 20 h
(2.0 equiv)
R
R
O
1
2
O
O
O
O
N
N
N
Bu
N Bu
2c
2c'
b
2a,
81%; 85%
2b,
O
93%
89% (1 : 2.6)
O
N
O
O
F
9
N
N
10
11
12
13
14
15
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Scope of N-Substituted Benzylamines.a
2d,
PdCl2 (10 mol %)
86%
2e,
2f, 84%
83%
Cu(OAc)2 (1.5 equiv)
Et3N (2.0 equiv)
R
O
O
N
O
N
+
TFBen
N R
MeOOC
Cl
Br
H
PivOH (2.0 equiv)
toluene/DMSO (10:1) (2.2 mL)
110 °C, 20 h
N
(2.0 equiv)
N
O
1
2
2g,
86%
2h,
O
N
65%
O
O
2i,
O
75%
O
N
O
O
N
N
NC
N
N
N
2s,
50%
O
2t,
91%
2u,
57%
2v,
61%
2k
2k'
Bu
O
2j,
51%
O
89% (1 : 3.7)
O
N
N
Cy
N
O
O
O
CN
O
N
O
N
Ph
O
O
O
N
Bu
N
Bu
N
Bu
2w,
2x,
66%
95%
2z,
43%
2y,
64%
O
aReaction conditions: 1 (0.5 mmol), TFBen (2.0 equiv), PdCl2 (10
2m
2m'
2l'
2l
mol %), Cu(OAc)2 (1.5 equiv.), Et3N (2.0 equiv), PivOH (2.0
95% (1 : 3.3)
92% (1 : 1.4)
o
equiv), toluene/DMSO (10:1) (2.2 mL), 110 C, 20 h, isolated
aReaction conditions: 1 (0.5 mmol), TFBen (2.0 equiv), PdCl2 (10
mol %), Cu(OAc)2 (1.5 equiv), Et3N (2.0 equiv), PivOH (2.0
equiv), toluene/DMSO (10:1) (2.2 mL), 110 C, 20 h, isolated
yield. b 2 mmol scale.
yield.
o
In order to study the reaction rate of different substrates, electron
donating group and electron withdrawing group substituted
substrates 1b and 1g were selected and combined as 1:1 ratio.
Under our standard reaction conditions, the corresponding
products were obtained in almost the same ratio (Scheme 6).
Next, we turned our attention to the scope of α-substituted
benzylamines (Scheme 4). These compounds were prepared via
the condensation of ketones and amines and subsequent reduction
with NaBH4. For compounds bearing linear alkyl α-substituents,
the reaction afforded the corresponding products 2n and 2o in
excellent yields. The reaction with a compound having the
carbocycle unit gave the desired product 2p in 86% yield.
Interestingly, the substrate containing a tetrahydronaphthalene
system could undergo the C-H carbonylation to generate the
polycyclic product 2q in 52% yield. Additionally, a high yield of the
product 2r was obtained when benzylamines with aryl α-
substituent was subjected to the same condition.
Scheme 6. Reaction rate study.
O
H
N
N
2b
1b
46%
standard
+
conditions
Cl
+
O
H
N
Cl
2g
42%
N
1g
1b 1g
:
= 1 : 1
2b 2g
:
= 1 : 0.9
Scheme 4. Scope of α-Substituted Benzylamines.a
On the basis of previous reports,12-14 a plausible mechanism is
proposed to account for the C-H carbonylation of benzylamines
(Scheme 7). Initially, the Pd(II) catalyst coordinates with
benzylamine 1 and activates ortho-C-H bond to generate the five-
palladacycle A. Then, coordination of CO, generated in-situ from
TFBen, leads to the formation of the intermediate B. Subsequently,
CO insertion of B forms the acyl Pd(II) complex C, which can
undergo reductive elimination to give the final product 2 and a
Pd(0) species. Finally, oxidation of the Pd(0) species by Cu(II) salt
regenerates the active Pd(II) catalyst.
PdCl2 (10 mol %)
R
R
Cu(OAc)2 (1.5 equiv)
Et3N (2.0 equiv)
Bu
N
N
Bu
Bu
+
TFBen
H
PivOH (2.0 equiv)
toluene/DMSO (10:1) (2.2 mL)
110 °C, 20 h
(2.0 equiv)
O
2
1
O
O
O
N
O
O
N
Bu
N
Bu
Bu
N
Bu
N
Cy
Ph
2o,
2n,
93%
92%
2q,
2r,
81%
52%
2p,
86%
aReaction conditions: 1 (0.5 mmol), TFBen (2.0 equiv), PdCl2 (10
mol %), Cu(OAc)2 (1.5 equiv), Et3N (2.0 equiv), PivOH (2.0
equiv), toluene/DMSO (10:1) (2.2 mL), 110 C, 20 h, isolated
Scheme 7. Plausible Mechanism.
o
yield.
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Cu(I)
The mixture was stirred for 4 h in a water bath and then diluted
H
Pd(II)Ln
N
R
1
2
3
4
5
6
7
8
Cu(II)
with toluene (100 mL), washed with H2O (50 mL) two times.
1
o
Keep the organic phase in fridge (2-8 C) for overnight. Then
Pd(0)L(n-2)
O
filtered and dried in vacuo to afford the desired product benzene-
1,3,5-triyl triformate (TFBen) (5.1 g, 55%) as a white solid. mp
L(n-2)
Pd(II)
N
R
o
1
2
N R
53.2-55.6 C. H NMR (400 MHz, CDCl3) δ 8.24 (s, 3H), 6.97 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ = 158.1, 150.3, 112.6.
General Procedure for the Syntheses of the Secondary
Amines 1a-1m’ and 1t-1z19. To a solution of aldehyde (3 mmol,
1.0 equiv.) in MeOH (15 mL) at 0 °C was added primary amine
(3.6 mmol, 1.2 equiv.) slowly, and the reaction mixture was stirred
at 0 °C for 0.5 h, then at rt for 5 h. The reaction mixture was again
cooled to 0 °C, and NaBH4 (4.5 mmol, 1.5 equiv.) was added every
10 min in three portions. Then it was stirred at rt for 1h. The
reaction was quenched by the addition of H2O (10 mL) and
Na2CO3 (0.252 g). The reaction mixture was washed with CH2Cl2
(20 mL), then the organic phase was separated and aqueous phase
was further extracted with CH2Cl2 (20 mL  2). Combined organic
layer was dried over anhydrous Na2SO4, filtered, and concentrated.
The crude mixture was purified by flash column chromatography
on silica gel eluted with petroleum ether / ethyl acetate (2 / 1) to
give the secondary amine products 1a-1m’ and 1t-1z.
O
A
TFBen
Pd(II)L(n-2)
N
R
CO
C
CO
Pd(II)L(n-3)
9
10
11
12
13
14
15
16
17
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24
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N
R
B
Finally, a few functionalizations of the isoindolinone 2a have
been demonstrated as well (Scheme 8).18 Treatment of 2a with
lithium diisopropylamide (LDA) at -78 oC followed by the addition
of alkyl bromide can give the 3-substituted isoindolinones 3, an
important skeleton in biologically active compounds exhibiting
antipsychotic, antihypertensive, antiulcer and anxiolytic
properties.18a The reaction of 2a with allyl bromide and phenyl
bromide provided good yields of 3a (82%) and 3b (63%),
respectively. When 2a was treated with propargyl bromide, a lower
yield (37%) of 3c was obtained. Moreover, the alkyl group can be
removed easily as well.18b
General Procedure for the Syntheses of the Secondary
Amines 1n-1r20. Titanium(IV) isopropoxide (4 mmol, 1.3 equiv.)
was added to a solution of n-butylamine in MeOH (2 M, 4.5 mL, 3
equiv.) followed by the addition of the ketone (3 mmol, 1.0 equiv.).
The reaction mixture was stirred at rt for 5 h, after was cooled to 0
°C and NaBH4 (3 mmol, 1.0 equiv.) was added and the resulting
mixture was further stirred for 2 h. The reaction was then quenched
by the addition of water (1 mL), the resulting inorganic precipitate
was filtered and washed with CH2Cl2 (20 mL). The organic layer
was separated and the aqueous phase was further extracted with
CH2Cl2 (20 mL  2). The combined CH2Cl2 extracts were washed
with HCl (2 M, 10 mL  2). The acidic aqueous solution was made
alkaline (pH = 10) by slow addition of (10%, w / v) aqueous
NaOH and extracted with CH2Cl2 (20 mL  2). Combined organic
layer was dried over anhydrous Na2SO4, filtered, and concentrated.
The crude mixture was purified by flash column chromatography
on silica gel eluted with petroleum ether / ethyl acetate (10 / 1) to
give the secondary amine products 1n-1r.
Scheme 8. Functionalizations of the Isoindolinone 2a.
O
O
1) LDA (1.1 equiv), THF (2 mL)
-78 oC, 15 min
N
N
2) RBr (1.5 equiv), -78 oC to r.t., 2 h
3) H3O+
R
2a, 0.3 mmol
O
3
O
O
N
N
N
Ph
63%
3c,
37%
3b,
3a,
82%
In conclusion, we have developed a facile approach for the
synthesis of the isoindolinone skeleton via Pd-catalyzed C-H
carbonylation of benzylamines using TFBen as a convenient CO
source. The reaction proceeds smoothly with a wide range of
benzylamine substrates, affording various isoindolinone derivatives
in 43-95% yields.
1
N-benzylbutan-1-amine, 1a21. 455.1 mg, 93%, Pale yellow oil. H
NMR (400 MHz, CDCl3) δ 7.31 (d, J = 4.3 Hz, 4H), 7.24 (dd, J =
8.0, 4.0 Hz, 1H), 3.78 (s, 2H), 2.62 (t, J = 7.2 Hz, 2H), 1.54 (s,
1H), 1.48 (dd, J = 14.8, 7.5 Hz, 2H), 1.40 – 1.29 (m, 2H), 0.91 (t, J
13
= 7.3 Hz, 3H). C{1H} NMR (101 MHz, CDCl3) δ 140.4, 128.2,
EXPERIMENTAL SECTION
Unless otherwise noted, all reactions were carried out under a
nitrogen atmosphere. All reagents and 1s were obtained from
commercial sources and used as received without further
purification. Column chromatography was performed on silica gel
(200−300 mesh) using petroleum ether (bp 60−90 °C) and ethyl
acetate as eluent. 1H and 13C NMR spectra were taken on 400 MHz
instruments, and spectral data were reported in ppm relative to
tetramethylsilane (TMS) as internal standard and CDCl3 as
solvent.
127.9, 126.7, 53.9, 49.1, 32.1, 20.4, 13.9.
N-(4-methylbenzyl)butan-1-amine, 1b21. 488.4 mg, 92%, Pale
yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 8.0 Hz, 2H),
7.12 (d, J = 7.8 Hz, 2H), 3.74 (s, 2H), 2.68 – 2.56 (m, 2H), 2.32 (s,
3H), 1.62 (s, 1H), 1.49 (dt, J = 14.5, 7.1 Hz, 2H), 1.34 (dq, J =
14.5, 7.3 Hz, 2H), 0.90 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 137.4, 136.3, 128.9, 128.0, 53.7, 49.0, 32.1, 20.9,
20.4, 13.9.
N-(3-methylbenzyl)butan-1-amine, 1c. 504.5 mg, 95%, Pale
yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.21 (td, J = 7.5, 2.8 Hz,
1H), 7.17 – 7.08 (m, 2H), 7.05 (d, J = 7.2 Hz, 1H), 3.75 (s, 2H),
2.63 (t, J = 7.0 Hz, 2H), 2.34 (d, J = 2.5 Hz, 3H), 1.77 (s, 1H), 1.57
– 1.43 (m, 2H), 1.42 – 1.27 (m, 2H), 0.91 (td, J = 7.3, 2.8 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 140.2, 137.9, 128.9, 128.2,
Preparation of Benzene-1,3,5-triyl triformate (TFBen)17.
Formic acid (8.4 mL, 222.8 mmol, 5.0 equiv.) was added to acetic
anhydride (16.8 mL, 178.2 mmol, 4.0 equiv.) at rt. The mixture was
stirred at 60 C for 1 h and cooled to rt. The resulting solution was
poured into a flask containing 1,3,5-trihydroxybenzene (5.62 g,
44.6 mmol, 1.0 equiv.) and AcONa (1.83 g, 22.3 mmol, 0.5 equiv.).
o
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The Journal of Organic Chemistry
127.6, 125.1, 53.9, 49.1, 32.1, 21.3, 20.4, 13.9. HRMS (ESI-TOF):
147.8, 133.2, 120.0, 111.3, 110.9, 55.8, 55.7, 53.7, 49.0, 32.1, 20.3,
13.8.
[M+H+] calcd. for C12H20N+, 178.1590; found, 178.1595.
1
2
3
N-(2-methylbenzyl)butan-1-amine, 1d21. 472.6 mg, 89%, Pale
N-(naphthalen-2-ylmethyl)butan-1-amine, 1m25. 517.6 mg, 81%,
1
1
yellow oil. H NMR (400 MHz, CDCl3) δ 7.34 – 7.25 (m, 1H),
Yellow oil. H NMR (400 MHz, CDCl3) δ 7.82 – 7.75 (m, 3H),
7.20 – 7.08 (m, 3H), 3.75 (s, 2H), 2.75 – 2.58 (m, 2H), 2.34 (s,
3H), 1.51 (dt, J = 14.6, 7.1 Hz, 2H), 1.36 (dq, J = 14.4, 7.2 Hz, 3H),
0.92 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
138.5, 136.1, 130.2, 128.2, 126.8, 125.8, 51.6, 49.5, 32.3, 20.5, 18.9,
13.9.
N-(4-methoxybenzyl)butan-1-amine, 1e21. 526.8 mg, 91%, Pale
yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.25 (dd, J = 8.8, 6.1 Hz,
2H), 6.88 – 6.82 (m, 2H), 3.78 (s, 3H), 3.72 (s, 2H), 2.66 – 2.56
(m, 2H), 1.78 (s, 1H), 1.49 (dt, J = 20.2, 7.1 Hz, 2H), 1.34 (dq, J =
14.3, 7.2 Hz, 2H), 0.94 – 0.84 (m, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 158.6, 132.5, 129.2, 113.7, 55.2, 53.3, 48.9, 32.1, 20.4,
13.9.
7.73 (s, 1H), 7.46 – 7.37 (m, 3H), 3.91 (s, 2H), 2.68 – 2.59 (m,
2H), 1.50 (dt, J = 14.7, 7.2 Hz, 3H), 1.39 – 1.29 (m, 2H), 0.90 (t, J
= 7.3 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 138.0, 133.4,
132.5, 127.9, 127.6, 127.5, 126.5, 126.3, 125.8, 125.3, 54.1, 49.1,
32.2, 20.4, 13.9.
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5
6
7
8
9
N-(1-phenylethyl)butan-1-amine, 1n20. 456.7 mg, 86%, Pale
1
yellow oil. H NMR (400 MHz, CDCl3) δ 7.36 – 7.27 (m, 4H),
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7.23 (ddd, J = 11.3, 5.4, 2.8 Hz, 1H), 3.75 (q, J = 6.6 Hz, 1H), 2.57
– 2.36 (m, 2H), 1.52 – 1.39 (m, 3H), 1.36 – 1.33 (m, 3H), 1.29
(tdd, J = 9.8, 7.4, 2.1 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 145.9, 128.3, 126.7, 126.5, 58.4, 47.5,
32.4, 24.3, 20.5, 13.9.
N-(4-fluorobenzyl)butan-1-amine, 1f21. 445.3 mg, 82%, Pale
yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.28 (dd, J = 8.2, 5.6 Hz,
2H), 6.99 (t, J = 8.7 Hz, 2H), 3.74 (s, 2H), 2.61 (t, J = 7.2 Hz, 2H),
1.49 (dt, J = 14.5, 7.1 Hz, 3H), 1.34 (dq, J = 14.3, 7.2 Hz, 2H), 0.91
(t, J = 7.3 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 161.9 (d, J
= 245.2 Hz), 136.3, 129.6 (d, J = 7.9 Hz), 115.1 (d, J = 20.8 Hz),
53.3, 49.1, 32.2, 20.4, 13.9.
N-butyl-1-phenylbutan-1-amine, 1o. 516.6 mg, 84%, Pale yellow
oil. 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.18 (m, 5H), 3.55 (dd, J
= 7.7, 6.2 Hz, 1H), 2.47 – 2.33 (m, 2H), 1.69 (ddt, J = 11.9, 10.3,
5.9 Hz, 1H), 1.64 – 1.53 (m, 1H), 1.41 (tdd, J = 9.2, 7.6, 3.5 Hz,
2H), 1.33 – 1.20 (m, 3H), 1.21 – 1.09 (m, 1H), 0.86 (td, J = 7.3, 2.9
Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 144.7, 128.2, 127.1,
126.7, 63.3, 47.4, 40.5, 32.4, 20.4, 19.5, 14.0, 13.9. HRMS (ESI-
TOF): [M+H+] calcd. for C14H24N+, 206.1903; found, 206.1910.
N-(cyclohexyl(phenyl)methyl)butan-1-amine, 1p. 551.2 mg, 75%,
N-(4-Chlorobenzyl)butan-1-amine, 1g22. 520.0 mg, 88%, Pale
1
yellow oil. H NMR (400 MHz, CDCl3) δ 7.37 – 7.14 (m, 1H),
1
3.74 (s, 1H), 2.73 – 2.44 (m, 1H), 1.48 (dt, J = 14.5, 7.1 Hz, 2H),
1.42 (s, 1H), 1.34 (dq, J = 14.3, 7.2 Hz, 1H), 0.91 (t, J = 7.3 Hz,
1H). 13C{1H} NMR (101 MHz, CDCl3) δ 139.1, 132.4, 129.3,
128.4, 53.3, 49.1, 32.2, 20.4, 13.9.
N-(4-Bromobenzyl)butan-1-amine, 1h21. 643.4 mg, 89%, Pale
yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.3 Hz, 2H),
7.20 (d, J = 8.3 Hz, 2H), 3.73 (s, 2H), 2.60 (t, J = 7.2 Hz, 2H), 1.57
(s, 1H), 1.53 – 1.42 (m, 2H), 1.34 (dq, J = 14.3, 7.2 Hz, 2H), 0.90
(t, J = 7.3 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 139.5,
131.3, 129.8, 120.6, 53.3, 49.0, 32.1, 20.4, 13.9.
Pale yellow oil. H NMR (400 MHz, CDCl3) δ 7.33 – 7.26 (m,
2H), 7.24 – 7.19 (m, 3H), 3.31 (d, J = 7.1 Hz, 1H), 2.35 (td, J = 7.4,
1.9 Hz, 2H), 1.99 – 1.88 (m, 1H), 1.77 – 1.69 (m, 1H), 1.61 (dt, J =
8.8, 7.9 Hz, 2H), 1.55 – 1.46 (m, 2H), 1.44 – 1.35 (m, 3H), 1.34 –
1.18 (m, 3H), 1.17 – 1.04 (m, 2H), 1.01 – 0.90 (m, 1H), 0.87 –
0.79 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 143.4, 128.0,
127.8, 126.5, 69.0, 47.7, 44.3, 32.4, 30.4, 29.9, 26.6, 26.4, 26.3, 20.4,
13.9. HRMS (ESI-TOF): [M+H+] calcd. for C17H28N+, 246.2216;
found, 246.2222.
N-butyl-1,2,3,4-tetrahydronaphthalen-1-amine, 1q. 444.6 mg,
Methyl 4-((butylamino)methyl)benzoate, 1i23. 590.1 mg, 89, Pale
yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.1 Hz, 2H),
7.39 (d, J = 8.1 Hz, 2H), 3.90 (s, 3H), 3.84 (s, 2H), 2.62 (t, J = 7.1
Hz, 2H), 1.55 – 1.44 (m, 3H), 1.35 (dq, J = 14.3, 7.2 Hz, 2H), 0.91
(t, J = 7.3 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.9,
145.9, 129.6, 128.7, 127.8, 53.6, 51.9, 49.2, 32.2, 20.4, 13.9.
4-((Butylamino)methyl)benzonitrile, 1j23. 423.0 mg, 75%, Pale
yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.2 Hz, 2H),
7.45 (d, J = 8.2 Hz, 2H), 3.85 (s, 2H), 2.61 (t, J = 7.1 Hz, 2H), 1.54
– 1.45 (m, 2H), 1.44 (s, 1H), 1.36 (dq, J = 14.3, 7.2 Hz, 2H), 0.91
73%, Yellow oil. H NMR (400 MHz, CDCl3) δ 7.36 – 7.30 (m,
1
1H), 7.19 – 7.09 (m, 2H), 7.09 – 7.03 (m, 1H), 3.74 (t, J = 4.9 Hz,
1H), 2.85 – 2.60 (m, 4H), 2.02 – 1.89 (m, 1H), 1.85 (dt, J = 3.5, 3.1
Hz, 2H), 1.78 – 1.66 (m, 1H), 1.54 – 1.44 (m, 2H), 1.44 – 1.31 (m,
13
2H), 1.23 (s, 1H), 0.92 (dd, J = 7.8, 6.8 Hz, 3H). C{1H} NMR
(101 MHz, CDCl3) δ 139.5, 137.3, 128.9, 128.6, 126.5, 125.6, 55.4,
47.1, 32.7, 29.3, 28.4, 20.5, 18.9, 13.9. HRMS (ESI-TOF): [M+H+]
calcd. for C14H22N+, 204.1747; found, 204.1754.
N-benzhydrylbutan-1-amine, 1r20. 473.2 mg, 66%, Pale yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 7.6 Hz, 4H), 7.27 (t, J =
7.6 Hz, 4H), 7.17 (t, J = 7.3 Hz, 2H), 4.80 (s, 1H), 2.56 (t, J = 7.1
Hz, 2H), 1.49 (dq, J = 14.5, 7.1 Hz, 3H), 1.39 – 1.28 (m, 2H), 0.88
13
(t, J = 7.3 Hz, 3H). C{1H} NMR (101 MHz, CDCl3) δ 146.3,
132.1, 128.5, 118.9, 110.6, 53.5, 49.2, 32.2, 20.3, 13.9.
13
N-(3,4-dimethylbenzyl)butan-1-amine, 1k. 504.2 mg, 88%, Pale
yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.08 (d, J = 7.8 Hz, 2H),
7.03 (d, J = 7.7 Hz, 1H), 3.71 (s, 2H), 2.67 – 2.56 (m, 2H), 2.25 (s,
3H), 2.24 (s, 3H), 1.49 (dt, J = 20.1, 7.2 Hz, 3H), 1.34 (dq, J =
(t, J = 7.3 Hz, 3H). C{1H} NMR (101 MHz, CDCl3) δ 144.4,
128.4, 127.2, 126.8, 67.6, 47.9, 32.4, 20.4, 13.9.
N-benzylpropan-1-amine, 1t12b. 421.8 mg, 95%, Pale yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.30 (dd, J = 10.1, 2.8 Hz, 4H),
7.27 – 7.20 (m, 1H), 3.78 (s, 2H), 2.65 – 2.52 (m, 2H), 1.58 – 1.48
(m, 2H), 1.44 (s, 1H), 0.92 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 140.5, 128.3, 128.0, 126.7, 53.9, 51.3, 23.1, 11.7.
N-benzylpropan-2-amine, 1u26. 388.8 mg, 87%, Pale yellow oil. 1H
NMR (400 MHz, CDCl3) δ 7.31 (d, J = 4.5 Hz, 4H), 7.27 – 7.20
(m, 1H), 3.78 (s, 2H), 2.85 (hept, J = 6.2 Hz, 1H), 1.42 (s, 1H),
1.09 (d, J = 6.2 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ
140.8, 128.3, 128.0, 126.8, 51.6, 48.0, 22.9.
13
14.3, 7.2 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H). C{1H} NMR (101
MHz, CDCl3) δ 137.9, 136.4, 134.9, 129.5, 129.5, 125.5, 53.8, 49.2,
32.2, 20.5, 19.6, 19.3, 13.9. HRMS (ESI-TOF): [M+H+] calcd. for
C13H22N+, 192.1747; found, 192.1753.
N-(3,4-dimethoxybenzyl)butan-1-amine, 1l24. 568.6 mg, 85%, Pale
yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.89 (s, 1H), 6.87 – 6.79
(m, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 3.73 (s, 2H), 2.63 (t, J = 7.2
Hz, 2H), 1.50 (dt, J = 14.6, 7.1 Hz, 3H), 1.40 – 1.30 (m, 2H), 0.91
(t, J = 7.3 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 148.8,
N-benzylcyclopentanamine, 1v27. 435.7 mg, 83%, Pale yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.34 – 7.28 (m, 4H), 7.26 – 7.20
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(m, 1H), 3.76 (s, 2H), 3.11 (p, J = 6.7 Hz, 1H), 1.90 – 1.78 (m,
Page 6 of 10
49.6, 42.0, 30.5, 21.2, 19.9, 13.7. HRMS (ESI-TOF): [M+Na+]
calcd. for C13H17NNaO+, 226.1202; found, 226.1205.
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5
6
7
8
2H), 1.75 – 1.64 (m, 2H), 1.63 – 1.44 (m, 3H), 1.37 (qd, J = 8.0,
1.5 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 140.7, 128.3,
128.1, 126.7, 59.1, 52.7, 33.1, 24.0.
2-butyl-7-methylisoindolin-1-one, 2c. 25.4 mg, 25% yield, colorless
oil. 1H NMR (400 MHz, CDCl3) δ 7.37 (t, J = 7.5 Hz, 1H), 7.23 (d,
J = 7.5 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H), 4.31 (s, 2H), 3.59 (t, J =
7.3 Hz, 2H), 2.73 (s, 3H), 1.63 (dd, J = 14.8, 7.6 Hz, 2H), 1.45 –
N-benzylcyclohexanamine, 1w27. 504.6 mg, 89%, Pale yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 4.4 Hz, 4H), 7.27 –
7.20 (m, 1H), 3.80 (s, 2H), 2.48 (tt, J = 10.1, 3.7 Hz, 1H), 1.99 –
1.85 (m, 2H), 1.78 – 1.68 (m, 2H), 1.66 – 1.55 (m, 1H), 1.42 (s,
1.32 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). C{1H} NMR (101 MHz,
13
CDCl3) δ 169.3, 141.6, 137.5, 130.5, 130.1, 129.9, 119.9, 49.3, 41.9,
30.5, 20.1, 17.1, 13.7. HRMS (ESI-TOF): [M+Na+] calcd. for
C13H17NNaO+, 226.1202; found, 226.1205.
13
1H), 1.32 – 1.06 (m, 5H). C{1H} NMR (101 MHz, CDCl3) δ
140.9, 128.3, 128.0, 126.7, 56.2, 51.0, 33.5, 26.2, 24.9.
9
1
Dibenzylamine, 1x27. 531.9 mg, 90%, Pale yellow oil. H NMR
2-butyl-5-methylisoindolin-1-one, 2c’. 65.0 mg, 64% yield,
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1
(400 MHz, CDCl3) δ 7.31 (dd, J = 7.9, 5.2 Hz, 7H), 7.27 – 7.19 (m,
2H), 3.79 (s, 4H), 1.71 (s, 1H). 13C{1H} NMR (101 MHz, CDCl3)
δ 140.3, 128.3, 128.1, 126.9, 53.1.
colorless oil. H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.7 Hz,
1H), 7.24 (d, J = 9.6 Hz, 2H), 4.32 (s, 2H), 3.60 (t, J = 7.4 Hz, 2H),
2.44 (s, 3H), 1.69 – 1.58 (m, 2H), 1.44 – 1.32 (m, 2H), 0.95 (t, J =
7.4 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.5, 141.5,
141.5, 130.5, 128.9, 123.3, 123.0, 49.6, 41.9, 30.5, 21.7, 19.9, 13.7.
HRMS (ESI-TOF): [M+Na+] calcd. for C13H17NNaO+, 226.1202;
found, 226.1207.
N-benzyl-2-methoxyethan-1-amine, 1y28. 351.4 mg, 71%, Pale
1
yellow oil. H NMR (400 MHz, CDCl3) δ 7.35 – 7.28 (m, 4H),
7.27 – 7.21 (m, 1H), 3.81 (s, 2H), 3.53 – 3.48 (m, 2H), 3.35 (s,
3H), 2.83 – 2.77 (m, 2H), 1.80 (s, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 140.2, 128.3, 128.1, 126.9, 72.0, 58.7, 53.9, 48.7.
2-butyl-4-methylisoindolin-1-one, 2d. 87.3 mg, 86% yield, colorless
oil. 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.4 Hz, 1H), 7.36 (t,
J = 7.5 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 4.27 (s, 2H), 3.63 (t, J =
7.3 Hz, 2H), 2.34 (s, 3H), 1.70 – 1.62 (m, 2H), 1.44 – 1.33 (m,
2H), 0.96 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
168.8, 139.9, 132.7, 132.2, 131.8, 128.1, 121.0, 49.0, 42.0, 30.5,
20.0, 17.4, 13.7. HRMS (ESI-TOF): [M+Na+] calcd. for
C13H17NNaO+, 226.1202; found, 226.1209.
3-(benzylamino)propanenitrile, 1z29. 297.6 mg, 62%, Pale yellow
1
oil. H NMR (400 MHz, CDCl3) δ 7.36 – 7.28 (m, 4H), 7.27 –
7.19 (m, 1H), 3.79 (s, 2H), 2.86 (td, J = 6.6, 2.6 Hz, 2H), 2.44 (td, J
= 6.6, 2.6 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 139.3,
128.3, 127.8, 126.9, 118.6, 52.8, 44.1, 18.5.
General Procedure for Carbonylative Synthesis of
Isoindolinone from Benzylamines. PdCl2 (0.05 mmol, 10
mol%), Cu(OAc)2 (0.75 mmol, 1.5 equiv.), and a 2.5 mL vial
containing TFBen (1.0 mmol, 2.0 equiv.) were added to an oven-
dried tube (15 mL) which was then placed under vacuum and
refilled with nitrogen three times. An amine 1 (0.5 mmol, 1.0
equiv.), PivOH (1.0 mmol, 2.0 equiv.), Et3N (1.0 mmol, 2.0
equiv.), toluene (2.0 mL) and DMSO (0.2 mL) were added into
2-butyl-6-methoxyisoindolin-1-one, 2e. 90.9 mg, 83% yield,
1
colorless oil. H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 2.4 Hz,
1H), 7.31 (d, J = 8.7 Hz, 1H), 7.08 (dd, J = 8.2, 2.4 Hz, 1H), 4.30
(s, 2H), 3.86 (s, 3H), 3.61 (t, J = 7.3 Hz, 2H), 1.69 – 1.60 (m, 2H),
1.43 – 1.33 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 168.4, 159.9, 134.4, 133.2, 123.3, 119.4, 106.4, 55.6, 49.4,
42.2, 30.5, 19.9, 13.7. HRMS (ESI-TOF): [M+H+] calcd. for
o
the tube via syringe. The tube was sealed and stirred at 110 C for
+
20 h. Upon the reaction was completed, the mixture was diluted
with EtOAc and washed with water three times. The crude mixture
was purified by silica gel column chromatography (PE/EtOAc =
5/1 to 2/1) to obtain the desired products 2.
C13H18NO2 , 220.1332; found, 220.1341.
2-butyl-6-fluoroisoindolin-1-one, 2f. 86.9 mg, 84% yield, colorless
1
oil. H NMR (400 MHz, CDCl3) δ 7.50 (dd, J = 7.7, 2.4 Hz, 1H),
7.40 (dd, J = 8.2, 4.5 Hz, 1H), 7.22 (td, J = 8.7, 2.4 Hz, 1H), 4.35 (s,
2H), 3.61 (t, J = 7.4 Hz, 2H), 1.72 – 1.57 (m, 2H), 1.46 – 1.30 (m,
2H), 0.96 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
167.4 (d, J = 3.4 Hz), 162.9 (d, J = 244.7 Hz), 136.4 (d, J = 2.3 Hz),
135.2 (d, J = 9.4 Hz), 124.1 (d, J = 8.3 Hz), 118.6 (d, J = 23.6 Hz),
110.3 (d, J = 23.5 Hz), 49.4, 42.2, 30.4, 19.9, 13.6. HRMS (ESI-
TOF): [M+Na+] calcd. for C12H14FNNaO+, 230.0952; found,
230.0958.
Procedure for 2 mmol scale: PdCl2 (10 mol%), Cu(OAc)2 (1.5
equiv.), and a 5 mL vial containing TFBen (2.0 equiv.) were added
to an oven-dried tube (25 mL) which was then placed under
vacuum and refilled with nitrogen three times. An amine 1 (2
mmol, 1.0 equiv.), PivOH (2.0 equiv.), Et3N (2.0 equiv.), toluene
(8.0 mL) and DMSO (0.8 mL) were added into the tube via
o
syringe. The tube was sealed and stirred at 110 C for 20 h. Upon
the reaction was completed, the mixture was diluted with EtOAc
and washed with water three times. The crude mixture was purified
by silica gel column chromatography (PE/EtOAc = 5/1 to 2/1) to
obtain the desired products 2.
2-butyl-6-chloroisoindolin-1-one, 2g. 95.9 mg, 86% yield, white
solid, mp 59.5-61.4 oC. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J =
1.4 Hz, 1H), 7.47 (dd, J = 8.0, 1.9 Hz, 1H), 7.37 (d, J = 8.1 Hz,
1H), 4.35 (s, 2H), 3.60 (t, J = 7.4 Hz, 2H), 1.70 – 1.58 (m, 2H),
2-butylisoindolin-1-one, 2a12b. 76.6 mg, 81% yield (2 mmol scale,
85% yield, 321.3 mg), colorless oil. 1H NMR (400 MHz, CDCl3) δ
7.84 (d, J = 7.3 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.2 Hz,
2H), 4.37 (s, 2H), 3.62 (t, J = 7.4 Hz, 2H), 1.72 – 1.59 (m, 2H),
1.43 – 1.31 (m, 2H), 1.01 – 0.91 (m, 3H). C{1H} NMR (101
13
MHz, CDCl3) δ 166.9, 139.1, 134.8, 134.1, 131.1, 123.8, 123.6,
49.4, 42.1, 30.3, 19.9, 13.6. HRMS (ESI-TOF): [M+Na+] calcd. for
C12H14ClNNaO+, 246.0656; found, 246.0660.
13
1.45 – 1.32 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). C{1H} NMR (101
6-bromo-2-butylisoindolin-1-one, 2h. 86.8 mg, 65% yield, white
solid, mp 60.3-64.5 oC. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J =
1.6 Hz, 1H), 7.62 (dd, J = 8.0, 1.8 Hz, 1H), 7.32 (d, J = 8.1 Hz,
1H), 4.33 (s, 2H), 3.60 (t, J = 7.4 Hz, 2H), 1.69 – 1.60 (m, 2H),
MHz, CDCl3) δ 168.3, 141.0, 133.0, 130.9, 127.8, 123.5, 122.5,
49.8, 42.0, 30.4, 19.9, 13.7.
2-butyl-6-methylisoindolin-1-one, 2b. 94.5 mg, 93% yield, colorless
oil. 1H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 7.31 (s, 2H), 4.32
(s, 2H), 3.60 (t, J = 7.3 Hz, 2H), 2.43 (s, 3H), 1.68 – 1.58 (m, 2H),
13
1.43 – 1.32 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). C{1H} NMR (101
MHz, CDCl3) δ 166.9, 139.6, 135.1, 133.9, 126.7, 124.2, 121.9,
49.5, 42.2, 30.3, 19.9, 13.6. HRMS (ESI-TOF): [M+Na+] calcd. for
C12H14BrNNaO+, 290.0151; found, 290.0157.
13
1.44 – 1.32 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). C{1H} NMR (101
MHz, CDCl3) δ 168.5, 138.2, 137.8, 133.2, 131.9, 123.8, 122.2,
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The Journal of Organic Chemistry
methyl 2-butyl-3-oxoisoindoline-5-carboxylate, 2i. 92.7 mg, 75%
(s, 1H), 7.59 – 7.48 (m, 2H), 4.49 (s, 2H), 3.66 (t, J = 7.4 Hz, 2H),
1.73 – 1.64 (m, 2H), 1.46 – 1.35 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 168.2, 136.1, 135.0, 132.9,
131.0, 129.5, 127.9, 127.4, 126.2, 123.7, 121.4, 49.6, 42.4, 30.3,
20.1, 13.8. HRMS (ESI-TOF): [M+Na+] calcd. for C16H17NNaO+,
262.1202; found, 262.1208.
yield, white solid, mp 59.3-62.9 oC. 1H NMR (400 MHz, CDCl3) δ
8.49 (s, 1H), 8.22 (dd, J = 7.9, 1.5 Hz, 1H), 7.52 (d, J = 7.9 Hz,
1H), 4.44 (s, 2H), 3.95 (s, 3H), 3.63 (t, J = 7.4 Hz, 2H), 1.72 – 1.59
(m, 2H), 1.45 – 1.33 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 167.4, 166.3, 145.5, 133.5, 132.3,
130.4, 124.9, 122.7, 52.2, 49.9, 42.1, 30.4, 20.0, 13.7. HRMS (ESI-
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5
6
7
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2-butyl-3-methylisoindolin-1-one, 2n30. 93.4 mg, 92% yield,
+
1
TOF): [M+Na+] calcd. for C14H17NNaO3 , 270.1101; found,
colorless oil. H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.5 Hz,
270.1106.
1H), 7.52 (t, J = 7.4 Hz, 1H), 7.43 (dd, J = 12.2, 7.5 Hz, 2H), 4.55
(q, J = 6.7 Hz, 1H), 3.96 (dt, J = 14.1, 8.1 Hz, 1H), 3.21 (ddd, J =
10.6, 8.5, 5.2 Hz, 1H), 1.70 – 1.52 (m, 2H), 1.46 (dd, J = 6.7, 3.2
Hz, 3H), 1.43 – 1.32 (m, 2H), 0.95 (td, J = 7.3, 3.1 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 167.8, 146.8, 132.0, 131.1,
127.9, 123.4, 121.7, 55.2, 39.4, 30.4, 20.1, 18.0, 13.7.
2-butyl-3-oxoisoindoline-5-carbonitrile, 2j. 54.6 mg, 51% yield,
9
o
1
white solid, mp 102.6-105.7 C. H NMR (400 MHz, CDCl3) δ
8.11 (s, 1H), 7.80 (dd, J = 7.8, 1.3 Hz, 1H), 7.59 (d, J = 7.8 Hz,
1H), 4.47 (s, 2H), 3.64 (t, J = 7.4 Hz, 2H), 1.71 – 1.56 (m, 2H),
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49
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52
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58
59
60
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1.49 – 1.31 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). C{1H} NMR (101
MHz, CDCl3) δ 166.2, 145.3, 134.4, 134.2, 127.6, 123.8, 118.1,
112.3, 49.9, 42.2, 30.3, 19.9, 13.6. HRMS (ESI-TOF): [M+H+]
calcd. for C13H15N2O+, 215.1179; found, 215.1187.
2-butyl-3-propylisoindolin-1-one, 2o31. 107.5 mg, 93% yield,
1
colorless oil. H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.3 Hz,
1H), 7.54 – 7.48 (m, 1H), 7.42 (t, J = 7.4 Hz, 2H), 4.60 (dd, J = 5.1,
3.7 Hz, 1H), 4.02 (dt, J = 13.9, 8.0 Hz, 1H), 3.09 (ddd, J = 13.8, 8.4,
5.2 Hz, 1H), 2.08 – 1.82 (m, 2H), 1.76 – 1.47 (m, 2H), 1.46 – 1.31
(m, 2H), 1.16 – 1.01 (m, 1H), 0.95 (t, J = 7.4 Hz, 3H), 0.90 – 0.73
(m, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.2, 145.1, 132.7,
130.9, 127.7, 123.3, 121.8, 58.8, 39.3, 32.5, 30.3, 20.0, 15.6, 13.8,
13.6.
2-butyl-6,7-dimethylisoindolin-1-one, 2k. 20.6 mg, 19% yield,
o
1
white solid, mp 44.6-46.3 C. H NMR (400 MHz, CDCl3) δ 7.26
(d, J = 7.6 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 4.25 (s, 2H), 3.58 (t, J
= 7.3 Hz, 2H), 2.69 (s, 3H), 2.32 (s, 3H), 1.68 – 1.56 (m, 2H), 1.38
13
(dq, J = 14.6, 7.3 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H). C{1H} NMR
(101 MHz, CDCl3) δ 169.6, 139.3, 137.1, 136.3, 132.1, 129.9,
119.5, 48.7, 42.0, 30.5, 20.1, 19.2, 13.8, 12.8. HRMS (ESI-TOF):
[M+H+] calcd. for C14H20NO+, 218.1539; found, 218.1552.
2-butyl-5,6-dimethylisoindolin-1-one, 2k’. 76.0 mg, 70% yield,
2-butyl-3-cyclohexylisoindolin-1-one, 2p. 116.6 mg, 86% yield,
1
colorless oil. H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.4 Hz,
1H), 7.53 – 7.39 (m, 3H), 4.42 (d, J = 3.1 Hz, 1H), 4.11 – 3.99 (m,
1H), 3.12 (ddd, J = 13.8, 8.6, 5.0 Hz, 1H), 2.01 (tq, J = 12.1, 2.9 Hz,
1H), 1.84 (t, J = 12.9 Hz, 2H), 1.70 – 1.48 (m, 5H), 1.42 – 1.24 (m,
4H), 1.23 – 1.01 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H), 0.42 (qd, J =
12.6, 3.4 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.4,
143.8, 133.2, 130.5, 127.7, 123.4, 123.0, 63.8, 39.7, 39.5, 30.2, 29.7,
26.8, 26.3, 25.9, 25.7, 20.1, 13.7. HRMS (ESI-TOF): [M+H+]
calcd. for C18H26NO+, 272.2009; found, 272.2022.
o
1
white solid, mp 57.5-60.5 C. H NMR (400 MHz, CDCl3) δ 7.60
(s, 1H), 7.19 (s, 1H), 4.29 (s, 2H), 3.59 (t, J = 7.3 Hz, 2H), 2.33 (d,
J = 4.5 Hz, 6H), 1.71 – 1.58 (m, 2H), 1.42 – 1.31 (m, 2H), 0.95 (t, J
= 7.4 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.7, 140.34,
138.9, 136.6, 130.9, 124.2, 123.5, 49.51, 42.0, 30.5, 20.3, 20.0, 19.8,
13.7. HRMS (ESI-TOF): [M+Na+] calcd. for C14H19NNaO+,
240.1359; found, 240.1369.
2-butyl-6,7-dimethoxyisoindolin-1-one, 2l. 27.4 mg, 22% yield,
colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.10 – 7.03 (m, 2H),
4.27 (s, 2H), 4.08 (s, 3H), 3.89 (s, 3H), 3.56 (t, J = 7.3 Hz, 2H),
1.68 – 1.58 (m, 2H), 1.43 – 1.32 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 166.6, 152.3, 147.3, 134.5,
125.3, 117.5, 116.3, 62.5, 56.8, 48.9, 42.1, 30.4, 20.0, 13.7. HRMS
1-butyl-6,7,8,8a-tetrahydrobenzo[cd]indol-2(1H)-one, 2q. 59.6
1
mg, 52% yield, colorless oil. H NMR (400 MHz, CDCl3) δ 7.59
(d, J = 7.5 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 7.6 Hz,
1H), 4.25 (dd, J = 11.8, 4.8 Hz, 1H), 3.72 – 3.62 (m, 1H), 3.55 –
3.40 (m, 1H), 3.04 (dd, J = 17.6, 8.0 Hz, 1H), 2.74 (dt, J = 17.6, 8.8
Hz, 1H), 2.39 (dq, J = 11.9, 4.0 Hz, 1H), 2.18 (dddd, J = 14.2, 7.7,
6.3, 3.7 Hz, 1H), 1.99 (dtd, J = 13.8, 9.4, 4.2 Hz, 1H), 1.69 – 1.60
(m, 2H), 1.45 – 1.34 (m, 2H), 1.15 (qd, J = 12.0, 4.1 Hz, 1H), 0.96
(t, J = 7.4 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.1,
144.2, 133.5, 130.9, 129.9, 128.6, 120.6, 58.2, 40.9, 31.1, 26.4, 25.1,
20.8, 20.2, 13.8. HRMS (ESI-TOF): [M+H+] calcd. for
C15H20NO+, 230.1539; found, 230.1549.
+
(ESI-TOF): [M+Na+] calcd. for C14H19NNaO3 , 272.1257; found,
272.1265.
2-butyl-5,6-dimethoxyisoindolin-1-one, 2l’7. 90.9 mg, 73% yield,
colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.31 (s, 1H), 6.92 (s,
1H), 4.28 (s, 2H), 3.94 (d, J = 1.3 Hz, 6H), 3.59 (t, J = 7.3 Hz, 2H),
1.68 – 1.58 (m, 2H), 1.38 (dq, J = 14.7, 7.4 Hz, 2H), 0.96 (t, J = 7.4
13
Hz, 3H). C{1H} NMR (101 MHz, CDCl3) δ 168.6, 152.2, 149.6,
2-butyl-3-phenylisoindolin-1-one, 2r32. 107.4 mg, 81% yield,
1
134.5, 125.3, 105.3, 104.9, 56.1, 49.4, 42.0, 30.5, 19.9, 13.6. HRMS
colorless oil. H NMR (400 MHz, CDCl3) δ 7.92 – 7.85 (m, 1H),
+
(ESI-TOF): [M+Na+] calcd. for C14H19NNaO3 , 272.1257; found,
7.48 – 7.39 (m, 2H), 7.38 – 7.29 (m, 3H), 7.21 – 7.06 (m, 3H),
5.45 (s, 1H), 3.95 (dt, J = 14.0, 7.9 Hz, 1H), 2.92 – 2.81 (m, 1H),
1.59 – 1.46 (m, 2H), 1.35 – 1.26 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 168.4, 146.1, 137.0, 131.6,
131.5, 128.9, 128.5, 128.1, 127.4, 123.3, 122.9, 64.3, 39.8, 30.2,
19.9, 13.6.
2-methylisoindolin-1-one, 2s7a. 36.8 mg, 50% yield, white solid. 1H
NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.5 Hz, 1H), 7.52 (td, J =
7.4, 1.1 Hz, 1H), 7.48 – 7.39 (m, 2H), 4.37 (s, 2H), 3.20 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 168.6, 140.9, 132.9, 131.1,
127.9, 123.6, 122.5, 51.9, 29.4.
2-propylisoindolin-1-one, 2t12b. 79.7 mg, 91% yield, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.84 (dd, J = 7.0, 1.5 Hz, 1H), 7.55
– 7.48 (m, 1H), 7.44 (t, J = 7.0 Hz, 2H), 4.37 (s, 2H), 3.71 – 3.46
272.1263.
2-butyl-2,3-dihydro-1H-benzo[e]isoindol-1-one, 2m. 45.4 mg, 38%
yield, yellow oil. 1H NMR (400 MHz, CDCl3) δ 9.25 (d, J = 8.3 Hz,
1H), 7.94 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.67 – 7.59
(m, 1H), 7.57 – 7.50 (m, 1H), 7.46 (d, J = 8.3 Hz, 1H), 4.39 (s,
2H), 3.66 (t, J = 7.3 Hz, 2H), 1.77 – 1.59 (m, 2H), 1.50 – 1.31 (m,
2H), 0.97 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
169.4, 141.5, 133.0, 131.8, 129.4, 127.9, 127.6, 126.8, 126.3, 123.8,
119.9, 49.7, 41.9, 30.7, 20.1, 13.7. HRMS (ESI-TOF): [M+H+]
calcd. for C16H18NO+, 240.1383; found, 240.1390.
2-butyl-2,3-dihydro-1H-benzo[f]isoindol-1-one, 2m’. 64.6 mg, 54%
yield, white solid, mp 82.8-85.8 oC. 1H NMR (400 MHz, CDCl3) δ
8.34 (s, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.83
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13
(m, 2H), 1.78 – 1.56 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). C{1H}
119.1, 58.4, 39.5, 35.3, 30.4, 20.1, 13.7. HRMS (ESI-TOF):
[M+Na+] calcd. for C15H19NNaO+, 252.1359; found, 252.1359.
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NMR (101 MHz, CDCl3) δ 168.4, 141.0, 133.0, 131.0, 127.8,
123.5, 122.5, 49.8, 43.9, 21.6, 11.2.
2-isopropylisoindolin-1-one, 2u12a. 49.4 mg, 57% yield, colorless
3-benzyl-2-butylisoindolin-1-one, 3b. 51.9 mg, 63% yield, colorless
1
oil. H NMR (400 MHz, CDCl3) δ 7.81 (dd, J = 8.4, 3.3 Hz, 1H),
1
oil. H NMR (400 MHz, CDCl3) δ 7.84 (dd, J = 6.5, 2.0 Hz, 1H),
7.42 (dd, J = 6.2, 2.4 Hz, 2H), 7.29 (d, J = 7.6 Hz, 3H), 7.14 – 7.10
(m, 2H), 6.95 (dd, J = 8.0, 4.5 Hz, 1H), 4.83 (dd, J = 7.9, 4.8 Hz,
1H), 4.13 (dt, J = 14.2, 8.1 Hz, 1H), 3.42 (dd, J = 13.8, 4.8 Hz, 1H),
3.25 (ddd, J = 13.8, 8.4, 5.2 Hz, 1H), 2.86 (dd, J = 13.8, 8.0 Hz,
1H), 1.77 – 1.57 (m, 2H), 1.45 – 1.31 (m, 2H), 0.98 (t, J = 7.4 Hz,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.1, 144.7, 135.9,
132.4, 130.7, 129.4, 128.4, 128.0, 126.9, 123.4, 122.8, 59.9, 39.8,
38.3, 30.4, 20.1, 13.7. HRMS (ESI-TOF): [M+H+] calcd. for
C19H21NNaO+, 302.1515; found, 302.1532.
7.55 – 7.49 (m, 1H), 7.48 – 7.41 (m, 2H), 4.68 (hept, J = 6.8 Hz,
1H), 4.34 (s, 2H), 1.29 (d, J = 6.8 Hz, 6H). 13C{1H} NMR (101
MHz, CDCl3) δ 167.8, 141.1, 133.3, 130.9, 127.8, 123.5, 122.6,
44.9, 42.5, 20.7.
2-cyclopentylisoindolin-1-one, 2v30. 61.3 mg, 61% yield, colorless
oil. H NMR (400 MHz, CDCl3) δ 7.87 – 7.79 (m, 1H), 7.55 –
7.47 (m, 1H), 7.47 – 7.41 (m, 2H), 4.83 – 4.71 (m, 1H), 4.35 (s,
2H), 2.07 – 1.94 (m, 2H), 1.87 – 1.74 (m, 2H), 1.73 – 1.58 (m,
4H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.3, 141.0, 133.2,
130.9, 127.8, 123.4, 122.6, 77.3, 77.0, 76.7, 52.5, 46.0, 30.0, 24.0.
2-cyclohexylisoindolin-1-one, 2w33. 70.9 mg, 66% yield, white
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2-butyl-3-(prop-2-yn-1-yl)isoindolin-1-one, 3c. 25.2 mg, 37% yield,
1
colorless oil. H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.4 Hz,
1H), 7.63 (d, J = 7.5 Hz, 1H), 7.55 (td, J = 7.4, 1.1 Hz, 1H), 7.48 (t,
J = 7.3 Hz, 1H), 4.63 (dd, J = 6.5, 4.3 Hz, 1H), 4.07 – 3.92 (m, 1H),
3.25 (ddd, J = 13.9, 8.6, 5.1 Hz, 1H), 2.86 (ddd, J = 16.9, 4.2, 2.7
Hz, 1H), 2.66 (ddd, J = 16.9, 6.7, 2.6 Hz, 1H), 1.98 (t, J = 2.6 Hz,
1H), 1.73 – 1.55 (m, 2H), 1.44 – 1.30 (m, 2H), 0.96 (t, J = 7.4 Hz,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.2, 144.2, 132.5,
131.3, 128.5, 123.5, 122.3, 78.5, 71.6, 57.5, 39.7, 30.4, 22.6, 20.1,
13.7. HRMS (ESI-TOF): [M+H+] calcd. for C15H17NNaO+,
250.1202; found, 250.1212.
1
solid. H NMR (400 MHz, CDCl3) δ 7.88 – 7.80 (m, 1H), 7.54 –
7.47 (m, 1H), 7.48 – 7.41 (m, 2H), 4.34 (s, 2H), 4.24 (dt, J = 11.4,
5.5 Hz, 1H), 1.86 (t, J = 9.8 Hz, 4H), 1.72 (d, J = 12.6 Hz, 1H),
13
1.57 – 1.37 (m, 4H), 1.17 (tdd, J = 12.8, 6.2, 3.5 Hz, 1H). C{1H}
NMR (101 MHz, CDCl3) δ 167.7, 141.2, 133.3, 130.8, 127.7,
123.4, 122.5, 50.4, 45.9, 31.3, 25.5, 25.4.
2-benzylisoindolin-1-one, 2x34. 105.9 mg, 95% yield, white solid.
1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.3 Hz, 1H), 7.46 (dt, J
= 20.8, 7.4 Hz, 2H), 7.37 – 7.25 (m, 6H), 4.78 (s, 2H), 4.22 (s,
2H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.3, 141.1, 136.9,
132.4, 131.2, 128.6, 127.9, 127.8, 127.5, 123.6, 122.6, 49.2, 46.2.
2-(2-methoxyethyl)isoindolin-1-one, 2y. 61.1 mg, 64% yield,
ASSOCIATED CONTENT
Supporting Information
1
colorless oil. H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.4 Hz,
1H), 7.56 – 7.49 (m, 1H), 7.44 (t, J = 7.6 Hz, 2H), 4.52 (s, 2H),
3.80 (t, J = 5.1 Hz, 2H), 3.64 (t, J = 5.1 Hz, 2H), 3.36 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 168.5, 141.6, 132.7, 131.1,
127.8, 123.5, 122.5, 71.6, 58.6, 51.5, 42.3. HRMS (ESI-TOF):
The Supporting Information is available free of charge on the ACS
Publications website.
NMR spectra for substrates and products (PDF)
+
[M+H+] calcd. for C11H14NO2 , 192.1019; found, 192.1027.
3-(1-oxoisoindolin-2-yl)propanenitrile, 2z. 40.0 mg, 43% yield,
yellow solid, mp 90.8-94.5 oC. 1H NMR (400 MHz, CDCl3) δ 7.85
(d, J = 7.5 Hz, 1H), 7.58 (td, J = 7.4, 1.0 Hz, 1H), 7.48 (t, J = 8.2
Hz, 2H), 4.61 (s, 2H), 3.91 (t, J = 6.4 Hz, 2H), 2.77 (t, J = 6.4 Hz,
2H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.8, 141.2, 131.8,
128.2, 123.8, 122.8, 118.2, 50.9, 39.1, 17.5. HRMS (ESI-TOF):
[M+H+] calcd. for C11H11N2O+, 187.0866; found, 187.0872.
Functionalizations of the Isoindolinone 2a. To a solution of
2a (0.3 mmol, 1.0 equiv.) in THF (2 mL) at -78 °C was added LDA
(0.33 mmol, 1.1 equiv.) slowly, and the reaction mixture was stirred
for 15 min. Then an alkyl bromide (0.45 mmol, 1.5 equiv.) in THF
(1mL) was added slowly via syringe and the reaction continued at
rt for 2h. Upon completion, the reaction mixture was quenched
with saturated NH4Cl solution and extracted with CH2Cl2 (10 mL
 3). The organic layer was combined, dried over anhydrous
Na2SO4, filtered, concentrated and purified by silica gel column
chromatography (PE/EtOAc = 10/1) to obtain the desired
products 3.
AUTHOR INFORMATION
Corresponding Author
*E-mail: yingjun@zstu.edu.cn
*E-mail: xiao-feng.wu@catalysis.de
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors thank the financial supports from Zhejiang Natural
Science Fund for Young Scholars (LQ18B020008), Zhejiang Sci-Tech
University (17062078-Y), NSFC(21472174, 21772177) and Zhejiang
Natural Science Fund for Distinguished Young Scholars
(LR16B020002).
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