Synthesis of imidazoisoindol-3-ones by a palladium-catalyzed intramolecular C-H insertion reaction

Article abstract of DOI:10.1016/j.tetlet.2009.01.019

A simple protocol for the synthesis of various imidazoisoindol-3-ones is described by employing a palladium-catalyzed intramolecular C-H insertion reaction of substituted 2-haloaryl imidazolin-2-ones.

Full text of DOI:10.1016/j.tetlet.2009.01.019

Tetrahedron Letters 50 (2009) 1395–1398
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Synthesis of imidazoisoindol-3-ones by a palladium-catalyzed
intramolecular C–H insertion reaction
*
Srinivasa Reddy Dandepally, Alfred L. Williams
Department of Pharmaceutical Sciences, Biomanufacturing Research Institute and Technology Enterprise (BRITE), North Carolina Central University, Durham, NC 27707, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple protocol for the synthesis of various imidazoisoindol-3-ones is described by employing a palla-
dium-catalyzed intramolecular C–H insertion reaction of substituted 2-haloaryl imidazolin-2-ones.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 22 November 2008
Revised 30 December 2008
Accepted 7 January 2009
Available online 13 January 2009
Heterocyclic compounds are commonly used as scaffolds in
designing biologically active compounds.1 Imidazolone-based het-
erocyclic molecules play an important role in various biochemical
processes, and their use as building blocks in developing new drugs
such as COX-2 inhibitors,2a anti-inflammatory,2b anticancer,2c,d
cardioactive agents,2e angiotensin II receptor antagonists,2f and
others2g–i is well documented. Imidazoisoindolones with phenolic
subunits have been reported to exhibit high fluorescent proper-
ties.3 Recently, imidazoisoindolone-based orally active drug candi-
dates for the treatment of respiratory syncytial virus were
explored.4
by treating with a mixture of trifluoroacetic anhydride (TFAA)12
and TFA in CH2Cl2 furnished 1-benzyl-3-(2-bromobenzyl)-1H-imi-
dazol-2(3H)-one (4) (Scheme 1).
(i) NaH (1 eq.), BnBr
Bn
Bn
O
(i) LiAlH4, Et2O
0
TBAI (cat.), DMF
O
N
N
oC-rt, 4 h, 94%
NH
0
oC-rt, 12 h, 95%
O
O
N
N
Br
Br
O
N
H
(ii) TFAA-TFA (1:1)
CH2Cl2 , rt, 12 h
98%
Br
Br
2
1
3
4
(ii) NaH (1 eq.), TBAI (cat.)
DMF, 0 oC-rt, 12 h, 87%
Transition metal-catalyzed C–H activation reactions have
gained significant importance over the years.5 Functional group-di-
rected C–H insertion reactions are widely used for the synthesis of
various heterocyclic ring systems.6 Among these, palladium-cata-
lyzed C-arylation reaction is a valuable synthetic tool for the for-
mation of a wide variety of oxygen and nitrogen heterocycles.7
Palladium-catalyzed intermolecular C–H functionalization of imi-
dazolin-2-one under ligand-less conditions has been published
recently by Chen and co-workers.8 Herein, we report an intramo-
lecular C–H insertion reaction of 2-haloaryl imidazolinones to syn-
thesize aryl imidazoisoindolones.9
Although imidazolin-2-one is commercially available, we have
prepared 2-bromobenzyl imidazolinone derivative 4 from com-
mercially cheaply available hydantoin (1) in four steps rather than
from the quite expensive imidazolin-2-one.10 Hydantoin (1) was
first subjected to monobenzylation11 by treating with NaH, benzyl
bromide, and a catalytic amount of tetrabutylammonium iodide
(TBAI) in anhydrous DMF, and then reacted with 2-bromobenzyl
bromide (2) under same conditions to furnish N,N-diarylated
hydantoin 3. Selective reduction of the amide carbonyl of 3 by
LiAlH4 (1 equiv) in Et2O, and the subsequent elimination of aminol
Scheme 1.
Our study began with the cyclization of 1-benzyl-3-(2-bromob-
enzyl)-1H-imidazol-2(3H)-one (4). In the very first attempt, 4 was
treated with Pd(OAc)2, PPh3, and Cs2CO3 in anhydrous DMF at
80 °C. We were delighted to observe the complete consumption
of 4 in 12 h to furnish 2-benzyl-2H-imidazo[5,1-a]isoindol-3(5H)-
one (5) in 66% yield (Scheme 2). In an attempt to improve the yield
of 5, we carried out a series of experiments with different palla-
dium catalysts, ligands, and bases (Table 1). The best observed
reaction conditions for C–H insertion reaction were Pd(OAc)2 with
bidentate ligand 1,2-bis(diphenylphosphino)ethane (dppe) (Table
1, entry 4) and Pd(PPh3)4 (Table 1, entry 8) with yields of 79%
Bn
Bn
N
N
Pd(0) or Pd(II) - ligand
base, solvent, heat
O
O
Br
N
N
4
5
* Corresponding author. Tel.: +1 919 530 6706; fax: +1 919 530 6600.
E-mail address: awilliams@nccu.edu (A.L. Williams).
Scheme 2.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.019

1396
S. R. Dandepally, A. L. Williams / Tetrahedron Letters 50 (2009) 1395–1398
Table 1
Boc
N
Optimization of reaction conditionsa
NH
NH
K3PO4.H2O, MeOH
Pd(PPh3)4, Cs2CO3
O
O
O
Yieldb (%)
N
N
Br
Br
N
Entry
Catalyst
Ligand
Base
Time (h)
DMF, 80 oC, 5 h, 53%
(2 steps)
reflux, 30 min
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
PPh3
PPh3
dppp
dppe
dppb
( )BINAP
Xantophos
—
Cs2CO3
K2CO3
10
10
3
3
3
24
24
12
24
24
66
60
53
80
72
40c
40c
79
—
7
8
9
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NaOAcÁ3H2O
NaOAc
Scheme 4.
compound 7 was allowed to react, only a 26% yield of cyclized
product 7a was obtained.13
—
—
10
—
We next decided to attempt the C–H insertion reaction while
retaining the free hydrogen on the imidazolin-2-one. Recently,
we have developed a mild and efficient method for the N-Boc
deprotection under basic conditions in boiling MeOH.14 The N-
Boc moiety on 7 was cleaved under mild basic conditions using
K3PO4ÁH2O in refluxing MeOH within a short reaction time of
30 min to afford 1-(2-bromobenzyl)-1H-imidazol-2(3H)-one (8)
(Scheme 4). With suitable reaction conditions in hand, we exam-
ined the palladium-catalyzed intramolecular C–H insertion reac-
tion on 8. When 8 was treated with 20 mol % of Pd(PPh3)4 and
Cs2CO3 in DMF, we obtained 2H-imidazo[5,1-a]isoindol-3(5H)-
one (9) in 53% yield for 2 steps (Scheme 4).15
As an extension of this methodology, we decided to elaborate
this for differentially substituted 2-haloaryl imidazolone deriva-
tives. Accordingly, we have prepared 2-iodobenzyl imidazolone
derivative 10 (Table 2, entry 2) by adopting the same reaction
sequence from hydantoin (1) and 2-iodobenzyl bromide. N-Boc
moiety in 10 was deprotected with K3PO4ÁH2O in refluxing MeOH,
and the resulted compound was then treated with 20 mol % of
Pd(PPh3)4 and Cs2CO3 in DMF to give 2H-imidazo[5,1-a]isoindol-
3(5H)-one (9) in an improved yield of 84% (Table 2, entry 2).
Replacement of bromine with iodine increased the reaction rate
and the yield of C–H insertion product.
Our next objective was to study the scope of this protocol for
differentially substituted 2-bromoaryl imidazolone derivatives.
Hence, we have prepared various substituted 2-bromoaryl-imi-
dazolone derivatives with both electron-deficient aryl bromides
and electron-rich aryl bromides by employing the appropriate
synthetic sequences. Palladium-catalyzed intramolecular C–H
insertion reactions of the substituted 2-bromoaryl-imidazolone
derivatives were carried out and they produced various imidaz-
oisoindol-3-ones (Table 2).16 The reaction tolerated a variety of
different aryl substitution. As shown in Table 2, the nature as
well as the position of the substituents on the aromatic ring
affects the yields of the reaction. Substitution with electron-
a
Conditions: Pd catalyst (10 mol %), ligand (20 mol %), base (1.5 equiv), DMF
(entries 1–8), DMSO (entries 9 and 10), 80 °C.
Isolated yield.
b
c
Conversion based on TLC.
and 80%, respectively. Attempted C–H insertion of 4 under ligand-
less conditions8 using Pd(OAc)2 and NaOAc in DMSO gave multiple
products (Table 1, entries 9 and 10).
2-Benzyl-2H-imidazo[5,1-a]isoindol-3(5H)-one (5) was charac-
terized by NMR spectroscopy (1H and 13C) and MS. But to our sur-
prise, 5 decomposed in CDCl3 within an hour resulting in multiple
spots. The compound 5 is quite stable in CD3OD for several days
when stored in the freezer, and somewhat stable in acetone-d6,
as we noticed approximately 15% decomposition in 24 h at room
temperature.
Owing to the unusual decomposition of 5, we first sought to
replace the benzyl protecting group with a Boc group. Thus, the
2-bromobenzyl group was first introduced onto hydantoin (1) by
reacting with 2-bromobenzyl bromide (2) and NaH, and then
transformed it to the Boc protected 2-bromobenzyl derivative 6.
Selective reduction of the amide carbonyl with NaBH4 in EtOH
and elimination of the resulted aminol by MsCl and excess of
Et3N in CH2Cl2 afforded the tert-butyl 3-(2-bromobenzyl)-2-oxo-
2,3-dihydro-1H-imidazole-1-carboxylate (7) (Scheme 3). When
Scheme 3.
Table 2
Entry
Substratea
C–H insertion reaction time (h)
Product
Yieldb (%)
Boc
O
NH
NH
N
O
O
N
N
1
N
N
5
53
Br
9
9
7
Boc
O
N
2
1
84
I
10

S. R. Dandepally, A. L. Williams / Tetrahedron Letters 50 (2009) 1395–1398
1397
Table 2 (continued)
Entry
Substratea
C–H insertion reaction time (h)
Product
Yieldb (%)
Boc
O
N
NH
O
N
N
N
Br
F
N
3
4
5
6
7
5
69
90
60
55
44
11
F
12
Boc
O
N
NH
O
Br
Cl
N
4
3
4
7
13
Cl
14
Boc
O
N
NH
O
Br
N
15
O2N
16
NO2
Boc
O
NH
N
O
N
N
Br
Me
17
18
Me
Boc
N
NH
O
O
N
N
Br
MeO
MeO
20
19
MeO
OMe
Boc
O
N
NH
O
N
Br
N
8
7
28
O
O
22
O
21
O
a
Conditions: Boc deprotection: K3PO4ÁH2O (20 mol %), MeOH, reflux, 30 min. C–H insertion: Pd(PPh3)4 (20 mol %), Cs2CO3 (1.5 equiv), DMF, 80 °C.
b
Isolated yields after 2 steps (Boc deprotection and C–H insertion).
donating groups resulted in lower yields (Table 2, entries 7 and
8). The lower yields appear to be attributed to the decomposi-
tion of the cyclized products 20 and 22 during the work-up
and/or purification step. Analysis of the reaction by LC/MS
showed that, after 7 h, the starting materials were all consumed
to give the products 20 and 22, and there was no detection of
any bromo-reduced by-products.17
In conclusion, we have developed an efficient methodology for
the synthesis of various imadazoisoindol-3-ones by palladium-cat-
alyzed intramolecular C–H insertion reaction. The synthetic utility
of this method for the construction of imidazoisoquinolone, aryl
imidazoazipinone ring systems, and their application toward natu-
ral product synthesis is under investigation, and the results will be
published in due course.
Acknowledgments
We gratefully acknowledge The Golden LEAF Foundation, Rocky
Mount, NC, for the financial support. We thank Dr. Li-An Yeh,
Director, BRITE, for the encouragement, and Dr. Sabapathy Sankar,
Lab Supervisor for NMR facility, Department of Chemistry, NC State
University, for NMR discussions. We also thank the Department of
Chemistry at NC Central University for using their NMR facility.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.01.019.

1398
S. R. Dandepally, A. L. Williams / Tetrahedron Letters 50 (2009) 1395–1398
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Gaunt, M. J. J. Am. Chem. Soc. 2006, 128, 2528–2529; (d) Bressy, C.; Alberico, D.;
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14. Dandepally, S. R.; Williams, A. L. Tetrahedron Lett. 2009, 50, 1071–1074.
15. Representative procedure for Boc deprotection and C–H insertion reaction: Step 1:
To
a
solution of tert-butyl 3-(2-bromobenzyl)-2-oxo-2,3-dihydro-1H-
imidazole-1-carboxylate (7) (0.2 g, 0.566 mmol) in MeOH (4 mL) was added
K3PO4ÁH2O (0.026 g, 0.113 mmol) and heated at reflux for 30 min. Reaction
mixture was filtered through a pad of Celite and the filtrate was evaporated
under vacuo to give a crude 1-(2-bromobenzyl)-1H-imidazol-2(3H)-one (8),
which was carried forward without further purification. Step 2: After
dissolving
8 in anhydrous DMF (4 mL) were added Pd(PPh3)4 (0.131 g,
0.113 mmol) and Cs2CO3 (0.277 g, 0.849 mmol), and heated at 80 °C under
nitrogen atmosphere for 5 h. After completion of the reaction, solvent was
removed under vacuo and the crude mixture was purified by flash silica gel
column chromatography by eluting with MeOH–CH2Cl2 (1:19) to furnish a
pure colorless solid, 2H-imidazo[5,1-a]isoindol-3(5H)-one (9) (0.052 g, 53% for
2 steps).
16. Spectroscopic data of the final imadazoisoindol-3-ones: 2-Benzyl-2H-imidazo[5,1-
a]isoindol-3(5H)-one (5): Colorless syrup. 1H NMR (300 MHz, CD3OD) d (ppm)
4.83 (s, 2H), 4.88 (s, 2H), 6.73 (s, 1H), 7.27–7.34 (m, 7H), 7.49 (t, 2H, J = 7.8 Hz).
13C NMR (75 MHz, CD3OD) d (ppm) 49.4 (2C), 104.3, 122.0, 126.0, 129.4, 129.6,
129.7, 130.2, 130.7, 131.8, 139.5, 142.4. APCI/ESI-MS: m/z 263 [M+H]+. 2H-
imidazo[5,1-a]isoindol-3(5H)-one (9): White solid, mp: 224–226 °C. 1H NMR
(300 MHz, CD3OD) d (ppm) 4.78 (s, 2H), 6.67 (s, 1H), 7.29 (dt, 1H, J = 1.2,
7.5 Hz), 7.37 (t, 1H, J = 7.5 Hz), 7.47 (d, 1H, J = 7.5 Hz), 7.53 (d, 1H, J = 7.5 Hz).
13C NMR (75 MHz, CD3OD) d (ppm) 48.1, 100.6, 121.0, 125.1, 128.3, 129.3,
131.1, 141.8. APCI/ESI-MS: m/z 173 [M+H]+. 7-Fluoro-2H-imidazo[5,1-a]isoindol-
3(5H)-one (12): Light yellow solid, mp: 241–243 °C. 1H NMR (300 MHz,
CD3OD+CDCl3) d (ppm) 4.80 (s, 2H), 6.60 (s, 1H), 7.11 (dt, 1H, J = 2.4, 8.4 Hz),
7.24 (dd, 1H, J = 2.7, 8.4 Hz), 7.51 (dd, 1H, J = 4.8, 8.4 Hz). 13C NMR (75 MHz,
CD3OD+CDCl3) d (ppm) 47.9 (d), 100.0 (d), 112,4 (d), 116.3 (d), 122.1 (d), 127.2
(d), 143.7 (d), 161.6, 164.9. APCI/ESI-MS: m/z 191 [M+H]+. 7-Chloro-2H-
imidazo[5,1-a]isoindol-3(5H)-one (14): Light yellow solid, mp: 226–228 °C. 1H
NMR (300 MHz, CD3OD) d (ppm) 4.81 (s, 2H), 6.66 (s, 1H), 7.37 (dt, 1H, J = 1.8,
8.1 Hz), 7.47–7.51 (m, 2H). 13C NMR (75 MHz, CD3OD) d (ppm) 47.7, 101.0,
121.9, 125.3, 129.4, 133.8, 143.3. APCI/ESI-MS: m/z 207 [M+H]+. 7-Nitro-2H-
imidazo[5,1-a]isoindol-3(5H)-one (16): Brown solid, mp
>
300 °C. 1H NMR
(300 MHz, DMSO-d6) d (ppm) 4.87 (s, 2H), 7.07 (d, 1H, J = 2.4 Hz), 7.73 (d, 1H,
J = 8.7 Hz), 8.27 (dd, 1H, J = 2.4, 8.7 Hz), 8.36 (s, 1H), 10.50 (br s, 1H, NH). 13C
NMR (75 MHz, DMSO-d6) d (ppm) 46.7, 104.3, 119.8, 120.0, 124.3, 136.5, 142.0.
APCI/ESI-MS: m/z 218 [M+H]+. 8-Methyl-2H-imidazo[5,1-a]isoindol-3(5H)-one
(18): Light yellow solid, mp: 226–228 °C. 1H NMR (300 MHz, CD3OD) d (ppm)
2.39 (s, 3H), 4.73 (s, 2H), 6.59 (s, 1H), 7.11 (d, 1H, J = 8.1 Hz), 7.30–7.34 (m, 2H).
13C NMR (75 MHz, CD3OD+CDCl3) d (ppm) 21.6, 47.7, 100.1, 121.3, 124.5, 129.1,
130.8, 131.0, 138.5, 139.2, 152.5. APCI/ESI-MS: m/z 178 [M+H]+. 7,8-Dimethoxy-
2H-imidazo[5,1-a]isoindol-3(5H)-one (20): White solid, mp: 234–236 °C. 1H
NMR (300 MHz, CD3OD) d (ppm) 3.86 (s, 6H), 4.70 (s, 2H), 6.54 (s, 1H), 7.12 (s,
1H), 7.15 (s, 1H). 13C NMR (75 MHz, CDCl3+CD3OD) d (ppm) 46.9, 56.0 (2C),
97.3, 102.8, 106.8, 122.3, 129.9, 132.6, 148.9, 149.4. APCI/ESI-MS: m/z 233
[M+H]+. 6H-[1,3]Dioxolo[4,5-f]imidazo[5,1-a]isoindol-7(9H)-one (22): Brown
solid, mp > 300 °C. 1H NMR (300 MHz, CD3OD+CDCl3) d (ppm) 4.68 (s, 2H),
6.01 (s, 2H), 6.51 (s, 1H), 6.96 (s, 1H), 6.99 (s, 1H). 13C NMR (75 MHz,
CD3OD+CDCl3) d (ppm) 47.9, 98.9, 101.4, 103.0, 105.6, 124.6, 135.2, 149.6.
APCI/ESI-MS: m/z 217 [M+H]+.
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8. Lu, J.; Tan, X.; Chen, C. J. Am. Chem. Soc. 2007, 129, 7768–7769.
9. For intramolecular C-arylation of imidazole and pyrrole see: Arai, N.;
Takahashi, M.; Mitani, M.; Mori, A. Synlett 2006, 3170–3172.
10. The price of imidazolin-2-one for 1 g: $950 from a leading chemical supplier,
Focus Synthesis LLC, San Diego, CA, USA.
11. Martinez, A.; Alonso, M.; Castro, A.; Dorronsoro, I.; Gelpi, J. L.; Luque, F. J.;
Perez, C.; Moreno, F. J. J. Med. Chem. 2005, 48, 7103–7112.
12. Liao, Z. K.; Kohn, H. J. Org. Chem. 1984, 49, 4745–4752.
13. Reaction conditions for the cyclization of compound 7. The low yield is
attributed to the decomposition of the product 7a. Similar to compound 5, fast
decomposition of 7a was observed in CDCl3. The structure of 7a was confirmed
by 1H NMR spectroscopy
17. See Supplementary data for the LC/MS analysis data.