Facile preparation of 6-(Aminomethyl)isoindolin-1-one realizing complete reduction of double aromatic cyano groups

Article abstract of DOI:10.14233/ajchem.2014.17169

6-(Aminomethyl)isoindolin-1-one is a key intermediate enroute to many investigational therapeutic agents. The need for it prompts a concise synthesis, which includes; (1) cyanation without using costly transition metal catalysts; (2) complete hydrogenation of the resulting dicyanide. This synthetic route emphasizes high atom-efficiency and simple operation. 5-(Aminomethyl)isoindolin-1-one, a structural analogue, is synthesized via this route as well.

Full text of DOI:10.14233/ajchem.2014.17169

Asian Journal of Chemistry; Vol. 26, No. 19 (2014), 6655-6657
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.17169
Facile Preparation of 6-(Aminomethyl)isoindolin-1-one
Realizing Complete Reduction of Double Aromatic Cyano Groups
1,*
1
2,*
LEI BI , CHENCHAO FU and LEI YAO
1School of Chemistry and Chemical Engineering, Anhui University of Technology, 59 Hudong Road, Maanshan 243002, Anhui, P.R. China
2School of Pharmacy, Yantai University, 32 Qingquan Road, Yantai, Shandong 264005, P.R. China
*Corresponding authors: E-mail: lei_bi@hotmail.com; yaoleiytu@163.com
Received: 5 February 2014;
Accepted: 6 June 2014;
Published online: 16 September 2014;
AJC-15981
6-(Aminomethyl)isoindolin-1-one is a key intermediate enroute to many investigational therapeutic agents. The need for it prompts a
concise synthesis, which includes; (1) cyanation without using costly transition metal catalysts; (2) complete hydrogenation of the resulting
dicyanide. This synthetic route emphasizes high atom-efficiency and simple operation. 5-(Aminomethyl)isoindolin-1-one, a structural
analogue, is synthesized via this route as well.
Keywords: Isoindoline, Complete reduction, Dicyanide.
melting point apparatus. The IR spectra were recorded on a
Perkin Elmer Spectrum 65 FT-IR spectrophotometer in
KBr pellets. The 1H and 13C NMR spectra were recorded on a
Bruker DRX-300 instrument using deuterated dimethyl
sulfoxide (DMSO-d6) as the solvent and tetramethylsilane
(TMS) as the internal standard. The mass spectra were recorded
on an agilent, 1200 HPLC-6120 MS spectrometer. Elemental
analysis was performed on a Perkin Elmer PE 2400II CHNS/O
instrument. The reaction progress was monitored by using
silica gel GF254, precoated TLC plates (0.2 mm thickness)
and visualized under UV light (254 and 365 nm) and by iodine
vapor.
INTRODUCTION
Isoindoline is a [6,5] fused bicyclic nitrogen heterocyle.
As such, it has been found in the structures of numerous natural
products1,2. At the same time, various small molecule thera-
peutics have incorporated this structure into their design as
well3,4. Among them, thalidamide could arguably be the most
famous (or infamous) case.
This trend has continued in the new century. The pharma-
ceutical industry has extended the application of this structural
motif on newer molecular targets such as chemokine receptors5
and histamine-3 receptor6. The intended therapeutic areas
include cancer7 as well as other life-threatening diseases8. In
particular, the isoindoline structure studied in these unrelated
research programs, from different corporations, could be cate-
gorized as multi-N-substituted 6-(aminomethyl) isoindolin-
1-one. Nonetheless, the previously reported syntheses to this
core structure are lengthy, utilizing reactions such as reductive
amination or [2 + 2 + 2] cycloaddition9. Typically, each indivi-
dual synthesis is case specific and for screening purpose only
(at the scale of milligrams). We herein report a concise and
general synthesis of 6-(aminomethyl)isoindolin-1-one,
applicable in large scale.
Synthesis of 6-(aminomethyl)isoindolin-1-one hydrochloride
Step 1: To a 2 L round-bottom flask, 2,5-dibromobenzoic
acid (250 g, 0.90 mol) in MeOH (2 L) and concentrated H2SO4
(18.4 g, 0.19 mol) were added. The mixture was refluxed
overnight before cooled to room temperature. The resulting
precipitate was then filtered, washed with cold methanol and
dried under vacuum. It yielded 203.6 g methyl 2,5-dibromo-
benzoate as a yellow solid. To a 2 L round-bottom flask was
added 2,5-dibromobenzoate (198.2 g, 0.68 mol) in 1 L dry
DMF. CuCN (122 g, 1.36 mol) and NaI (22.8 g, 0.15 mol)
were introduced next. The mixture was stirred overnight at
130 °C under nitrogen atmosphere. After the reaction was
complete, it was extracted with ethyl acetate (500 mL × 3),
washed with water (500 mL) and purified over silica gel (PE/
EtOAc = 5/1) to give 95.2 g methyl 2,5-dicyanobenzoate as a
brown solid (yield: 75.1 %).
EXPERIMENTAL
Chemicals were either laboratory prepared or purchased
from local vendors. Melting points were uncorrected and were
taken in open glass capillaries using an INESAWRS-1B digital

6656 Bi et al.
Asian J. Chem.
Step 2: To a 5 L round-bottom flask were added methyl
RESULTS AND DISCUSSION
2,5-dicyanobenzoate (93.3 g, 0.50 mol) and Raney-Ni (180 g,
wet), suspended in NH3/MeOH (2.5 L). The mixture was stirred
overnight at room temperature under H2 at 35 psi. The mixture
was filtered and washed with MeOH (2 L). The filtrate was
concentrated and purified over silica gel (DCM/MeOH = 10/1)
to give 6-(aminomethyl)isoindolin-1-one as a pale-yellow
solid. It was then dissolved in HCl/MeOH and sirred overnight
at room temperature. The solution was concentrated, washed
with methyl t-butyl ether and dried under vacuum to give 6-
(aminomethyl)isoindolin-1-one hydrochloride as a white solid
(70.6 g, yield: 71.1 %): m.p. 155-157 °C; Anal. Calcd. for
C9H10N2O: C, 66.65; H, 6.21; N, 17.27. Found: C, 66.62; H,
6.23; N, 17.30. IR (KBr, νmax, cm-1): 3435 (N-H), 1685 (C=O);
1H NMR (300 MHz, DMSO-d6, δ/ppm): 8.68 (1H, s, CONH),
8.61 (3H, s, +NH3), 7.83 (1H, s, aromatic), 7.72-7.74 (1H, d,
J = 6 Hz, aromatic), 7.62-7.60 (1H, d, J = 6 Hz, aromatic),
4.39 (2H, s, CH2), 4.14-4.10 (2H, q, J = 3 Hz, CH2) . 13C NMR
(75 MHz, DMSO-d6, δ/ppm): 169.6, 143.2, 134.3, 131.7,
130.1, 128.9, 127.3, 48.3, 42.8. MS (m/z): 163.1 ([m + 1]+).
On account of concerns on commercial availability and
cost, 2,5-dibromobenzoic acid was chosen as the starting
material, converted to its methyl ester by Fisher esterification.
Since the ester group was electron-withdrawing, methyl 2,5-
dibromobenzoate underwent an SNAr reaction with copper(I)
cyanide and sodium iodide at elevated temperature (Fig. 1).
Rarely as in this instance, cyanation did not require a transition-
metal coupling catalyst, for example, palladium with suitable
ligands10,11. Methyl 2,5-dicyanobenzoate was prepared by this
method conveniently and economically.
CuCN, NaI
Synthesis of 5-(aminomethyl)isoindolin-1-one hydrochloride
Step 1: To a 2 L round-bottom flask, 2,4-dibromobenzoic
acid (250 g, 0.90 mol) in MeOH (2 L) and concentrated H2SO4
(18.4 g, 0.19 mol) were added. The mixture was refluxed
overnight before cooled to room temperature. The resulting
precipitate was then filtered, washed with cold methanol and
dried under vacuum. It yielded 213.6 g methyl 2,4-dibromo-
benzoate as a yellow solid. To a 2 L round-bottom flask was
added 2,4-dibromobenzoate (200.7 g, 0.69 mol) in 1 L dry
DMF. CuCN (123.8 g, 1.38 mol) and NaI (22.8 g, 0.15 mol)
were introduced next. The mixture was stirred overnight at
160 °C under nitrogen atmosphere. After the reaction was
complete, it was extracted with ethyl acetate (500 mL × 3),
washed with water (500 mL) and purified over silica gel (PE/
EtOAc = 5/1) to give 93.5 g methyl 2,4-dicyanobenzoate as a
brown solid (yield: 72.8 %).
Fig. 1. Synthesis of methyl 2,5-dicyanobenzoate
Next, we envisioned by thorough reduction of both cyano
groups to amino groups, the target molecule would be furnished
in a single step12,13. However, this transformation turned out to
be troublesome. After numerous attempts, multiple products
were consistently found by TLC, supposedly as the result of
incomplete reduction.
This hurdle prompted us to take close examination of the
proposed conversion. Cyanide (carbon-nitrogen triple bond)
reduction had been a long-time common endeavor, with
various means developed to suit different needs14,15. It went
through the stage of imine, which was also nucleophilic and
could further react with fully reduced amine, resulting in
secondary or even tertiary amines as by-products. On the other
hand, astonishingly, the occurrence of concurrent reduction
of two or more cyano groups was sporadic in the literature16
and it is particularly difficult to find aromatic cases (cyano
groups on aromatic rings), if not unforeseen.
Step 2: To a 5 L round-bottom flask were added
methyl 2,4-dicyanobenzoate (93.1 g, 0.50 mol) and Raney-
Ni (180 g, wet), suspended in NH3/MeOH (2.5 L). The
mixture was stirred overnight at room temperature under
H2 at 35 psi. The mixture was filtered and washed with
MeOH (2 L). The filtrate was concentrated and purified
over silica gel (DCM/MeOH = 10/1) to give 5-(amino-
methyl)isoindolin-1-one as a pale-yellow solid. It was then
dissolved in HCl/MeOH and sirred overnight at room
temperature. The solution was concentrated, washed with
methyl t-butyl ether and dried under vacuum to give 5-
(aminomethyl)isoindolin-1-one hydrochloride as a white
solid (75.8 g, yield: 76.5 %): m.p. 171-173 °C; Anal. Calcd.
for C9H10N2O: C, 66.65; H, 6.21; N, 17.27. Found: C, 66.67;
H, 6.18; N, 17.32. IR (KBr, νmax, cm-1): 3430 (N-H), 1675
(C=O); 1H NMR (300 MHz, DMSO-d6, δ/ppm): 8.67 (1H,
s, CONH), 8.64 (3H, s, +NH3), 7.71-7.69 (2H, d, J = 6 Hz,
aromatic), 7.63-7.61 (1H, d, J = 6 Hz, aromatic), 4.39 (2H,
s, CH2), 4.15-4.11 (2H, q, J = 3 Hz, CH2). 13C NMR (75
MHz, DMSO-d6, δ/ppm): 175.2, 145.3, 133.9, 125.6, 124.3,
123.9, 123.8, 51.7, 45.8. MS (m/z): 163.2 ([m + 1]+).
TABLE-1
REACTION CONDITIONS FOR THE DICYANIDE REDUCTION
Entry
Condition
BH3·THF
Result
1
2
3
4
5
Amide bond reduced as well
CoCl6, NaBH4
Pd/C, H2
Multiple by-products, partial reduction
Multiple by-products, partial reduction
Raney Ni, 0.1 eq, H2 Multiple by-products, partial reduction
Raney Ni, 0.5 eq, H2 Desired product
We thus did screening on the reduction conditions (Table-1)
From the table, hydride sources, for example, boron hydride
(entry 1) reduced not only nitrile but also the amide group in
the desired product. Similarly, the use of LiAlH4 was elimi-
nated. Molecular hydrogen (entries 2-5) was then chosen as
the reducing source given the fact that ester or amide would
stay intact17 with H2. However, in situ generation of hydrogen

Vol. 26, No. 19 (2014)
Facile Preparation of 6-(Aminomethyl)isoindolin-1-one 6657
(entry 2) or direct hydrogenation (entry 3) both led to a mixture
of as a result of incomplete reduction (vide supra). Further
analysis indicated that with two or more cyano groups, unless
all groups were converted into amino groups in a rather smooth
fashion, partial reduction of any cyano group would lead to
undesired by-products. Thus, the careful selection of reducing
agents was key to the desired transformation18. Arguably,
reduction took preference at position a for steric reasons. The
highly reactive Raney nickel was employed as the hydroge-
nation catalyst. When the catalyst loading was increased from
0.1 eq to 0.5 eq, clean transformation to the title compound
was finally achieved (Fig. 2).
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Fig. 2. Synthesis of 6-(aminomethyl)isoindolin-1-one hydrochloride
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ACKNOWLEDGEMENTS
This project is supported by Natural Science Research
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