4,7-Diaminoisoindoline-1,3-dione

Full text of DOI:10.1080/00304948.2018.1462072

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: 0030-4948 (Print) 1945-5453 (Online) Journal homepage: http://www.tandfonline.com/loi/uopp20
4,7-Diaminoisoindoline-1,3-dione
Krishna Kumar Gnanasekaran, Mario Rivera & Richard A. Bunce
To cite this article: Krishna Kumar Gnanasekaran, Mario Rivera & Richard A. Bunce (2018) 4,7-
Diaminoisoindoline-1,3-dione, Organic Preparations and Procedures International, 50:3, 372-374,
DOI: 10.1080/00304948.2018.1462072
To link to this article: https://doi.org/10.1080/00304948.2018.1462072
Published online: 17 May 2018.
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Organic Preparations and Procedures International, 50:372–374, 2018
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2018.1462072
OPPI BRIEF
4,7-Diaminoisoindoline-1,3-dione
Krishna Kumar Gnanasekaran,1 Mario Rivera,2 and Richard
A. Bunce1
1Department of Chemistry, Oklahoma State University, Stillwater, OK
74078-3071, USA
2Department of Chemistry, R. N. Adams Institute for Bioanalytical Chemistry,
University of Kansas, Lawrence, KS 66047-1620, USA
A recent synthesis in our drug discovery program required access to 4,7-diaminoisoindo-
line-1,3-dione (1, also 3,6-diaminophthalimide) in 250–500 mg quantities. This com-
pound has been previously reported from the known 4,7-dichloroisobenzofuran-1,3-dione
(also 3,6-dichlorophthalic anhydride).1 The preparation of this anhydride involved zinc
promoted hydrodechlorination of 3,4,5,6-tetrachlorophthalic anhydride under basic con-
ditions to initially give 3,4,6-trichlorophthalic acid.2–4 Further dechlorination with zinc
generated 3,6-dichlorophthalic acid,2–4 and boiling in toluene with azeotropic removal of
water gave 3,6-dichlorophthalic anhydride.3,4 We repeated this sequence on a small scale
to get all of these compounds with physical and spectral properties identical to those
reported.2–4 Subsequent reaction of 3,6-dichlorophthalic anhydride with excess aq NH3
and CuI (sealed tube, 120–130ꢀC, 8 h) according to the literature procedure,1 however,
gave a product that melted at 273–275ꢀC, which did not match the reported value.
Spectral analysis of this material suggested that it was 4-amino-7-chloroisoindoline-1,3-
dione rather than the diamino compound. The 1H NMR spectrum displayed a singlet at d
11.1 (1H) for the imide proton, two doublets at d 7.38 and d 7.02 (1H each) for the cou-
pled protons at C6 and C7, and a broad singlet at d 6.53 (2H) for the amino protons.
Additionally, the 13C NMR showed eight carbons rather than four carbons expected for
the symmetrically substituted phthalimide, and the mass spectrum gave parent ion peaks
at 196 and 198 in an approximate 3:1 ratio.5 Though the original work apparently did
yield the correct product from 3,6-dichlorophthalimide, problems were documented when
3,6-dichlorophthalic anhydride was used as the starting material. Since the 4-amino-7-
chloro derivative did not meet our needs and the procedure was rather labor intensive,
this approach was not repeated, but instead, we opted to develop our own route to the 4,7-
diamino compound. Our findings are reported below.
The successful synthesis required two steps and was more straightforward than the
Received September 22, 2017; in final form December 14, 2017.
Address correspondence to Richard A. Bunce, Department of Chemistry, Oklahoma State Uni-
versity, 107 Physical Sciences, Stillwater, OK 74078-3071. E-mail: rab@okstate.edu
372

4,7-Diaminoisoindoline-1,3-dione
373
earlier procedure. Commercially available 4-aminoisoindoline-1,3-dione (2, also
3-aminophthalimide) was brominated with N-bromosuccinimide in methanol to give
7-bromo-4-aminoisoindoline-1,3-dione (3) as the exclusive product in 75% yield. Since
this compound precipitated directly from the reaction mixture, an extensive work-up
procedure was not necessary.
NH2
NH2
NH2
3a
O
O
O
3
4
aq NH3
NBS
5
6
2
NH
NH
NH
1
CuI/L-proline
MeOH
7a
7
O
O
O
Br
NH2
2
3
1
The bromide was simply filtered and dried prior to use in the next reaction. Treat-
ment of 3 under conditions modified from those reported by Ma and co-workers6
(excess aq NH3, 10 mol% of CuI, 20 mol% of L-proline, sealed tube, 110ꢀC, 3 h)
afforded 4,7-diaminoisoindoline-1,3-dione (1) in 42% yield. Again, upon cooling,
the product crystallized directly from the reaction mixture and required only filtra-
tion and drying before use.
In conclusion, we have developed a short, efficient synthesis of 4,7-diamino-
isoindoline-1,3-dione. Though the starting 4-aminoisoindoline-1,3-dione is more
expensive than the tetrachlorophthalic anhydride used in the earlier approach, the
current procedure is much faster and reliably affords a 32% overall yield of the final
product.
Experimental Section
All commercial reagents were used as received. 4-Aminoisoindoline-1,3-dione (2) was
purchased from Oxchem Corporation (Wood Dale, IL). Unless otherwise specified, all
reactions were run under dry N2 in oven-dried glassware. Reactions were monitored by
thin layer chromatography (TLC) on silica gel GF plates (Analtech, No 21521). Melting
points were uncorrected. 1H- and 13C-NMR spectra were measured at 400 MHz (1H) and
101 MHz (13C). Chemical shifts (d) are referenced to internal (CH3)4Si and coupling con-
stants (J) are given in Hz. Low-resolution mass spectra (EI/DP) were obtained at 30 eV.
Elemental analyses were performed by Atlantic Microlabs, Norcross, GA.
4-Amino-7-bromo-1,3-dione (3)
4-Aminoisoindoline-1,3-dione (2, 2.00 g, 12.3 mmol) was dissolved in MeOH
(200 mL), and the solution was treated with N-bromosuccinimide (2.19 g,
12.3 mmol). The reaction was stirred at room temperature for 50 min. The solid that
precipitated was collected by filtration and washed with MeOH to give bromide 3
1
(2.21 g, 9.21 mmol, 75%) as a yellow powder, mp 287–289ꢀC. H NMR (DMSO-
d6): d 11.1 (s, 1H), 7.51 (d, J D 8.9 Hz, 1H), 6.90 (d, J D 8.9 Hz, 1H), 6.53 (br s,
2H); 13C NMR (DMSO-d6): d 170.0, 167.7, 146.5, 139.6, 130.2, 123.6, 112.4, 101.6;
MS: m/z 240, 242 (C8H5BrN2O2, MC¢, ca. 1:1).
Anal. Calcd for C8H5BrN2O2: C, 42.51; H, 1.78; N, 6.20. Found: C, 42.63; H, 1.86;
N, 6.14.

374
Bunce et al.
4,7-Diaminoisoindoline-1,3-dione (1)
A clean, dried 100-mL Chemglass screw cap pressure vesselÒ (CG-1880-R-02) with a
perfluoro O-ring (CG-309-210) was charged with bromide 3 (1.00 g, 4.17 mmol), copper
(I) iodide (80 mg, 10 mol%), L-proline (100 mg, 20 mol%) and aq NH3 (15 mL of
15 M, ca 225 mmol). The screw cap was replaced and the reaction was heated to 110ꢀC
for 3 h. The reaction was cooled to 23ꢀC and red needles of the product separated. These
crystals were filtered, washed with water and dried under vacuum to provide diamine 1
(310 mg, 1.75 mmol, 42%) as a red solid, mp 294–296ꢀC [lit4 mp 298ꢀC (dec)]. 1H NMR
(DMSO-d6): d 10.5 (s, 1H), 6.82 (s, 2H), 5.75 (s, 4H); 13C NMR (DMSO-d6): d 170.8,
138.5, 125.6, 108.8; MS: m/z 177 (C8H7N3O2, MC¢).
Anal. Calcd for C8H7N3O2: C, 54.24; H, 3.98; N, 23.72. Found: C, 54.35; H, 4.04; N,
23.61.
Acknowledgments
The authors acknowledge support of this work by the National Institute of Allergy and
Infectious Diseases of the NIH (AI125529). The authors also wish to acknowledge Mr.
Kevin Meraz for acquiring the mass spectrum of the 4-amino-7-chloroisoindoline-1,3-
dione. Finally, the authors are grateful to the OSU College of Arts and Sciences for funds
that allowed the Chemistry Department to purchase a new 400 MHz NMR for our State-
wide NMR facility. This facility was originally established with support from the NSF
(BIR-9512269), the Oklahoma State Regents for Higher Education, the W. M. Keck
Foundation, and Conoco, Inc. This paper is dedicated to the memory of Prof. J.-P.
Anselme for his advice, guidance, and friendship over the past 35 years.
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procedural details or characterization data, see H. Kanter, German Patent DE 2843873, 1980,
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