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Investigations on the Pathway of the Fluorescence Reaction of a Pharmaceutically Important 13-Diamine with 2-Benzoylbenzaldehyde.

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Investigations on the Pathway of the Fluorescence Reaction of a
Pharmaceutically Important 1,3-Diamine with 2-Benzoylbenzaldehyde *
Reinhard Troschiitz” and Oliver Heinemann
Institut fur Pharmazie und Lebensmittelchemie der Friedrich-Alexander-Universitat,Erlangen-Numberg, Schuhstr. 19, D-91052 Erlangen, Germany
Key Words: Fluorescence reaction; deuteration experiments; reaction pathway; 2-benzoylbenzaldehyde; 1,j-diamine
Results and Discussion
The reaction of 2-benmyibenzd&hyde (1) with primary diamine
2, generated by reanangenlent and hydrolysis of Oxazepam, in
CD30D leads to intensely fluorescing deuterated isoindoloquinazolines 3 and 4. Reduction of ethyI 2-benzoylbenzoate (5) with
LiA1D4 followed by oxidation with Mn@ yields Z-benzoylbent[D]aldehyde (7). The condensation of 7 with diamine 2 leads
to isoindoloquinazoline12,free of deuterium.On the basis of these
experimentsa plausible pathway is proposed for the “fluorescence
Phthalaldehyde represents a widely used reagent for the
fluorimetric assay of primary amines [14], especially biogenic amines such as histamine, tryptamine, and serotonin as
well as amino acids [5,61. The reaction of phthalaldehyde or
its analogue 2-benzoylbenzaldehyde (l),respectively, with
2-amino-5-chlorobenzhydrylamine(2), a primary 1,3diamine, obtained by rearrangement and hydrolysis from
Oxazepam, in CH30H at 20 “C gave rise to strongly fluorescent isoindoloquinazolines. This reaction enables a highly
specific TLC-fluorescence detection of Oxazepam and
Lorazepam L71.
In continuation of these investigations, special experiments
were set up to elucidate the pathway of this fluorescence
In order to confirm our proposal of the reaction pathway,
an experiment in deuterated methanol was undertaken. The
reaction of 2-benzoylbenzaldehyde (1) with 2-amino-5-chlorobenzhydrylamine (2) in CD30D yielded the fluorescent
and deuterated compounds 3 and 4 as shown by ‘H-NMR and
MS data. The UV spectrum of 4 exhibits a maximum at h =
338 nm with some shoulders, attributed to the “azastilbene”
chromophore, which was not observed in 3. Consequently 4
is an isoindolo[l,2-b]quinazolinederivative and 3 is a derivative of isoindolo[2,1-a]quinazoline. The relative configuration of the deuterium-free congeners of 3 and 4 was
determined by NO experiments L71. Therefore, we assume that
the deuterated compounds 3 and 4 have, in all probability, the
same relative configuration. With regard to the phenyl
groups, 3 is trans- and 4 cis-configurated.
In order to prove or exclude an intramolecular hydride shift
during the formation of isoindoloquinazolines, a monodeuterated 2-benzoylbenzaldehyde (7) was used. Its preparation
started with the reduction of ethyl 2-benzoylbenzoate(5) with
LiAlD4 yielding the deuterated diol6 which was oxidized to
2-benzoylbenz[D]aldehyde (7) by MnO2 at 20 “C.
The deuterated ketoaldehyde 7 reacted with 2-amino-5chlorobenzhydrylamine (2) to give the solely isolated deuterium free isoindolo[ 1,2-b]quinazoline 12, as shown by
‘H-NMR and MS data. Compound 12 is identical with the
Scheme 1
Arch. P h a n . P h a n . Med. Chem.
0 VCH Verlagsgesellschaft mbH, 0-6945 1 Weinheim, 1996
0365-6233/96/0505-0267$5.00 + .25/0
Troschutz and Heinemann
product obtained from the reaction of 2-benzoylbenzaldehyde (1) and 2 in methanol 17].
Based on these experiments the following reaction path is
Initially the N,N-acetal 8 is formed from the ketoaldehyde
7 and the 1,3-diamine 2, cyclizing intramolecularly to a
1 0-hydroxyisoindoloquinazolinederivative 9. After protonation of the hydroxy group in 9, a carbenium-immonium ion
10 is generated, transforming into a reactive 1-aminoisoindole intermediate 11 after elimination of DO. 11 contains a
vinylogous enamine structure, which is responsible for the
nucleophilic reactivity at C-10. Protonation of C-10 by
methanol and elimination of the N-H proton gives rise to
10,I2-dihydroisoindolo[ I ,2-b]quinazoline 12, containing no
The observed incorporation of deuterium, as outlined in
Scheme 1, can be plausibly explained by a reaction of a
nucleophilic 1-aminoisoindole intermediate of type 11 with
a deuteron from C D 3 0 D .
LIAID4, Et20 A
78 mg (0.33 mmol) of 2 and 69 mg (0.33 mmol) of 2-benzoylbenzaldehyde
(1) were dissolved in CD30D. Under nitrogen and absence of light the
mixture was gently stirred at 20 “C for 3 h. The mixture was reduced to 113
of its volume and set aside. After 10 h the precipitated solid was chromatographed by MPLC on silica gel (CHCI31CH3OH 98:2).
Yield 31 mg (23%) colorless powder.- mp 166-167 ”C.- IR (KBr): v =
3066 cm-’, 3015 (Ar), 2970, 2938 (CH), 1619-1490 (C=N, C=C).- UV
(CH3OH): hman(log E) = 240.8 nm (4.20), 297.4 (3.70), 3 10.4 (3.63);addition
of HCI 252.6 (4.10), 297.4 nm (3.70), 320.0 (3.66).- ‘H-NMR (250.14 MHz,
CDC13):6=6.02ppm(s, 1H,5-H),6.57(d,J=9Hz3IH, l-H),7.02(dd,Ji
=9 Hz, J 2 = 2.5 Hz, IH, 2-H), 7.13 (d,J = 2.5 Ha, IH, 4-H), 7.20-7.45 (m,
13H, 8-H, 9-H, 10-H, 2’-H-6‘-H, 2”-H-6”-H), 7.93-7.97 (m, IH, 7-H).- MS
(70 eV): m/z (%) = 4091407 (7/22) [M’], 3331331 (31/100) [M+-C6Hs].
[1,2-b]quinazoline (4)
Isolated as a further compound from the reaction of 1 and 2.
Yield 36 mg (27%) colorless crystals.- mp 176-178 T - IR (KBr): v =
3034 cm-’ (Ar), 2922,2859 (CH), 1626-1494 (C=N, C=C).- UV (CH30H):
hmax (log &) = 245.0nm(4.25), 325.0 (sh, 3.88), 338.1 (3.97), 350.0 (sh, 3.90),
371.4 (sh, 3.54); addition of HCI 257.2 (4.13), 313.6 (3.92).- ‘H-NMR
(250.14 MHz, CDC13): 6 = 5.77 ppm (s, IH, 12-H), 6.55 (dd, J I = 2.5 Hz, Jz
= 1 Hz, IH, LH), 6.70 (br. s, IH, 2”-H-6”-H), 6.81-7.03 (m, 9H, 9-H,
2’-H4’-H, 3”-H-S”-H), 7.19 (dd, JI = 8 Hz, J2 = 2.5 Hz, IH, 3-H), 7.30 (d,
J = 8 H z , IH,4-H),7.41 (ddd,Ji=7.5Hz,J2=6Hz,J3=1.5Hz,1H,8-H),
7.52 (ddd, J i =J2 = 7.5 Hz,J3 = 1.5 Hz, lH, 7-H), 8.11 (br d, J = 7.5 Hz, lH,
6-H).- MS (70 eV): d z (5%) = 4091407 (7122) [M’], (311100) [M+-CsHsl.
0 U
Scheme 2
1.0 g (3.9 mmol) of ethyl 2-benzoylbenzoate (10) was dissolved in
absolute ether (25 ml) and added over 1 h to a refluxing suspension of 1.0 g
(23.8 mmol) of LiAID4 in EtzO (50 ml). After 3 h the suspension was cooled,
hydrolyzed with ice water and acidified with diluted sulfuric acid and
extracted 3 times with 30 ml of EtzO; the organic layer was dried over
NazS04 and evaporated in vucuo. The resulting oil was chromatographed by
MPLC on silica gel (CHCb1CH30H 9:l).
Yield 626 mg (74%) colorless powder.- mp 72-73 “C.- IR (KBr): v =
3624cm-’ (OH), 3027, 3013 (Ar), 2945, 2899 (CD, CDz), 1603-1449
(C=C).- UV (CH30H): h,,, (log E) = no stimulation.- ‘H-NMR (360.14
MHz, [D6]DMSO): 6 = 5.08 ppm (s, IH, CDz-OH, D20-exchdnge), 5.75 (s,
IH, CD-OH, Dz0 exchange), 7.15-7.33 (m, 9H, Haromat).-MS(70 eV): d z
(%) = 198 (64) [M+-HDO], 197 (100).
0.5 g (2.3 mmol) of 2-hydroxy[D2]methyl-diphenyl[D]methanol( 6 ) was
dissolved in 50 ml of CH2C12 and gently stirred at 20 “C with 5.0 g
(57.5 mmol) of MnOz for 12 h. After filtration the crude brown residue was
extracted 3 times with CHzCIz (20 ml). The organic layer was dried over
Na2SOq and evaporated in vucuo to yield a residue, which was chromatographed by MPLC on silica gel (CHzCIz).
Yield 285 mg (58%) colorless powder.- mp 66-68 “C.- 1R (KBr): v =
3066 cm-I, 3024, 3016 (Ar), 1710, 1673 (C=O), 1597-1486 (C=C).- UV
(CH30H): hman(log E) = 248.4 nm (3.77).- ‘H-NMR (250.14 MHz, CDC13):
6 = 7.44-8.06 ppm (m, 9H, Haromat).- MS (70 eV): d z (%) = 21 1 (96) [M’],
inazoline (12)
General: Mp: Buchi 530 (uncorr.).- Fl-IR: Perkin-Elmer 1740.- UV:
Perkin-Elmer Lambda 5.- ‘H-NMR and ”C-NMR: Bruker AM 360; Bruker
AC 250; Jeol FX 90 Q (standard: TMS).- EI-MS: Finnigan MAT TSQ 70.High Resolution EI-MS: Varian MAT 31 1 A or Varian MAT 312.- Silica
gel for MPLC: silica gel 60 Macherey Nagel & Co.
Prepared according to 3 from 123 mg (0.6 mmol) of 2 and 126 mg (0.6
mmol) of 7 in methanol.
Yield 93 mg ( 38 %).- mp 176-177 “C ( 175-177 “C ref.”’).
Arch. Phum. Phumz. Med. Chem. 329,267-269 (1966)
Fluorescence Reaction of a n Important I ,3-Diamine
Dedicated to Prof. Dr. G. Rucker, Bonn, on the occasion of his 65th
[ 11 W.B. Shelley, L. Juhlin, J. Chromatogr. 1966,22, 130-138.
[2] D. Turner, S.L. Wightman, J. Chromatogr. 1 9 6 8 , 3 2 , 315-322.
[4] H.E. Geissler, E. Mutschler, Arzneim. Forsch. 1976,26, 75-78.
[5] B. Algermissen, M. Nudel, E. Riedel, GIT Fachz. Lab. 1 9 8 9 , 9 , 783790.
[6] M. Roth, Anal. Chem. 1971,43,880-883.
171 .R. Troschiitz, 0. Heinemann, R. Waihel, J. Troschiitz, Arch. Pharm.
(Weinheim), 1995, 328, 557-563.
R.P. Maikel, F.P. Miller, Anal. Chem. 1966, 38(13), 1937-1938.
Received: January 25,1995 [FP089]
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Arch. Phamz. Pharm. Med. Chem. 329,267-269 (1966)
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investigation, reaction, fluorescence, benzoylbenzaldehyde, importance, pathways, pharmaceutical, diamine
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