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Aminations with O-Diphenylphosphinylhydroxylamine A Critical EvaluationGeorge Sosnovsky* and Klaus PurgstallerDepartment of Chemistry, University of W isconsin-M ilwaukee. Milwaukee. WI 53201. USA

Z. Naturforsch. 44b, 582 — 586 (1989); received September 23. 1988

Synthesis. O -Diphenylphosphinylhydroxylam ine, Hydroxylamine-O-sulfonic Acid,N-Am ino Derivatives, N-A m ino H eterocyclic Compounds

A critical evaluation is presented of the scope of amination reactions with O-diphenylphos- phinylhydroxylamine (O D PH ) as compared to those using hydroxylamine-O-sulfonic acid (H O SA ). Aminations with O D PH of isopropyl, r-butyl and cyclohexyl carbanions derived from the corresponding Grignard reagents, gave the corresponding amines in 36, 34 and 50 percent yields, respectively. The amination with H O SA of the same carbanions under similar conditions was unsuccessful. The aminative quarternization of the tertiary nitrogen of pyridine andquinoline with ODPH proceeded with comparable yields to those obtained with H O SA. An improved one flask amination with O DPH of indole, skatole and carbazole was achieved in 52—62 percent yields. The amination under the same conditions using H O SA gave consistently lower yields. Several other amination reactions which have been reported for HOSA were unsuccessful using O DPH. The conclusion is reached that overall the O DPH reagent is much less versatile than H OSA. Nevertheless, in the aminations of NH groups of heterocyclic compounds ODPH appears to be superior to H O SA and is the reagent of choice, in particular, since the preparation of ODPH is much less harzardous than that of H O SA.

Introduction

Hydroxylamine-O-sulfonic acid ( l,H O S A ) is a versatile reagent which has been extensively used over the years for various aminations at the carbon nuclei of aliphatic, alicyclic, aromatic and hetero- aromatic compounds, and at various nitrogen, sulfur and phosphorus moieties.

H f N - O - S O f1

Depending on the reaction conditions, the amina­tion can proceed either by nucleophilic, elec- trophilic, or radical mechanisms. Several reviews [1—3] are available which cover either partly or ex­clusively the chemistry of 1 .

In the early eighties a phosphorus analog of 1, theO-diphenylphosphinylhydroxylamine (2, ODPH) was proposed [4—8] as an alternative reagent for the amination of carbon, nitrogen, sulfur and phos­phorus nuclei. However, for the amination of sulfur and phosphorus only one example each, i.e. di- methylsulfid and triphenylphosphine, were reported[4]. Although compound 2 was prepared about twen­ty years earlier [9], the structure was believed to be

* Reprint requests to Prof. Dr. G. Sosnovsky.

Verlag der Zeitschrift für Naturforschung, D-7400 Tübingen0932-0776/89/0500-0582/$ 01.00/0

0

0 ,-------------- (C6H5)2 P - 0 - N H 2

( c 6 h 5 )2 p c i + h o n h 2 ^

\ ° x - * - ( C6 H 5 )2 p - n h o h

3Scheme I.

that of N-diphenylphosphinylhydroxylamine (3), and it was not until 1979 that the correct structure 2 was elucidated [1 0 ] on the basis of derivatizations and spectroscopy. To date, as compared to 1, only a small number [4—8] of amination reactions have been reported using 2. Thus, the reactions of carban­ions, derived either from lithium or Grignard rea­gents, with 2 gave the corresponding amines in low to good yields, depending on the nature of the carban- ion [5,6].

In another study [7,8], the amination of the NH group of imidazoles and xanthines with 2 resulted in superior yields of N-amino products, than those ob­tained using 1. Thus, amination of imidazole (4a), 2- nitroimidazole (4b), 2-methyl-4-nitroimidazole (4c), and theophilline (4d) and theobromine (4e) gave the corresponding amino derivatives (5a—e), whereby the amination occurred at the N 1(7)(R') position of the imidazole ring when this position was unsubsti-

G. Sosnovsky —K. Purgstaller • O DPH — A Critical Evaluation 583

Scheme II.

R Na N=CHC,Hr NH,I I I IR1v ^ N R1\ ^ N R1vs_^-N R1\ - - NT W 1 °°PH . T Vr‘t f X / CHjOH RU L / 2 H C I , H 20 „ , J L / r 2 J L /

3. C6H5CH0

A a . R 1 = r 2 = r 3 = r ‘* = h 5 aA b : R 1 =R2 r R 3 = H, r 4 = no 2 5 bA c : R1 = R3= H, r 2 = no2 , Ri,=CH3 5 cA d : R 1 r 2 = c — n - c — n , r 3 = r 4 = h 5 d

II I II lo c h 3 o c h 3

A e : R 1 r 2 = c — n - c - n , r 3 = c h 3 , r 4 = h 5 e : r 1 r 2 = c - n - c - nII H || I ------- II I II Io o c h 3 o n h 2 o c h 3

tuted (5a—d), and at the N I position of the py­rimidine ring when the N7 position was substituted (5e). In contrast to previous results [4], the anima­tion of phthalimide and pyridine was also successful [7,8]. Now an attempt was made to explore the scope of the amination reactions using ODPH (2).

Results and Discussion

The preparation of 2, with minor modification, was based on the previously reported [4—10] recipes. A number of amination reactions were tried with 2, which have been reported [1—3] using 2 , albeit with negative results. Thus, the Friedel-Crafts type ami­

nation of toluene in the presence of aluminum chloride, the free radical amination of toluene in the presence of ferrous ions, the Beckmann rearrange­ment of cyclohexanone via the corresponding oxime, the conversion of benzaldehyde to benzonitrile, and the syntheses of l-methyl-3,3-penta-methylene- and l-methyl-3-phenyl-diaziridines from the correspond­ing Schiff bases were unsuccessful.

As an extension of previous studies [5, 6 ], the reac­tions of two branched and one alicyclic carbanions using the corresponding Grignard reagents gave the expected products (Table I). Thus, the amination of isopropyl, r-butyl and cyclohexyl halides with 2 re­sulted in low yields of the corresponding amines in

Table I. Preparation and properties of various aminated products.

Product1 Molecular Method O D PH h H O SA c m. p. Lit. m .p. Mol. w t.dformula yield [%] yield [%] [°C] [°C] MS

7a C ,H 1(INC1 (95.57) A 36 e 2 0 6 -2 0 7 (dec.)7b Q H p N C l (104.60) A 50 e 136-138 (dec.) 136-138 (dec.)7c C8H ,sN 0 4 (189.21) A 24 e > 2 5 0 (dec.)9a CsH7NT (220.01) B 62 63 162-164 161-1629b CyHc,NT (272.08) B 20 50 180-182 186-18411a C8H8N 2 (132.15) C 60 32f.g 4 1 -4 2 .5 4 1 -4 1 .5 133l i b Q H 10N , (146.18) C 52 27 —32lg 6 0 -6 1 .5 5 9 -6 0 .5 14711c C 12H I()N, (182.21) C 62 51f

44s92h50'

147-148.5

147 (dec.)

145-146 183

a Microanalyses (C, H. N) were in agreement with the calculated values (± 0 .4 % ); h average of four experiments, the yields are based on ODPH; c average of two experiments, the yields are based on H OSA: d by chemical ionization (M + + 1); e no product was obtained with H OSA; 1 at 60—65 °C for 3 h; 8 at 25 °C for 1 or 3 h; h two-stage reaction via N- nitroso derivative. Isolation by TLC. Yield only for last stage provided (Ref. [15]); ' two-stage reaction via N-nitroso derivative (Ref. [17]).Method A: amination via Grignard reagent, product isolated as hydrogen chloride or oxalic acid salt.M ethod B: isolated the N-amino product as quarternary salt using HI.Method C: one-flask amination.

584 G. Sosnovsky-K . Purgstaller • O DPH — A Critical Evaluation

analogy with results of other earbanions. However, this amination was unsuccessful using 1 under com­parable conditions.

R - X1. Mg / E t 202. O D P H / - 7 8 ° C3. HCl or oxal i c acid

6a: r = ( c h 3 ) 2 ch

6b: r = ( c h 3 ) 3 c

6c: R=

r - n h 2

7a7b7c

X = Br , C l , Y = HCl or oxal ic acid

Scheme I I I .

Conflicting results were previously obtained [4, 7] in the aminative quarternization of pyridine with 2 . Now it was found that the amination of pyridine and quinoline with 2 proceeded with comparable yields to those using HOSA. The products were isolated as the hydroiodide salts (Table I).

i n 1. Q D P H / 8 0 C / 1 h _

2. K2 C 0 3

3. 57 % H I / - 2 0 / 1 hXX

N H ,

8 a : R1 = r 2 = h 9a8b: R1 r 2 = c h = c h — c h = c h 9b

Scheme I V .

In analogy to previous results [7,8], with imidazoles and xanthines, the amination of the in­dole type NH moiety with 2 in the presence of potas­sium hydroxide in a dimethylformamide solution gave the corresponding N-amino derivatives. In con­trast to the previous work [7,8], no intermediate preparation of the sodio derivatives and Schiff bases was necessary, and the amination could be achieved by one-flask procedure. Thus, the reactions of indole (1 0 a), skatole (1 0 b), and carbazole ( 1 0 c) with 2 at 60—65 °C gave consistently higher yields of 52—62 percent of products than those obtained with 1. It was found that raising or lowering of the reaction temperature or extending the reaction time for 1 or 2

caused neither a decrease in yield using 2 nor a change in yield using 1 (Table I).

Although a series of C-amino derivatives of indole and carbazole derivatives are known [1 1 , 1 2 ], surpris­

o u c O OP H / K O H6 0 - 6 5 ° C / 3 h * OX

10a: R 1 = r 2 = h

10b: r 1 = c h 3; r 2 = H

10c: R 1 R 2 = CH = CH— CH = CH

11a1 1 b1 1 c

Scheme V .

ingly, the information concerning the synthesis and uses of N-amino derivatives is rather scanty in spite of the fact that this type of derivatives should com­prise desirable starting materials for a variety of products, including novel heterocyclic compounds [13,14], The low activity in this field could be attri­buted to a lack of good one-step methodologies for the preparation of N-amino derivatives of indoles and carbazoles. In the past, several N-amino indoles were prepared [13,14] in 30—40 percent yield using 1 in the presence of a base. In contrast, N-amino car­bazole was synthesized [15 — 17] by a two-step route via the N-nitrosocarbazole which was then reduced either with lithium aluminium hydride [15], lithium borohydride [15], a titanium(II) reagent [16], or zink dust and acetic acid [17]. Hence, it is felt that the preparation of amino indoles (1 1 a, b) and amino car­bazole (1 1 c) using 2 is an improvement over the pre­vious methods [15 — 17],

Conclusions

OD PH lacks the overall versatility of HOSA. However, in some special cases the aminations with O D PH are either as effective, or superior to those using HOSA. In particular, the aminative quarterni­zation at nitrogen and aminations of NH groups of heterocyclic compounds can be achieved in moderate to good yields.

The conversion of secondary and tertiary halides via the lithium or Grignard derivatives results in the amination at carbon to give the corresponding amines in poor to good yields.

Since the preparation of ODPH in quantity from diphenylphosphinic acid chloride and hydroxylamine in the presence of triethylamine is much less hazard­ous than the preparation of HOSA using a 30 percent fuming sulfuric acid, the proposed one-flask amina­tions of indoles and carbazole with ODPH can be­come the method of choice.

G. Sosnovsky—K. Purgstaller ■ O D PH — A Critical Evaluation 585

ExperimentalMaterials

All starting materials were obtained from Aldrich Chemical Company, Milwaukee, WI, and used with­out further purification.

AnalyticalAll melting and decomposition points were ob­

tained using a Thomas Hoover Capillary Melting point apparatus, model 6400 K and a calibrated ther­mometer. Microanalyses were performed on Car­bon, Hydrogen, Nitrogen Perkin-Elmer 240 C Ele­mental Analyzer. Molecular weights were deter­mined on a Hewlett-Packard Mass Spectrometer, model 5985 GS using a direct insertion probe, a source pressure of 2 x l0 ~ 7 Torr, and methane as reactant gas for chemical ionization. Therefore, the molecular weight data ara reported as M + 1. Purity was monitored by both thin layer chromatography using precoated silica gel plates from Merck Chemi­cal Co. and methylene chloride as the eluant, and gas chromatography using a 1 0 % carboxax column of 180 cm length with helium as the carrier gas.

SynthesisPreparation o f O-Diphenylphosphinyl- hydroxylamine (ODPH)

To a mixture of hydroxylamine hydrochloride (3.82 g, 55 mmol) in methylene chloride (100 ml) at —20 °C, was added with stirring triethylamine (12.14 g, 120 mmol) in methylene chloride (20 ml). After stirring at —20 °C for 1.5 h, diphenylphos- phinic acid chloride (11.55 g, 49 mmol) in methylene chloride ( 2 0 ml) was added with stirring and cooling to maintain the temperature at —20 °C. The solution was stirred for another 1.5 h. During this time the reaction mixture attained 25 °C and a precipitate was formed composed of triethylamine hydrochloride and ODPH. To this mixture water was added ( 1 0 0 ml) to dissolve the triethylamine hydrochloride salts, and the remaining ODPH was filtered. This product was washed with anhydrous ether, and dried over phosphorus pentoxide at 25 °C/10 Torr over­night to yield 6.81 g (60%) ODPH, m .p. 133-134 °C (Lit. m .p. 134-135 °C).

Method A

To magnesium (30 mmol) in anhydrous tetrahy- drofuran (10 ml) was added ethylene dibromide (3 drops) to initiate the formation of the Grignard rea­gent. After the start of the reaction, a solution of the halide ( 6 mmol) in tetrahydrofuran ( 1 0 ml) was ad­ded dropwise causing the mixture to reflux. After the

addition was completed, the reaction mixture was boiled with reflux for another 2 h, then cooled to —78 °C. At this temperature a solution of ODPH (3 mmol) in tetrahydrofuran (20 ml) was added. The reaction mixture was allowed to warm to room tem p­erature and stirred overnight. The reaction mixture was concentrated on a rotating evaporator at 35 °C/ 15 Torr. To the residue was added aqueous am­monium chloride ( 1 0 0 ml) and the mixture was ex­tracted with ether (3x50 ml). The aqueous solution was adjusted to a pH 9 with aqueous 40% sodium hydroxide, and re-extracted with ether (3x50 ml). The extracts were dried over anhydrous magnesium sulfate and filtered. Introduction of gaseous hydro­gen chloride into the filtrate gave the corresponding hydrochloride salt of the amine. In the case of the oxalate derivative, to the dried ether extract was ad­ded a saturated solution of oxalic acid in ether. The precipitated oxalate salt was filtered and washed with ether (Table I).

Method BTo a solution of either pyridine or quinoline

(3 mmol) in water (10 ml) at 80 °C, was added in small portions, ODPH (3 mmol). The solution was stirred at 80 °C for 1 h, then a solution of potassium carbonate (3 mmol) in water ( 6 ml) was added drop- wise. Concentration of the mixture on a rotating evaporator at 90 °C/15 Torr gave a residue which was dissolved in absolute ethanol and filtered. To the filtrate was added at —20 °C, 57% aqueous hy- droiodic acid (0.75 ml, 10 mmol). The reaction mix­ture was allowed to stand at —20 °C for 1 h. The precipitated solid was collected by filtration and dried at 25 °C/15 Torr (Table I).

Method CTo a solution of either indole or carbazole

(3 mmol) and KOH (0.051) in dimethylformamide (25 ml), was added a solution of ODPH (5 mmol) in dimethylformamide (25 ml). The reaction mixture was stirred at 60—65 °C for 3 h, then water (100 ml) was added and the solution extracted with benzene (3x50 ml). The benzene extracts were dried over magnesium sulfate and filtered. The filtrate was con­centrated on a rotating evaporator at 35 °C/15 Torr. The oily residue was purified by flash chromatogra­phy on a silica gel column using methylene chloride as the eluant. Removal of the solvent from the com­bined fractions on a rotating evaporator at 35 °C/15 Torr gave the pure products (Table I).

One of the authors (K. P.) would like to thank the Graduate School of the University of Wisconsin-Mil­waukee for a research assistantship.

586 G. Sosnovsky—K. Purgstaller • O DPH — A Critical Evaluation

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