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2007

Effect of N-halosucinimides on 5-, 7- and5,7-8-quinolinol sulfonic acids / Herman Gershon,Muriel Gershon, and Donald D. Clark HardingLaboratory, the New York Botanical Garde,Fordham University, Bronx, New York 10458, USAHerman GershonNew York Botanical Garden. Harding Laboratory

Muriel GershonNew York Botanical Garden. Harding Laboratory

Donald Dudley Clarke PhDFordham University, clarke@fordham.edu

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Recommended CitationGershon, Herman; Gershon, Muriel; and Clarke, Donald Dudley PhD, "Effect of N-halosucinimides on 5-, 7- and 5,7-8-quinolinolsulfonic acids / Herman Gershon, Muriel Gershon, and Donald D. Clark Harding Laboratory, the New York Botanical Garde,Fordham University, Bronx, New York 10458, USA" (2007). Chemistry Faculty Publications. 8.https://fordham.bepress.com/chem_facultypubs/8

-~~ •· e n d s i n I I c t c a· o c y c I i c C' h c 111 i s t ··- y

Vol. 12, 2007

Effect ofN-halosucinimides on 5-, 7- and 5,7-8-quinolinol sulfonic acids Herman Gershon1'*, Muriel Gershon1 and Donald D. Clarke2

1Harding Laboratory, The New York Botanical Garden, and 2Fordham University, Bronx, New York 10458, USA

ABSTRACT

8-Quinolinol 5-, 7- and 5,7-sulfonic acids were treated with N-halosuccinimides (NXS) where the halogen atom was chlorine, bromine or iodine under different conditions of solvent, temperature and time. Under neutral or basic conditions the sulfonic acid group was retained while in dilute acid the S03H group was largely displaced by halogen. Excess NXS caused additional electrophilic substitution. Mild hydrolysis of 5-iodo-8-quinolinol-7-sulfonic acid and 7-iodo-8-quinolinol-5-sulfonic acid with 15% sulfuric acid in acetic acid formed the 5- and 7-iodo-8-quinolinol respectively in high yield.

KEYWORDS: 5-iodo-8-quinolinol, 7-iodo-8-quinolinol, 5-, 7- and 5, 7-8-quinolinolsulfonic acids, reaction with NXS

INTRODUCTION

We have found that methods employing N-halosuccinimides (NXS) where X = Cl, Br, or I were superior halogenating agents to the classical methods using elemental halogens. Mixed halogen containing agents were not as convenient or efffective. Since 5-, 7- and 5,7-8-quinolinol sulfonic acids were available [ 1] as well as a number of halogenated products of the 8-quinolinol sulfonic acids prepared by different halogenating agents, we did a study comparing the NXSs with other halogenating agents. The

*Deceased Feb 5, 2007

object was to determine conditions of halogenation and formation of by products [2-5]. A review of the literature described the preparation of halo-8-quinolinol sulfonic acids and some by products [ 6]. Other studies on the halogenation of 8-quinolinol, its copper(II) biscomplex and 8-methoxyquinoline, showed that the prototropic form, temperature, concentration of halogen and solvent medium control the orientation of the incoming halogen [2, 7, 8]. The data here are a compilation of results obtained at different times rather than a systematic study. However it yields conclusions regarding the orientation of incoming electrophiles, and the displacement of sulfonic acid substituents under certain conditions.

MATERIALS AND METHODS

All compounds in this study are in Table I and are identified by reference. Their structures are shown in Schemes 1-3. It should be noted that the results obtained in the present work are based on isolated product yields and not on identifications of materials resulting from gas chromatographic data [2, 7, 8]. Since all of the products in this study were known, identifications were made by melting points, mixed melting points and in many cases by 1H NMR spectra. Methods employed in carrying out these reactions are found in the corresponding references in Table 1. This work is concerned with 8-quinolinols in which the sulfonic acid substituents are in the 5 7 or 5 7

' ' ' positions. Washings of reaction mixtures were evaporated in most cases, and residues were identified.

Table 1. Halogenation of 8-quinoJinol sulfonic acids with N-halosuccinimides (NXS). X= Cl, Br, I and other halogenating agents.

8-Quinolinol-sulfonic acids and substituents

Ratio of NXSto substrate

-3-CI-5-S03H (la) [2] NCS = 1:1

-6-Cl-5-S03H (I b) [5] NCS = 1:1

-5-S03H (5a) [2] a NBS= 1:1

-5-S03H (5a) [2] a NBS= 2:1

-1-S03H (5b) [1] a NBS=2:1

-5,7-(S03H)2 (5c) [l]b NBS= 1:1

Solvent medium, temperature

H20 (KOH), pH 7, r.t., 0.5 h

H20 (KOH), pH 7, r.t., 0.5 h

H20 (KOH), pH 7, r.t., 0.5 h

Sulfonic acid, substituents, Quinoline byproducts, yield, mp substituents, yield, mp

3, 7-CI2 -5-S03H, (2) [2], 3,5, 1-Cl3, (3) [2], 9%,

0 85%, 322-5 dec 149-150°

Other method, sulfonic acid, yield, mp

NONE

6, 7-Cl2 -5-S03H, ( 4) [5], 5,6,7-Cl3 ( 4a) [5], 20%, NONE

0 66%, 182-3 dec 213-214 °

7-Br-5-S03H (5t) [2], NONE H20 (KOBr), pH 7

0 95%, 280-2 dec. 0

[2], 66%, 280 dec.

0 CH3CN, AcOH (1: l), heat 60 , NONE 5, 7-Br2 (6), [6], 100%, NONE

10 min 202-7 °

0 CH3CN, AcOH (1 :1), heat 60 , NONE 5,7-Br2 (6), [6], 89%, NONE

10 min 195-196 °

0 CH3CN, AcOH (1 :1), heat 60 , NONE 5,7-Br2 (6), [6], 48%, NONE

10 min 195 °

0\ 00

:I: (1)

8 ~ a (1) .., en ::r 0 ::s ~ -~ ~

Table I continued ..

-3-Br-5-S03H (5d) [3] NBS= l: 1

-6-Br-5-S03H (5e) [3]

-7-Br-5-S03H (5f) [9]

-1-S03H (5b) [1]

-5-I-7-S03H (9g) [1]

d -7-I-5-S03H (9)

d

NBS= 1:1

NBS= l:l

NIS =(I: 1)

NONE

NONE

H20 (KOH), pH 7, r.t., 0.5 h 3.7-Br2-5-S03H (5g) [3],

0 56%, 320-1 dec

H20 (KOH) pH 7, r.t., 0.5 h 6.7-Br2-5-S03H (5h) [3],

54%, 194-8 dec

95% aq CH30H, r.t., 7 days 7-Br-5-S03H (5f) [3] 66%,

290-300 dec

95% aq CH30H, r.t., 24 h 5-I-7-S03H (9g) [1] 89%,

0 274-5 dec

15% H2S04, AcOH (w/v), NONE

heat until in solution

15% H2S04, AcOH (w/v), NONE

heat25 h

a Where no reference is given, the work was not previously reported

b Lit m.p. 195-6 [6, p 711]

c Ox= 8-quinolinol

d 5- and 7 -iodo-8-quinolinols after corrections of previously assigned structures [9-11]

acetone washings not

evaporated

acetone washings not

evaporated

5,7-Br20x (6), [6], 10%,

196 °

NONE

5-IOxd (12) [11]. 90%,

107-8 °, Ox c (11), [5]

10%, 75 °

7-IOx d (1 0) [11]. 72%,

122-3 °, Ox c (11), [5]

9%,75°

NONE

NONE

NONE

same procedurea

with ICI (9g),

0 72%. 274-5 dec

NONE

NONE

::c: ~ -0 I

00 I

..c s:: -· ::::s 0 --· 0 0 -C/l

~ 0.. C/l s:: -~ = -· (")

~ (") -· 0.. C/l

70

A

OH 1

Cl Cl

Herman Gershon et al.

1: A-D=H

1 a: A= Cl; B- D = H

1 b: C= Cl; A, B, D = H

1 NCS H 20 (KOH) pH7

OH OH lb OH 4

I NCS H 20 (KOH) + pH 7

y

Cl Cl +

Cl Cl Cl

OH OH 3 OH 4a 2

Scheme 1

RESULTS

When 3-chloro (la) or 6-chloro-8-quinolinol-5-sulfonic acids (l b) in the anionic form were further chlorinated with NCS at room temperature the ?-substituted products were obtained along with significant yields of by products 3,5, 7- (3a) and 5,6,7-trichloro-8-quinolinols(4a). Similarly upon bromination with NBS, 8-quinolinol-5-sulfonic acid (Sa) yielded 95% of the 7-bromo product (Sf) and no by-product. By treating the 8-quinolinol-5-sulfonic acid (Sa) with two equiva­lents of NBS to one of substrate in a mixture of acetonitrile, acetic acid ( 1:1) no sulfonic acid was obtained, and 100% of 5,7-dibromo-8-quinolinol (6) was the sole product. The ?-sulfonic acid (Sb) under the same conditions yielded 84% of 6. 8-Quinolinol-5,7-disulfonic acid (Sc) when treated with NBS in ( l: 1) ratio in the same solvent mixture afforded (6) in 48% yield, and no other

products were obtained. Upon bromination 3-bromo (5d) and 6-bromo-8-quinolinol-5-sulfonic acid (5e) in the anionic forms, the 7-bromo products 5g and 5h formed in 56% and 64% respectively. Not having worked up the washings might explain the relatively low yields of sulfonic acids.

When 7-bromo-8-quinolinol-5-sulfonic acid (5f) was treated with NBS (1: 1) in 95% aqueous methanol for seven days at room temperature, 66% 5g and 10% 5, 7-dibromo-8-quinolinol (6) were obtained. Upon reacting 8-quinolinol-5-sulfonic acid (Sb) with NIS (1:1) in aqueous methanol 89% 5-iodo-8-quinolinol-7-sulfonic acid (9g) was obtained. Using the same procedure with iodine monochloride in place of NIS 72% of 9g was formed. Hydrolysis of 9g with 15°/o sulfuric acid in acetic acid with heating until all of the substrate went into solution, yielded 90% 5-iodo-8-quinolinol (12) and 10% of 11. When

•

Halo-8-quinolinols and sulfonic acids

OH 5a

H20 (KOH) pH 71NBS

Br

Br

OH 5f

OH 5e

OH 5

2NBS CH~N Ac0H(l:1)

Br

A

OH 5b

2 NBS CH 3CN AcOH ( 1: 1)

OH 1 NBS CH 3CN

Ac OH (1 : 1) 60 ° 0 3H

1 NBS H 20 (KOH)

heat 6rf

OH

OH

Scheme 2

5c

5h

Sa: E =S03 H~ A. C,D =H 5b: D= S03H~A. C,E=H Sc: E, D = S03H; A. C = H 5d: E- S03 H~ A= Br; C, D- H Se· E = SO H · C = Br· A D = H . 3 , , ,

Sf E=S03H: D=Br~A,C=H Sg· E =SO H A D = Br C = H . 3 , ' ' S h: E = S O:J H ; C, D = Br; A = H

Br

Br

OH 5d

H 20 (KOH)

pH 7NBS 1h

OH 5g

Br

15% H2S04 AcOHheat 4h

Br

OH ?

h­N

Br

71

72

D

OH 9

I

OH

9

I

AcOH (w/v) heat 24 h

15% H 2S04

9: E = S03H; D = I

9g: E = I, .D = S03H

I

OH

I

,......

10

Herman Gershon et al.

+

OH

11

+ 11 H03S. AcOH ( 1:1 wlv)

OH heat until dissolved OH

9g 12

Scheme 3

7-iodo-8-quinolinol-5-sulfonic acid (9) was the substrate and heated three hours as 9g, the products were 72% 7-iodo-8-quinolinol (10) and 7o/o of 11.

DISCUSSION

The sulfonic acid group has often been used as a protective group in the synthesis of aromatic compounds because it is readily replaced by H+ on heating in dilute acid ·solution. It can also be replaced by electrophiles other than W, e.g. Br+ and Cl+. Thus treatment with NCS or NBS in dilute acid solution leads to replacement of the S03H group by halogen. Examples in this work are Sa, 5b and 5c being converted to 6 and 5g to 7 (cf Scheme 2).

When the aromatic sulfonic acid is neutralized the resulting S03- is a good nucJeophile and hence a poor leaving group. Thus halogenation after neutralization with KOH leads to retention of the

S03H group, while the halogen attacks other positions activated for electrophilic substitution. Examples in this work are 1a to 2, 1 b to 4, ( cf Scheme 1) Sa to Sf, Sd to 5g, and Se to 5h ( cf Scheme 2). The yield of by-products is distinctly greater with NCS than with NBS. This suggests that under altered reaction conditions NCS might yield fewer side products.

While Cl or Br substituents on an aromatic ring are not readily replaced by an entering electro­phile, an iodo substituent may be replaced. Thus on removal of a S03H group under conditions where Cl or Br substituents are unaffected, iodine can be ren1oved, e.g. by heating . for 24h in 15°/o H2S04, acetic acid (1: I) 7-iodo-8-quinolinol 5-sulfonic acid (9) is converted to 8-quinolinol (11 ). However on heating 9 for 3h, iodine is retained to give 7-iodo-8-quinolinol (10) in 90°/o yield. Similarly 5-iodo-8-quinolinol-7-sulfonic acid (9g) is converted to 5-iodo-8-quinolinol (12) in 72% yield (cf Scheme 3 and Table 1).

..

..

•

Halo-8-quinolinols and sulfonic acids

REFERENCES

1. Gershon, H., and McNeil, M. W. 1971, J. Org. Chern., 36, 3494.

2. Gershon, H., and McNeil, M. W., and Grefig, A. T. 1969, J. Org. Chern., 34, 3268.

3. Gershon, H., Clarke, D. D., McMahon, J. J., and Gershon, M. 2002, Monatsh Chern., 133, 833.

4. Gershon, H., Clarke, D. D., and Gershon, M. 2001, Monatsh Chern., 132, 1075 .

5. Gershon, H., Clarke, D. D., and Gershon, M. 1999, Monatsh Chern., 130, 653.

6. Hollingshead, R. G. W. 1956, Oxine and its Derivatives Vol III Part 1, Butterworth

73

Scientific Publications London, pp 841-843, 844-5, 847-8.7.

7. Gershon, H., McNeil, M. W., and Schulman, S. G. 1971, J. Org. Chern., 36, 1616.

8. Gershon, H., McNeil, M. W., and Schulman, S. G. 1972, J. Org. Chern., 37, 4078.

9. Ramelo, C. T., Faez, R., Ribeiro, C. A., and Crespi, M. S. 1995, Eclectica Quim., 20, 40.

10. Shoja, M., Gershon, H., and Clarke, D. D. 2000, Zeit Kristall., 215, 273.

11. Clarke, D. D., Gershon, H., Shoja, M., and Yen, M-W.1998, Monatsh Chern., 129,419.

12. Gershon_, H., and Clarke, D. D. 2005, Trends Heterocycl. Chern., I 0, 67 .