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N-Aryl-O-acylhydroxylamines Preparation by O-Acylation or N O Transacylation and Reaction with Amines; Model Reactions for Key Steps Connected with the Carcinogenicity of Aromatic Amines.

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[I21 The use of (.Z-benzyl I-butenyl ether gave the corresponding cycloadducts in comparable yield but with lower selectivity.
1131 L. F. Tietze, U. Beifuss, Angew. Chem. 97 (1985) 1067; Angew. Chem.
Int. Ed. Engl. 24 (1985) 1042.
1141 e.xo/endo, position of the OR group relative to the heterodiene; E/Z,
configuration of the reacting heterodiene, the reacting CO group hereby
has a higher priority than the nonreacting CO group; anti/syn position
of the H atoms at the prostereogenic centers between which C-C bonds
are to be formed.
1151 The descriptors Re and Si refer to the absolute configuration of 5 given
in the formulas. Cf. V. Prelog, G. Helmchen, Angew. Chem. 94 (1982)
614: Angew. Chem. I n t . Ed. Engl. 21 (1982) 567.
[I61 L. F. Tietze,T. Brumby, M. Pretor, G. Remberg, J. Org. Chem. 53(1988)
810; G. Desimoni, G. Colombo, P. P. Righetti, G. Tacconi, Tetrahedron
29 (1973) 2635; cf. also L. F. Tietze, S. Brand, T. Pfeiffer, J. Antel, K.
Harms, G. M. Sheldrick, J. Am. Chem. SOC.109 (1987) 921.
1171 8 a : 'H-NMR (200 MHz, C2D2C14,lOO"C, TMS): 6=0.93 (t, J = 7 Hz;
3H, 18-H,), 1.0-3.0 (m; 8 H , 6-H2, 14-H2, 15-H, 19-H2, 20-H), 3.19 (s;
3 H , N-CH,), 3.37 (s; 3H, N-CH,), 3.43 (m; 1 H, 5-H,,), 4.43 (dd,
J = 13.5 Hz, J=4.5 Hz; 1 H, 5-H,,), 4.75 (d, J = 12.5 Hz; 1 H, OCH>Ph),
4.85 (d, J = 12.5 Hz; 1 H, OCH,Ph), 5.10 (m; 2H, OCOCH2Ph), 5.26 (d,
J=5.2 Hz; I H, 21-H), 5.81 (dd, J=7.0 Hz, J=3.5 Hz; I H, 3-H), 6.977.46 (m: 14H, phenyl-H), 8.83 (s; 1 H, NH). The structural assignment of
8c and 8d is based on the signal for 21-H in 8c (6=5.30, J20.H.ZI.~=9.0
H < 1 Hz). Thus, H-20 and H-21 occupy
Hz) and 8d (6=5.39, J Z ~2.i .H
trans-diaxial positions in 8c and trans-diequatorial positions in 8d.
Since the substituent at C-15 always is in a pseudoaxial position, the
ethyl group and the substituent at C-I5 in 8c must have a cis arrangement and those in 8d a trans arrangement. l l a : 'H-NMR (200 MHz,
CDCI,/CD3OD, 2 0 ° C TMS): 6=0.81 (t, J=7.0 Hz; 3 H, 18-H,), 0.9-3.8
br,J=7.5
(m; 13H),3.24(s; 3H, N-CHI),3.34(s;3H,N-CHl),3.90(t
Hz; 1 H, 3-H), 7.00-7.51 (m; 4 H , phenyl-H), 10.52 (s br; NH); "C-NMR
(50 MHz, CD,OD, 20"C, TMS): 6=11.17 (C-18), 20.30 (C-6), 24.88 ( C 19), 27.74 (N-CH,), 28.50 (N-CHI), 32.64 (C-l4), 38.03 (C-15), 53.74
(C-5).59.98 (C-21). 63.04 (C-3), 88.92 (C-l6), 106.35 (C-7), 112.52 (C-l2),
119.1 1 (C-9), 120.66 (C-Il), 123.43 (C-lo), 127.34 (C-8), 130.60 (C-2),
138.38 (C-13), 154.74 (CO), 164.60 (CO), 165.90 (CO). The assignment of
the signals was made in analogy to the work of E. Wenkert et al. as well
as of F W. Wehrli and T. Nishida: E. Wenkert, J. S. Bindra, C.-J. Chang,
D. W. Cochran, F. U. Schell, Arc. Chem. Res. 7 (1974) 46; F. W. Wehrli,
T.Nishida, Fortschr. Chem. Org. Naturst. 36 (1979) 1.
[ 181 P. Deslongcharnps: Stereoelectronic Effects in Organic Synthesis, Pergamon Press, Oxford 1983, p. 209ff.
[I91 G. M. Sheldrick, J. Antel, J. Bachmann, L. F. Tietze, unpublished results.
1201 L. F. Tietze, J. Bachmann, unpublished resuits.
N- Aryl-0-acylhydroxylamines:
Preparation by 0-Acylation or N+ 0 Transacylation
and Reaction with Amines; Model Reactions for
Key Steps Connected with the Carcinogenicity of
Aromatic Amines**
By Gernot Boche.* Ferdinand Bosold, and Stefan Schroder
The following reaction steps are considered to be important for the transformation of a n aromatic amine into the
active metabolite (ultimate carcinogen) and its decisive
further reaction with bionucleophiles:"]
After oxidation of the amine 1 to the hydroxylamine 3
or of the acetamide 2 t o the hydroxamic acid 4, O-acetylation of 3 o r N - 0 transacetylation of 4121should lead to
the N-aryl-0-acetylhydroxylamine 5, a n active metabolite.
It is assumed that such compounds react in the next step as
electrophilic aminating reagents with bionucleophiles like
D N A to give "adducts".I'] Herein we report on the in-vitro
preparation of o-acyl derivatives of type 5 from 3 or from
acylhydroxyamic acids such as 4,and on the reaction of 5
with nucleophiles.
[*] Prof. Dr. G. Boche, F. Bosold, DipLChem. S. Schroder
Fachbereich Chemie der Universitat
*
Hans-Meerwein-Strasse, D-3550 Marburg (FRG)
[**I This work was supported by the Fonds der Chemisfhen hdustrie, by the
Deutsche Forschungsgerneinschaft, and by BASF AG.
Angew. Chem.
Int.
Ed. Engl. 27 11988) No. 7
/
Avl-N
1
\
H
L
,
-
Avl-N
H
H
Avl-N
/
\
COCH,
2
H
oxidation
oxidation
3
/
L
\
Avl-N
/
\
COCH,
4
OH
0 -acetytation
5
Avl-N
/
H
bionucleophile
adduct
___3
\
OCOCH,
First of all we prepared the 0-acylhydroxylamines 5aa,
sap, 5ba, and 5bp by 0-acylation of the corresponding
hydroxylamines 313-51
and investigated their reactivity towards the amines 6 and 7. The h y d r a ~ i n e s ' ~ 8. ~ and
'
9,
respectively, are formed. The results are summarized in
Table 1.")
i
a : R' = rn-Br
a: R2 = CH,
b: R'
,9: R2 = C(CH,),
= H
Table I. Reactions of the 0-acyl compounds 5 with the amines 6 ( 5 : 1.0 M in
6 ) or 7 ( 5 : 0.93 M in 7) to give the hydrazines 8 and 9 , respectively.
No.
5
R'
R2
Arnine Hydrazine
[W
5aa
5aa
5aa
Sap
Sap
5ba
5ba
5bB
5bP
m-Br
m-Br
m-Br
m-Br
m-Br
H
H
H
H
CH,
CH,
CHI
C(CH,),
C(CH,),
CH,
CH,
C(CH,),
C(CHa),
6
6
7
6
7
6
7
6
7
8 , 40
8, 16
9, 88
8,67
9,85
8.27
9,90
8, 20
9, 50
T
I"C1
55
20
80
55
20
20
20
20
20
t
[hl
Byproduct
A lo4 la1
0.5 [bj
20
I [c]
1 [c]
72
5
55
77
14
-
73
5
-
16
16
72
45
[a] A = azoxy compound R'-C,H,-N=N"(O')-C,H.-R'
[5b, 91. [b] 5aa
was added in 6 , which had been heated to 55°C. [c] The reaction partners
were heated together.
The amination of N-nucleophiles by O-acylhydroxylamines 5, especially by the 0-acetyl compounds 5aa and
5ba,thus affords an in-vitro proof for the in-vivo reaction
of this class of compounds with bionucleophiles.". I'
In addition, we were able to simulate in vitro the enzymatic N - t 0-transacetylation 4a --+ 5alZ1by amine catalysis.
0 YCH Verlagsgesellschaft mbH. 0-6940 Weinheim, 1988
0570-0833/88/0707-0973 $ 02.50/0
973
To this end hydroxamic acids 4 were allowed to react with
diethylamine 6 (pK, = 18.75["]) and the intermediary 0acylhydroxylamines 5 were trapped by the same amine to
give the hydrazines 8. In a second series of experiments
the hydrazines 9 could likewise be obtained from the corresponding hydroxamic acid 4 by reaction with the less
basic N-methylaniline 7 (pK, ca. 1 11"]), but only after trzethylamine (pK, = 18.46["]) had been introduced for the catalysis of the N-0-transacylation (see Table 2).
Table 2. Reactions of hydroxamic acids 4 with the amines 6 ( 4 : 1.0 M in 6)
or 7 ( 4 : 0.83 M in a 1 : I mixture of 7 and triethylamine) to give the hydrazines 8 and 9 , respectively.
No.
R'
4
1
2
3
4
4aa
4aa
4ap
4ap
5
4ba
6
7
8
4ba
4bp
4bp
[a] E
=
m-Br
m-Br
m-Br
m-Br
H
H
H
H
R'
CH3
CH3
C(CH,),
C(CH,),
CHI
CH,
C(CH,)>
C(CH,),
Amine Product
[W
6
7
6
7
6
7
6
7
8 , 84
9, 85
8, 92
9,94
8,49
9,62
8 , 80
9, 95
T
["Cl
55
80
55
80
55
80
55
80
f
Ihl
Byproduct
E I%] Ial
40
68
8
2
30
30
20
2
Educt
If the rate of formation of the 0-acylhydroxylamine 5 is
rapid, i.e. compared to its back reaction to the hydroxamic
acid 4 and to any further reaction, it can be isolated. Thus,
on treatment of the hydroxamic acid 4 4 with triethylamine at 80°C for 1 h the 0-pivaloylhydroxylamine 5aS
The higher stability of the 0is obtained in 95%
pivaloyl derivative compared to the N-pivaloyl derivative
was confirmed by M N D O calculations: according to the
enthalpies of formation A#, 5bS (-25.2 kcal mol-') is
preferred over 4bJ3 (-20.1 kcal mol-') by AA#=5.1
kcal mol-'.
Contrary to this finding, in the case of the acetyl compounds occurring in vivo the hydroxamic acid isomers are
more stable. This was demonstrated by the reaction of 5aa
with two molar equivalents of 1,8-diazabicyclo[5.4.O]undec-7-ene (DBU), the most effective amine catalyst
(pK, = 24.32'1'1),['2' in triethylamine, which led after 10 min
at 20°C to 4aa in 98% yield. This experiment also proves
the presence of an equilibrium, at least between 5aa and
4aa. The preferred formation of the acetylhydroxamic acid
compared to the 0-acetyl compound was again confirmed
by the M N D O enthalpies of formation: 4ba (A@= -21.0
kcal mol-') is 5.7 kcal mol-' stabler than 5ba (AH:=
-15.3 kcal mol-I). It is therefore not surprising that all
attempts to convert 4aa and 4ba with DBU (in triethylIn
amine) into 5aa and 5ba respectively, were in
view of the in-vivo finding mentioned at the outset, however, it is decisive that acetylhydroxamic acids such as 4aa
and 4ba can react via small equilibrium concentrations of
the active metabolites 5aa and 5ba respectively with nucleophiles to give a d d u c t ~ . [ ' ~ ~
Summary: The N-aryl-0-acylhydroxylamines 5 described here can be prepared in vitro by 0-acylation of the
corresponding hydroxylamines 3 and by N- O-transacylation from the corresponding hydroxamic acids 4 ; they
react with amines to give hydrazines such as 8 and 9.
Hence, reactions which are of fundamental importance for
the carcinogenicity of aromatic amines could be simulated
in vitro.
974
0 VCH Verlagsgeseilschaff mbH, 0-6940 Weinherm, I988
Received: February 11, 1988;
supplemented: April 20, 1988 [Z 2617/2618 I€]
German version: Angew. Chem. 100 (1988) 965
CAS Registry numbers:
4aa, 38373-20-5; 4ap, 114838-67-4; 4ba, 1795-83-1; 4b0, I 11750-22-2; 5aa,
114838-63-0; sap, 107986-35-6; 5ba, 71825-04-2; 5b0, 114838-64-1; 6, 109-
89-7; 7, 100-61-8: 8a, 114838-65.2: 8b, 39837-50-8; 9a, 114838-66-3: 9b,
37682-91-0; Aa, 23377-24-4; Ab, 495-48-7.
[I] a) J. A. Miller, Cancer Res. 30 (1970) 559; b) E. Kriek, Biochim. Biophys.
Acta 335 (1974) 177; c) E. Miller, Cancer Res. 38 (1978) 1479; d ) E. C.
Miller, J . A. Miller, Cancer (Amsterdam) 47 (1981) 2327; e) S . S . Thorgeirsson in H. Greim, R. Jung, M. Kramer, H. Marquard, F. Oesch
(Eds.): Biochemical Basis of Chemical Carcinogenesis, Raven Press, New
York 1984, p. 47.
[2] a) G. Booth, Biochem. J . 100 (1966) 745: b) F. A. Beland, W. T. Allaben,
F. E. Evans, Cancer Res. 40 (1980) 834; c) W. T. Allaben, C . C. Weiss, N.
F. Fullerton, F. A. Beland, Carcinogenesis (Londonj 4 (1983) 1067; d) C
M. King, N. R. Traub, Z. M. Lortz, M. R. Thissen, Cancer Res. 39 (1979)
3369; e) V. C. Marhevka, N. A. Ehner, R. D. Sehon, P. E. Hanna, J .
Med. Chem. 28 (1985) 18, and references cited therein; f) see [le], and
references cited therein; g) W. Lenk, Lecture at the 2nd European Meeting of the International Society for the Study of Xenobiotics, Frankfurt,
March 21LApril 3, 1987.
131 Details o n the preparation of 5aa, 5ap, 5ba, and 5bp as well as other
N-aryl-0-acylhydroxylaminesby acylation of hydroxylamines 3 with
acetyl or pivaloyl cyanide will be given in a full paper.
141 All the new compounds were characterized analytically (C,H,N), mass
spectroscopically and IR spectroscopically or by their 400-MHz ' H NMR spectra.
[51 Numerous attempts have been made to synthesize N-aryl-0-acylhydrox.~
ylamines because of their importance in connection with the carcinogenicity of aromatic amines, but very few have been successful: a) N-acetoxy-2,4-dinitrophenylamine:
W. Borsche, Chem. Ber. 56 (1923) 1494; A.
C. Huggett, J. L. Cone, S. S. Thorgeirsson, P. P. Roller, J . Org. Chem. 52
(1987) 4933; b) the 0-acylation of the arylhydroxylamines 3 with arylcarbonyl o r acetyl cyanides has so far been the favored general method:
S. Prabhakar, A. M. Loho, M. M. Marques, Tetrahedron Let?. 23 (1982)
1391; A. M. Lobo, M. M. Marques, S. Prabhakar, H. S. Rzepa, J . Chem.
SOC.Chem. Commun. 1985. 1113; J . Org. Chem. 52 (1987) 2925; c ) N(3-bromophenyl)-O-pivaloylhydroxylaminesap: M. Novak, L. H. Rovin, M. Pelecanou, J. J. Mulero, R. K. Lagerman, ibid. S2 (1987) 2002:
see also: d) T. R. Juneja, H. Dannenberg, Tetrahedron 31 (1975) 701; e)
E. S. Hand, W. W. Paudler, J. ffeterocyci. C/rem. 12 (1975) 1063; f) Y .
Kawazoe, 0. Ogama, G.-F. Hung, Tetrahedron 36 (1980) 2933; g ) L.
Christensen, P. E. Iversen, Acfa Chem. Scand. 8 3 3 (1979) 352; h) Y.
Hashimoto, K. Shudo, T. Okamoto, J . Am. Chem SOC.104 (1982) 7636;
I) T. R. Juneja, A. Ojha, R. L. Gupta, Indian J . Chem 2 3 5 (1984) 60; j)
M. Demeunynck, M.-F. Lhomme, J. Lhomme, J . 0 r g . Chem. 48 (1983)
1171; k) M. Demeunynck, N. Tohme, M.-F. Lhomme, J. M. Mellor, J.
Lhomme, J. Am. Chem. SOC.108 (1986) 3539.
a) Hydrazines have also been observed in reactions of N-aryl-0-(diphenylphosphinoy1)hydroxylamines with amines: see G. Boche, R. H. Sommerlade, F. Bosold, Angew. Chem. 98 (1986) 563; Angew. Chem. Int. Ed
Engl 25 (1986) 562: b) see also [5h].
Orfho rearrangement products such as frequently occur in the case of
N-aryl-0-acylhydroxylamines,or products in which the amine is in the
phenyl ring [81, were not observed under the above reaction conditions.
See [5b, c]. and references cited therein.
The formation of the azoxy compounds A in reactions of arylhydroxylamine derivatives is sufficiently well known; see also P. A. Smith:
Open Chain Nitrogen Compounds. Vol 2, W. A. Benjamin, Menlo Park
1966, p. 4.
P. D. Lotlikar, M. B. Wasserman, Biochem. J . I20 (1970) 661, and references cited therein.
The pKJ values of diethylamine and triethylamine in acefonirrih are
quoted in J. F. Coetzee, G. R. Padmanabhan, J . Am. Chem. Soc. 87
(1965) 5005. The pK, value for N-methylaniline in aretonrfrile has not
yet been determined: it therefore had to be estimated from that for aniline (10.56). We thank Dr. R . Schwesinger, Universitat Freiburg, for his
help. The pK, value for DBU in acetonitrile has already been reported:
R. Schwisinger, Angew. Chem. 99 (1987) 1209: Angew. Chem. In/. Ed.
Engl. 26 (1987) 1164.
Catalysis by DBU, cf. 13).
If one assumes that AA#=5.8 kcal mol-' corresponds to the AGO
value at 25°C. only 6 x 10-% of the 0-acetyl compound 5ba is present
in the equilibrium besides acetylhydroxamic acid 4ba.
The amine-catalyzed transacylation proceeds intramolecularly, as demonstrated by crossover experiments and kinetic investigations.
0570-0833/88/0707-0974 $ 02 50/0
Angew. Chem Inf Ed Engl 27J1988) No 7
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