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N-Aryl-O-(diphenylphosphinoyl)hydroxylamines Electrophilic Amination of Amines to Hydrazines; a Model Reaction for the Carcinogenicity of Aromatic Amines.

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Chim. Pays Bas. 101 (1982) 317, S. 323, Fig. I ) into the vapor phase and
thermolyzed at 55O'CiIO-' mbar in a quartz tube. The anthracene 3
formed during thermolysis separated out in the cooler portion of the
tube, while the 1,3,2-dioxaboroles 7a-e were collected in a cold-trap.
Yield 95%: consistent 'H-NMR, "C-NMR, MS, and elemental analysis
data. Representative ' H - N M R and "C-NMR data of the vinylic protons
and C atoms (CDCIJTMS): S('H)/S(''C): 7a: 6.93/132.75; 7b: 6.76i
132.57; 7c: 6.99/133.33; 7 d : 7.08/133.14; 7e: 7.06/132.57.
151 Ratio of amounts determined by "C-NMR spectroscopy. The yields obtained upon reaction of 7c with acetaldehyde (8f) (molar ratio 1 :2) are:
10%1of 9f + IOf, 40% of 13, 20% of the products by triple addition of 7c,
30% of unidentified high molecular addition products. By using a large
excess of 8f, yields of up to 30% of 9f 10f could be obtained.
161 Copolymer 14 : Preparation by radical polymerization from styrene, 12%
m-diisopropenylbenzene,2.5% 2-(4-vinylphenyl)- I ,3,2-dioxaborolane.
171 1:Ribose: [a],, 18.8 (c= 1.5, H20); W. A. Van Ekenstein, J. J. Banksma,
Chem. Weekbl. 6 (1909) 373.
[8] a) M. Cherest, H. Felkin, N. Prudent, Terrahedron Leu. 1968. 2199; b) N.
T. Anh, Top. Curr. Chem. 88 (1980) 145.
[9] When carried out in the D-series, the very elegant synthesis described by
Sharpless and Masamune et al. (A. W M. Leej, V. S. Martin, S. Masamune, K. B. Sharpless, F. J. Walker, J. Am. Chem. SOC.I04 (1982) 3515),
using 2,3-O-isopropylidene-(R)-glyceraldehydeas starting material gave
the protected D-ribose derivative in a five-step reaction (42% yield).
We report here on the reaction of the N-aryl-0-(diphenylphosphinoyl)hydroxylamines 519]with the amines 6. In
contrast to 3a-e, neither a rearrangement to the o-aminophenol derivatives nor a reaction of the nucleophile with
the phenyl ring of 5 was observed. Instead, exclusive electrophilic amination to give the hydrazines 7 took place
(Table l).['ol
+
+
N- Aryl-0-(diphenylphosphinoy1)hydroxylamines :
Electrophilic Amination of Amines to Hydrazines;
a Model Reaction for the Carcinogenicity of
Aromatic Amines**
By Gernot Boche,* Reinhard H . Sommerlade, and
Ferdinand Bosold
The carcinogenicity of aromatic amines Aryl-NH2 is due
to their reactive metabolites, the N-arylhydroxamate esters
1 and the N-arylhydroxylamine esters 2, which react with
nucleophilic centers in nucleic acids and peptides.",*'
Aryl-N(COCH3)-OX
Aryl- N H-OX
1
50,
R'
=
H; 5b, R'
= p-Cl;
5c, R' = rn-CN; 5d, R' = p-CH,
Table I . Reaction of the N-aryl-0-(diphenylphosphinoy1)hydroxylamines
5a-d with the amines 6 to give the hydrazines 7 [a].
R'
No.
R'
R2
I
2
3
4
5
6
7
8
9
10
I1
12
13
14
15
16
17
18
19
H
H
H
H
H
H
H
H
p-CI
p-CI
m-CN
p-CH,
H
H
H
H
H
H
n-CdHy
H
CH2C6Hs
H
CH2C02C2H5
H
c - C t I~
H
H
CH(CH312
C6Ha-C02C2H$-(m)
H
C6H4-C0,C2H5-@)
H
C,H,-CH,-(o)
H
C,H,FeC,H,
H
H
C6H4-COZC2HS(m)
C6Ha-CH,-(o)
H
H
ChHs
CsH1
H
CH,
CHI
C~HS
CH?
n-C,HU
C~HS
H>C-CH=CHZ
HlC-CH=CH>
H2C-C-CH
CH,
- C H S H > O C H C H --
20
H
85
21
22
23
24
25
26
H
H
H
H
p-CI
m-CN
58
60
34
60
87
62
H
Yield [%]
45 LbI
46 Icl
38
25
0
94
32
83
54
97
93
94
40
80
56
85
69
80
48
2
X = SOY, COCH,, PO:'
The rearrangement of the species 3a-d to the o-aminophenol derivatives 4a-d[3",4.5.6a-c1
is
. regarded as confirmation13"]that the nitrenium (aminylium) ion Aryl-fi-R is
the ultimate carcinogen."] Furthermore, it is known that,
upon solvolysis of 3a, R'=p-CH3, in methanol'3b1and of
3e, R'=p-CH3 or p-OCH3, in water,[6d.eithe nucleophiles
attack the phenyl ring of 3.1Ri
[a] The hydrazines 7 were characterized by 'H-NMR spectroscopy-and, if
they were new compounds-by elemental analysis and mass spectroscopy.
[b] Isolated as the azo compound. [c] Isolated as N-benzylidene-N'-phenylhydrazine.
OX
BN:"x
R'
R
R'
R
4
3
3. 4
R
X
Ref.
a
COCH,
H
COCbHS
COCHl
COCH,
S02CH,
S02R"
S02R"
Pal
[41
[51
[6a-c]
[6d, el
b
C
d
e
SO?
COC(CH,h
R'=H, CH,, C02CH3,CF,, CN, CI, Br, OCH,, NO2
[*I
[**I
562
Prof. Dr. G. Boche, DipLChem. R. H. Sommerlade, F. Bosold
Fachbereich Chemie der Universitat
Hans-Meerwein-Strasse, D-3550 Marburg (FRG)
This work was supported by the Fonds der Chemischen lndustrie and
the Deutsche Forschungsgemeinschaft.
0 VCH Verlagsgesellschaft mbH, 0-6940 Weinheim. 1986
Notes to Table 1:
Reactions 1-5: Primary aliphatic amines 6 afford the
hydrazines 7 in only moderate yields; branching at the CLC atom of 6 lowers the yields still further.
Reactions 6-13: Primary aromatic amines 6 give the hydrazines 7 (also called hydrazo compounds) usually in
good yields. Since hydrazo compounds can be easily oxidized to azo compounds,"'] this provides a new route to
symmetric and unsymmetric azo compounds.
Reactions 14-26: With secondary amines 6, trisubstituted hydrazines 7 bearing virtually any substituents RZ
and R3 are formed. In addition, deprotonation and subsequent alkylation can be used to introduce a fourth substituent R4.[l2] In this way, R2, R3, and R4 can be introduced
regioselectively without the use of protecting groups and
N-nitroso compounds and without the formation of hydrazinium salts.
0570-0833/86/0606-0562 $ 02.50/0
Angew. Chem. Inr. Ed. Engl. 25 (1986) No. 6
R
R
I
I
[ 111
[I21
[13]
8a
8b
nc
8d
8e
R
X
COCH3
COCH,
(’OCH,
H
H
H
Po:@
SOY, COCH3
R
9
(141
COCH?, H
ica Acfa 13 (1980) 3; d) W. Klotzer, H. Baldinger, E. M. Karpitschka, J.
Knoflach, Synthesis 1982. 592.
K. H. Schundehiitte in Houben- Weyl-Muller:Methoden der Organischen
Chemie. Band X / 3 , Thieme, Stuttgart 1965, p. 317.
U. Lerch, I. Konig, Synthesis 1983. 157.
P. D. Lotlikar, M. B. Wasserman, Biochem. J. 120 (1970) 661, and references cited therein.
0-Arenecarbonyl-N-arylhydroxylamines:S. Prabhakar, A. M. Lobo, M.
M. Marques, Tetrahedron L e f f .23 (1982) 1391: see also W. P. Jencks, J .
Am. Chem. SOC.80 (1958) 4581.
H
COCH,
Spontaneous Intramolecular Ring Opening of the
Cyclopropyl Group at a
Metal-Metal Double Bond**
For the investigation of the carcinogenicity of aromatic
amines, the N-aryl-0-(diphenylphosphinoy1)hydroxylamines 5 and the reaction of their electrophilic N atom with
amines 6 are important for the following reasons:
1. The compounds 5 are the first models for the product
Sb, which is formed when the extremely carcinogenic N(2-fluoreny1)acetohydroxamic acid 8a (and related compounds) undergo in vivo activation with phosphate.“31
2. N-arylhydroxamate esters such as 3a, c-e and 8b, c
are in general considerably more stable that the corresponding hydroxylamine compounds; 3b is not isolable.
With the synthesis of 5a-d, 0-substituted N-arylhydroxylamines without second substituents on the N atoms are
now easily a c ~ e s s i b l e . ~They
’ ~ ] are of interest, because, for
example, 8a can be enzymatically activated not only by
transformation to Sb, c , etc., but also by deacylation to 8d
or transacylation to Se.l’,t3’
3. The carcinogenic 8a reacts with guanine-containing
substances such as guanosine or DNA in vivo and in vitro
under a variety of conditions, giving predominantly the
fluorenylamino (or amido) guanine derivatives 9, i.e., the
products of a n electrophilic amination. Precisely this reaction, which is apparently crucial for the carcinogenicity of
8a,1’.’31
can be simulated by the reactions of 5a-d described here.
By Wolfgang A . Herrmann,* Eberhardt Herdtweck, and
Cornelia Weber
Cyclopropane occupies a special position among the alkanes even in organometallic reactions. Although systematic investigations of its behavior toward metal-compiex
fragments are lacking, it may be assumed as a working hypothesis that electron-rich metal centers cleave CH bonds
by nucleophilic attack, whereas electron-deficient metal
centers cleave C C bonds by electrophilic attack.[‘-31 However, the latter reactions are only commonly observed for
the C , structural unit as a building block of strained, polycyclic hydrocarbons; e.g., quadricyclane undergoes isomerization to norbornadiene at Rh’ and R”
We
have now observed, for the first time, a spontaneous carbon-carbon bond breaking process at an (electrophilic)
metal-metal double bond, namely, in a cyclopropyl group
anchored to a binuclear p-alkylidene complex.
Treatment of the binuclear rhodium complex 1 with the
diazo compounds 2a and 2b, generated in situ from their
hydrazone precursor compounds, results in the formation
of the new dimetallacyclopropanes 3,141 once again confirming the generality of o u r well-documented synthetic
strategy for the preparation of p-alkylidene complexes.[’]
Received: February 10, 1986;
revised: February 28, 1986 [Z 1661 IE]
German version: Angew. Chem. 98 (1986) 563
[ I ] a) J. A. Miller, Cancer Res. 30 (1970) 559; b) E. Kriek, Biochim. Biophys.
Acra 335 (1974) 177; c) E. Miller, Cancer Res. 38 (1978) 1479: d) E. C.
Miller, J. A. Miller, Cancer(Amsterdam) 47 (1981) 2327.
[2] Reactions of N-(acy1oxy)purines with nucleophiles: a) U. Wolcke, W.
Pfleiderer, T. J Delia, G. B. Brown, J. Org. Chem. 34 (1969) 981; b) J. C.
Parham, M. A. Templeton, ibid. 47 (1982) 652, and references cited
therein.
[3] a) P G . Gassman, J. E. Granrud, J. Am. Chem. SOC.106 (1984) 1498; b)
ibrd. 106 (1984) 2448.
[4] G T. Tisue, M. Grassrnann, W. Lwowski, Tetrahedron 24 (1968) 999.
151 U. Gessner, A Heesing, L. Keller, W. Kleine Homann. Chem. Ber. 115
(1982) 2865, and references cited therein.
[6] a) M. Novak, M. Pelecanou, A. K. Roy, A. F. Andronico, F. M. Ploude,
T. M. Olefirowicz, T. I. Curtin, J. Am. Chem. Soc. 106 (1984) 5623; b) M.
Novak, A. K. Roy, J. Org. Chem. 50 (1985) 571; c) M. Pelecanou, M.
Novak, J. Am. Chem. SOC.107 (1985) 4499; d ) M. Novak, A. K. Roy, J.
or$.Chem. 50 (1985) 4884: e) M. Novak, M. Pelecanou, L. Pollack, J.
Am. Chem. Soc. 108 (1986) 112; see also [7].
171 N,O-I~iacyl-N-arylhydroxylamines
undergo radical rearrangement to
N.0-diacylated o-aminophenols: L. Horner, H. Steppan, Justus Liebigs
Ann Chem. 606 (1957) 24, and references cited therein.
[81 See also J. D. Scribner, J. Am. Chem. SOC. 99 (1977) 7383.
191 The compounds 5a-d were prepared analogously to other 0-(diphenylphosphinoy1)hydroxylamines: M . Bernheim, G. Boche, Angew. Chem. 92
(1980) 1043: Angew. Chem. fni. Ed. Enql 19(1980) 1010.
I101 Until now only the electrophilic amination of amines with H2N reagents
was known: a) F. Rdschig, Chem. Ber. 40 (1907) 4580; b) Y . Tamura, J .
Minamikawa. M. lkeda, Synthesrs 1977, I ; c) R. G. Wallace, AldrichimAngew Chem. Inr. Ed. Engl. 25 (1986) No. 6
1
-CO
4
5
-=CH,,
hv
a,R=CH3; b.R=
-4
[*I
Prof. Dr. W. A. Herrmann, Dr. E. Herdtweck, Dr. C . Weber
Anorganisch-chemisches Institut der Technischen Universitat
Munchen
Lichtenbergstrasse 4, D-8046 Garching (FRG)
[**I Transition Metal Methylene Complexes, Part 62. This work was supported by the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie, BASF AG, Hiils AG, DEGUSSA AG, and the Bundesministerium fur Forschung und Technologie. Part 61 : W. A. Herrmann,
C. Weber, M. L. Ziegler, 0. Serhadli, J. Organornet. Chem. 297 (1985)
245.
0 VCH Verlagsgese!lschaji mbH. 0-6940 Weinheim, 1986
0570-0833/86/0606-0563$ 02.50/0
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carcinogenic, diphenylphosphino, amination, hydroxylaminen, electrophilic, mode, hydrazine, reaction, amines, aromatic, aryl
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