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Asymmetric Synthesis of Amines by Carbon-Carbon Coupling in the -Position to Nitrogen.

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/R2
H,C\
H3C\
N-N
(5b), R2 = H; (6b). R2 = CH3
@
N-N
,CH3
N-N
i 7)
Hydrogenation of the radicals (4) (0.5 mol H,, Pd) leads to
the leuco compounds (5) which are again dehydrogenated to
(4) on exposure to air. Alkylation of (5), e.g. methylation,
yields stable tetrahydro-s-tetrazine derivatives (6).
This radical preparation is not limited to monoaldehydes
such as (2). Analogous reaction of (1) with glyoxal bis(sodium hydrogen sulfite) hydrate gave the C-3, C-3' linked diradical (7), as black crystals from chloroform. On the basis of
its ESR half-field resonance, (7) is seen to have a zero field
splitting parameter of D'zz 320 G .
The 6-oxoverdazyls (4) and (7) are sufficiently soluble in
water for ESR studies. Their isolation demonstrates that the
N-aryl substituents of the verdazyls['] can be replaced by methyl groups without any significant loss of stability.
Selected physical data of the compounds synthesized are
listed in Table 1 .
Table 1. Compounds (3) to (7). All the compounds gave a molecular peak of
100% intensity in their mass spectra.
Cpd.
M.p.
["CI
Yield
(3a)
110--111
73
(36) 121
138-139
76
Cpd.
M.p.
["Cl
Yield
[%I
UV [b]
(4a)
52 -53
72--73
83-84
60-61
258.-260
(dec.)
33
80
429 (3.08). 374 (3.13)
492 (2.68). 413 (3.21). 248 (4.46)
(46)
(5b) [c]
(66)
(7)
(methoxymethy1)pyrrolidine [SDMP, (9)] as chiral agent'''.
We describe here the use of (9) for the asymmetric synthesis
of the amines (7) and (8) and their secondary products. The
key reaction is the diastereoselective coupling of the carboncarbon bond at the a-position to the amine nitrogen.
Propargylamine (1) is first converted into the amidine
(2)[2a1
(colorless oil). H/Li exchange at the acetylene function
in (2) with n-butyllithium ( 5 min) leads, after addition of
freshly distilled trimethylsilyl chloride, to the 3-silylated propargylamine derivative (3)[2bl.The so protected amine (3) is
metalated with n-butyllithium to (4) (30 min). After addition
of the electrophile R'X at - 78 "C, the reaction mixture is allowed to warm to room temperature. Aqueous workup affords the substituted amidines (5). The completely alkylated
derivative (6) is obtained from (5) by repeating the metalation and alkylation with R2X (see Scheme 1). 'H-NMR and
IR spectra show that (4) reacts regioselectively with RX at C-I.
Neither allene products (alkylation at C-3) nor enyne products (alkylation at the amidine C ) were observed.
The a-substituted propargylamines (7) and (8) are obtained from (5) and (6), respectively, by hydrolysis of the amidine function with hydrazine hydrate and cleavage of the silyl protecting group with sodium methoxide (see Scheme 1).
The pyrrolidine derivative (s)-(lO) liberated from (5) and (6)
can be reconverted into (9).
'H-NMR [a]
1x1
2.91 (s, 6H. CH,). 3.68 (t, J - 9 Hz. 2H,
CH2), 4.28 (t, 2H, NH)
2.97 (s. 6H, CH,), 4.93 (br. s, 1 H, CH), 5.64
(br s, 2H, NH), 7.2-7.7 (m, 5H. aromatic
H)
.t
+--
317 (3.74), 260 (4.09)
500 (3.02). 420 (3.34). 383 (3.58). 241 (4.44)
[a] 6 values, in [D&dimethyl sulfoxide. [b] A,,
[cm 'I. in KI: i s = 3200, 3160 (NH).
[nm] ( I g E ) . in dioxane. [c] IR
Received: January 21, 1980 [Z 555 IE]
German version: Angew. Chem. 92, 766 (1980)
CAS Registry numbers:
( I ) , 13782-38-2; (2) (R'=H), 50-00-0;(2) (R'=C,H5), 100-52-7; (3a). 74808-99-4;
(36). 74809-00-0; (4a), 74809-01-1; (4b). 74809-02-2; (Sb). 74809-03-3; (6b),
74809-04-4; (71, 74809-05-5
G.Oflmonn, Angew. Chem. 79,315 (1967); Angew.
Chem. Int. Ed. Engl. 6, 363 (1967).
[2] (36) has already been synthesized [I] but was regarded as l-benzylidene-2.4dimethylcarbonohydrazide[I];
however, this assignment is incompatible with
the 'H-NMR spectrum (see Table 1).
[3] F. A . Neugebauer. Angew. Chem. 85, 485 (1973): Angew. Chem. Int. Ed.
Engl 12. 455 (1973).
[ I ] L. Raphaelian, H . Hooks,
Asymmetric Synthesis of Amines by Carbon-Carbon
Coupling in the a-Position to Nitrogen
By Michael Kolb and Jacqueline Barth"]
We recently reported on the asymmetric synthesis of a substituted a-amino acids with (S)-l-(dimethoxymethyl)-2[*] Dr. M. Kolb, J. Barth
Centre de Recherche Merrell International
16 rue dAnkara, F-67084 Strasbourg (France)
Angew. Chem. Inr. Ed. Engl. 19 (1980) No. 9
kiMe,
(4), R = H
Scheme 1. a) (1)-(9)= 1:l; without solvent, 3 h, 80°C oilbath temperature. b)
(2): n-BuLi= 1: 1.1; in tetrahydrofuran (THF), -78°C. c) 1 . 1 equiv. Me3SiCI, 5
min at -78°C. then 30 rnin at 25°C. d) (4): R ' X = 1 : 1 . 1 . e) (S): R 2 X = 1 :1.1. f)
(5) or (6)' H2NNH2-H20=1:5-10 in anhydrous ethanol. 2 4 h, reflux. g ) 1
equiv. CH,ONa in CH,OH, 2-3 h, 25 "C. h) R u 0 2 , NalO,
The yield and optical rotation of the reaction products are
collected in Table 1. The enantiomeric purity of the amines
(7) and (8) was determined by oxidation to the corresponding amino acids (11) and (12), respectively[']. The asymmetric induction increases with increasing size of the electrophile
(see Table 1, a-methylphenylalanine and a-methylnorleucine). As to be expected, the preferred configuration at the
asymmetrically substituted carbon atom in (8) changes if the
electrophiles R i X and R2X are added in the reverse order.
0 Verlag Chemie, GmbH, 6940 Weinheim, 1980
0570-0833/80/0909-0725
8 02.50/0
725
Table 1. Chiral propargylamlnes (7) and (8) and their protected precursors (5) and (6);enantiomeric excess (e.e.) of the amino acids (If) and (12) obtained from (7)and (8).
respectively.
~~
R'X
(5)
La12
Chem. yield
[%I la1
CHiI
n-C4H91
C6H5-CH2Br
(71
Chem. yield
1x1 [a1
[bl
84
85
66
-.39
161
55
72
bl?
(81
Chem. yield
[%I [a1
(111-HCI
b1:o
e.e. [%]
Config.
~
R'X
(6)
R2X
Chem. yield
[%I [a1
CHJ
CH3I
CH31
n-C4H91
C2Hsl
n-GH9I
C,H5-CH2Br
CHJ
CaH5-CH2Br
CHpI
[bl
76
71 ISI
75
- 29.5
+ 22
- 36
77 M
79
La1E
e.e. I".]
Contig.
+ 5.0 14
68
86
84
56
77
- 27
(12)-HC1
+8.1 [c. 81
- 5.6 [fl
- 4.9 [C. 81
~ 4 . 5[el
(9L7. 81
( S ) (81
84 (s) 191
( R )[81
67 ( R ) 191
[a] Yield of isolated, analytically pure product. [b] c=2, benzene. [c] c=2. H20. [dl L-norleucine.HCI: [a]?= + 13.8 (c=2, H20). [el ~-phenylalanine. [a]::= - 12.5
( c = 2 , H20). [fj c = 1, H2O. [g] The yield in the alkylation step and in the asymmetric induction does not change if the solution of (4) in THF prepared at -78°C is stirred
for 20 min at 25OC before addition of the electrophile.
The propargylamine derivatives (7) and (8) synthesized
are configuratively related, since the chelates (4) in the configuration depicted in Scheme 1 are preferably alkylated from
the upper side. This is in complete contrast to the described
asymmetric synthesis of a-alkylated a-amino acids with the
same reagent SDMP, whereby preferred alkylation from the
lower side has been observed['].
The method described here for the preparation of the optically active propargylamines (7) and (8) is not only of importance for the enantioselective synthesis of a-alkylated a-amino acids. The ethynyl group in the products corresponds to a
di/d2-synthon[41,i. e. an extremely versatile function[51,which
in combination with the asymmetric synthesis describe here
offers numerous possibilities for the enantioselective preparation of nitrogen compounds.
Received: September 7, 1979 [Z 556 I€]
Publication delayed at authors' request
German version: Angew. Chem. 92. 753 (1980)
[I] M. Kolb, J . Barth, Tetrahedron Lett. 1979, 2999
[2] a) B.p. 78-8O0C/O.05 tom; 'H-NMR (CDCIdTMS): 6=7.73 (s, N=CH);
IR (CHCI,): 3320 (H-C-C),
1660 (N=CH) c m - ' ; [a]?= -56.2 (c=2,
ChH& b) b.p. 105-108 "C/0.05 tom; 'H-NMR (CDCIJTMS): 6=7.70 (s,
N=CH), 0.20 [s, Si(CH1)J; IR (CCI,): 2170 (C-C), 1650 (N-CH) cm -';
[a]:?=-47.3 (c=2, CnH,).
131 H. Gopal, A. J. Gordon, Tetrahedron Lett. 1971, 2941.
141 D. Seebach, Angew. Chem. 91, 259 (1979); Angew. Chem. Int. Ed. Engl. 18,
239 (1979).
[S] V. Jiiger, H . G. Viehe in Houben-Weyl-Muller: Methoden der Organischen
Chemie. 4th edit., Vol. V/Za. Thieme, Stuttgart 1977; R. A . Raphael. Acetylenic Compounds in Organic Synthesis. Butterworth, London 1955.
[6] Optically pure (R)-( +)-1-methylpropargylaminewas obtained in 2% yield on
resolution of the racemic mixture; A. Lindqulst, B. RingdahL U.Suensson. R.
Dahlbom, Acta Chem. Scand. B 30, 517 (1976); A. Marszak-Fleury, Ann
Chim. (Paris) 13,656 (1958).
was obtained in
[7] Optically pure (S)-(+ ) - 1 -ethyl-1-methylpropargylamine
14% yield on resolution of the racemic mmture. B. Ringdahl, R. Dahlbom,
Acta Chem. Scand. B 30, 993 (1976).
[S] K. Wemges, B. Sremmfe,Chem. Ber. 106, 2291 (1971).
191 S. Terashimo, K. Achiwa, S. Yamada, Chem. Pharm. Bull. 14. 1138 (1966).
vestigated the preparation and reactions of tripropylcarbazoyllithium (3).
i
i
(3) is readily obtained by carbonylation of lithium tripropylhydrazide (2) in tetrahydrofuran (THF)/hexane solution13](cu. 0.5 M) at cu. - 75 "C and normal pressure, as demonstrated by its reactions. (2) is prepared by lithiation of
tripropylhydrazine (l)I4'with n-butyllithium. (3) is inert towards CO (cf. [Ic1),
but reacts rapidly[51and cleanly, at
-75 "C, with aldehydes and ketones: Addition of the reactants 10.7-1.2 mol per mol of ( I ) ] to the solution of (3) and
subsequent hydrolysis leads to the hydroxycarbohydrazides
(4)-(8) [high-boiling oils, yields 60-85%]. Under these simplest experimental conditions [e.g . without inverse addition
of (3)],(3) does not react with the hydrazide function of the
I
I
Tripropylcarbazoyllithium
By Valentin Rautenstrauch and Fraqois Delay[*]
Can structural modifications lead to synthetically useful
acyllithiumsf'I? To answer this question furtherI2'we have inI*] Dr. V Rautenstrauch [ +],Dr. F. Delay
Firmenich SA. Laboratoires de Recherche
b.p. 239, CH-1211 Geneve 8 (Switzerland)
[ '1 Author to whom correspondence should be addressed.
726
0 Verlag Chemie, GmbH, 6940 Wernherm. 1980
alcoholates of (4)-(8) (cf. ["I). Although the hydrazide function of the adducts (4)-(8) is greatly hindered, they can be
smoothly cleaved, by reaction with lithium in liquid NH3/
THF and subsequent hydrolysis, to give the unhindered pro.
"C, yield ca.
pylamides [cf. [Id], e.g. (4)+(9), m . ~ 88-89
90%; (6)-(fO), m.p. 105--106"C, yield cu. 85961.
Addition of water to the solution of (3) gives the formohydrazide (11) and addition of D 2 0gives the labeled hydrazide
0570-0833/80/0909-0726
d 02.50/0
Angew. Chem. Inl. Ed. Engl. I9 (1980) No. 9
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