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Diastereomerically Pure Mannich Bases from the Addition of Enamines to Ternary Iminium Salts.

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to be mentioned: one by Porri et al., who converted methallylnorbornylnickel acetate into methallylnickel bromide and norbornene by exchange of the acetate with a bromide anion,[61the
other by Maitlis et al., who achieved the elimination of styrene
by adding HCI to a 2-pentamethylcyclopentadienyl-2-phenylethylpalladium chloride.['] In our case, however, elimination is
not caused by anion exchange or HCI addition but occurs spontaneously to form an 0.0-disubstituted aryl group which stabilizes complex 218]with respect to 8. The elimination of cyclopentadiene from a ruthenacycle containing norbornenerglis entirely
at variance with the behavior reported here, since a retro-DielsAlder and not a deinsertion reaction is involved in liberation of
Since aryl bromides or iodides are known to react with norbornene in the presence of Pdo to give arylnorbornylpalladium
complexes of type
(Scheme 3), the function of norbornene
in the overall process that involves norbornene insertion and
deinsertion can be viewed that of a protecting group. It assists
in the oxidative addition of alkyl halides and disubstitution of
arenes through intermediate palladacycles and is finally expelled.
[2] M. Catellani, B. E. Mann. J. Organornet. Chem. 1990. 3Y0, 251.
[3] M. Catellani, G. P. Chiusoh, J: Organomel. Chem. 1985, 286. C13; M. Catellani. G. P. Chiusoli. C. Castagnoli. ibid. 1991,407, C30; 0. Reiser. M. Weber,
A. de Meijere, Angew. Chem. 1989, 101, 1071; Anpew. Chem. I n r . Ed. EngI.
1989,28, 1037; K. Albrecht, 0. Reiser, M. Weber. B. Knieriem. A. de Meijere.
Tetruhdroti 1994. SO, 383.
[4] G. Bocelli, M. Catellani. S. Ghelli, J: Orgunomer.Chem. 1993, 458. C12.
[ S ] J. TSUJI.K. Ohno, J. . h i . C17m7. So?. 1968, YO, 94; P I. Graig. M . Green, J.
Chem. See. A 1969. 157.
[6] M. C. Gallazzi, L. Porri, G. Vitulli. J. Orgunomet. Cheni 1975. Y7, 131.
[7] T. Hosokawa, P. M . Maitlis, J: A m . Chmi. Soc. 1972. Y4, 3238.
/8] J. Chatt. B. L. Shaw. JT Chem. SOL..1959, 4020.
[9] T. Mitsudo, Y Watanabe, H. Naruse, T. Kondo, Y Ozaki. Angew. Chem 1994.
106. 595: Angcw. Chem. l n l . Ed. Engl. 1994, 33. 580.
[lo] a) C.-S. Li. C.-H. Cheng. F.-L Liao. S.-L. Wdng. J. Chcm So<. Chem. Commun.
1991. 710; C:S. Li, D.-C. Jou, C.-H. Cheng, Organomctullics 1993. 12. 3945:
b) H. Horino. M. Arai, N. Inoue, Elrahedron Lrrr. 1974, 647.
[ I l l 1. Fuchu. T. Tanahe. S. Fukuokn (Asahi Chemical Industry), JP-A 02160742,
1990 [Chem. Abstr. 1990. 113. 190920x1
[12] J. P. Collman. L. S. Hegedus, J. R. Norton. R. G. Finke, Principles and Appliculions of Orgunorruiurrion M e t d Chrm
University Science Books. Mill
Valley. CA. 1987. To our knowledge only a palladium complex with ?,2'bipyridyl and fumaronitrile ligands has been shown to prevent fi-ehmination of
hydrogen in a coupling reaction of alkyl halides with Me&: R. Sustmaiin, J.
Lau. M. Zipp. nti-ahrdron Leir. 1986. 27, 5207.
[13] ' H N M R data (400 MHz. CDCI,): 9: 6 =7.20 (t, J = 7 . 2 HL. 1H. H s ) , 7.147.08 (4H. AA' part of an AA'BBX system, protons IWIU to lluorine). 7.026.97 (3H. H,, H, + H, at 6.9X), 6.98-6.93 (4H. BB' part of an AA'BB'X
system. protons orrho to lluorine), 3.90 (4H. CH2). 2: ' H N M R . (400 MHr.
CDCI,): d = 8.57-8.53 (4H. A A part of an AA'BB system. protons orr/7o to
nitrogen). 7.47-7.42 (4H, BB' part of an AA'BB' system, protons mt'iu to
nitrogen), 6.98 (t. J =7.3 Hz. IH. H4). 6.92 6.84 (4H, AA' part of an
AA'BBX system. protons in&( to fluorine). 6 79 (d. J =7.3 Hz. 2H, H,, H5).
6.75-6.67 (4H. BB' part of an AABB'X system. protons ortho to fluorine),
4.81 (s, 4H. CH,), 3.93 (s, 6H, OCH,).
Scheme 3. X
Br, I ; L
= PPh,
Although the reaction is general for alkyl and benzyl halides,
p-fluorobenzyl bromide proved to be appropriate for our study
because it led in good yield to the formation of fluorinated
products, which is useful for N M R determinations. Incidentally
product 9 (R = p-fluorobenzyl) turns out to be an intermediate
for the synthesis of polyether-polyketones.['ll Other alkyl
halides also react with high yield. It is remarkable that no belimination of hydrogen occurs owing to the unpdvorable stereochemistry. Thus this general drawback of many metal-catalyzed
reactions[121i s absent in the present process.
Experimental Procedure
To complex 1 [lob] (0.100 g. 0.32 mmol) dissolved in anhydrous D M F (8 mL) are
added K,CO, (0.090 g. 0.65 mmol) and p-fluorobenzyl bromide (0.122 g,
0.64 mmol). The mixture is stii-red at room temperature for 7 h tinder nitrogen.
Hydrogen is then bubbled through the solution to precipitate palladium black. After
conventional workup and purification by column chromatography with hexane,'
ethyl acetate as eluent. compound 9 (R = p-fluorobenzyl) 1131 is obtained in 87%
yield together with a small amount of mono- and dialkylated phenylnorbornanes.
If instead of passing hydrogen through the reaction mixture, methyl isonicotinate
(0.088 g, 0.64 mmol) is added. and D M F is removed under vacuum, complex 2
( L = methyl isonicotinate) [13] is obtained. After filtration through Celite. recrystallization from a mixture of chloroform and hexane gives light orange crystals in
63% yield. Analogously. carrying out the reaction with ethyl iodide as halide
(0.100 g. 0.64 mmol) leads to compound 9 (R = ethyl) in 84% yield.
Received: May 3 . 1994
Revised version: July 11, 1994 [Z6896IE]
German version: Angew. Chem. 1994. 106. 2559
[i] P. K. Byers. A. J. Canty, B. W. Skelton, A. H. White. J Chern. Sot.. Chenz.
C'ommun. 1986, 1722; A. J. Canty, Ace. Cheni. RCJ.1992. 25. 83 and references
therein; W. de Graaf, J. Boersma. D. Grove, A. L. Spek, G. van Koten. Red.
T r u . Chim. Puy.~-Bas 1988, 107. 299: M. Catellani, G. P. Chiusoli. .
Organontrr. Chern. 1988, 346, C27: R. van Asselt, E. Rijnberg, C. J. Elsevier.
1994. 13. 706.
VCH ~ ~ r l u ~ ~ ~ g ~ ~ emhH,
/ l . ~ 0-69451
c h a f l Wf+iheim, 1994
Diastereomerically Pure Mannich Bases from
the Addition of Enamines to Ternary Iminium
Nikolaus Risch* and Michael Arend
p-Amino carbonyl compounds are an attractive class of substances and are useful polyfunctional synthetic units in a variety
of applications, for example, the synthesis of pharmaceutical,
plant-protection, and natural products.IZ1Efficient access to stereochemically pure Mannich bases, apart from p-amino acids
and their derivatives, has hardly been developed until now.[31
Our method of reacting (E)-enamines 1 (derived from aldehydes or ketones) with preformed ternary iminium salts 2 has
fundamental advantages over the classic Mannich reactionI'I
(Scheme 1 ) . The reaction can be carried out in aprotic solvents,
and the high iminium ion concentration guarantees high reaction rates even at low temperatures.
Because of the mild reaction conditions, no unwanted byproducts were formed. Good to excellent yields of almost stereochemically pure p-amino aldehydes or p-amino ketones anti3 were obtained (Table l), which were generally crystalline.
Ternary iminium salts 2 have long been known and are readily
but have, surprisingly, in contrast to the
methylene iminium salts such as Eschenmoser's salt, hardly
Prof. Dr. N . Risch. DipILChem. M. Arend
Fachbereich Cheinie und Chemietechnik der Universitdt-Gesamthochschule
Warburger Strasse 100. D-33098 Paderhorn (FRG)
Telefax: Int. code + (5251)60-3245
[**I Stereoselective Synthesis of Mannich Bases. Part 2. This work was supported
by the Deutsche Forschungsgememschaft and the Fonds der Chemischen Industrie. Part 1: [l].
0570-083319412323-2422S 10.00+ .25:0
Angew Chem. Int. Ed. Engl. 1994. 33. No. 23:24
1) CH2Ch, - 80 ' C
0 NR2
3) NH3 i HzO
Scheme 1 Diaatereoselective addition of(€)-enamines 1 to ternary iminium salts 2.
found any applications up until now.141Their use allows the
scope of the classic Mannich reaction to be extended from
arninon?pth?,lation to aminoalkylation. In addition, it should be
emphasized that our method uses inexpensive, readily available
chemicals and can be applied to sensitive substrates (mild reaction conditions).
Surprisingly, our investigations to date have shown (Table 1)
that the stereoselectivity of addition is not influenced by the type
of (E)-enamine or ternary iminium salt used. Variation in R3,
N R ? , and X - always led to comparable results: with one exception (Table 1, entry 6), the ' H N M R spectra of the crude products only show the signals for a single diastereoisomer. Similarly, changing the reaction medium from CH,Cl, to the more
strongly complexing T H F had, at least at low temperatures, no
obvious influence on the stereochemistry of the reaction. The
Table I . Diaatereoselective addition of (€)-enamins 1 to ternary iminium salts 2.
X - [a]
~ y n - 3[b]
299: I 1
299: 5 1
299: 5 1
1 c lc1
299: I 1
299: 5 1
299: 5 1
r b
296: 5 4
CI -
296: 1 4
2 9 9 : 11
299: I 1
299: 5 1
CI -
296: 1 4
Entry R '
fact that the reaction was less stereoselective under reflux in
T H F than in CH,Cl, is probably explained by the higher temperature (due to the higher boiling point of T H F ) (Table 1, entry
I c ) . One product (Table 1, entry 2) was unambiguously assigned the anti configuration by comparing its N M R data to
those reported in the literature for an authentic sample (X-ray
structure analysis available).[3b,clOn the basis of the N M R
spectra and considering that the probability of a total reversal of
the stereochemical progress of the reaction as a result of the
changes made is small, we assume that the other Mannich bases
also have the anti configuration.
The scope of the method, the consistently high yields, and the
excellent de values, which are only achieved in exceptional cases-if at all-by other methods, demand that the mechanism of
the reaction be examined. The results can basically be explained
by a similar model to that described by Seebach et al., namely,
a transition state stabilized by electrostatic forces analogous to
that formed in the aldol additi0n.1~'~
However, a mechanism of
the polar [2s 2s]-cycloaddition type, such as has already been
postulated for numerous reactions between very electron-rich
and very electron-poor alkenes,[" cannot, a priori, be excluded.
Evidence in favor of this mechanism includes the fact that the
reaction between ynamines and iminium salts is thought to proceed via a four-membered cyclic intermediate.l']
Elucidation of the mechanism will also give further impetus to
the extension of our method to an enantioselective variant,['' the
synthesis of primary and secondary Mannich bases, and the use
of (Zbenamines
and auaternarv iminium salts. It would also be
interesting to investigate whether a third stereogenic center can
be formed selectivelv bv diastereoselective reactions (ex.. reduction or addition of organometallic compounds) at the prochiral
carbonyl group.
Experimental Procedure
unti-3: The reaction was carried out under argon and anhydrous conditions. A
solution ofthe (€)-emmine l ( 2 . 5 mmol) in anhydrous CH,CI, (2.5 mL) was cooled
to -80°C. The iminium salt 2 (2.5 mmol) was then added in one portion with
stirring. The mixture was stirred and the temperature allowed to rise to - 30 C over
2-3 h. In order to ensure a good yield in all cases, it is advantageous to store the
reaction mixture at this temperature in a refrigerator for ca. 15 h before workup.
Aqueous hydrochloric acid ( 5 mL, conc. HCl/water l / l ) was then added. The mixture was stirred for ca. 10 min and then extracted several times with Et,O. Dilute
ammonia (25 mL, 25% NH,/H,O 1/4) was added with vigorous stirring, and the
Mannich base unti-3 was extracted with CH,CI, or Et,O ( 3 x 50 mL, 1 min each
time) [XI. The combined organic phases were dried over Na,SO,. The solvent was
finally removed in a rotary evaporator without heating.
Received. May 28, 1994 [Z6977IE]
German version: Angew. Chem. 1994. 106, 2531
[l] N. Risch. A. Esser, Liebigs Ann. Chem. 1992, 233.
[a] Tetrachloroaluminates are easily accessible (by reaction of the iminium chloride
with AICI, in CH,CI, at 0 ° C ; the tetrachloroaluminates are finally precipitated
with Et,O). only slightly hygroscopic. and therefore especially easy to handle (similar to methylene iminium tetrachloroaluminates) [ 5 ] . Because of the formation of
a n AI(OH), precipitate during workup, however, they are less suitable for the
preparation of Mannich bases in multigram quantities. Here. better results are
obtained by using the freshly prepared iminium chlorides. [b] The diastereoisomeric
ratios were always determined for the crude products by means of ' H or "C N M R
spectroscopy (integration of the signals for C H N protons). [c] Similar results (92 YO,
2 9 9 % [I.\) were obtained in T H E Under reflux conditions (10 min). the Mannich
base was obtained in 7 8 % yield with 94% ds (in T H F : 87%, 82% d~v).Analogous
results were obtained with the corresponding chloride and perchlorate. The reaction
failed in EtiO. probably because the iminium salt is practically insoluble in this
AngrM-. Chiwi. Int. Ed. Engl. 1994. 33. No. 23/24
121 M. TrdmoIItini. L. Angiolini, Telruhedron 1990. 46, 1791.
[3] a) J. P. Yardley, H. Fletcher 111, P. B. Russel, Experientiu 1978, 34, 1124: b) G.
Oszbach, A. Neszmelyi, Liebigs Ann. Chem. 1990, 211; c) A. Neszmelyi. H.
Lotter, A. Kiss, 1. Pelczer, G. Oszbach, ibld. 1991, 917; d) D. Seebach. C.
Betschart, M. Schiess. HeIv. Chim. Actu 1984, 67. 1593; e) D. Seebach, M.
Schiess. W. B. Schweizer. Chimiu 1985, 39,272; f) A. R. Katritzky. P. A. Harris,
Tetrahedron 1990,46. 987; g) E. G. N o h , A. Allocco, M. Broody. A. Zuppa.
Tetrahedron Lett. 1991, 32, 73.
[4] a) H. Bohme. M. Haake. A h . Org. Chem. 1976, 9. 107. b) E. F. Kleinman in
C~mprehensiveOrganic Synthesis, Vol. 2 (Ed.: B. M. Trost), ith edition. Pergamon, Oxford, 1991, p. 893; c) E. Winterfeldt, J. Prakt. Chem. 1994. 336. 91; d )
U. Westerwelle, N. Risch, Tetruhedron Lett. 1993. 34, 1775; e) U. Westerwelle,
A. Esser, N . Risch, Chem. Ber. 1991, 124, 571.
[5] N. Risch, A. Esser. Z . Naturforsch. B 1989, 44. 208.
[6] J. E. Baldwin in Comprehensive Organic Synthesis. Vul. 5 (Ed.: B. M . Trost). 1st
ed., Pergamon, Oxford, 1991, p. 63.
[7] R. Fuks, G. S. King, H. G. Viehe. Angew. Chem. 1969.81, 702; Angrw. Chem.
Im. Ed. Engl. 1969, 8 , 675.
[XI Some Mannich bases of the type unti-3 tend to decompose. to varying extents,
in aqueous alkaline solutions. However, this can he almost entirely avoided by
rapid workup.
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base, salt, iminium, ternary, mannich, additional, diastereomerically, pure, enamine
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