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MO Model for the Stereochemistry of Bromination of 1 6-Methano[10]annulene.

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GPRCH3=0.92
d,
GPcCH,=0.89
d,
GCoCH,= -1.10
dt
L,?J(PCoCH)=8.9/7.8
Hzl,
6 C H 2 = -0.28
dd
['J(PCH)=4.9,
,,:J(PCoCH)=7.1, ,,a,,:J(PC~CH)=O Hz]; "P('HI-NMR (36.43 MHz,
-7OOC): &PA= -24.8 dd, 6PB= f 3 0 . 5 d, GPc=+26.l d 12J(PP):
AB = 208, AC = 43, BC < 6 Hz].
[4] A solution of (Me,P),Me2CoBr (5 mmol) in tetrahydrofuran under an
inert gas atmosphere is stirred for 3 h with LiCH2PMe2or LiCH(PMe2)2
(5 mmol) at -40 "C. After removal of the solvent, the residue is taken u p
in 20 m L pentane, filtered, concentrated and cooled, whereupon 1.3 g 3
(69%) or 1.2 g 5 (70%) crystallize. Addition of 1.4 g PMe2Ph to the reaction solution of 3 and analogous work-up yield 1.4 g 4 (56%).
[5] H. H. Karsch, Z. Nafutjiorsch. B 34 (1979) 1171, 1178, and literature cited
therein.
causes poor yields due to the thermal instability of the
products was unnecessary.
Mannich bases which are highly sensitive to heat, e.g.
from pinacolone are readily accessible. The relatively
bulky phenyl isopropyl ketone reacts readily with a base,
and even with diisopropylamine produces the expected
Mannich base.
Diethyl methyl- and phenylmalonates also underwent
the normal Mannich reaction.
Thus, the present procedure is considered to be a mild
as well as powerful method of the aminomethylation, and
gives good yields even with sterically demanding educts.
Received: August 5, 1982 [Z 122 IE]
German version: Angew. Chem. 94 (1982) 937
Synthesis under High Pressure:
Mannich Reaction of Ketones and Esters with
Dichloromethane and Secondary Amines**
By Kiyoshi Matsumoio*
The Mannich reaction, which is also involved in the biosynthesis of alkaloids, can be used to yield a variety of aminomethyl derivatives (Mannich bases), which, e. g . have
many synthetic and pharmacological applications"]. This
reaction is plagued by some shortcomings, e. g. highly
branched carbonyl compounds such as diethyl alkyl- or
arylmalonates d o not respond to the classical Mannich
reaction, although several modifications have appearedL2].
In the course of studies of Michael addition under high
pressure[31,we discovered that CH2C12underwe%t a Menschutkin reaction with Et3N to give (CICH2)NEt3.ClQ.
This prompted us to investigate possible transformations
using CH,C12 as a C , ~ y n t h o n [ ~and
l , we report the Mannich reaction of carbonyl compounds with CH2CI2 and
secondary amines at a pressure of 6-9 kbarL5](Table 1).
Table 1. Yields and reaction conditions in the synthesis of Mannich Bases
from carbonyl compounds, CH2C12and Secondary Amines [a].
Substrate
[bl
~
P
[kbar]
T
["C]
t
[h]
pyrrolidine
piperidine
(EtbNH
(i-Pr)2NH
pyrrolidine
(i-Pr)2NH
(EthNH
( Et)2NH
( Et)2NH
pyrrolidine
( Et)2NH
9
8
9
8
9
20
40
22
40
40
48
40
48
48
48
22
72
24
43
39
48
72
48
61
48
72
48
Isolated
yield [%] [c]
~
PhCOCH,
PhCOCH,
PhCOCH2CH,
PhCOCH2CH3
PhCOCH(CH,)2
PhCOCH(CH3)2
t-BuCOCH,
CH,CH(C02Et)2
PhCH(C02Et),
CH3C02-nBu
cyclohexanone
~
Amine
9
6
6
9
9
9
By RolfGleiter*, Michael C. Bohm. and Emanuel Vogel
~
In most cases the present method affords virtually pure
Mannich bases after simple work-up; distillation, which
[*] Prof. Dr. K. Matsumoto
College of Liberal Arts and Sciences
Kyoto University, Kyoto 606 (Japan)
[**I This work was supported by the Japanese Ministry of Education (Project No. 56430008).
0 Verlag Chemie GmbH. 6940 Weinheim, 1982
[I] Reviews: F. F. Blick, Org. React. I(1942) 303; H. Hellmann, G. Opitz: aAminoalkylrenmg, Verlag Chemie, Weinheim, 1960; M. Tramontini, Synthesis 1973, 703; K. Matsumoto, Jikken Kagaku Koza Vol. 14-111, Tokyo,
Maruzen, 1978, p. 1373ff.
[2] See e.g. J. Schreiber, H. Maag, N. Hashimoto, A. Eschenmoser, Angew.
Chem. 83 (1971) 355; Angew. Chem. I n t . Ed. Engl. I0 (1971) 330: T. A.
Bryson, G. H. Bonitz, C. J. Reichel, R. E. Dardis, J . Org. Chem. 45 (1980)
524.
[3] K. Matsumoto, Angew. Chem. 92 (1980) 1046; Angew. Chem. Int. Ed.
Engl. 19 (1980) 1013; 93 (1981) 803; 20 (1981) 770.
[4] The Mannich reaction using CH2CII: S. Miyano, A. Mori, H. Hokori, K.
Ohta, H. Hashimoto, Bull. Chem. Sot. Jpn. 55 (1982) 1331.
[5] Experimental: A mixture of the carbonyl compound (10 mmol), CH2C12
(20 mmol), and amine (30 mmol) is diluted with methanol in a 10 mL Teflon capsule which is stored for 24-72 h under high pressures (Table I).
The reaction mixture is diluted with I M HCI (100 mL) and extracted with
several portions of hexane. The aqueous phase is made basic with NaOH,
extracted with ether (20 mL x 3), washed with 2 M Na2C03,brine, and water and then dried over CaSO,. Evaporation of the solvent and unchanged amine under reduced pressure gives a virtually pure Mannich
base.
MO Model for the Stereochemistry of Bromination
of 1,6-MethanollOlannulene**
[a] The Mannich bases were characterized by elemental analyses and spectroscopic data ("C- and 'H-NMR, and IR). [b] Aminomethylation occurs at
the C atom shown in italics (in the case of cyclohexanone in the a-position to
the carbonyl group). [c] Yields of isolated products; in parentheses yields
based upon consumed substrates. [d] With CH212 1.6Oh yield was obtained [4].
[el CH2CI I gave only a trace of the Mannich base. [flCH2Br2gave tar-like
material with complete consumption of the substrate [4]. [g] According to the
method described in [4], this reaction fails. [h] Higher temperatures (e.g.
40 "C) lead to bis-aminomethylation.
922
CAS Registry numbers:
CH2C12, 75-09-2; PhCOCH3, 98-86-2; PhCOCHzCH,,
93-55-0;
PhCOCH(CH,)>, 61 1-70-1; t-BuCOCH3, 75-97-8; CH,CH(C02Et)2, 609-085 ; PhCH(C02Et)2, 83-13-6; CH,C02(CH2)3CH,, 123-86-4; (Et)ZNH, 109-897; (i-Pr),NH, 108-18-9; CH212,75-1 1-6; CH2CII, 593-71-5; CH2Br2,74-95-3;
cyclohexanon, 108-94-1; pyrrolidin, 123-75- 1 ; PhCOCH, pyrrolidine Mannich product, 94-39-3; PhCOCH2CH3 (Et)2NH Mannich product, 38847-755; PhCOCH2CH3 (i-Pr)2NH Mannich product, 837 10-39-8: PhCOCH(CH,)2
pyrrolidine Mannich product, 35929-19-2; PhCOCH(CH3)Z(i-Pr)2NH Mannich product, 83710-40-1 ; fBuCOCH, (Et)2NH Mannich product, 3492-06-6;
CH3CH(C02Et)2 (Et)2NH Mannich product, 80073-77-4; PhCH(C02Et)2
(Et)2NH Mannich product, 83710-41-2; CH3COZ(CH2),CH3 pyrrolidine
Mannich product, 59629-69-5: cyclohexanone (Et),NH Mannich product,
37408-85-8.
At low temperatures bromine adds to 1,6-methano[lO]annulene 1 syn to the CH,-bridge['I to afford the labile dibromide 2.
This result, which is surprising for stereochemical reasons, can be explained by n/o interactions, which have
[*I Prof. Dr. R. Gleiter, Dr. M. C. Bohm
Organisch-chemisches lnstitut der Universitat
Im Neuenheimer Feld 270, D-6900 Heidelberg (Germany)
Prof. Dr. E. Vogel
lnstitut fur Organische Chemie der Universitat
Greinstrasse 4, D-5000 Koln 41 (Germany)
["*I This work was supported by the Fonds der Chemischen Industrie and
BASF Aktiengesellschaft, Ludwigshafen.
0570-0833/82/1212-0922 $02.50/0
Angew. Chem. Int. Ed. Engl. 21 (1982) No. 12
PCMO s
CMO s
Fig. I . Schematic representation of the most important precmonical MO's of
1 which interact with the T[ orbitals (left), as well as the resulting canonical n
orbitals 7a2 and 9b2 (right).
been discussed for similar d o nonorthogonal systemsf2].
Semiempirical MO calculations on 1 using a modified
INDO methodf3]predict a large o/n interaction. A quantitative analysis according to ref.["i indicates that each of the
two high-lying n orbitals of the perimeter interacts considerably with two precanonical o orbitals (PCMO's) (Fig. 1).
The resulting canonical n orbitals (CMO's) 7a2 and 9b2I5]
are also shown in Figure 1. The d o interaction causes rotation of the pn atomic orbitals at the C(2)/C(5)and C(7)/
C( 10) centers.
Assuming that a bromine molecule approaches annulene
1 either parallel (3a) or perpendicular (3b) to the plane of
the perimeter the antibonding interaction between the occupied levels of the halogen [for (3a) TI and n*, for (3b) n*
and o]and 9b2 and 7a2 in syn-addition is smaller than that
[ I ] Th.Scholl, J. Lex, E. Vogel, Angew. Chem. 94 (1982) 924; Angew. Chem.
Inr. Ed. Enql. 21 (1982) 920.
[2] a) S. Inagaki, H. Fujimoto, K. Fukui, J. Am. Chem. SOC.98 (1976) 4054;
b) L. A. Paquette, L. W. Hertel, R. Gleiter, M. C. Bohm, ibid. 100 (1978)
6510; M. C. Bbhm, R. V. C. Carr, R. Gleiter, L. A. Paquette, ibid. I02
(1980) 7218; L. A. Paquette, F. Bellamy, M. C. Bohm, R. Gleiter, J. Org.
Chem. 45 (1980) 4913; c) K. Takahashi, K. Takase, T. Kagawa, J. Am.
Chem. Sac. 103 (1981) 1186; L. A. Paquette, P. Charumilind, ibid. 1U4
(1982) 3749.
[3] M. C. Bohm, R. Gleiter, Theor. Chim. Acra 59 (1981) 127.
i4] E. Heilbronner, A. Schmelzer, Helu. Chim. Acta 58 (1975) 936.
[ 5 ] The calculated o-contribution to both orbitals amounts to 10% (7a2) and
30% (9b2) respectively.
Synthesis of Specifically Substituted
1-Azaadamantanes
By Nikolaus Risch* and Wolfgang Saak
I- Azaadamantanes"' and related products are fascinating because of their interesting and, in part, surprising
chemical and spectroscopic propertiesf2].We have found a
synthetic route, which for the first time provides a straightforward access to methyl 5,7-dialkyl-4,6-dioxo- 1 -azaadamantane-3-carboxylates 1 (Table l), the first l-azaadamantanes with completely C-substituted bridgehead atoms.
The key step involves a triple Mannich reaction.
Table I. Examples of Compounds 1 [a].
in anti-addition. This is shown in Figure 2 for the approach parallel to the plane of the perimeter (3a). The
main reason for the above mentioned difference is the
smaller overlapi2b1
between the n orbitals at the C ( 2 ) / C ( 5 )
or C(7)/C( 10) centers of 1 and the corresponding orbitals
of bromine in syn-addition compared to anti-addition. The
rotation of the CMO's demonstrated in Figure 1 also occurs in the norcaradiene valence tautomer of 1.
b
+
,\
1
R'
R2
M. p. [ "C]
Yield [%I
a
CH3
CH3
CH3
CH3
CH3
CzHs
n-CsHI,
C6H5CH2-
226
156
I07
I92
81
b
C
d
77
68
70
[a] Spectroscopic characterization of la, as example: 'H-NMR (80 MHz,
CDCI,) l.l0(~,3H),1.18(s,3H),2.11(AB,2H),3.08-3.66(m,6H),3.80(s,
3H). IR (KBr) 1739, 1723, 1692, 1269 cm-'.
Michael addition and subsequent intramolecular
Claisen condensation of the relatively easily available
educts 2 and dimethyl malonate lead to the six-membered
ring derivatives 3, only a few of which have been described in the literature. A particular feature of 3 is the
manifold possibilities of forming tautomers and stereoisomers.
CH2
II
CH~O~CCH~COICH,
R~-C-C-CH
2
s
*
2 - ~ 1
CH,O~ICH,OH
C02CH,
0
Fig. 2. Qualitative diagram for the interaction between the highest occupied
molecular orbitals of Br2 and the C M O S of 1 (7a2 and 9b2) for anti- (left)
and syn-addition (right), assuming that Br2 approaches parallel to the plane
of the perimeter (see 3a).
Received: August 5 , 1982 [Z 125 IE]
German version: Angew. Chem. 94 (1982) 925
CAS Registry number:
1. 2443-46- I
Anqew Chem. 1nt. Ed. Engl. 21 (1982) No. 12
3
.....
OH
0
R'
We have found that refluxing 3 with 1,3,5,7-tetraazaadamantane (hexamethylenetetramine) in methanol/dichloromethane produces the I -azaadamantane derivative 1 as
[*] Dr. N. Risch, W. Saak
Fakultat fur Chemie der Universitat
Universitatsstrasse, D-4800 Bielefeld (Germany)
0 Verlag Chemie GmbH. 6940 Weinheim. 1982
U570-0833/82/I212-0923 $ 02.50/0
923
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