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Imine Substituent Effects on [2+2]Cycloadditions with Ketenes.

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fragment along the axis of the cumulene, as has been observed for [ Fe($Me,C=C=CMe,)(CO),I
91 and [PtCl,(q2Me,C=C=CMe,)].['O1 could not be detected.
In the same way as for 6 and 8, on treatment of 13 and 14 with
C O (benzene. 10 C. 1 min) the olefinic ligdnd can be displaced
leading to the 1 .I -diphenylallene 15, which is already known.[2t1
and the allene derivative 16. which has been characterized by
'H.' " C , and "'F NMR spectroscopy (see Table 1 ) .
Receibed: December 18. 1995 [Z86591E]
German version: Anfrii. Chmi. 1996. 108. 1330- 1332
A. Hohn. H. Werner. J Orguiionier. C/iw?i. 1990. 382 -755- 272. b) M. D.
Fryzuk. L Huang. N. T. McManus. P. Paglia. S J. Rettig. Ci. S. White.
1992. 11. 2979 - 2990
General procedure for 13 and 14: A solution of 1 o r 2 (0.20 inmol) in benrene
(5 mL) was stirred under a H, atmosphere for 40 h ( I ) oi- 30 min (2).After the
solvent had been removed. the yellow residue was washed with pentane (0 C )
( 2 x 1 mL) and dried in vacuo: yield 95"/0.
H. Werner. .I Wolf. A. Hohn. J. Orgunoriicr. C%eiii. 1985. 287. 395-407.
R. Ben-Shoshan. R. Pettit. J. A i i i . C/i<,in Soc-. 1967. HY. 2-731 2232.
K . Vrieze. H. C. Volger. A P. Praat. J. Orgurioiiwi. ( % c n i . 1970. 21. 467.475.
P Beltrame. D. Pitea, A. Marzo. M. Simonetta. J ( / i ? i i i . SOC. B 1967.
Keywords: allenylidene complexes * butatrienes isomerizations
* rhodium compounds
I-. J. C;arci;i Alonso. A Hohn. J. Wolf, H. Otto. H. Werner. Angrii. Cheni.
1985. Y7. 401 -402: Airgm Chcni. In!. Ed. Eiigl. 1985. 24, 406-407; b) H.
Werner. F. _I Garcia Alonso, H. Otto. J. Wolf. 2 Noiirrfor.\c/i. B 1988. 43.
721 726: c ) ti. Werner. U. Brekau. ;hid 1989. 44. 1438-1446.
126, 669-678; b) H. Werner, N.
[Z] a ) H. Wernei-. T. Rappert. Chriii. B P ~1993.
M:ihi. T Rappert. R. Wiedenyann. J. Wolf. Ol-gunoinerri/lic,\ 1994. 13. 2721 2737
[3] F; J. (inrcia 4lonso. U Brekau, unpublished results.
[4] The synthesis of 1 has been reported [2a]. compounds 2 and 3 are analogously
;icce.;,ible from [(RhCI(PiPr,),iJ and HC=CCPh(R)OH ( R = CF,. rBu) in
YO %I!<, yield.
[S] Genexi1 procedure for 4 6: A solution of 1. 2. or 3 (0.18 mmol) in benzene
( 3 mL) waz treated dropwise with a 0.28 M solution of CH,N, ( I .5 mL) in ether
;it room temperature. After the solution had been stirred for 5 min. the solvent
\*;is removed. and the residue was recrystallized from p e n t m e ( -78 C). Bright
red 14). ied 15). or orange crystals ( 6 ) .yield 98%.
[hl Dat;i lor Stray structure analysis: crystals from pentane ( - 10 C).
C,,H,,CIP,Rh (663.1): crystal dimensions 0.3 x 0.3 x 0.4 mm: monoclinic:
rpace g i o u p 1'1, L (No. 14): u = I 8 5211). h =11.193(3). < =16.523(9)
/I = 93.35(3) . Z = 4. I' = 3420(3) A': oirird = 1 288 gcm-'. T = 293(2) K :
m a y . 211 = 4X : 5867 reflections measured; 5351 unique. 4654 observed
Enrsf-Nonius CAD4 diffractometer. Mo,, radiation ( i =
0.70930 A). gi~iphitemonochromated. zirkon filter (factor 16.4). Lorentz polari7ation and cmpirical absorption correction ("scan method. min. transrniscion Y7 49 I % ) . P'itterson method. refinement with full-matrix. least-squares
method: X1 = 0.0214. wR2 = 0.0568 [for 4654 reflections with I >20(/)].
R1 = 13.0305. 1 1 K3 = 0.0610 (for all 5351 data): data-to-parameter ratio 8.33.
residual electron density +0.296 - 0.1 70e k ' .Crystallographic data (excluding structure factors) for the structure reported in this paper have been
depwitcd bbith the Ciimbridge Crystallographic Data Centre as supplemenrary
piihlicalion no CCDC-179-30 Copies of the data can be obtained free of
charge on :ippliciition t o The Director. CCDC, 12 Union Road. Cambridge
CB3 IEZ. U K ( l h x int. code +(1223) 336-033; e-mail: techedWchemcrys. u k )
[7] H. Werner. D. Schneider. M. Schulz. J Orguiiomer. C/ic~ni.1993, 451. 1751x2
[ X I J. Pu. T - S . Peng. A. M Arif. J. A. Gladysz. Orguiioiiierrrllic.~1992. If. 32323241
[9] a ) L. Hapelee. K. West. J. Calabrese. J. Norman. J. ,4117. CJiefii.Soc. 1979. fOf.
4888 4x93. h ) P. J. Stang. M. R White. G . Maas, O~guiioi7i~rciliics
1983. 2.
770 725
[lo] M. R. White. P J. Stang. Oifa~ionirrn/lirc1983, 2. 1654-1688.
[ I l l M. Schder. N Mahr. J Wolf, H . Werner. A i i g m C/imi. 1993, 105. 1377
1379: . $ i i , y o i . ( ' / i r i ~ i . 1ni Ed h g l . 1993. 32. 1315-1318
[I21 a ) C Biisetto. .4. D'Alfonso, F. Maspero. G. Perego, A. Zazzetta, J C/imi. So<.
Dolrofi /?mi\.1977. 1828- 1834; b) K . Wang. G. P. Rosini. S. P. Nolan. A. S.
Goldman. .I Am C/i<wi.So< 1995. I17. 5082 - 5088.
[I31 W. Runse. W. 'r. Brady. f / i p C/iefiii.strj~of K<,renes. Allmc~.sui7d Rc~lfircdCoiirp m / \ fii/. I ( k d . S. Patai). Wiley. New York. 1980.
[I41 H. Wrstinijze. I Nap. J. Meijer. H. Kleijn. P. Vermeer. R e d Ex..Chini.
Pui.\-&i$ 1983. 103. 184- 157. and references therein.
[IS] Prepar;itivc procedure for 12. A solution of l(88 mg. 0.14 mmol) and Na,C0,3
(800 mg. 4 72 mmol) in acetone.THF (1.1) (4 m L ) was treated dropwise with
CH,I (61) 1iL. 135 mg. 0.95 mmol) a t room temperature. After the solution had
been stiri-ed for 6 h. the solvent was removed. and the residue was extracted
with CH,CI, ( 3 inL). The extract was concentrated to dryness in vacuo. the
residue was dissolved in T H F (4 mL). and KI (300 mg. 1.8t mmol) was added
10the solution. After the mixture had been stirred at room temperature for 3 h,
the solvent w'ii\ removed. the residue was extracted with benzene ( 5 m L ) . the
extrdct was conccnmitcd. and the yello- precipilate was washed with acetone
( 3 x 2 n i l ) (0 C ) . yield 83 mg (X2%). m.p. 146 C decomp.
lmine Substituent Effects on
12 + 2ICycloadditions with Ketenes**
Claudio Palorno,* Jesus M. Aizpurua,* Marta Legido,
Regina Galarza, Pere M. Deya, Jacques Dunogues,
Jean Paul Picard, Alfred0 Ricci, and Giancarlo Seconi
The cycloaddition of imines with ketenes, generated from acid
chlorides and tertiary amines, is recognized as one of the most
convenient approaches to /_(-lactams.['lHowever. virtually all of
the investigations have dealt with the use of non-enolizable
imines derived from aldehydes and, therefore, subsequent steps
are often required to obtain the desired target product. In fact,
ketene-enolizable aldimine cycloadditions, which would generate a wider range of substitution patterns at the C, position of
the /]-lactam ring, have not been viable, because of the instability of the starting imines and the presence of competitive deprotonations. We report herein on our initial findings on the development of this approach to a general asymmetric synthesis of
3-amino-4-alkyl /_(-lactams. The significance of these compounds as valuable precursors of /_(-lactamantibiotics, more
complex organic compounds. large and medium heterocycles,
and amino acid derivatives is apparent.I2] We thought that 2(trimethylsily1)methyl i m i n e ~ ' ~might
provide a solution to the
above-mentioned problems for two reasons: first. because of the
ability of silyl groups to stabilize electron-deficient carbon centers in the /3- and/or y - p o ~ i t i o n [and.
~ ] second. because of the
zwitterionic character of the reaction intermediate proposed for
this kind of cy~loaddition.'~]
[*] Prof. Dr C . Palomo. Dr. J. M. Aizpurua, M. Legido. R. C;alarm
Departamento de Quimica Orginica
Universidad del Pais Vasco. Facultad de Quimica
Apdo 1072. E-20080 San Sebastidn (Spain)
Fax. lnt. code +(43)212236
e-mail: qppaiipj(n
Dr. P. M . Deyd
Departament de Quimica
Universitat de les Illes Balears. E-07071 Palma de Mallorc'i (Spain)
Prof Dr. J. Dunogues, Dr. J. P. Picard
Laboratoire de C h i m e Organique et Organometallique Universite de
Bordeaux. F-33405 Talence (France)
Prof. Dr. A. Ricci
Dipartimento di Chimicd Organica. Universiti di Bologna
1-40136 Bologna (Italy)
Dr G. Seconi
C. N. R.-Istituto dei Composti del Carbonio contenenti Eteroatomi e loro
1-40064 Bologna (Italy)
[*"I This work was supported by the E. U. (Project: SCl CT 91 ;Oh461 and. in part.
by Basque Government (Project: P19386). Grants to M L from Spanish
Education Ministry and to R. G. from Gobierno Navarro are acknowledged.
The reaction of 1r6] with 2f7]resulted exclusively in the formation of p-lactams c i s 3 and fvans-3 with good to excellent
diastereomeric selectivities and, most notably, with complete
asymmetric induction at the C, position. The results summarized in Table 1 illustrate the efficiency of this method for the
Table 1. Cycloddditions of 1 with the imines 2 [a].
Crnpd. [b] R
[%.I [c]
ch-3-Isomer [el
rruns-3 [dl m.p. [ C]
b), c)
CH,CI, [fJ 48
81 : 19
65 (70) [g]
60 (75) [g] >98:2
70 (75) [g]
83: 17
72 [SI
82 [g]
55 [g]
90: 10
78 [g]
88: 12
+ 91.9
+ 74.1
+67 1
+ 80.0
+ 73.x
[a] Reactions were conducted on a 10 inmol scale in refluxing benzene o r CHCI,, ratio of
acid chloride:imine:triethylamine1.2:1: 1.4. [b] The crude imines were used directly. For
i n m e 2a the E:Z isomer ratio was 90: 10. All other imines showed E : Z ratios >98:2 as
de!ermined by ‘H N M R spectroscopy (300 MHz). [c] Yield of the corresponding mixture
of cis and Irnns 6-lactams. Id] Determined by integration of the doublets at 6-4.51 and
24.40. which correspond t o the ci.s- and rrons-positioned protons at C3, respectively. [el
Pure compounds crystallized from hexanes/CH,CI, (lO/l), All data recorded in CH,CI,
(c = 1.O). [f] Reaction carried out at - 78 C to room temperature overnight. [g] Reaction
carried out using a twofold excess of acid chloride and triethyldmine.
: CHo
Scheme 1. a)NEt,,CHC13.reflux20 h ; b)Li(6equiv),NH3,THF, rBuOH(33,10,
1 equiv). -78 C, 10 min; c) (Boc),O. CH,CI,. room temperature, 3 h; d )
(NH,),Ce(NO,),. MeCN. H,O. O’C. 6 h ; e) NaHCO,, NaHSO,, Na,CO,, H,O.
Me,CO, room temperature, 5 h.
products 4, we also found that prolonged exposure of 8-lactams
3 to ammonium cerium(iv) nitrate in methanol instead of in
acetonitrile/water led directly to the corresponding N-unsubstituted p-lactams in almost quantitative yields. This is illustrated
(Scheme 2) by the synthesis of the loracarbef precursor 7
from 3h.[l31
direct construction of homochiral p-lactams with linear as
well as branched chains at the C, position. In each case tested,
yields were uniformly good when the reactions were carried out
in boiling benzene or chIoroform, and the use of a twofold
excess of acid chloride 1resulted in a noticeable increase in the
yield, particularly when chloroform was used as solvent. Lowering the reaction temperatures led to a decrease in yield with
no significant improvement in the ratio of cis to trans
diastereomers. Noteworthy, even the imine 2e derived from the
easily enolizable phenylacetaldehyde, afforded the expected
B-lactam, whereas the corresponding N-benzyl or N-(4methoxy)phenyl imines gave only enamides and hydrolysis
The absolute stereochemistry of the cycloaddition products
was established by the conversion of the azetidinone cis-3a into
the known compound 6a (Scheme I),[”and a uniform reaction
mechanism was assumed for the other derivatives. Thus, cleavage of the oxazolidinone moiety and subsequent N-Boc protection (Boc = tert-butoxycarbonyl) of the resulting free amino
derivative gave 4a [syrup, [x]:’ = + 32.8 (c = 1.O in CH,CI,)]
in 72 YO yield. Subsequent removal of the bis(trimethylsily1)methyl moiety by treatment with ammonium cerium(1v) nitrate
in acetonitrile/water afforded the corresponding N-formyl/I-lactam 5a in 92% yield. Remarkably, this novel method of
deprotection of N-[bis(trimethylsilyI)methyl] amides expands
considerably their usefulness in synthesis, complementing, as
a cationic umpolung. the known fluoride-mediated reactivity
of a-amido carbanions.[”I The cleavage of the formyl group
from the ring N atom[”] in compound 5a, which was carried
out in a slightly basic medium, afforded 6a in almost quantitative yield.~’21In addition to this two-step method to remove
the N-[bis(trimethylsilyI)methyl] substituent from cycloaddition
VCH ~~rlu~.s~e.sell.srhnJt
mhH, D-6945/Weinl7~im.I996
Scheme 3 a) (NH,),Ce(NO,),,
MeOH. 0 C. 6 h
In summary, our results help to fill the gap with regard to the
unexplained behavior of enolizable aldimines in [2 + 2]cycloadditions with ketenes[I41 and offer for the first time a general
asymmetric convergent synthesis to 3-amino-4-a1kyl-/l-lactams.
It is expected that this new methodology for preventing enolization could be extended to further reactions involving zwitterionic species.
E.uperimenta1 Procedure
Preparation of /I-lactams 3: C,C-bis(trimethyisi1yl)methylamine
(1 75 g, 10 mmol)
was added to a solution of the corresponding enolizable aldehyde (10 mmol) in dry
dichlorornethane (10 mL) containing 4 inolecular sieves. The mixture was stirred
at 20 C and monitored by GC-MS until completion (typically, 30 min). The molecular sieves were filtered off, the solvent was evaporated, and replaced by new dried
molecular sieves (3 g) and freshly distilled dry chloroform (30 mL). To this solution,
kept under nitrogen. triethylamine (5.6 mL. 40 mmol) and a solution of 1 (4.78 g.
2Ommol) in chloroform (10 mL) were added dropwise at 0 ‘C, and the resulting
mixture was heated to reflux for approximately 20 h. After work-up [lob] the corresponding 0-lactams 3a- h were obtained.
Deprotection of the /&lactams 3: To a solution of the appropriate 0-lactam 3
( 5 mmol) in dry methanol (40 mL). ammonium cerium (iv) nitrate (10.96 g.
20 mmol) was added at 25 C. and the suspension was stirred at the same temperature and monitored by TLC. After 6 h. the reaction mixture was taken up in water
(50mL) and extracted with ethyl acetate ( 3 x 80mL) The organic layer was
washed successively with aqueous NaHCO, (100 mL. saturated solution). aqueous
0570-0833/96/3511-/240$ 15.00+ ,2510
Angex. Clirm. 1171. Ed Engl. 1996, 35,No. 11
aqueous NaHSO, ( 3 x 50 mL. 40%). aqueous NaHCO, (100 mL, saturated solution). and aqueous NaCI (100 mL, saturated solution). Drying and evaporation of
solvents yielded quantitatively fairly pure 6.
Received: November 14, 1995
Revised version: February 23. 1996 [28528 IE]
German version: Angeir. Chem. 1996. 108. 1317-1318
Keywords: asymmetric syntheses
- cycloadditions -
111 For coiiiprehcnsive reviews. see: a ) J. Backes in Methoden Org. Chrtn.
i H ~ i u h r / i - W c ~4th
/ i , ed. EundE16B. 1991. p. 31; b) L. Ghosez, J. MarchandOrgunic. Sinthr,m. Vol. 5 (Eds.: B. Trost, I FlemBrynaert i n C'~jrii/7re/i~,n.sii,[,
ing). Pergamon. Oxford, 1991. p. 85: c) R. C. Thomas in Recent Progress in the
CZrmrwl $in/hc4s uf Anrihiotrc,.\ (Eds.: G . Lukacs, M. Ohno). Springer.
Berlin. 1988. p. 533: d ) F.H. Van der Steen, G . Van Koten, Trtruhrrfron 1991.
47. 7503. f ) G . 1 Georg, V. T. Ravikumar in The Orgunic Chemisrr?.qf'fl-Lucrum\. (Ed. G I . Georg). VCH, New York, 1992. p. 295.
121 For some reviews on [j-lactam antibiotics, see: a ) W. Durkheimer. J. Blumbach.
R Lnttrell. K H Scheunemann Angeii. Chrm. 1985, 97, 183; Angew. Chriir
l r r r . G I 01pi. 19x5, 24. 180. h) C h e m u r r ~und Biologi~of fl-Lucrurn Antihiorrcs.
Voi. / - . 3 (Eds.. R B. Morin. M. Gorman), Academic Press. New York, 1982
For reviews on amino acids and heterocycles derived from 8-lactams, see: c)
M. S. Manhiis. D. R. Wagle. J. Chiang, A. K. Bose, Hf4erocrcks 1988, 27.
1755. d ) M. Hesse in Ring Enlurgement in OrgrmrL. Chemictrj-. VCH. Weinheim.
1991; e) 1. Ojima i n Thc Orgunic. Chernisrrj. o/fl-Luc.tum.s. (Ed.: G. I. Georg).
VCH. New York. 1992. p.197.
[3] a ) A. Capperucci. A. Ricci, G Seconi, J. Dunogues, S. Grelier. J. P. Picard, C.
Palomo. 1. M. Aizpurua, J. Orgunomet. Chrm. 1993, 458, C l ; b) M. Dal Colle,
G . Distefano. D. Jones. A. Guerrini. G . Seconi, A. Modelli. J. Chrtn. Soc.
Perkin Troiis. 2 1994. 789.
[4] a) L. A. Paquette. S [ . i c w e 1982. 217, 793, b) J. B. Lambert. Terruhetlron 1990.
46. 2677.. c) J M . White, Aust. J. Chem..1995, 48. 1227. The fl-silyl effect was
suggested by Colcin to govern the regiochemistry of the cycloaddition between
allylsilanes and chlorosulfonyl isocyanate to give race mi^ [j-lactams. see: d)
E. W. Colvin. M. A. Loreto. M. Monteith, 1. Tommasini in Frontrers of
Orgunosiliwn Cherni.s/r>,.(Eds.: A. R. Bassindale. P. P. Gaspar), The Royal
Society of Chemistry, London. 1991, p. 356.
151 a) J. A. Sordo. 3. Gonziilez, T. Sordo, J. Am. Cheni. Sot 1992, 114, 6249; b)
F. P. Cossio, J. M. Ugalde, X. Lopez, B. Lecea. C . Palomo. r h d 1993, 115.995.
[6] a) D. A. Evans. E. B. Sjogren, Tetrahedron Lerr 1985. 26.3783; b) tdc.,n.. ibtd.
1985, 26. 3787.
[7] These ketimines were prepared from the corresponding aldehydes and C,Cbis(trimethylsilyl)methylamine. For the preparation of the latter compound in
multigram quantities from the commercially available N,N-dimethylcyanamide, see: S. Grelier. T. Constantieux, D. Deffieux. M. Bordeau, J.
Dunogues, J. P. Picard, C. Palomo. J M. Aizpurua. Orguri/Jr?ieraNirs
1994, 13,
[8] The same enolization trend was observed for N-(4-methoxy)phenyl imines
derived from acetaldehyde, propionaldehyde, and phenylacetaldehyde. See also: D. Dugat, G. Just. S. Sahoo, Can J Chem. 1987. 65, 88.
191 L. S. Hegedus, J. Montgomery, Y. Narukawa, D. C. Snustad. J. Am. Chem.
So<..1991. 113. 5784.
[lo] a) C. Palomo, J. M. Aizpurua. J. M. Garcia. I. Ganboa, F. P Cossio, B. Lecea,
M.C. Lopez, J. Org. Chem. 1990.55,2498; b) C . Palomo, J. M. Aizpurua, I. M.
Garcia, J. P. Picard. J. Dunogues. Terr-uhedronLett. 1990, 31. 1921: c) C. Palomo. J. M. Aizpurua. M. Legido, J. P. Picard, J. Dunogues. T. Constantieux.
rhid. 1992. 33, 3903.
1111 G. 1. Georg. P. He, J. Kant, 2. J. Wu, J. Org. Cheni. 1993. .i#
[12] A similar transformation sequence was achieved starting from truns-3a that
confirmed the (5')-configuration at C3 in all diastereomers obtained. Selected
data. 5 M.p 156-157-C, [1]i5= - 43.4 (c = 1 0 in CH,CI,): 6: M.p. 182183 C. [%]is = + 55.0 (c =1.0 in MeOH).
[13] For a comprehensive review, see: R. D. G . Cooper in The C%rmts/rjof [<-Luctun?s (Ed.: M. 1. Page), Chapman and Hall, London, 1992. p. 272.
[I41 A semiempirical SCF-MO AM1 theoretical study carried out in our laboratories to establish the dependence of the enamide or p-lactam pathway upon
imine nitrogen substituents (CH, or CH(SiMe,),) was consistent with experimental results, and suggests that the "/$effect" exerted by the two u HC-SiMe,
bonds is the responible for the chemoselectivity observed. These results will be
published in due course.
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