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New Nickel-Catalyzed Carbozincation of Alkynes A Short Synthesis of (Z)-Tamoxifen.

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studied recently. An example of a structure built from
tetrahedral units is the Ge,MnS,, framework in [ (CH,),N],Ge,MnS,o,[151 which is identical to the framework of cristohalite,["] if one substitutes MnS, for one half of the SiO,
groups, and the adamantane-shaped Ge,S group for the other
half. Furthermore, starting from the ReO,-type["] (AB,) we
can view the framework of pharmacosiderite, KFe,(OH),(As0,);6
H,O, and its many isostructural compounds as examples of structures built from octahedral units. It consists of A
groups [M(O,OH)], (with M = Fe, Al, Ge, M o and other
cations in octahedral coordinations) made up of four fused octahedra tetrahedrally arranged, and of 6/2 tetrahedral B groups
TO, (with T = As, P, G e and others['s1) surrounding it octahedrally. Even N a 3 Z n 4 0 ( P 0 4 ) 3 ~ 6 H 2 0 ~belongs
L 9 1 to this series
because four fused Zn coordination tetrahedra around a central
oxygen atom replace the four octahedra of the pharmacosiderite
In terms of new microporous materials it is important to find
more open frameworks by searching for additional square-planar four-connected groups analogous to the V,O,(PO,), and
Mo,O,(PO,), units, and possibly larger ones, and to synthesize
frameworks along the principles described here. Such materials
could be particularly useful if they contained reactive transition
elements, such as the V4+/V5+ pair.["] The new construction
principle is important: the inert tetrahedral phosphate groups
bridge the potentially reactive square-planar groupings. This
role of the phosphate groups could be played by other tetrahedral anions, and the central square-planar Mo,O, and V,O,
units could be replaced by other groups. The nets composed of
square-planar units that have been introduced here are thus
potential carriers of arbitrary functional groups.
Received: August 1, 1996 [Z9406IE]
German version: Angen. Chem. 1997, 109, 88-90
Keywords: microporosity
- vanadium - zeolites
[I] W M. Meier. D. H. Olson, C. Baerlocher, AtlasofZeohle Structure Qpes, 4th
ed.. Elsevier. London. 1996.
(21 M Schindler. W. Joswig, W. H. Baur. 2. Anorg Allg. Chem. 1997, press.
[3] M I. Khan, L. M. Meyer, R. C. Haushalter, A. L. Schweitzer, J. Zubieta, J. L.
Dye. Cfwm Muter. 1996, 8, 43.
[4] A. Muller, H Reuter. S. Dillinger, Angen Chem. 1995, 107, 2505, Angeir.
Chrm. 1111.Ed. Engl. 1995,34,2311; M. Pope, A. Muller, ibid. 1991,103,56 and
1991, 30. 34
[5] A. Muller. J. Doring, 2. Anorg. A& Chem. 1991, 595. 251.
[6] A. F. Wclls. Further Studies .f'TIiree-dimen.sional Nets, ACA Monograph No.
8. Pittsburgh. 1979
[7] J. V. Smrth. An?.Minerul. 1978.63.960; in Crystal Structures of Zeolites, Landolt-5drn.srein S m e s 111(Eds.: W. H. Baur, R. X. Fischer), Springer, Berlin,
1997. i n press.
[8] A. L. Bowman. T C Wallace, J L. Yarnell, R. G . Wenzel, Acta Crystallogr.
1966. 21, 843.
[9] L. Pauling, 2 KristulloRr. 1930, 74, 213.
[lo] R C. Haushalter. K. G. Strohmaier, F. W. Lai, Science 1989, 246, 1290.
( I 11 W H Baur. A Bieniok. R. D. Shannon, E. Prince, Z . Krisfullogr. 1989, 187,
[12] W. H. Baur. Arm Mineral 1964, 49, 697.
[13] A. Bieniok. K. Bornholdt, U. Brendel, W. H. Baur, J Muter. Chem 1996, 6 ,
27 1
[14] R L. Bedard. S. T. Wilson, L. D. Vail, J. M. Bennett, E. M. Flanigen. Stud.
Surl. Sci Curul. 1989,4Y, 375; K. Tan. Y. KO,J. B. Parise. A. Darovsky, Chem
Muter 1996,N. 448; X Wang, F. Liebau, J Solid State Chem. 1994, I l l , 385;
T. Jiang. A. J. Lough, G. A. Ozin, D. Young, Chem. Muter 1995, 7 , 245.
[I51 0. Achak, J. Y. Pivan, M. Maunaye. M. Louer, D. Louer, J Alloys Compd.
1995.219, 1 $ I
[16] W. Nieuwenkamp, Z. Krbtullogr. 1935. 92. 82.
[17] K . Meisel. 2 Antirg. All8 Chem. 1932, 207, 121.
I181 M. J. Buerger. W. A. Dollase, 1. Garaycochea-Wittke, Z. Kristallogr. 1967, 125,
92: H. E. King, L. A. Mundi, K. G. Strohmaier, R. C. Haushalter, J Solid
Stare Chem. 1991. 92, 154; J. Zemann, Acta Crystallogr. 1959, 12, 252.
[19] W T. A. Harrison. R. W. Broach, R. A. Bedard, T. E. Gier, X. Bu, G. D.
Stucky. Cheni. Muter. 1996.8, 691
[20] G. Centi. F. Trifirrj, J. B. Ebner, V. M. Franchetti, Chem. Rev. 1988, 88, 55.
AnReh.. Chrm Int Ed Enxl. 1997, 36. No. 112
New Nickel-Catalyzed Carbozincation of
Alkynes: A Short Synthesis of (2)-Tamoxifen**
Thomas Stiidemann and Paul Knochel*
Dedicated to Professor Waldemar Adam
on the occasion of his 60th birthday
The coordination of a double bond to a transition metal center strongly modifies the reactivity of the metal fragment and
that of the coordinated olefin."] This olefin activation is of great
importance for applications in organic synthesis, since it allows
the formation of new carbon -carbon bonds between unfunctionalized unsaturated molecules.'*1 Recently, we have shown
that the coordination of a double bond to a dialkylnickel(l1)
complex considerably facilitates the reductive elimination of the
organic ligands, making efficient nickel-catalyzed cross-coupling reactions between sp3-hybridized C centers possible for
the first time.i31 Here we report our attempts to extend this
reaction to alkynyl iodides (Scheme I), which led to the discovery of a highly stereoselective nickel-catalyzed carbozincation of
Scheme 1. Nickel-catalyzed cross-coupling of alkenyl and alkynql iodides with dialkylzinc compounds.
Our first experiments involved the treatment of trimethylsilylpentyne 2 with two dialkylzinc compounds, diethylzinc
(Et,Zn) and dipentylzinc (Pent,Zn). Like the corresponding alkenyl iodide, 2 undergoes smooth cross-coupling with
Et,Zn and Pent,Zn in THF/NMP (3/1) in the presence of a
catalytic amount of [Ni(acac),] (7.5 mol%, acac = acetylacetonate; -40"C, 20 h) to give the desired cross-coupling
products 3a and 3b in 60 and 61 % isolated yield, respectively
[Eq. (a)]. The coordination of the triple bond lowers the electron
EtzZn ( 2 equiv).
[ N i ( a c a ~ ) ~7.5
] ( mol % )
-78 ' C bis -40 'C, 20 h
3a : R = Et; 61 %
3b : R = Pent; 60 %
density a t the metal center (intermediate 1 in Scheme 1 ) and
facilitates the cross-coupling
In contrast, iodohexynes such as 4a that bear a more reactive
terminal alkyne group undergo tandem addition to the triple
bond, followed by coupling with the R group of R,Zn, to afford
exo-alkylidenecyclopentanes5. The reaction of 4a with Pent,Zn
or di(4-chlorobutyl)zinc in the presence of [Ni(acac),]
(7.5 mol%) furnishes cyclopentanes 5a (65%) and 5b (68%)
[Eq. (b)]. To determine the stereochemistry of the addition to
Prof. Dr. P. Knochel, DipLChem. T. Stiidemann
Fachbereich Chemie der Universitat
Hans-Meerwein-Strasse, D-35032 Marburg (Germany)
Fax: Int. code +(6421)282189
We thank the D F G (SFB 260) and the Fonds der Chemischen Industrie for
generous financial support. We thank Witco A G (Bergkamen), BASFAG
(Ludwigshafen), Bayer A G (Leverkusen), Chemetall GmbH (Frankfurt) and
SIPSY SA (Avrilli, France) for the generous gift of chemicals.
Verlagsgesel1.schUfrmbH, 0-69451 Weinheirn, 1997
$ 15.00+ .7.7,'11
R g n , THFlNMP
[Ni(acac)21(7.5 mol% )
-40 'G,20 h
5a : R = Pent; 65 %
5b : R = (CH&3; 68 %
the triple bond (syn or anti), the phenyl-substituted alkyne 4b
was treated with Pent,Zn (7.5 mol% [Ni(acac),]; THF/
NMP, -40 "C, 20 h). This led almost exclusively to the ( E )
stereoisomer 5c (E:Z> 99: l ) , which indicates a syn addition to
the triple bond. This result allows us to postulate the following
mechanism for this cyclization reaction. The insertion of in-situgenerated nickel(o) into the carbon- iodine bond of 4b followed
by transmetalation with Pent,Zn affords the nickel(I1) complex
6, which effected syn carbonickelation of the alkyne and formation of the alkenyl alkyl nickel(1r) complex 7. Reductive eliminationCs1then leads to the (E)-exo-alkylidenecyclopentane 5c
(Scheme 2).
Table 1. Trisuhstituted styrenes obtained by the addition of Me,Zn, Et,Zn, Ph,Zn,
or Pent,Zn to substituted phenylacetylenes 8 in the presence of [Ni(acac),]
(25 mol?h) in THF/NMP.
P h ~ : h
2 98
-40 'C, 20 h
[a] Yields of analytically pure isolated products. [h] Only the regioisomer depicted
is obtained. [c] The hydrometalation product (2)-stilbenewas obtained in 2 % yield.
5 C : 62%;€:2>99:1
Scheme 2. Mechanism of the nickel-catalyzed cyclization of 4b to E.
The syn stereoselectivity of the carbonickelation encouraged
us to examine the intermolecular version of this reaction.
Whereas internal dialkylacetylenes display moderate reactivity,
the intermolecular carbozincation of internal phenylacetylenes[61proceeds with good to excellent regioselectivity and almost complete syn stereoselectivity. Thus, the reaction of 1phenyl-1-decyne (8a) with Et,Zn in THF/NMP in the presence
of [Ni(acac),] (25 mol%) at -35°C for 20 h affords the synethylated products 9a (Z:E>98:2) and 9b in an 88:12 ratio
(78% yield) and the hydrometalated product 10 in 6 % yield
[Eq. (c)]. With phenylacetylenes bearing smaller alkyl groups in
diphenylacetylene (8d), it is formed in less than 2 YOyield. Interestingly, with 2-trimethykilyl-1 -phenylacetylene (set, the opposite regioselectivity of the carbozincation is observed (nos. 6 and
7 in Table 1). The addition of dimethylzinc to the silylated
acetylene 8e also gives the desired sp-addition product with
high stereoselectivity (E:Z = 2:98; 64% yield).[71The trisubstituted alkenylzincs obtained by nickel-catalyzed carbozincation
can be trapped with several electrophiles to give tetrasubstituted
olefins with high stereoselectivity. Thus, the addition of Et,Zn
to 1,2-diphenylacetylene (8d) in the presence of [Ni(acac),]
(THF/NMP; - 35 "C, 3 h) furnishes the (E)-alkenylethylzinc 11
(no. 4 in Table I ) , which in the presence of CuCN.2LiClrS1
reacts with acetyl chloride (-10°C, 10 h) or ethyl (cr-bro( - 10 "C, 1 h) to give the tetrasubstituted
olefins 12a and 12b in 58% and 71 YOyield, respectively.
-35 'C, 20 h
1) C ~ C N
Q ~icl
1) CUCN -2LlCl Et
12b : 71 %
Z : E>99:1
Scheme 3. Synthesis of the tetrasubstituted alkenes 12a and 12b from the alkenylzinc compound 11.
9a :69%; Z:€>96 : 2
12a ; 50 %
2:E > 9 9 : 1
9b :9 %
the 2-position, far better regioselectivities are obtained
(Table 1). Varying the reaction conditions (solvent, temperature) and the catalyst (NiCI,, [Ni(cod),]) did not lead to a dramatic improvement in the regioselectivity. Moreover, the hydrometalation product of type 10 was observed only with
Et,Zn. In the case of more reactive acetylenes such as 1,294
Yield [%I [a]
8 VCH Verlagsgesellschafi mbH, 0-69451 Weinhelm, 1997
The reaction with diphenylzinc['O1proceeds even more readily. Addition to 1-phenyl-1-butyne (8c) (THF, - 35 "C, 3 h) and
subsequent iodolysis gives the pure (2)-alkene 13 in 88 YOyield
(2:E> 99: 1, Scheme 4). This adduct has been converted in one
step into (2)-tamoxifen (14), an anti-estrogenic anticancer drug
that is effective for the treatment of metastatic breast cancer.["]
Thus, the reaction of 13 with the arylzinc bromide 15 in the
presence of [Pd(dba),] (4 mol YO; dba = dibenzylideneacetone)
and PPh, (16molYo) in THF (55"C, 10 h) provides (Z)-tamoxifen (14) in 75% yield (Z:E>99:1).
$ 15.00+ 2510
Angew. Chem Inr. Ed. Eng[ 1997, 36, No 112
[7] Methylcuprates undergo addition to alkynes only with difficulty: P. Knochel
in Coniprehensive Organic Synrhesi.,, Vol. 4 (Eds.: B. M. Trost, 1. Fleming,
M. F. Semmelhack), Pergamon, 1991, pp. 865-912; good results could be
achieved only by using zirconium-mediated carboalumination : E. Negishi,
D. E. Van Horn, T Yoshidd, J Am. Chem. Soc. 1985, 107. 6639-6641.
1988, 53,
[8] a) P. Knochel, M. C. P. Yeh, S. C. Berk, J. Talbert. J. 0 , ~Chem.
2390-2392; b) P. Knochel, Synlerr 1995,393-403.
[9] J. Villieras. M. Rambaud, S.ynthesis 1982. 924-926.
[lo] Pure diphenylzinc was obtained by the reaction of phenyllithium with zinc
chloride (0.5 equiv) followed by sublimation: W. Strohmeier. Chem. Ber. 1955,
88. 1218-1223.
1111 a) R. B. Miller. M. I. Al-Hassan, J Org. Chem. 1985, 50, 2121- 2123; b) M. I.
Al-Hassan,Swth. Commun. 1987,17. 1 2 4 7 - 1 2 5 1 ; c ) S ~ n r l i ~ ~1987,816-817.
[Ni(acac),l(25 rnoi%) Ph
-35 'C,3 h
€ 9 9:1
2) 12
HN+Me2 C I -
IPd(dba)n](4 rnol%)
Ph,P (16 rnol%)
THF. 55 'C,10 h. then HCI
14 : (Z)-tamoxiten
75%;Z: € > 9 9 : 1
Scheme 4. Synthesis of (2)-tamoxifen (14).
In summary, we have reported a new intramolecular syn carbonickelation leading to alkylated exo-alkylidenecyclopentane
derivatives, as well as an intermolecular carbozincation of substituted phenylacetylenes that allows stereoselective (>98 % syn
addition) synthesis of tri- and tetrasubstituted phenylalkenes.
Experimental Procedures
(12b): [Ni(acac),] (320 mg, 1.25 mmol, 25 mol%) and 8d (0.89 g, 5 mmol, 1 equiv)
were dissolved in T H F (3 7 5 m L ) and N M P (1.25mL) at -4O'C under argon.
Diethylzinc ( I .O mL. 10 mmol, 2 equiv) was carefully added via syringe at - 78 "C.
The reaction mixture was allowed to warm to -35'C and stirred for 2.5 h. Meanwhile a mixture of CuCN (1 79 g, 20 mmol, 4 equiv) and LiCl (1 69 g, 40 mmol, 8
equiv) was dried in VaCUO at 130 "C for 2 h and then dissolved in T H F (10 mL). The
solution was cooled to -60°C and added by syringe to the reaction mixture at
-78 C . The resulting dark solution was warmed to 0 ° C for a few minutes and then
again cooled to - 78'C. Ethyl (a-brom~methyl)acrylate'~'(4.82 g, 25 mmol, 5
equiv) was added, and the reaction mixture warmed to 25°C and worked up. The
crude product was purified by flash-chromatography (hexanesiether 20/1), affording the ester 12b (1.13 g, 3.53 mmol, 71 % yield; Z : E > 9 9 : 1 ) as a white powder.
(5c): [Ni(acac)J (96 mg. 0.37 mmol, 7 mol%) was dissolved in T H F (3.75 mL) and
NMP (1 2 5 mL) at -40 'C under argon, and 1-iodo-4-phenyl-5-hexyne (4b) (I .41 g,
5 mmol, 1 equiv) was added At z 7 8 " C , Pent& (2.0 mL, 10 mmol, 2 equiv) was
carefully added by syringe. The reaction mixture was stirred for 30 h at -40°C.
After the usual workup. the solvents were distilled off, and the crude residue was
purified by chromatography (hexanes) to give the cyclized product 5c (0.74g
3.24mmol. 65% yield: E:Z>99:1) as a colorless oil.
Received' August 2, 1996 [29415IE]
German version: Angew. Chem. 1997, 109, 132- 134
Keywords: alkynes
homogeneous catalysis
[ l ] a) R. H. Crabtree, The Organometullic Chemistry of Transition Merols. Wiley,
New York, 1988: b) A. Yamamoto, Orgnnotransition Metal Chemistry, Fundamental Concepls and Applications, Wiley, New York, 1986: c) J. P. Collman,
L. S. Hegedus. J. R Norton, R. G. Finke, Principles and Applications of Transition Metul Chcmi.stry. University Science Books, Mill Valley, USA, 1987.
[2] a) S. Murai, F Kakiuchi, S. Sekine, Y Tanaka, A. Kamatani, M. Sonoda, N.
Chatani. Naruw 1993, 366, 529-531: b) B. M. Trost, K. Imi? 1. W. Davies, J
Am. Cliem. So<. 1995, 117, 5371 -5372.
[3] A. Devasagayaraj, T. Stiidemann, P. Knochel, Angel<. Chem. 1995,107,29522954; Angew. Chem. In!. Ed. Engl. 1995,34,2723-2725.
[4] For mechanistic studies showing that olefin coordination facilitates reductive
eliminations. see a) T. Yamamoto. A. Yamamoto, S. Ikeda, J Am. Chem. SOC.
1971, Y3.3350- 3359; b) R. Sustmann, J. Lau, M. Zipp, Tetrahedron Lett. 1986,
27,5207 5210. c) R. Sustmann, J. Lau, Chem. Ber. 1986, l l Y , 2531 -2541; d)
R. Sustmann, J Lau, M. Zipp, R e d . Traiz. Chim. Pays-Bas 1986,105,356-359;
e) R. Sustmann. P Hopp, P. Holl, Tetrahedron Lett. 1989,30,689-692; f) R.
van Asselt. C. .I. Elsevier. Tetrahedron 1994. 50, 323-334.
151 J. Montgomery. A. V Savchenko, J. Am Ckem. Soc. 1996, 118,2099-2100
[6] a) For a zirconium(1v)-catalyzed carbozincation of alkynes see E. Negishi,
D. E. Van Horn. T. Yoshida, C. L. Rand, Organometailics 1983, 2, 563-565;
h) B. B Sntder. R S E. Conn, M. Karras, Tetrahedron Le11. 1979. 16791682.
Angew. C h m . Inr C I En@. 1997, 36, N o . 112
Hydroxyamines as a New Motif for the
Molecular Recognition of Phosphodiesters:
Implications for Aminoglycoside- RNA
Martin Hendrix, Phil B. Alper, E. Scott Priestley,
and Chi-Huey Wong*
The molecular recognition of phosphodiesters has received
much attention due to their biological importance. In proteinnucleic acid complexes, binding of the phosphodiester backbone
is often achieved through a dense network of hydrogen bonding frequently involving a bidentate interaction with the guanidinium group of arginine.".
In order to identify the underlying principles of phosphodiester recognition in biological
systems, various phosphate receptor models have been developed, including synthetic receptors incorporating guanidinium
moieties,[31 linear and macrocyclic p o l y a m i n e ~ , [ u~~~ e a s , [ ~ ]
amidines,c6] aminopyridines,['] porphyrins,[*.91 and uranyl complexes.["]
Aminoglycoside antibiotics" have been shown to directly
interact with a number of RNA sequences['*] including two
important HIV regulatory domains, RRE[I3] and TAR.['41 We
speculated that the hydroxyamine substructures often found in
these molecules may play an important role in recognition. A
typical member of the class, neomycin B (1, Scheme I ) , has a
number of different 1,2- and 1,3-hydroxyamine substructures.
We therefore prepared the model compounds 2-5 to first evaluate their individual binding capacities to dimethylphosphate as
a model phosphodiester. To compare our results for phosphodiester binding by hydroxyamines we chose the well-characterized
bicyclic guanidine 6, since it has been used as a standard model
for phosphate re~ognition.[~"]
Compound 6 is symmetrical and
presents only one hydrogen bond donor, unlike arginine, which
has two, allowing straightforward interpretation of spectroscopically derived binding data.
1,3-Hydroxyamines 2-4[15] were synthesized conveniently
from the respective diol precursors via cyclic sulfate[' 61 intermediates as shown in Scheme 2. The galacto-configured hydroxyamine 4 was designed to mimic the 4 " , 6"'-hydroxyamine substructure found in the L-id0 ring of neomycin B, which exists in
a triaxial 4Ct chair conformation as shown in Scheme
[*I Prof. Dr C -H. Wong, M. Hendrix, P. B Alper, Dr. E. S. Priestley
Department of Chemistry, The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla. CA 92037 (USA)
Fax. Int. code +(619)784-2409
This project was supportcd b y Sandoz Pharma, Ltd E. S. P thanks the National Institutes of Health for a postdoctoral fellowship
VCH Veringsgesellsrhafi mbH. 0-69451 Wemheim, 1997
0570-08331Y7/3601-0OY5$ 15.00+ .2.i,fl
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nickell, short, synthesis, carbozincation, alkynes, tamoxifen, new, catalyzed
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