Nucleophilic trapping of π-allylpalladium intermediates generated by carbopalladation of bicyclopropylidene: A novel three-component reaction

Article abstract of DOI:10.1002/1521-3773(20010917)40:18<3411::AID-ANIE3411>3.0.CO;2-D

The primary carbopalladation intermediate resulting under Heck conditions from bicyclopropylidene and phenyl iodide in the presence of tris(α-furyl)phosphane rearranges to give a π-allylpalladium complex which is efficiently trapped by various nucleophiles R_nXH. This rearrangement leads to substituted methylenecyclopropanes in good to excellent yields (42-99%) [Eq. (1); X = C (n = 3), N (n = 2), O (n = 1)]. The intermediate 1,1-dimethyleneallylpalladium complex was isolated and fully characterized by an X-ray crystal-structure analysis.

Full text of DOI:10.1002/1521-3773(20010917)40:18<3411::AID-ANIE3411>3.0.CO;2-D

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ino Heck ± Diels ± Alder reaction of bicyclopropylidene (1).[2]
This sequence involves the Heck-type coupling of bicyclo-
propylidene (1)[3] with haloarenes and -alkenes to form
1-substituted allylidenecyclopropanes which then undergo
[4‡2] cycloadditions with dienophiles yielding 7-substituted
spiro[2.5]oct-7-enes in a one-pot operation. In the course of a
more extensive study of this methodology we became aware
of a new reaction mode through the isolation of the side
product 3, the formation of which can only be rationalized by
an intermolecular nucleophilic attack of an acetate anion
stemming from the catalyst precursor on an intermediate p-
allylpalladium species 8 (Scheme 1).[4]
308C. The resulting crystals were collected, washed with a minimum
amount of cold hexane, and dried in vacuum. Yield of 4: 2.9 g (44%
related to 1). Mg turnings (302 mg, 12.4 mmol) were placed in a three-
necked flask (100 mL) and treated with diethyl ether (10 mL). A
solution
of
3,5-bis(trifluoromethyl)-1-bromobenzene
(3.6 g,
12.4 mmol) in diethyl ether (10 mL) was added dropwise to the
magnetically stirred mixture. After 1 h the solution was transferred
into a dropping funnel and slowly added to a solution of 4 (1.5 g,
3.1 mmol) in THF (25 mL). The mixture was then heated at reflux
until the reaction was complete (ꢀ2 h). After removal of the solvents
in vacuum the residue was dissolved in toluene. The solution was
washed with degassed water and dried with anhydrous Na2SO4. The
toluene was removed in vacuum, and the residue was recrystallized
from acetone/methanol. Yield of 5a: 3.3 g (89%).
[14] L. M. Engelhardt, W.-P. Leung, C. L. Raston, G. Salem, P. Twiss, A. H.
White, J. Chem. Soc. Dalton Trans. 1988, 2403 ± 2409.
[15] J. Sakaki, W. B. Schweizer, D. Seebach, Helv. Chim. Acta 1993, 76,
2654 ± 2665.
[16] a) J. D. Unruh, J. R. Christenson, J. Mol. Catal. 1982, 14, 19 ± 34;
b) C. P. Casey, E. L. Paulsen, E. W. Beuttenmueller, B. R. Proft, L. M.
Petrovich, B. A. Matter, D. R. Powell, J. Am. Chem. Soc. 1997, 119,
11817 ± 11825.
[17] L. A. van der Veen, M. D. K. Boele, F. R. Bregman, P. C. J. Kamer,
P. W. N. M. van Leeuwen, K. Goubitz, J. Fraanje, H. Schenk, C. Bo, J.
Am. Chem. Soc. 1998, 120, 11616 ± 11626.
[18] Preformation of the rhodium/phosphane catalyst mixture does not
lead to superior product yields.
Nucleophilic Trapping of p-Allylpalladium
Intermediates Generated by
Carbopalladation of Bicyclopropylidene:
A Novel Three-Component Reaction**
Scheme 1. Mechanism of the nucleophilic trapping of p-allylintermediate
8. A) 5 mol% Pd(OAc)2, 10 mol% TFP, 5.0 equiv LiOAc, K2CO3, Et4NCl,
MeCN, 808C, 24 h.
Hanno Nüske, Mathias Noltemeyer, and
Armin de Meijere*
The p-allylpalladium intermediate 8 must be formed after
the initial carbopalladation and b-hydride elimination by
readdition of the hydridopalladium species onto the newly
formed double bond[5] via a s-allylpalladium complex 9. The
ligand tris-(a-furyl)phosphane (TFP), which is known to
retard b-hydride elimination[6] and thus favor the readdition
of the hydridopalladium complex onto the double bond,
proved to be best for this reaction, and the yield of the allyl
acetate 3 could be raised up to 50% by using LiOAc as an
additional source of acetate.
Dedicated to Professor Barry M. Trost
on the occasion of his 60th birthday
The construction of complex molecules from simple start-
ing materials is a challenging task for chemists. One of the
most elegant ways to achieve this is by utilizing so-called
domino reactions.[1] Multicomponent reactions such as the
Mannich and the Ugi reaction are examples of all-intermo-
lecular domino reactions. Recently, our group has published a
new all-carbon-coupling three-component reaction, the dom-
In view of previous observations on the nucleophilic
substitution reactions on 1,1-dimethyleneallylpalladium inter-
mediates,[7] stabilized enolates and other carbon nucleophiles
were tested. These were generated by separately deprotonat-
ing malononitriles and diethyl malonates with sodium hydride
and then adding to the reaction mixture from 1, the palladium
precatalyst, and iodobenzene (2) to give the malonic acid
derivatives 11a ± c in up to 77% yield.[8] In accordance with
earlier findings,[7] only products of the nucleophilic attack at
the sterically less encumbered terminus of the allyl moiety
were obtained (Scheme 2).
Especially interesting is the possible preparation of amino
acid derivatives by this method. With OꢁDonnellꢁs nucleo-
philic glycine equivalent 12[9] the methylenecyclopropane
derivative 13, a substituted isomer of hypoglycin A in a
protected form,[10] was obtained in 76% yield (Scheme 3).
Glycine methyl ester 14a, in the presence of triethylamine in
[*] Prof. Dr. A. de Meijere, Dr. H. Nüske
Institut für Organische Chemie
Georg-August-Universität Göttingen
Tammannstrasse 2, 37077 Göttingen (Germany)
Fax : (‡49)551-399475
E-mail: Armin.deMeijere@chemie.uni-goettingen.de
Dr. M. Noltemeyer
Institut für Anorganische Chemie
Georg-August-Universität Göttingen
Röntgenstrukturabteilung
Tammannstrasse 4, 37077 Göttingen (Germany)
[**] Cyclopropyl Building Blocks in Organic Synthesis, Part 73. This work
was supported by the Fonds der Chemischen Industrie and Bayer AG.
We are indebted to Dr. B. Knieriem, Göttingen, for his careful
proofreading of the final manuscript. Part 72: A. de Meijere, M. von
Seebach, S. I. Kozhushkov, S. Cicchi, T. Dimoulas, A. Brandi, Eur. J.
Org. Chem. 2001, in press; Part 71: A. de Meijere, S. I. Kozhushkov, D.
Faber, V. Bagutskii, R. Boese, T. Haumann, R. Walsh, Eur. J. Org.
Chem. 2001, in press.
Angew. Chem. Int. Ed. 2001, 40, No. 18
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Secondary amines should not be too bulky, as diethylamine
(14g) (Table 1, entry 6) gave 15 f in 75% yield, while
dibenzylamine and diisobutylamine gave no coupling prod-
ucts. Piperidine (14h) and morpholine (14i) afforded com-
pounds 15h and 15i in 79 and 99% yield, respectively, after
only 1 h. In these cases prolonged heating also led to the
formation of the thermodynamically favored products, for
example after 48 h the products from 14h and 14i were
completely converted to 16h and 16i. Interestingly, in the
presence of tris(o-tolyl)phosphane, products of type 15 were
formed exclusively, even after 48 h (Table 1, entry 13).
Scheme 2. Malonic ester derivatives as nucleophiles. A) 5 mol%
Pd(OAc)2, 10 mol% TFP, Et3N, THF, 808C, 24 ± 96 h.
The allylamine 15b from bicyclopropylidene (1), iodoben-
zene (2), and n-butylamine (14b) was further elaborated
(Scheme 4). Alkylation of 15b with 2,3-dibromopropene gave
Scheme 3. Preparation of C- and N-substituted amino acids. A) 1.0 equiv
1, 0.5 equiv 2, 5 mol% Pd(OAc)2, 10 mol% TFP, Et3N, 80 8C. E ˆ CO2Me.
Scheme 4. Intramolecular cross-coupling of the 4-aza-2-bromo-1,6-diene
18. A) 1) K2CO3, CH2Cl2; 2) 2,3-dibromopropene, 0 !258C, 20 h. B)
5 mol% Pd(OAc)2, 10 mol% PPh3, Et3N, DMF, 808C, 24 h. [a] Yield based
on amount of Pd(OAc)2 used.
this one-pot transformation, gave the substitution product 15a
after 5 h in nearly quantitative yield (96%). Interestingly,
upon prolonged heating (24 h) of the reaction mixture, the
yield of 15a decreased to 63%, and in addition 29% of the
regioisomer 16a was isolated as a mixture of E and Z isomers
(5:1). This indicates that the nucleophilic substitution of 8
with 14a is reversible and that 16a is the thermodynamically
more stable product.
The successful application of the glycine ester as a nitrogen
nucleophile led to the evaluation of a number of primary and
secondary amines (Table 1). Very good results were achieved
with primary amines, and the products were formed in good to
excellent yields. No twofold substitution of the amine, which is
a common side reaction of primary amines,[11] was detected.
the 4-aza-2-bromo-1,6-diene 18, which underwent an intra-
molecular Heck-type cross coupling with opening of the
cyclopropane ring to yield the cross-conjugated 5-methylene-
4-ethenyl-1,2,5,6-tetrahydropyridine 19 in 45% yield and, in
addition, the 1,1-dimethyleneallylpalladium complex 20 (44%
yield based on Pd(OAc)2 used) could be isolated.[12]
The X-ray structure analysis of 20 (Figure 1) discloses that
all three allyl carbon atoms are located at nearly the same
distance[13] from the metal atom, with C(5) just barely closer
to the palladium than C(3).[14] Thus, the preferred initial
attack of any nucleophile at C(5) of a p-allylpalladium
complex of type 20 must be attributed to the less pronounced
Table 1. The use of amines as nucleophiles in the new three-component
reaction.[a]
Entry Amine
t
Product
(E/Z)
Yield
[%]
[h]
1
2
H2NnBu (14b)
H2NnBu (14b)
48
24
15b
73[a]
15
19
73
95
98
60
28
41
75
79
67
99
42
16b (6:1)
17 (5:1)
15c
15d
15e
16e (10:1)
17 (5:1)
15 f
15g
15h
3
4
5
6
H2NiBu (14c)
H2NtBu (14d)
H2NBn (14e)
H2NBn (14e)
48
48
1
48
7
8
9
10
11
12
(3-methylbut-1-yne-3-yl)amine (14 f) 24
HNEt2 (14g)
piperidine (14h)
piperidine (14h)
morpholine (14i)
morpholine (14i)
48
1
24
16h (5:1)
1.5 15i
20
48
15i
16i (>20:1) 14
15i
70[b]
13
morpholine (14i)
[a] Conditions: 2.00 equiv 1, 1.00 equiv 4, 3.00 equiv amine, 5 mol%
Pd(OAc)2, 10 mol% TFP, DMF, 808C. [b] 10 mol% P(oTol)3.
Figure 1. Structure of the p-allylpalladium complex 20 in the crystal.[12]
3412
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Angew. Chem. Int. Ed. 2001, 40, No. 18

COMMUNICATIONS
Crystallographic Data Centre as supplementary publication no.
CCDC-162027. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax:
(‡44)1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
steric encumbrance at this site and the fact that an SN2-type
attack on the cyclopropyl carbon C(3) has to pass through a
highly strained transition structure.[15] The formation of
complex 20 from 18 also shows that the attack at least of
nitrogen nucleophiles on p-allylpalladium intermediates of
type 8 must be reversible.
In conclusion, this new three-component reaction bears a
significant combinatorial potential in that all three compo-
nents may be varied just as in the previously described domino
Heck ± Diels ± Alder sequence,[2] leading to a three-dimen-
sional library of small molecules.
[13] a) P. S. Manchand, H. S. Wong, J. F. Blount, J. Org. Chem. 1978, 43,
4769 ± 4774; b) D. P. Grant, N. W. Murrall, A. J. Welch, J. Organomet.
Chem. 1987, 333, 403 ± 414; c) C.-C. Su, J.-T. Chen, G.-H. Lee, Y. Wang,
J. Am. Chem. Soc. 1994, 116, 4999 ± 5000; d) P. von Matt, G. C. Lloyd-
Jones, A. B. E. Minidis, A. Pfaltz, L. Macko, M. Neuburger, M.
Zehnder, H. Rüegger, P. S. Pregosin, Helv. Chim. Acta 1995, 78, 265 ±
284.
[14] To the best of our knowledge this is the first structure analysis of a p-
allylpalladium complex with a primary ± tertiary unsymmetrically
substituted allyl ligand. Complexes with primary ± secondary allyl
ligands have previously been characterized. See: N. W. Murrall, A. J.
Welch, J. Organomet. Chem. 1986, 301, 109 ± 130.
Received: April 17, 2001 [Z16950]
[15] Y. I. Golꢁdfarb, L. I. Belenꢁkii, Russ. Chem. Rev. 1960, 29, 214 ± 235.
[1] a) K. Neuschütz, J. Velker, R. Neier, Synthesis 1998, 227 ± 255; b) L. F.
Tietze, Chem. Rev. 1996, 96, 115 ± 136.
[2] a) S. Bräse, A. de Meijere, Angew. Chem. 1995, 107, 2741 ± 2743;
Angew. Chem. Int. Ed. Engl. 1995, 34, 2545 ± 2547; b) A. de Meijere,
H. Nüske, M. Es-Sayed, T. Labahn, M. Schroen, S. Bräse, Angew.
Chem. 1999, 111, 3881 ± 3884; Angew. Chem. Int. Ed. 1999, 38, 3669 ±
3672.
[3] Bicyclopropylidene (1) is now easily accessible in three simple steps.
See: A. de Meijere, S. I. Kozhushkov, T. Späth, Org. Synth. 2000, 78,
142 ± 151.
Insertion Reactions of Nitriles into the P C
Bond of [(h1-C5Me5)P{W(CO)5}2]ÐA Novel
Approach to Phosphorus-Containing
Heterocycles**
[4] All new compounds were fully characterized by IR, MS, 1H NMR,
13C NMR, HRMS and/or elemental analysis.
[5] a) R. C. Larock, K. Takagi, Tetrahedron Lett. 1983, 24, 3457 ± 3460;
b) R. C. Larock, S. Varaprath, J. Org. Chem. 1984, 49, 3432 ± 3435.
[6] a) V. Farina, S. R. Baker, D. A. Benigni, C. Sapino, Jr., Tetrahedron
Michael Schiffer and Manfred Scheer*
Â
Lett. 1988, 29, 5739 ± 5742; b) M. Cavicchioli, D. Bouyssi, J. Gore, G.
Dedicated to Professor Dieter Sellmann
in occasion of his 60th birthday
Â
Balme, Tetrahedron Lett. 1996, 37, 1429 ± 1432; c) K. J. Szabo, Organo-
metallics 1996, 15, 1128 ± 1133.
[7] a) A. Stolle, J. Salaün, A. de Meijere, Synlett 1991, 327 ± 330; b) A.
Stolle, J. Ollivier, P. P. Piras, J. Salaün, A. de Meijere, J. Am. Chem.
Soc. 1992, 114, 4051 ± 4067.
In the thermal activation of [Cp*P{W(CO)5}2] (1; Cp* ˆ h1-
C5Me5), a Cp* migration from the P atom to the transition
metal atom occurs to form the highly reactive intermediate
[8] Representative procedure: 1-Cyclopropylidene-1-phenyl-2-morpholi-
nopropane (15i): Morpholine (14i) (261 mg, 3.00 mmol) was added to
a solution containing Pd(OAc)2 (11.2 mg, 50.0 mmol; 5 mol%), TFP
(23.2 mg, 100 mmol; 10 mol%), iodobenzene (2) (204 mg, 1.00 mmol),
and bicyclopropylidene (1) (160 mg, 2.00 mmol) in DMF (0.5 mL),
and the mixture was stirred for 1.5 h at 808C. After cooling to room
temperature, the solution was added to water (10 mL), the mixture
extracted with diethyl ether (5 Â 20 mL), and the combined organic
phases dried (MgSO4). After removal of the solvent in a rotatory
evaporator the residue was chromatographed on silica gel (25 g,
column 2 Â 20 cm, pentane/diethyl ether 5/1) to yield 15i (240 mg,
[Cp*(CO)2W P !W(CO)5] A.[1] The chemistry of this highly
ꢁ
reactive intermediate A offers promising synthetic routes to a
large variety of new phosphametallaheterocycles. Thus, the
trapping reaction of A with phosphaalkynes[1] and alkynes[2]
proceeds by formal [2‡2] cycloaddition reactions to form
novel main group element transition metal cage compounds.
In continuation of these reactivity studies we attempted to
employ nitriles for trapping reactions of intermediate A.
Surprisingly, however, we observed insertion reactions into
the P C bond of the starting material.
99%) as a yellowish oil, Rf ˆ 0.55. IR (film): nÄ ˆ 3052, 2971, 2851, 2805
1
(C N), 1598, 1494, 1447, 1373, 1261, 1118, 1071, 926, 762, 698 cm
;
1H NMR (250 MHz, CDCl3): d ˆ 1.21 ± 1.43 (m, 4H; cPr-H), 1.28 (d,
3J ˆ 6.7 Hz, 3H; 3-H), 2.42 ± 2.63 (m, 4H; CH2NCH2), 3.58 (q, 3J ˆ
6.7 Hz, 1H; 2-H), 3.69 ± 3.78 (m, 4H; CH2OCH2), 7.23 (dd, 3J ˆ 7.0,
Insertion reactions of organonitriles into metal ± hydrogen
and metal ± carbon bonds are established processes.[3] Fur-
thermore, it is known that nitriles insert into the Mo Cl bond
3
4J ˆ 1.1 Hz, 1H; 4'-H), 7.32 (dd, 3J ˆ 7.0, J ˆ 7.2 Hz, 2H; 3'-H, 5'-H),
7.82 (dd, 3J ˆ 7.2, 4J ˆ 1.1 Hz, 2H; 2'-H, 6'-H); 13C NMR (62.9 MHz,
CDCl3, DEPT): d ˆ 2.74 ( , cPr-C), 3.74 ( , cPr-C), 15.77 (‡, C-3),
50.73 ( , C-2'', C-6''), 64.99 (‡, C-2), 67.36 ( , C-3'', C-5''), 123.76
(Cquat, cPr-C), 126.35 (‡, C-4'), 127.23 (‡, Ar-C), 127.77 (‡, Ar-C),
128.59 (Cquat, Ar-C), 139.99 (Cquat, C-1); MS (70 eV): m/z (%): 243 (12)
[5]
of MoCl5,[4] into the Zr O bond of [Cp2 Zr O], and into
ˆ
*
E N bonds (E ˆ B,[6] Al,[7] P, [8] Pt[9]). Recently, Neumüller
et al. reported on CsX-catalyzed trimerization reactions of
acetonitrile with EMe3 (E ˆ element of Group 13) under
elimination of CH4 and formation of [Me2E{HNC(Me)}2-
‡
‡
‡
‡
[M ], 228 (5) [M
CH3], 198 (1) [M
C2H4O], 156 (1) [M
‡
morpholine H], 128 (6) [M
morpholine C2H4], 114 (100)
‡
[M
C6H5 C4H4]; elemental analysis calcd for (%) C16H21NO
(243.4) calcd: C 78.97, H 8.70, N 5.76; found: C 79.20, H 8.69, N 5.92.
[9] M. J. OꢁDonnell, X. Yang, M. Li, Tetrahedron Lett. 1990, 31, 5135 ±
5138.
[10] K. Voigt, A. Stolle, J. Salaün, A. de Meijere, Synlett 1995, 226 ± 228.
[11] a) R. Tamura, L. S. Hegedus, J. Am. Chem. Soc. 1982, 104, 3727 ± 3729;
[*] Prof. Dr. M. Scheer, Dr. M. Schiffer
Institut für Anorganische Chemie der Universität Karlsruhe
76128 Karlsruhe (Germany)
Fax : (‡49)721-608-7021
E-mail: mascheer@chemie.uni-karlsruhe.de
Ã
b) J. P. Genet, M. Balabane, J. E. Bäckvall, J. E. Nyström, Tetrahedron
[**] This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie. M. Schiffer thanks the Fonds
der Chemischen Industrie for a PhD fellowship.
Lett. 1983, 24, 2745 ± 2748.
[12] Crystallographic data (excluding structure factors) for the structure
reported in this paper have been deposited with the Cambridge
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