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Carbonylation of Doubly Lithiated N-Pivaloylanilines. A Novel Approach to Dioxindoles via Intramolecular Trapping of Aromatic Acyllithiums

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calixspherands (D. N.Reinhoudt, D. J. Dijkstra, P. J. A. in't Veld, K. E.
Bugge, S Harkema, R. Ungaro. E. Ghidini, J. Am. Chem. Soc. 109 (1987)
4761) should be mentioned too Finally, the methylene groups may also be
converted, e.g., into keto groups by oxidation (G. Gormar, K. Seiffarth,
M. Schulz, J. Zimmermann, G. Flamig, Makromol. Chem., in press). These
few examples demonstrate the wide variety of possibilities.
141 V. Bohmer, H. Goldmann, W. Vogt. J. Vicens, Z Asiari. Terrahedron Lerr.
30 (1989) 1391.
[S] V. Bohmer, W. Vogt, S . J. Harris, R. G. Leonard, E. M. Collins, M. Deasy,
M. A. McKervey. M. Owens, J Chem. SOC.Perkins Trans. 1 , in press.
I61 Other types of host molecules have been combined in a similar way to
ditopic receptor molecules, e.g. crown ethers (G. W. Gokel, S. H.
Korzeniowski. Macrocyclic Polyether Synthesis, Springer, Berlin 1982,
p 34), quarternary-ammonium cages (F. P. Schmidtchen. J. Am. Chem.
Soc. 108 (1986) 8249), cyclophanes (C -F. Lai, K. Odashima. K. Koga.
Terruhedron Letr. 26 (1985) 5179), and cyclodextrins (R. Breslow, N.
Greenspoon, T. Guo, R. Zarzycki, J. Am. Chem. So?. 111 (1989) 8296).
[7] ' H N M R (400 MHz, CDCI,): 3: 6 = 7.143 (s, 2 H . Ar-H), 7.133 (s, 2 H ;
Ar-H), 6.621 (d, J,, = 2.4 Hz, 2 H ; Ar-H), 6.526 (d, JAR = 2.4Hz, 2 H ;
Ar-H), 4.939 (s, 2 H ; 0-CH,-CO), 4.859 (d. JAR= 15.7 Hz, 2 H ; 0CHAH&O), 4.574 ( s , 2 H ; O-CH2-CO), 4.350 (d, J,, = 15.7 Hz, 2 H ;
O-CH,,H,-CO), 4.963 (d, JAN= 12.8 Hz, 2 H ; Ar-CH,H,-Ar), 4.589 (d,
JAR
= 12.5 Hz, 2 H ; Ar-CH,H,-Ar),
3.248 (d, JAB
= 12.8 Hz, 2 H : ArCH,H,-Ar). 3.187 (d, J,, = 12.9 Hz, 2 H ; Ar-CH,H,-Ar), 4.251 (4.
J = 7.2 Hz, 4 H ; 0-CH,-CH,), 4 208 (9, J = 7.2 Hz, 2H; 0-CH,-CH,),
following protonation during workup, good yields of 3-tertbutyldioxindoles. The reactions were undertaken in order to
investigate whether intramolecular trapping of intermediate
acyllithiums might lead to more convenient and more generally useful synthetic procedures than those currently available for acyllithiums. The results bear out the validity of the
hypothesis and the reactions provide an interesting new access to indole derivatives.
Whereas reactions of organolithium compounds with carbon dioxide are widely used for the synthesis of carboxylic
acids, reactions with carbon monoxide are almost never used
in synthetic organic chemistry. This latter fact presumably
results from the instability and high reactivity of acyllithiums, which can decompose, dimerize, take up further carbon
monoxide, o r in other ways lead to products other than those
derived by simple electrophilic trapping."] To circumvent
this problem, organic chemists have devised a range of acyl
carbanion equivalents with which to effect nucleophilic acylation reactions.['] Useful though these reagents are, however, they necessitate the use of additional steps to unmask the
~ . ~ ~ O ( ~ , J = ~ . ~ H Z , ~ H ; O - C H , - C H , ) . ~ . ~ ~ ~ ( ~ . J carbonyl
= ~ . ~ H Zfunctionality,
. ~ H ; O - C H ,lack
- the appeal of genuine acyllithiCH,, disturbed by superposition with rerr-butyl), 1.316 (s, 9 H ; C(CH,),),
ums, and preclude the use of isotopically substituted carbon
1.305 (s, 9 H , C(CH,),), 0.815 (s, 18H; C(CH,),).
monoxide for introduction of an isotopic label. Thus, there
4: 8.687 (br. s, 2 H , -NH-), 6.789(s34H;ArH), 6.766(s, 8 H ; ArH), 6.695
is still much to be gained by direct carbonylation of organo(s, 4 H ; ArH), 5.012 (d, J,,, = 16.2 Hz, 4 H ; 0-CH,H,-CO), 4.632 (d,
lithium reagents.
JAn
= 16 2 Hz, 4 H ; 0-CH,H,-CO), 4.698 (s, 4 H ; 0-CH,-CO), 4 536 (s,
4 H : 0-CH,-CO), 4.735 (d, JAH
= 13.1 Hz, 4 H ; Ar-CH,H,-Ar), 4.702 (d,
Seyferth et al. have shown that it is possible to trap acylJAR
= 13.3 Hz, 4 H ; Ar-CH,H,-Ar),
3.226 (d, J,, = 13.3 Hz, 4 H ; Arlithiums formed via carbonylation of alkyllithium reagents
= 13.1 Hz, 4 H : Ar-CH,H,-Ar),
4.214 (4,
CH,H,-Ar), 3.207 (d, JAR
provided that the temperature is kept very low (preferably
J = 7.1-7.4Hz. 8 H ; CH2-CH3), 4.177 (4, J = 7 1-7.4Hz. 4 H ; CH,ca. -130°C) and the trapping electrophile can be used in
CH3),3.638(br.s,4H,CH,-CH,),1.238(t,J=7.1
Hz,lXH;CH,-CH,),
1.087 (s, 18H; C(CH,),), 1.056 (s, 36H; C(CH,),), 1.014 (s, 18H;
s i t ~ . [ These
~I
conditions are extremely restrictive, however,
C(CHd3).
and in any case are reported generally to be unsuccessful in
5 : 6.753 (s, 8 H ; ArH), 6.750 (s, 4 H ; ArH), 6.744 (s, 4 H ; ArH),4.822 (s,
the case of aryllithi~ms.[~]
4 H ; 0-CH,-CO), 4.773 (s, 8 H ; 0-CH,-CO), 4.764 (s, 4 H ; 0-CH,-CO),
Against this background we wondered if intramolecular
4.846 (d, JAR= 13.1 Hz, 4 H ; Ar-CH,H,-Ar), 4.806 (d, JAR= 12.7 Hz,
trapping of intermediate acyllithiums might provide a more
4 H ; Ar-CH,H,-Ar), 4.323 (s, 4 H ; CH,-CH,), 4.177 (q, J = 6.9 Hz, 4 H ;
= 13.0 Hz,
CH,-CH3),4.160(q, J = 7 0 Hz, 8H;CH,-CH3), 3 169(d, JAR
generally applicable synthetic approach for carbonylation
= 12.9 Hz, 4 H ; Ar-CH,CH,-Ar),
4 H ; Ar-CH,CH,-Ar), 3.161 (d, JAB
reactions of organolithium reagents. As a first attempt to
1.254 (t. J = 7.1 Hz, 6 H ; C H X H , ) , 1.241 (t. J = 7.1 Hz, 12H; CH,investigate this idea, we undertook the direct carbonylation
CH,), 1.052 (s, 36H; C(CH,),), 1.046 (s, 36H; C(CH,),).
of doubly lithiated N-pivaloylaniline (I)['] and were ex[8] The experimental conditions for FI and FDMS are described in detail by
H. D. Beckey, H -R. Schulten, Angew. Chem. 87(1975) 425; Angew. Chem.
tremely gratified to discover that carbon monoxide was
Inremat. Edit. 14 (1975) 403, H.-R. Schulten, Inr. J. Muss. Spectram. Ion
smoothly taken up, even at room temperature (Scheme 1).
Phys. 32 (1979) 97. Methanol was used as solvent for the FDMS of 4.
Protonation
and workup of the reaction mixture gave a sub[9] Compare the spectra of the tetra-tert-butyl ester derivates- A. Arduini, A
stantial yield of a crystalline product, identified as 3-terfPochini, S. Reverberi, R. Ungaro, G. D. Andreetti, F. Ugozzoli, Terrahedron 42 (1986) 2089. The X-ray structure of the K%omplex of a tebutyldioxindole (2).c6] The yield was even better (77 % after
traamide derivative (A. Arduini, E. Ghidini. A. Pochini, R. Ungaro, G. D.
purification) when the carbonylation was carried out at 0 "C.
Andreetti, G. Calestani, F. Ugozzoli, J Inclusion Phenom. 6 (1988) 119)
shows the Ke ion in a highly symmetrical polar cavity surrounded by eight
oxygen atoms (ether and carbonyl groups) A similar structure may be
assumed for these complexes in solution.
[lo] E. M. Collins, M. A. McKervey, S. J. Harris, J Chem. Sot. Perkin Truns.
1. 1989, 372.
2 Buh
1
lco
Carbonylation of Doubly Lithiated N-Pivaloylanilines. A Novel Approach to Dioxindoles via
Intramolecular Trapping of Aromatic Acyllithiums **
By Keith Smith* and Gareth 1 Pritchard
Doubly lithiated N-pivaloylanilines react smoothly with
carbon monoxide at 0 "C and atmospheric pressure to give,
[*I Prof. Dr. K. Smith, G. J. Pritchard
Department of Chemistry
University College of Swansea
GB-Swansea, S A 2 8 P P (UK)
["I We thank the University College of Swansea for providing the studentship
to G. J. P. which enabled this work to be carried out.
282
Q VCH Verlugsgesellschaft mbH. D 6940 Weinheim, 1990
4
2
Scheme 1
OS70-0X33/90/0303-0282 3 02 SO10
Angew. Chem. Inr. Ed Engl. 29 (1990) No. 3
In order to test the generality of the method for the synthesis of substituted 3-tert-butyldioxindoles 6, a range of ringsubstituted N-pivaloylanilines 5 was subjected to identical
reaction conditions without optimization of individual cases.
The yields of isolated products were good (Table 1). It is
known that dioxindoles such as 2 and 6 can be reduced to the
corresponding indoles.['.
Table 1. Synthesis of 3-tert-butyldioxindoles 5 from N-pivaloylanilines 6.
OH
4
d
5
6
516
R
M.p. of 6 ["C]
a
b
7-CF3
5-c1
5-Me
4-OMe
149
280-285 (dec.)
263 [b]
194-195
C
d
[CI
Yield of 6 [%I [a]
80
82
61
78
[a] Yield of isolated, purified product based on 5. [b] Ref. [8] 260-261 "C.
[c] The structure of 6 d has been verified by X-ray crystallography [12].
We have not investigated the mechanism of the reaction
leading to 2, but Scheme 1 shows a plausible pathway. There
is literature precedent for the rearrangement of 2-tert-butyldioxindole 2 under basic conditions,[7* 131 which adds credence to the intermediacy of species 3 and 4. Furthermore,
when the reaction of 5 6 was carried out with I3CO, the
product 6 b had the label at position 3, as evidenced by I3C
NMR.
This reaction appears to be the first generally applicable
carbonylation reaction of aryllithiums which allows trapping
of the acyllithium intermediate without incorporating a second aryl group from the original reagent. It also demonstrates the value of intramolecular trapping of intermediate
acyllithiums even when the trapping center is a weakly electrophilic amide anion. The ease of incorporation of carbon
monoxide into the indole nucleus holds out the prospect that
such reactions might be applicable to reactions of "C carbon monoxide (ti,2 = 20 min), which could present opportunities for use in positron emission tomography (PET).['41
The method also nicely complements Wender's recent method for the regiocontrolled synthesis of indoles.[151Finally, it
appears likely that other ring systems can be synthesized via
carbonylation of appropriately substituted organolithium
reagents.
Typical Experimental Procedure
A solution o f 5 b (1.OO g, 4.7 mmol) in T H F (20 mL) was stirred at 0 "C under
nitrogen for 2 h with nBuLi (6.5 mL, 1.6 M, 10.4 mmol). A balloon filled with
carbon monoxide (ca. 500 mL) was fitted to a needle and CO was allowed to
bleed into the reaction mixture. After 1 h the solution was poured into saturated
NH,CI solution (40 mL) and extracted with ethyl acetate (60 mL). The organic
layer was washed with water, dried (MgSO,), and evaporated. The solid obtained was recrystallized from ethyl acetate to give 6b (0.92 g, 82 YO),as a white
solid. 'H NMR ([DJDMSO, 250 MHz): 6 = 0.94 (s, 9H, tBu), 5.82 (s, 1 H,
OH), 6.76(d, J = 8 Hz, 1 H, H-7), 7.18 ( d , J = 2 Hz, 1 H, H-4). 7.22 (dd. J = 2,
8 Hz, 1 H. H-61, 10.26 (br. s, 1 H, NH). I3C NMR ([D,IDMSO, 62.9 MHz):
6 = 179.05, (s, C-21, 141.2 (s. C-7a), 133.5 (s, C-3a), 128.3 (d, C-6), 128.5 (d,
C-4). 124 8 ( s . C-5). 110.4 (d, C-7), 80.0 ( s , C-3, enriched in reactions utilizing
"CO). 36.7 (s, C(CH,),), 23.8 (q, C(CH,),). MS (ammonia CI, % intensity):
NHf'), 242 (23), 240 (84, M + He); accurate mass
m,/z259 (33), 257 (100, M
of M HQ ion 240.0791 (calcd for C,,H,,3SCIN0, = 240.0791).
+
+
Received: June 6, 1989;
revised: November 21, 1989 [Z 3380 IE]
German version: Angew. Chem. 102 (1990) 298
Angen. C'hem. Int. Ed. Engl. 29 (1990) No. 3
0 VCH
[l] L. S . Trzupek, T. L. Newirth, E. G. Kelly. N. E. Sharbati, G. M.
Whitesides, J. Am. Chem. SOC.95 (1973) 8118; for a recent review of
carbonylation reactions of organometallic reagents, see C. Narayama, M.
Periasamy. Synthesis 1985, 253.
[2] Selected reviews of this topic: D. Seebach, Angew. Chem. 81 (1969) 690;
Angew Chem. Int. Ed. Engl. 8 (1969) 639; 0. W Lever, Jr., Tetrahedron 32
(1976) 1943; P. Beak, D. R. Reitz, Chem. Rev. 78 (1978) 275; S . F. Martin,
Synthesis 1979,633;J. D. Alhrrght, Tetrahedron 39 (1983) 3207; T. A. Hose
(Ed.): Umpoled Synrhons. A Survey of Sources and Uses in S.wihesis. John
Wiley, New York 1987, for a novel type of acyl carbanion equivalent, see
M. Ashwell, R. F. W. Jackson, J. Chem. SOC.
Perkin Trans. 1 1989, 835.
[3] D. Seyferth, R. M. Weinstein, J. Am. Chem. SOC. 104 (1982) 5534, D.
Seyferth, R. M. Weinstein, W.-L. Wang, J. Org. Chem. 48 (1983) 1144,
3367; D. Seyferth, R M. Weinstein, W.-L. Wang, R. C. Hui. Tetrahedron
Lett. 24 (1983) 4907; D. Seyferth, R. C. Hui, Organometa1lic.s3 (1984) 327.
[4] D. Seyferth, W.-L. Wang, R. C. Hui, Tetrahedron Lett. 25 (1984) 1651.
[5] W. Fuhrer, H. W. Gschwend, J. Org. Chem. 44 (1979) 1133
[6] M.p. 224-225°C (dec.) (Lit. 220°C [7], 222°C [XI; 224-226'C [9]; 2 2 5
227°C [lo]). The isomeric 2-tert-butyldioxindole melts at 85'C [7].
[7] E. Brandeau, S . David, JLC. Fischer, Tetrahedron 30 (1974) 1445.
[8] F. Piozzi, M. Cecere, Atti. Accad. Naz. Llncei, CI. Sci. Fis. Mar. Nat. Rend.
28 (1960) 639; Chem. Abstr. 55 (1961) 9372d.
[9] M.-C. Battembourg, S. David, Bull. SOC.Chrm. Fr. 1962, 772.
[lo] M. A. Colle, S . David, Compt. Rend. 2SO (1960) 2226; Chrm. Abstr. 55
(1961) 23490f.
[I 11 R. Menicagli, C. Malanga, L. Lardicci, Chem. Ind. (Milan) 59 (1977) 652;
Chem. Abstr. 88 (1978) 50588k.
1121 We thank Prof. M . B. Hursthouse and the SERC X-ray crystallography
service for carrying out the structure determination.
[13] M. A. Sukari. J. M. Vernon, J. Chem. Sor. Perkin Trans. 1 1983, 2219.
[14] V. W. Pike in J. R. Jones (Ed.). Isotopes. Essential Chemistry and Applicat i o m R. SOC.
Chem. Spec. Publ. 68 (1988) 1.
[IS] P. A. Wender, A. W. White, Tetrahedron 39 (1983) 3767.
Mesolytic Cleavage of C-C Bonds. Comparison
with Homolytic and Heterolytic Processes in the
Same Substrate **
By Przemyslaw Maslak * and Javier N. Narvaez
Mechanistic information on cleavage of C-C bonds leading to formation of two fragments containing three-valent
carbon atoms has been limited for a long time to homolytic
reactions."] Only recently have examples of heterolytic scission12] been found and investigated in detail. Carbon-carbon bond cleavage may also be induced by one-electron red ~ c t i o n [or
~ .oxidationc5~~
71 of molecules. In such cases,
unimolecular fragmentation of the resulting radical ions
leads to radicals and ions in a process that may be viewed as
homolytic or heterolytic depending on electron apportionment to the fragments.[*] To reflect this mechanistic duality
we propose to call such processes mesolytic. Here we provide
the first kinetic and thermodynamic comparison of four different C-C bond cleavage modes in the same molecule. The
study illustrates the tremendous accelerations obtainable in
mesolytic processes. We show that this acceleration is due to
thermodynamic factors, and, most importantly, that almost
all of the thermodynamic advantage is expressed in the lowering of the transition-state energy, even for weakly endergonic processes.
When 1 was heated to 110-140°C in perdeuterio0-xylene in the presence of thiophenol (Scheme 11, a first-or-
[*I
[**I
Prof. P. Maslak, J. N. Narvaez
Department of Chemistry
The Pennsylvania State University
University Park, PA 16802 (USA)
This work was supported by a grant from the National Science Foundation and by the New Faculty Award from the Camille and Henry Dreyfus
Foundation.
Verlugsgesellschaft mbH, 0-6940 Wernheim. 1990
0570-0833~90~0303-02X3
3 02.5010
283
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carbonylation, intramolecular, lithiated, approach, acyllithiums, pivaloylanilines, dioxindoles, double, novem, aromatic, via, trapping
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