Oxonitriles: Multicomponent Grignard addition-alkylations

Article abstract of DOI:10.1002/anie.200352920

Three at a time: Sequential carbonyl addition, chelation-controlled conjugate addition, and alkylation triggers the multicomponent assembly of diverse nitriles. The chelation-controlled conjugate addition-alkylation installs three new stereocenters (see scheme), thereby generating substituted nitriles that are ideal terpenoid precursors as illustrated in the synthesis of epi-dehydroabietic acid.

Full text of DOI:10.1002/anie.200352920

Communications
Conjugate Addition–Alkylations
Oxonitriles: Multicomponent Grignard Addition–
Alkylations**
Fraser F. Fleming,* Zhiyu Zhang, Qunzhao Wang, and
Omar W. Steward
Dedicated to Professor Edward Piers
on the occasion of his retirement
Efficiently installing high molecular complexity is a funda-
mental pursuit in organic synthesis.[1] Several excellent
strategies have emerged for installing multiple bonds in a
single synthetic operation; bidirectional synthesis,[2] domino
reactions,[3] biomimetic cascades,[4] and multicomponent reac-
tions.[5] Each strategy exhibits complementary advantages,
with multicomponent reactions benefiting from an inherent
convergence that fulfills the synthetic criteria of assembling
complex targets from fragments of similar size.[6]
[*] Prof. Dr. F. F. Fleming, Z. Zhang, Q. Wang, Prof. Dr. O. W. Steward
Department of Chemistry and Biochemistry
Duquesne University
Pittsburgh, PA 15282-1530 (USA)
Fax: (+1)412-396-5683
E-mail: flemingf@duq.edu
[**] Financial support from the National Institutes of Health (USA) is
gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200352920
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As a subclass of multicomponent reactions, conjugate
addition–alkylation reactions install two new bonds and up to
three stereocenters in a single synthetic operation.[7] Chela-
tion-controlled conjugate addition–alkylations exhibit the
additional advantage of promoting conjugate additions with
less reactive Michael acceptors. The strategy is particularly
effective for g-hydroxyalkenenitriles (Scheme 1, 1!4)[8]
where chelation permits a facile conjugate addition–alkyla-
tion with a recalcitrant class of Michael acceptors that are
unreactive toward many conventional nucleophiles.[9]
conjugate addition affording the cyclic magnesiated nitrile
3b.[8] Intercepting this formal dianion with methyl iodide
installs a third stereocenter,[12] generating 4b as a single
stereoisomer.[13]
The efficient three-component addition–alkylation of 5b
is typical of the reactivity exhibited in a range of multi-
component reactions (Table 1). Grignard reagents react
significantly faster with the carbonyl group than in the
subsequent chelation-controlled conjugate addition, permit-
ting the sequential addition of two different Grignard
reagents, first to the ketone and second in the conjugate
addition (Table 1, entry 2). Employing w-haloalkyl Grignard
Table 1: Multicomponent oxonitrile conjugate addition–alkylations.
Entry
Oxonitrile
Reagents
Alkanenitrile
Yield[%]
1
MeMgCl,
MeI
86
Scheme 1. Chelation-controlled conjugate additions to alkenenitriles.
a) PhMgBr (3 equiv), THF, RT, 1.5 h, (58%).
2
3
MeMgCl,
71
53
PhMgCl,
MeI
The highly efficient chelation-controlled conjugate addi-
tions to g-hydroxyalkenenitriles 1 stimulated a multicompo-
nent variation with Grignard reagents and oxonitriles for
potentially installing three new stereocenters in one operation
(inset, Scheme 1). Conceptually, the addition of a Grignard
reagent to the g-oxonitrile 5a was envisaged to directly
generate an alkylmagnesium alkoxide intermediate 2, which
triggered conjugate addition and generated the dimagnesi-
ated nitrile 3 for potential alkylation (Scheme 1). Addition of
excess PhMgBr to oxonitrile 5a[10] triggers sequential carbon-
yl and conjugate additions, generating 4a as the sole stereo-
isomer.
Although the formation of 4a validates the multicompo-
nent concept, optimizing the reaction was frustrated by the
volatility and instability of 5a.[10a] Attention was therefore
redirected toward the more stable six-membered oxonitrile
5b[11] (Scheme 2). Addition of excess methylmagnesium
chloride to 5b triggers the sequential carbonyl addition–
MeMgCl,
4
5
iPrMgBr,
58
53
MeMgCl,
6
MeMgCl,
50[b]
[a] Stereochemistry assigned by X-ray crystallography.[14] [b] Prepared by
iPrMgCl exchange.[15] [c] An equivalent of tBuLi is added after addition of
6b to promote conjugate addition through the ate complex.[16]
Scheme 2. Multicomponent addition–alkylation with oxonitrile 5b.
a) MeMgCl, THF, ꢀ788C, 1 h; b) ꢀ788C!RT, 2 h, MeI, 86%.
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Communications
reagents, such as chlorobutylmagnesium bromide (6a) or the
[1] T. Hudlicky, Chem. Rev. 1996, 96, 3 .
[2] a) S. R. Magnuson, Tetrahedron 1995, 51, 2167; b) C. S. Poss,
S. L. Schreiber, Acc. Chem. Res. 1994, 27, 9.
[3] a) L. F. Tietze, Chem. Rev. 1996, 96, 115; b) T.-L. Ho, Tandem
Organic Reagents, Wiley, New York, 1992.
[4] U. Scholz, E. Winterfeldt, Nat. Prod. Rep. 2000, 17, 349.
[5] a) L. F. Tietze, A. Modi, Med. Res. Rev. 2000, 20, 3 04; b) A.
Dömling, I. Ugi, Angew. Chem. 2000, 112, 3300; Angew. Chem.
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[6] E. J. Corey, X.-C. Cheng, The Logic of Chemical Synthesis,
Wiley, New York, 1989, chap. 1.
[7] M. Hulce, M. J. Chapdelaine in Comprehensive Organic Syn-
thesis, Vol. 4 (Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford,
1991, pp. 237 – 268.
related Grignard reagent 6b, for the conjugate addition
allows a smooth annulation route to the cis-fused decalin 4d
and hydrindane 4e, respectively (Table 1, entries 3and 4,
respectively). Similarly, carbonyl additions to the correspond-
ing five-membered oxonitrile 5c,[11] followed by addition of
the w-haloalkyl Grignard reagents 6a and 6b, generates
nitrile-substituted hydrindane and octalin rings in one syn-
thetic operation (Table 1, entries 5 and 6).
The rapid installation of three new stereocenters makes
the multicomponent Grignard addition to oxonitriles ideally
suited to terpenoid synthesis. Combining the multicompo-
nent addition with cationic cyclization provides a particularly
efficient entry to the dehydroabietic acid skeleton, several
congeners of which exhibit antitumor, antibiotic, and cyto-
toxic actitvity.[17] Sequential addition of MeMgCl and
Grignard 6c[18] to 5b followed by methylation with MeI
installs the entire abietane carbon skeleton (Scheme 3).
[8] F. F. Fleming, Q. Wang, O. W. Steward, J. Org. Chem. 2003, 68,
4235.
[9] F. F. Fleming, Q. Wang, Chem. Rev. 2003, 103, 2035.
[10] Prepared by oxidation[10a] of 1, R1 = H.[10b] a) A. Nudelman, E.
Keinan, Synthesis 1982, 687; b) F. F. Fleming, Q. Wang, O. W.
Steward, J. Org. Chem. 2001, 66, 2171.
[11] Oxidation of cyclohexenecarbonitrile and cyclopentenecarboni-
trile with CrO3-3,5-dimethylpyrazole,[11a] rather than pyridi-
ne,[11b] afforded oxonitriles 5b and 5c in 65% and 25% yield,
respectively. a) J. N. Johnson, Encyclopedia of Reagents for
Organic Synthesis, Vol. 2 (Ed.: L. A. Paquette), Wiley, Chi-
chester, 1995, pp. 1275 – 1277. a) H. E. Zimmerman, R. J. Pas-
teris, J. Org. Chem. 1980, 45, 4864.
[12] 1H NMR analysis of the crude reaction mixture failed to identify
any of the independently prepared diastereomeric nitrile.
[13] Methylation of 3b corresponds to a retentive alkylation of the
chiral C-magnesiated nitrile, as consistently observed in the
inter- and intramolecular alkylations (Table 1). The retentive
alkylations of 3b contrast with invertive acylations of a closely
related magnesiated nitrile[8] implying an unusual electrophile-
dependent stereoselectivity analogous to that observed with
selected chiral organolithium reagents.[a] Interception of 3b with
a range of electrophiles is being pursued to determine if the
alkylation stereoselectivity of this magnesiated nitrile is indeed
electrophile dependent. a) A. Basu, S. Thayumanavan Angew.
Chem. 2002, 114, 740; Angew. Chem. Int. Ed. 2002, 41, 717.
[14] X-ray crystallography of 4b and 4c confirmed the stereochem-
ical assignment. CCDC-218678 (4b) and CCDC-218679 (4c)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.cam.
ac.uk/conts/retrieving.html (or from the Cambridge Crystallo-
graphic Data Centre, 12, Union Road, Cambridge CB21EZ,
UK; fax: (+ 44)1223-336-033; or deposit@ccdc.cam.ac.uk).
[15] M. Abarbri, J. Thibonnet, L. Bꢀrillon, F. Dehmel, M. Rottlꢁnder,
P. Knochel, J. Org. Chem. 2000, 65, 4618.
Scheme 3. Multicomponent epi-dehydroabietic acid synthesis.
a) MeMgCl, THF, 1 h; 6c, ꢀ788C!RT; MeI, 2 h, 54%; b) Me3SO3H,
MeNO2, 08C, 1.5 h, 75%; c) NaOH, H2O, diethylene glycol, 16 h,
1708C; 6 h, 2468C; HCl 90%.
Intramolecular Friedel–Crafts alkylation affords predomi-
nantly[19] the cis-abietane 9, illustrating the advantage of the
small, non-nucleophilic nitrile that permits arylation without
prior interception of the carbocation intermediate 8 that
occurs with the corresponding ester.[20] Nitrile hydrolysis
completes the synthesis of epi-dehydroabietic acid 10.[21]
Multicomponent Grignard addition–alkylations of oxo-
nitriles rapidly assembles highly substituted mono- and
bicyclic nitriles. Employing w-haloalkyl Grignard reagents
permits an efficient route to octalins, hydrindanes, and
decalins with aryl-substituted Grignards being ideally suited
for annulation by Friedel–Crafts alkylations. Collectively the
strategy rapidly assembles a diverse array of cyclic nitriles,
with complete control over the three stereogenic centers.
[16] F. F. Fleming, Z. Zhang, Q. Wang, O. W. Steward, Org. Lett.
2002, 4, 2493.
[17] a) Y. Kinouchi, H. Ohtsu, H. Tokuda, H. Nishino, S. Matsunaga,
R. Tanaka, J. Nat. Prod. 2000, 63, 817; b) A. M. El-Sayed,
Zagazig J. Pharm. Sci. 1998, 7, 80; c) I. Rogers, H. Mahood, J.
Servizi, R. Gordon, PulpPap. Can. 1979, 80, 94.
[18] The Grignard reagent 6c[18a] is synthesized from 1-bromo-3-
isopropylbenzene:[18b] 1. Mg; ethylene oxide. 2. Ph3P, CCl4.
a) R. D. Haworth, R. L. Barker, J. Chem. Soc. 1939, 1299.
b) Commercially available from Lancaster.
Received: September 19, 2003[Z52920]
[19] Cyclization affords a 9:1 ratio of cis:trans abietanes in favor of 9.
[20] a) K. Fuji, S.-Z. Zheng, M. Node, X.-J. Hao, Chem. Pharm. Bull.
1991, 39, 202. b) A 13% yield of the carbocyclic ester is formed
from a carbocationic cyclization from the corresponding alke-
ne.[18a]
Keywords: alkylation · Grignard reagents · Michael addition ·
.
multicomponent reactions · oxonitriles
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Chemie
[21] epi-Abietic acid 10 is used as a biological marker for diterpe-
noids[21a] in geochemical sediments and has been previously
synthesized.[21b,c] a) B. R. T. Simoneit, Geochim. Cosmochim.
Acta 1977, 41, 463; b) R. E. Ireland, R. C. Kierstead, J. Org.
Chem. 1966, 31, 2543; c) M. Sharma, U. R. Ghatak, P. C. Dutta,
Tetrahedron 1963, 19, 985.
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