Gamma-hydroxy-alpha,beta-alkenenitriles: chelation-controlled conjugate additions.

Article abstract of DOI:10.1021/jo0258150

Temporarily anchoring Grignard and organolithium reagents to gamma-hydroxy-alpha,beta-alkenenitriles promotes efficient conjugate additions to what are otherwise recalcitrant Michael acceptors. Sequential deprotonation and addition of a modest excess of a

Full text of DOI:10.1021/jo0258150

γ-Hyd r oxy-r,â-a lk en en itr iles: Ch ela tion -Con tr olled Con ju ga te
Ad d ition s1
†
Fraser F. Fleming,* Qunzhao Wang, Zhiyu Zhang, and Omar W. Steward
Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, Pennsylvania 15282-1530
flemingf@duq.edu
Received April 12, 2002
Temporarily anchoring Grignard and organolithium reagents to γ-hydroxy-R,â-alkenenitriles
promotes efficient conjugate additions to what are otherwise recalcitrant Michael acceptors.
Sequential deprotonation and addition of a modest excess of a second Grignard reagent allows
effective conjugate delivery of alkyl groups to cyclic and acyclic alkenenitriles. Mechanistically,
conjugate additions proceed through alkylmagnesium alkoxide complexes for all but the more
substituted alkenenitriles that require alkyl transfers from the more reactive ate complexes.
Synthetically, chelation-controlled conjugate additions rapidly, and stereoselectively, assemble
substituted nitriles, installing up to two new stereocenters in a single synthetic operation.
In tr od u ction
activated by conjugation with a ketone. Collectively, these
reactions exhibit a distinct correlation between reaction
efficiencyand increasingelectron densityon thenucleophile.
Anionic conjugate additions occupy a central niche for
creating carbon-carbon bonds. The centrality of anionic
conjugate additions stems from installing a new bond two
carbons removed from an electron-withdrawing group,
with the potential for additional C-C bond formation
through R-alkylation. Numerous Michael additions to
enones and enoates are featured as key steps in natural
product syntheses, attesting to the versatility and reli-
ability of conjugate additions for the stereoselective
6
b
2
Conjugate addition of carbon nucleophiles to unacti-
vated alkenenitriles is particularly demanding. The
challenge lies in overcoming the inherent propensity of
highly electron-rich organolithium and Grignard nucleo-
philes toward 1,2-addition,10 caused by the greater
polarization of the CtΝ group over the â-carbon of
alkenenitriles. Redirecting the addition to the â-carbon
by chelation, as pioneered with enones,11 potentially
overcomes 1,2-addition by temporarily anchoring a highly
charged nucleophile in close proximity to the poor accep-
tor and geometrically precludes intramolecular attack on
the nitrile group.
3
4
5
installation of strategic carbon-carbon bonds.
In contrast to unsaturated carbonyl compounds, an-
ionic conjugate additions to alkenenitriles are signifi-
6
cantly more demanding. Efforts to elucidate the funda-
mental requirements for conjugate additions to these
recalcitrant acceptors stimulated three approaches with
a biased proclivity toward conjugate addition: intra-
molecular additions with dithiane anions,6b intermolecu-
lar additions with highly nucleophilic sulfur and sele-
Exploratory reactions12 establish the viability of che-
lation-controlled conjugate additions to alkenenitriles. In
seeking to develop this strategy, a diverse array of
alkenenitriles have been subjected to additions with
various Grignard reagents. Collectively, these reactions
demonstrate a broad generality for chelation-controlled
conjugate additions, effectively installing quaternary
carbons, and up to two new stereocenters with virtually
complete stereocontrol, to provide a robust method for
rapidly assembling complex molecular fragments.
7
nium anions, and conjugate addition of Grignard re-
8
9
agents to oxonitriles where the alkenenitrile is further
†
Present address: Department of Chemistry, Cornell University,
Ithaca, NY.
(
1) Taken in part from Wang, Q. Ph.D. Thesis, Duquesne University,
Pittsburgh, PA, 2001.
2) Perlmutter, P. In Conjugate Addition Reactions in Organic
Synthesis; Pergamon: New York, 1992.
3) Hulce, M.; Chapdelaine, M. J . In Comprehensive Organic Syn-
(
Resu lts a n d Discu ssion
(
thesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford 1991;
Vol. 4, pp 237-268.
The exploratory addition of excess methylmagnesium
chloride to 4-hydroxybutenenitrile (1a ) triggers an ef-
(
4) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135.
(
5) Deslongchamps, P. In Stereoelectronic Effects in Organic Chem-
istry; Pergamon: Exeter, UK, 1983; pp 221-242.
6) (a) Rakita, P. E. In Handbook of Grignard Reagents; Silverman,
G. S., Rakita, P. E., Eds.; Marcel Dekker: New York, 1996; pp 381-
89. (b) Fleming, F. F.; Hussain, Z.; Weaver, D.; Norman, R. E. J . Org.
Chem. 1997, 62, 1305.
(10) For a summary of 1,2- vs 1,4-additions to alkenenitriles, see:
Grignard Reactions of Nonmetallic Substances; Kharasch, M. S.,
Reinmuth, O., Eds.; Prentice Hall: New York, 1954; pp 782-783.
(11) For pioneering chelation-controlled additions to enones, see: (a)
Swiss, K. A.; Hinkley, W.; Maryanoff, C. A.; Liotta, D. C. Synthesis
1992, 127. (b) Solomon, M.; J amison, W. C. L.; McCormick, M.; Liotta,
D.; Cherry, D. A.; Mills, J . E.; Shah, R. D.; Rodgers, J . D.; Maryanoff,
C. A. J . Am. Chem. Soc. 1988, 110, 3702.
(
3
(
(
(
7) Fleming, F. F.; Pak, J . J . J . Org. Chem. 1995, 60, 4299.
8) Fleming, F. F.; Pu, Y.; Tercek, F. J . Org. Chem. 1997, 62, 4883.
9) (a) Fleming, F. F.; Guo, J .; Wang, Q.; Weaver, D. J . Org. Chem.
1
999, 64, 8568. (b) Fleming, F. F.; Huang, A.; Sharief, V.; Pu, Y. J .
(12) For a preliminary account, see: Fleming, F. F.; Wang, Q.;
Steward, O. W. Org. Lett. 2000, 2, 1477.
Org. Chem. 1999, 64, 2830.
1
0.1021/jo0258150 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/17/2002
J . Org. Chem. 2002, 67, 5953-5956
5953

Fleming et al.
SCHEME 1. Ch ela tion -Con tr olled Con ju ga te
Ad d ition
TABLE 1. Ch ela tion -Con tr olled Con ju ga te Ad d ition s to
γ-Hyd r oxy-r,â-a lk en en itr ilesa
ficient chelation-controlled conjugate addition (Scheme
1
). Mechanistically, deprotonation at -78 °C generates
13
the chloromagnesium alkoxide 2a that rapidly engages
in a halogen-methyl exchange14 with the excess MeMgCl.
The resulting alkylmagnesium alkoxide 3 initiates a
smooth conjugate addition upon warming to room tem-
perature, ultimately generating the conjugate adduct 4.
The substantial rate difference between deprotonation
and conjugate addition at -78 °C allows t-BuMgCl or
PhMgCl15 to be employed as sacrificial bases. t-BuMgCl
is a particularly convenient base, effectively deprotonat-
ing a range of hydroxy alkenenitriles prior to an alkyl
transfer from a modest excess of a second, potentially
more valuable, Grignard reagent (Table 1). Sequential
2
deprotonation with t-BuMgCl and addition of sp-, sp -,
3
and sp -hybridized Grignard reagents triggers alkyl
transfer to variously substituted alkenenitriles, tolerating
alkyl chloride and acetal functionality despite internal
complexation of the Grignard reagent.16 Sterically de-
manding Grignard reagents add efficiently to acyclic and
cyclic alkenenitriles (Table 1, entries 1-9 and 10-13,
respectively) even with trisubstituted alkenenitriles where
alkyl substitution generally retards conjugate addition.17
Particularly significant are the conjugate additions to â,â-
disubstituted nitriles, permitting installation of quater-
nary centers with complete stereocontrol (Table 1, entries
9
and 13, respectively).
Conjugate additions to cyclic alkenenitriles are exquis-
itely stereoselective. Alkyl transfers to endocyclic and
exocyclic alkenenitriles (Table 1, entries 10-12 and 13,
respectively) install the new carbon bond from the same
face as the hydroxyl group,18 consistent with a stereo-
5
electronically controlled axial addition from an alkyl-
magnesium alkoxide (5). Highly selective axial protona-
tion of the resulting metalated nitrile 6 is particularly
unusual19 (Table 1, entries 10-12), perhaps transpiring
(
13) Turova, N. Y.; Turevskaya, E. P. J . Organomet. Chem. 1972,
4
2, 9.
(
14) Swiss, K. A.; Liotta, D. C.; Maryanoff, C. A. J . Am. Chem. Soc.
1
990, 112, 9393.
(15) For comparison, deprotonation of 1a with PhMgCl and conju-
gate addition of MeMgCl provided the methyl transfer product in 63%
yield, whereas t-BuMgCl provided a 74% yield.
(
(
(
16) Sworin, M.; Neumann, W. L. Tetrahedron Lett. 1987, 28, 3217.
17) Krief, A. Tetrahedron 1980, 36, 2531.
18) The stereochemistry of 4k was secured by X-ray analysis with
a
Typically, 1.0 equiv of t-BuMgCl was added at -78 °C followed,
after 5 min, by the Grignard reagent (1.0-1.1 equiv) and warming
to room temperature. b Compound 4b (11%) is also obtained,
resulting from the addition of ClMg(CH2)4MgBr formed during
the crystallographic data being deposited with the Cambridge Crystal-
lographic Data Center (CCDC 184135). The data can be obtained, upon
request, from the Director, Cambridge Crystallographic Data Center,
c
Grignard formation. Performed with 2.1-2.5 equiv of the Grig-
1
2 Union Road, Cambridge, CB2 1EZ, UK.
19) Gerlach, U.; Haubenreich, T.; H u¨ nig, S.; Keita, Y. Chem. Ber.
nard reagent. d Obtained as a 9:1 ratio of stereoisomers at the
(
nitrile-bearing carbon.
1
993, 126, 1205.
5
954 J . Org. Chem., Vol. 67, No. 17, 2002

γ-Hydroxy-R,â-alkenenitriles
from initial protonation on oxygen followed by intramo-
lecular delivery to the pyramidal20 nitrile anion. Syn-
thetically, the chelation-controlled conjugate addition
relays the alcohol stereochemistry into the controlled
installation of adjacent carbon-carbon and carbon-
hydrogen bonds with almost complete stereoselectivity.
demanding installation of adjacent quaternary-tertiary
stereocenters during the conjugate addition.
Chelation provides an effective method for the conju-
gate addition of alkyllithiums to alkenenitriles, as well
as Grignard reagents. Sequential deprotonation of 1l with
t-BuMgCl and addition of phenyllithium generates the
requisite alkylmagnesium alkoxide 5l, culminating in a
7
8% yield of the substituted nitrile 4l. The requirement
for a magnesium chelate is underscored by the lack of
conjugate addition upon exposure of 1l to excess PhLi.
Initial attempts to add sterically demanding t-BuMgBr
to alkenenitriles afforded primarily recovered nitrile. The
inefficient conjugate addition culminates from a facile
R-deprotonation, reflecting the increased basicity of the
tertiary Grignard reagent,21 as confirmed by sequential
addition of excess t-BuMgCl and deuteriolysis (1a f 3a
f 1o, Scheme 2). Presumably, R-deprotonation from
Mech a n ism
Chelation is essential for the conjugate addition of
Grignard reagents to alkenenitriles. Control experiments
involving addition of BuMgCl to 1p , and the MOM-
containing alkenenitrile 1q, afford only recovered start-
ing material.22 Similarly, exposure of 1p to MeMgOMe,
mimicking the reactivity of the intermediate chelates 3,
leads only to recovery of the nitrile. Chelation apparently
requires hydroxylation adjacent to the alkenenitrile since
relocating the hydroxyl group three or four carbons away,
as in 1r 23 and 1s, precludes conjugate addition.
SCHEME 2. Ad d ition of Ter tia r y Gr ign a r d
Rea gen ts
23
Chelation-controlled additions to alkenenitriles are
2
4
consistent with an intramolecular alkyl transfer from
an alkylmagnesium alkoxide.25 Although the exact mech-
anism remains speculative, an orbital symmetry analy-
2
6
27
alkylmagnesium alkoxide 3a occurs at -78 °C or prior
to obtaining the more moderate temperatures (0-25 °C)
required for the conjugate addition, since simply per-
forming the reaction at ambient temperature largely
overcomes deleterious deprotonation (59% of conjugate
adduct 4o and 18% of 1o). The preference for conjugate
addition over deprotonation is remarkable given the
sis favors a stepwise, anionic mechanism since the
node of the alkenenitrile π* LUMO prohibits a concerted
(22) Addition of BuMgCl to 1p using the general conjugate addition
procedure afforded 69% of the recovered nitrile and 11% of deconju-
gated isomers resulting from δ-deprotonation.
(23) Fleming, F. F.; Wang, Q.; Steward, O. W. J . Org. Chem. 2001,
66, 2171.
(24) Richey, H. G., J r.; Wilkins, C. W., J r.; Brown, B. S.; Moore, R.
E. Tetrahedron Lett. 1976, 723.
(25) (a) Fallis, A. G.; Forgione, P. Tetrahedron 2001, 57, 5899. (b)
Normant, J . F.; Alexakis, A. Synthesis 1981, 841.
(
20) Fleming, F. F.; Shook, B. C. Tetrahedron 2002, 58, 1.
(21) (a) Gonz a´ lez, B.; Gonz a´ lez, A. M.; Pulido, F. J . Synth. Commun.
1
1
995, 25, 1005. (b) Melamed, U.; Feit, B.-A. J . Org. Chem. 1983, 48,
928. (c) Schmidt, R. R.; Hirsenkorn, R. Tetrahedron 1983, 39, 2043.
(26) Kirby, A. J . In Stereoelectronic Effects; Oxford University
Press: Bath, UK, 1996; pp 46-47.
(27) The addition of PhMgCl and the more facile alkyl transfer from
MeMgCl over t-BuMgCl are consistent with an anionic mechanism and
not a radical mechanism: Blomberg, C. In Handbook of Grignard
Reagents; Silverman, G. S., Rakita, P. E., Eds.; Marcel Dekker: New
York, 1996; Chapters 11-12.
(
d) Feit, B. A.; Melamed, U.; Schmidt, R. R.; Speer, H. Tetrahedron
981, 37, 2143. (e) Schmidt, R. R.; Speer, H. Synthesis 1979, 797. (f)
Melamed, U.; Feit, B. A. J . Chem. Soc., Perkin Trans. 1 1978, 1228.
g) Schmidt, R. R.; Talbiersky, J . Angew. Chem., Int. Ed. Engl. 1977,
6, 853.
1
(
1
J . Org. Chem, Vol. 67, No. 17, 2002 5955

Fleming et al.
SCHEME 3. Mech a n ism : Step w ise, An ion ic Alk yl
Tr a n sfer
and MeMgCl (Table 1, entries 10 and 11). PhMgCl is
sufficiently reactive to stimulate conjugate addition to
1
j with 1.1 equiv through an alkylmagnesium alkoxide,
whereas 2.5 equiv of the less reactive MeMgCl are
required for alkyl transfer through the more reactive ate
complex (compare entries 10 and 11 in Table 1). Conceiv-
ably, all alkyl transfers could occur through catalytic
quantities of the ate complex, since the general procedure
employs a slight excess of the Grignard reagent; however,
the minimal methylation of 1j under the standard
conditions is more consistent with only the substituted
alkenenitrile additions requiring alkyl transfers through
the more reactive ate complex.
Con clu sion
SCHEME 4. Alk yl- a n d Ate-Con ju ga te Ad d ition
Mech a n ism s
Chelation provides a practical solution to the long-
standing difficulty of performing conjugate additions to
R,â-alkenenitriles. Cyclic and acyclic alkenenitriles ef-
ficiently participate in alkyl transfers from organolithium
and Grignard reagents, affording a diverse array of
substituted nitriles. Conjugate addition occurs through
alkylmagnesium alkoxides for modestly substituted alk-
enenitriles, whereas more highly substituted nitriles
participate in similarly efficient alkyl transfers from more
reactive ate complexes. Collectively, the chelation-
controlled conjugate additions demonstrate the rapid,
stereoselective assembly of substituted nitriles, installing
up to two new stereogenic centers in a single synthetic
operation.
Exp er im en ta l Section 30
Gen er a l Con ju ga te Ad d ition P r oced u r e. A THF solution
of t-BuMgCl (1.0 equiv, 1-2 M) was added to a cold (-78 °C)
THF solution (0.5-1 M) of the γ-hydroxy-R,â-alkenenitrile
under nitrogen. After 5 min, a THF solution of RMgX (1.1
equiv, 1-3 M) was added, and the cooling bath was removed.
orbital overlap28 between the Mg-Ph σ bond and the R-
and â-carbons during the alkyl transfer (9, Scheme 3).
Association of the nitrile with the Lewis-acidic metal salt,
MgX
2
or LiCl, likely promotes the anionic addition in
After 1.5 h, saturated, aqueous NH Cl was added, and the
4
directly generating the metalated nitrile anion 10.
Two distinct anionic mechanisms operate in chelation-
controlled conjugate additions to alkenenitriles: alkyl
transfer from an alkylmagnesium alkoxide 3t or through
the corresponding ate29 chelate 11t (Scheme 4). The key
signature for the intermediacy of an ate complex is the
necessity for 2 equiv of the Grignard reagent, a require-
ment observed with additions to the more demanding â,â-
disubstituted alkenenitriles (compare entries 6 and 9 in
Table 1). The trend parallels Michael additions to un-
saturated carbonyls where increasing substitution re-
aqueous phase was extracted with EtOAc. The combined
extracts were dried (Na SO ), concentrated, and then purified
2 4
by radial chromatography. A modified workup procedure was
developed for water-soluble products where HOAc (3.2 equiv)
4
was added after 1.5 h rather than saturated, aqueous NH Cl.
The solution was then diluted with EtOAc and the resulting
mixture filtered through silica gel. The crude product was
concentrated and purified by radial chromatography.
Ack n ow led gm en t. Financial support from NIH is
gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
tards conjugate addition through a combination of steric
1
13
and electronic effects.17
cedures and H and C NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Comparative additions to the R-substituted nitrile 1j
reveal an unusual reactivity difference between PhMgCl
J O0258150
(
28) For a related analysis, see: Gawley, R. E. Tetrahedron Lett.
999, 40, 4297.
29) Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. J . Org.
Chem. 2001, 66, 4333.
1
(30) For general experimental procedures, see ref 6b. The high-
resolution mass spectra were recorded at The Ohio State University
Campus Chemical Instrumentation Center.
(
5
956 J . Org. Chem., Vol. 67, No. 17, 2002