Morita-Baylis-Hillman cyclizations of arene-ruthenium-functionalized acrylamides

Article abstract of DOI:10.1002/anie.200605045

Enticed by metalation with a {CpRu^II} fragment, N-benzyl and N-phenethyl acrylamides participate in phosphine-promoted spirocyclizations even though they are normally unreactive in Morita-Baylis-Hillman (MBH)-type transformations. A ruthenium-arene cation serves as the electrophilic reaction partner for an in situ generated enolate ion in this organometallic variation of the MBH reaction. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200605045

Angewandte
Chemie
DOI: 10.1002/anie.200605045
Morita–Baylis–Hillman Reaction
Morita–Baylis–Hillman Cyclizations of Arene–Ruthenium-
Functionalized Acrylamides**
F. Christopher Pigge,* R. Dhanya, and Erik R. Hoefgen
The conventional Morita–Baylis–Hillman (MBH) reaction
entails condensation of an a,b-unsaturated carbonyl com-
pound with an aldehyde to afford an a-hydroxyalkyl enone.[1]
The reaction proceeds by initial conjugate addition between
an enone and a nucleophilic promoter (usually a tertiary
amine or trialkyl phosphine) to generate a zwitterionic
enolate.Addition to an aldehyde electrophile and elimination
of the nucleophilic promoter completes the reaction
(Scheme 1).The products of MBH reactions are useful
Scheme 2. Ruthenium–arene-mediated intramolecular MBH reaction.
Scheme 1. Conventional Morita–Baylis–Hillman reaction.
electrophilic reaction partner in these transformations, result-
synthetic intermediates and building blocks; hence, consid-
erable effort has been directed toward determining the
mechanistic details of this transformation.[2] Variations of
MBH reactions have been reported in which reactive enolates
are prepared from enones in the presence of transition-metal
or Lewis acid reagents.[1a] The range of electrophilic reaction
partners also has been expanded to include activated ketones,
other enones,[3] allylic electrophiles (including p-allyl–palla-
dium complexes),[4,5] alkyl halides,[6] epoxides,[7] and aryl
bismuth reagents.[8]
ing in formation of ruthenium–cyclohexadienyl complexes as
the initial products.Subsequent demetalation then delivers
highly functionalized spirolactams.These transformations
represent the first examples of direct metal–arene participa-
tion in MBH-type reactions.[10]
We first became interested in exploring the feasibility of
the reaction sequence shown in Scheme 2 after discovering
that both N-benzyl acetoacetamides (1) and N-benzyl-b-
amidophosphonates (2) can be converted to 2-azaspirocyclic
cyclohexadienyl complexes by an initial nucleophilic aromatic
Despite these noteworthy advances, the MBH reaction
remains limited in scope owing to the reluctant participation
of nonactivated and/or substituted a,b-unsaturated carbonyl
compounds.Acrylamides especially have proven to be
particularly difficult substrates, and only a few examples of
MBH reactions between simple acrylamides and activated
aldehydes have been reported.[9] In contrast to this generally
observed reactivity profile, we have found that N-benzyl
acrylamides metalated with a {CpRuII} fragment (Cp = cyclo-
pentadienyl) readily undergo intramolecular MBH cycliza-
tions in the presence of added nucleophile and base
(Scheme 2).The ruthenium–arene fragment serves as the
addition followed by enolate trapping and olefination,
respectively.[11,12] Generation of a reactive enolate by means
of an MBH-type reaction of a coordinated acrylamide,
however, offers a more direct and potentially more versatile
entry into the azaspiro[4.5]decane framework. Initial
attempts to effect the conversion of the simple (N-benzyl
acrylamide)–ruthenium complex 3 to the corresponding
spirocyclic derivative under MBH conditions seemingly
confirmed the sluggish reactivity of unsaturated amide
substrates.After considerable experimentation, however, we
were pleased to find that the reaction conditions shown in
Equation (1) delivered the desired product 4 in good yield
after a relatively short reaction time.As expected, nucleo-
philic addition to the ruthenium–arene fragment occurred
diastereoselectively from the face opposite the metal center,
[*] Prof. F. C. Pigge, Dr. R. Dhanya, E. R. Hoefgen
Department of Chemistry
University of Iowa
Iowa City, IA 52242 (USA)
Fax: (+1)319-335-1270
E-mail: chris-pigge@uiowa.edu
[**] We thank the U.S. National Science Foundation for financial support
(CHE-0544572).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Treatment
of
N-allyl-N-benzyl
acrylamide
with
[(CH3CN)3RuCp][PF6] resulted in h6-arene coordination
along with concomitant allyl isomerization to afford enamide
17.Spirocyclization under our standard MBH conditions then
gave the expected product 18.
The successful use of crotyl amide substrates in these
reactions prompted us to explore the suitability of b,b-
disubstituted acrylamides as spirocyclization precursors.In
the event, dimethyl acrylamide complexes 19a,b were found
to give a mixture of separable spirolactam isomers in favor of
b,g-unsaturated derivatives 21a,b in good yields (Scheme 3).
and the resulting cyclohexadienyl complex was spectroscopi-
cally indistinguishable from material prepared previously by
reaction of 2 and formaldehyde.[12] The choice of solvent
proved to be critical for the success of this transformation.
While reactions performed in CH3CN also provided 4 (albeit
in diminished yield relative to that in dimethoxyethane
(DME)), the use of CH2Cl2, THF, or dimethylformamide
(DMF) resulted in no reaction.Besides Bu P, 4-dimethyla-
3
minopyridine (DMAP) also was found to promote the
reaction. Other amines (1,4-diazabicyclo[2.2.2]octane
(DABCO),
1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU),
Hünigꢀs base) were ineffective.
The conversion of substituted ruthenium–arene com-
plexes to the corresponding spirocyclic cyclohexadienyl com-
plexes under the conditions shown in Equation (1) was next
examined.[13] As illustrated in Table 1, para- and ortho-
substituted arene complexes were efficiently converted to
spirolactams 6, 8, and 10 (entries 1–3, Table 1).Significantly,
substitution at the b position of the acrylamide was also
tolerated as evidenced by the isolation of ethylidene-func-
tionalized lactams 12, 14, and 16 (entries 4–6, Table 1;
Z isomers were obtained in each case).The success of these
latter transformations is noteworthy in view of the deleterious
effect that enone substitution normally has upon conventional
MBH reactions.[1] Benzylic substitution is also tolerated as
demonstrated in entry 6.The final entry in Table 1 illustrates
incorporation of a removable nitrogen protecting group.
Scheme 3. MBH-type cyclizations of b,b-disubstituted acrylamide com-
plexes (see [Eq. (1)] for reaction conditions).
The 4-methoxy substrate 19c afforded only the 2-isopropenyl
lactam 21c.Likewise, the cyclopentylidene derivative 22 was
smoothly converted to complex 23, and the conjugated amide
isomer was not detected.Presumably steric constraints in the
putative intermediate 24 are such that base-induced elimi-
Table 1: (Spirolactam)ruthenium complexes prepared under MBH reac-
tion conditions (100 mol% PBu3, 2 equiv NaH, DME, RT).
nation of PBu3 occurs by loss of Hg rather than loss of Ha.[14]
.
Entry
Substrate
Product
Yield [%]
Structurally related b,g-unsaturated products were not
observed in reactions involving N-benzyl crotyl amide com-
plexes (entries 4–6, Table 1).The observation that b-mono-
and b,b-disubstituted acrylamides participate in the reaction
is notable since they are less electrophilic than unsubstituted
acrylamides.
The construction of 6,6-spiro-fused heterocycles has also
been briefly examined.Crotyl amide (arene)ruthenium com-
plexes 25a,b were prepared from phenethylamine and sub-
jected to our standard cyclization reaction conditions
(Scheme 4).In each case an efficient spirocyclization was
1
2
3
4
5
5, R=4-OMe, R1 =H
7, R=4-Me, R1 =H
9, R=2-Cl, R1 =H
6
8
10
12
14
60
71
61
96
56
11, R=H, R1 =Me
13, R=4-OMe, R1 =Me
6
7
47
55
Scheme 4. Preparation of 6,6-spiro-fused complexes.
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observed, and the corresponding cyclohexadienyl complexes
26a,b were isolated in good yield.Thus, the greater conforma-
tional mobility of the ethyl-linked crotyl amide side chain
does not appear to adversely affect the spirocyclization
reaction manifold.In contrast, structurally related acetoace-
tamide complexes prepared from phenethylamine (i.e.,
analogues of 1) are not observed to participate in spirocyc-
lization reactions.[11] Additional work is planned in order to
identify the origin of the divergent reactivity exhibited in
these complexes.
step involves the addition of aldehyde to a zwitterionic
intermediate (step 2 in Scheme 1).[2] Activation of the alde-
hyde reactant (e.g., by the use of protic solvents) is often
attempted as a means to increase the rate and yield of MBH
reactions.In our system such tactics are not needed owing to
the use of a metalated arene as the electrophile.Thus, the
generation of a reactive nucleophile by conjugate addition of
the tributylphosphine promoter to the acrylamide moiety may
now be the rate-determining step.Consonant with this notion,
a competition experiment was performed in which 3 was
treated with Bu3P and NaH in the presence of p-nitro-
benzaldehyde.After 12 h, complex 4 was obtained as the sole
isolable product along with unreacted p-nitrobenzaldehyde,
thus establishing the superiority of the intramolecular reac-
tion manifold.Additionally, exposure of metal-free N-benzyl
acrylamide and p-nitrobenzaldehyde to Bu3P in DME
resulted in recovery of unreacted starting materials.This
outcome may simply reflect the unsuitability of these
substrates in a conventional MBH reaction.It is also possible
that inductive effects operative in metal-coordinated ana-
logues (such as 3) may enhance the electrophilicity of the
acrylamide moiety and facilitate addition of Bu3P.Future
studies will address this issue.
We have previously reported methods for converting
ruthenium–cyclohexadienyl
complexes
to
metal-free
azaspiro[4.5]decane derivatives.[12,15] These procedures are
applicable to the products of MBH-type spirocyclizations as
well.For example, mild oxidation of 14 and 26b cleanly
delivered the demetalated dienones 27 and 28, respectively
(Scheme 5).This reaction is facilitated by the presence of a
In summary, an intramolecular organometallic variation
of the Morita–Baylis–Hillman reaction has been developed in
which an ruthenium–arene complex is employed as an
electrophile capable of trapping an enolate ion generated in
situ.Studies aimed at expanding the scope of the intra-
molecular reaction and extending the process to include
intermolecular additions are in progress.Additionally, the
significant challenge of developing metal-catalyzed dearoma-
tization reactions remains to be addressed.
Scheme 5. Oxidative demetalation of methoxy-substituted cyclohexa-
dienyl complexes.
methoxy substituent in the periphery of the cyclohexadienyl
ligand.Substrates lacking such electronic activation are also
amenable to oxidative demetalation.A particularly salient
example is illustrated in Equation (2), in which chiral non-
racemic (S)-16 is converted to enantiomerically pure (À)-29 Experimental Section
Preparation of 4: To a solution of 3 (0.147 g, 0.300 mmol) in
anhydrous DME (5 mL) was added Bu3P (0.061 g, 0.300 mmol) and
NaH (60%, 0.015 g, 0.600 mmol). The mixture was stirred at room
temperature for 12 h.The solvent was evaporated and the residue
partitioned with CH2Cl2 and brine.The organic phase was separated,
dried over Na2SO4, filtered, concentrated, and purified by flash
column chromatography (hexanes/EtOAc 1:1).Isolated 4 (0.070 g,
66%) was spectroscopically identical with material previously
reported.[12]
Received: December 13, 2006
Published online: March 13, 2007
with recovery of the {CpRu} fragment.[12] Thus, this combi-
nation of metal-assisted cyclization followed by oxidative
demetalation results in heterocycle construction by means of
net Ru-mediated dearomatization.[16]
The facility with which N-benzyl and N-phenethyl acryl-
amide complexes participate in the spirocyclizations de-
scribed above is in stark contrast to the sluggish reactivity
normally displayed in conventional MBH-type reactions.[1,9]
The origin of this enhanced reactivity may lie both in the
intramolecular nature of these transformations and in the
choice of electrophilic partner (i.e., an ruthenium–arene
cation).While the mechanism of the conventional MBH
reaction appears to be more complex than originally envis-
aged, there is general agreement that the rate-determining
Keywords: arene ligands · dearomatization ·
.
nitrogen heterocycles · ruthenium · spiro compounds
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